Pocket Companion to Brenner and Rector's The Kidney, Eighth Edition

POCKET COMPANION TO BRENNER & RECTOR’S THE KIDNEY POCKET COMPANION TO BRENNER & RECTOR’S THE KIDNEY 8TH EDITION ...

Author: Michael R. Clarkson MB | Barry M. Brenner MD AM(Hon) DSc(Hon) DMSc(Hon) FRCP(Lond Hon) | Ciara Magee

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POCKET COMPANION TO

BRENNER & RECTOR’S

THE KIDNEY

POCKET COMPANION TO

BRENNER & RECTOR’S

THE KIDNEY 8TH

EDITION

MICHAEL R. CLARKSON, MD, FRCPI Consultant in Renal Medicine, Cork University Hospital; Senior Clinical Lecturer, Department of Medicine, University College Cork, Ireland CIARA N. MAGEE, MB, MRCPI Research Fellow in Medicine, Harvard Medical School; Research Fellow in Medicine, Renal Division, Transplantation Research Center, Brigham and Women’s Hospital, Boston, Massachusetts BARRY M. BRENNER,

MD, AM (HON), DSC (HON), DMSC (HON), MD (HON), DIPL (HON), FRCP

Samuel A. Levine Distinguished Professor of Medicine, Harvard Medical School; Director Emeritus, Renal Division, and Senior Physician, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

1600 John F. Kennedy Blvd., Ste 1800 Philadelphia, PA 19103-2899 POCKET COMPANION TO BRENNER & RECTOR’S ISBN: 978-1-4160-6640-8 THE KIDNEY, EIGHTH EDITION Copyright # 2010, 2005 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (þ1) 215 239 3804 (U.S.) or (þ44) 1865 843830 (U.K.); fax: (þ44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier Web site at http://www.elsevier.com/permissions. Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data Clarkson, Michael R. Pocket companion to Brenner & Rector’s the kidney, eighth edition / Michael R. Clarkson, Ciara N. Magee, Barry M. Brenner. p. ; cm. Companion v. to: Brenner & Rector’s the kidney / [edited by] Barry M. Brenner. 8th ed. c2008. ISBN 978-1-4160-6640-8 1. Kidneys—Diseases—Handbooks, manuals, etc. 2. Kidneys—Handbooks, manuals, etc. I. Magee, Ciara N. II. Brenner, Barry M. III. Brenner & Rector’s the kidney. IV. Title. V. Title: Pocket companion to Brenner & Rector’s the kidney, eighth edition. [DNLM: 1. Kidney Diseases. 2. Kidney—physiopathology. WJ 300 C613p 2010] RC902.K53 2008 Suppl. 616.60 1—dc22 2009053915 Acquisitions Editor: Adrianne Brigido Editorial Assistant: Taylor Ball Marketing Manager: Courtney Ingram Printed in the United States Last digit is the print number: 9

8 7 6

5 4 3

2 1

To sharing the inherent elegance of renal pathophysiology and clinical nephrology with physicians of today and tomorrow

Preface Given the dramatic expansion in the number of patients being treated for chronic kidney disease and end-stage renal failure over the past three decades, a working knowledge of renal medicine is a prerequisite for the practicing physician. Nephrology is often perceived as being among the more challenging and complex areas of internal medicine, and the major nephrology textbooks can appear daunting to the uninitiated at first glance. Therefore, in designing this edition of the Pocket Companion to Brenner & Rector’s The Kidney, we have endeavored to provide a readily accessible and current source of information on renal disease for medical students, residents, renal fellows, internists, urologists, and primary care physicians. To ensure that the text meets the requirements of the busy clinician, we have chosen the most clinically relevant chapters from Brenner & Rector’s The Kidney and distilled the essence of the pathophysiologic, diagnostic, and treatment issues pertaining to the practice of clinical nephrology. The goal of this pocket-sized Companion is not to replace the main textbook, but rather to provide a source of immediate information at the bedside and to act as a starting point for further in-depth reading of Brenner & Rector’s The Kidney and its companion volumes, Therapy in Nephrology and Hypertension, Molecular and Genetic Basis of Renal Disease, and Chronic Kidney Disease, Dialysis, and Transplantation. We wish to express our sincere gratitude to the professional staff at Elsevier for their encouragement, guidance, and support. Michael R. Clarkson Ciara N. Magee Barry M. Brenner

Chapter 1

Clinical Assessment of the Patient with Kidney Disease PRESENTATIONS IN KIDNEY DISEASE Differentiating acute from chronic kidney disease is an important distinction (Table 1-1). Kidney disease progresses toward the end stage in most patients with chronic kidney disease (CKD); in contrast, most patients with acute kidney injury (AKI) recover renal function, with no long-term sequelae. However, outcome in AKI depends on three factors: (1) early recognition, (2) establishment of cause, and (3) appropriate clinical management.

ACUTE KIDNEY INJURY AKI is characterized by a rapid (hours to weeks) decline in kidney function. Recently, a new definition and diagnostic classification scheme, referred to by the acronym RIFLE, was proposed, and has been widely endorsed and increasingly used in clinical practice (please refer to Chapter 10 for a more detailed discussion). Early manifestations of AKI vary and depend in part on context and underlying cause (Table 1-2).

History The history should initially focus on causes of renal hypoperfusion and nephrotoxin exposure. A meticulous review of the medical record should include a careful search for ischemic and nephrotoxic insults. Common causes of volume depletion such as vomiting, diarrhea, excessive sweating, burns, and renal salt wasting (e.g., diabetic ketoacidosis) must be investigated. Evidence of effective circulating volume depletion should also be evaluated (e.g., congestive heart failure, cirrhosis). A history of recent trauma with or without overt blood loss or muscle trauma should raise the possibility of ischemia, myoglobin-induced tubular necrosis, or both. Fever, rash, and joint pains are associated with lupus nephritis, vasculitides, endocarditis, drug allergy, and infectious diseases causing intrinsic acute kidney injury. A history of dyspnea or hemoptysis may be a sign of pulmonary vasculitis, but more typically

3

4 Table 1-1

Approach to the Patient with Renal Disease

I

Differentiation of Acute from Chronic Kidney Disease

Factor

Significance

History

Long-standing history suggests chronic kidney disease

Mineral bone disease/ renal osteodystrophy

Radiographic evidence of osteitis fibrosa cystica, osteomalacia suggests chronic kidney disease

Renal size (length) Small kidneys (e.g., 12 cm)

Renal biopsy

Table 1-2

Chronic kidney disease Acute kidney injury of any cause Chronic kidney disease HIV nephropathy Diabetic nephropathy Amyloidosis Autosomal dominant polycystic kidney disease Tuberous sclerosis Obstructive uropathy Histological diagnosis

Presentations of Kidney Disease

Symptomatic Presentation General Fatigue Weakness Genitourinary Hematuria Dysuria Cardiovascular Hypertension Pulmonary congestion Cough Dyspnea Hemoptysis Gastrointestinal Anorexia Nausea Vomiting Abdominal pain Bleeding

Neurologic Encephalopathy Seizure Peripheral neuropathy Musculoskeletal Muscle weakness Periarticular or articular pain Bone pain Cutaneous Pruritus Necrosis Vasculitis Bruising Asymptomatic Presentation Hypertension Proteinuria Hematuria Abnormal renal imaging

Table 1-3

Some Substances Reported to Cause Acute Kidney Injury

Endogenous Substances Myoglobin Uric acid Light chains Calcium phosphorus Atheroemboli Exogenous Substances Antibiotics Aminoglycosides Penicillins Cephalosporins Fluoroquinolones Sulfa drugs Pentamidine Foscarnet Cidofovir Acyclovir Chemotherapeutic agents Cisplatin Mitomycin C Methotrexate Cytosine arabinoside Interleukin 2 Angiotensin-converting enzyme inhibitors Radiocontrast agents Angiotensin II receptor 1 antagonists Continued

Clinical Assessment of the Patient with Kidney Disease

results from pulmonary edema due to volume overload. Obstruc- 5 tive uropathy and acute inflammation of the kidney can cause painful stretching of the renal capsule. Flank pain may be seen in renal vein thrombosis; upper quadrant pain may indicate acute renal infarction (e.g., renal artery emboli). Prominent neu- CH 1 rologic signs are often observed in thrombotic thrombocytopenic purpura (TTP), toxic nephropathies, and poisonings. Constitutional and nonspecific symptoms, such as malaise, weakness, fatigue, anorexia, nausea, and vomiting are common in patients with AKI but do not alone establish a cause. A history of nephrotoxin exposure is an extremely important component of the evaluation of a patient with AKI. Both endogenous and exogenous toxins can give rise to kidney injury (Table 1-3). A thorough review of the patient’s history and medical record for evidence of nephrotoxin exposure is

6 Table 1-3

Some Substances Reported to Cause Acute Kidney Injury—Cont’d

Mannitol


I

Analgesics and nonsteroidal anti-inflammatory drugs Acetaminophen Aspirin Nonselective cyclooxygenase inhibitors Cyclooxygenase-2 inhibitors Heavy metals and poisons Mercury Arsenic Cadmium Lead Ethylene glycol Calcineurin inhibitors Cyclosporine Tacrolimus Reverse transcriptase inhibitors Indinavir Stavudine Immunomodulatory agents Interferon-a Therapeutic immunoglobulins Antidepressants and anticonvulsants Celexa Phenytoin Carbamazepine

essential; all medications, particularly those new to the patient’s regimen, should be considered. The potential toxicity of over-the-counter drugs (including herbal and health care products) and poisons should be considered in all patients in whom the cause of AKI is not readily apparent. Endogenous toxins include myoglobin, hemoglobin, uric acid, paraproteins, and calcium-phosphorus complexes. Tumor lysis, usually occurring in patients with bulky abdominal lymphomas, can be caused by acute uric acid nephropathy or deposition of calcium and phosphorus, and can lead to severe, even anuric, AKI. AKI may be the presenting feature in patients with nontraumatic rhabdomyolysis from cocaine use, infections, or tonic-clonic seizures. Occupational exposure to heavy metals can cause acute tubular necrosis (ATN). A history of AIDS may indicate kidney injury due to either underlying disease or associated nephrotoxic drugs. Cancers, including solid tumors and lymphoma, may also cause intrinsic renal failure as a result of hypercalcemia or tumor infiltration.

Physical Examination The physical examination can provide many clues to the underlying cause of and potential therapy for AKI.

Skin Petechiae, purpura, and ecchymoses suggest inflammatory or vascular causes of kidney failure. Cutaneous infarcts may result from embolic phenomena; cutaneous vasculitis manifesting as palpable purpura occurs in patients with septic shock, atheroembolic disease, systemic vasculitis, and infective endocarditis. Diffuse erythematous maculopapular rash may be observed in cases of drug-induced allergic interstitial nephritis or in systemic collagen vascular disease such as systemic lupus erythematosus. Reduced skin turgor may corroborate the presence of volume depletion, but is less reliable in the elderly.

Eye The eyes are examined for uveitis (interstitial nephritis and necrotizing vasculitis), ocular muscle paralysis (ethylene glycol poisoning and necrotizing vasculitis), signs of severe hypertension, atheroembolic lesions, Roth spots (endocarditis), and cytoid bodies (cotton-wool exudates seen in acute lupus nephritis). Conjunctivitis can be a result of vasculitis or drug toxicity or a manifestation of end-stage renal disease (ESRD) (“red eyes of renal failure”), the latter due to conjunctival calcium deposition.

Cardiovascular and Volume Status Meticulous assessment of the cardiovascular and volume status is the most important aspect in the diagnosis and initial management of AKI. Evidence of volume depletion, including orthostatic hypotension, dry mucous membranes, and decreased skin turgor, as well as signs of sepsis,

Clinical Assessment of the Patient with Kidney Disease

A history of the color and volume of the patient’s urine as 7 well as the pattern of urination can be useful in some settings. For example, abrupt anuria suggests urinary obstruction, severe acute glomerulonephritis or tubulointerstitial nephritis, or vascular obstruction due to renal artery emboli CH 1 or atherosclerotic occlusion of the aortorenal bifurcation. A history of gradually diminishing urine output may indicate urethral stricture or, in an older man, bladder outlet obstruction due to prostate enlargement. Gross hematuria in the setting of AKI suggests acute glomerulonephritis or ureteral obstruction by tumor, blood clots, or sloughed renal papillae.

8 congestive heart failure, and cardiac tamponade should be


sought in patients with low blood pressure or overt hypotension. However, it is often difficult to assess the volume status from physical findings alone, and in some cases it may I be necessary to place a central venous catheter or pulmonary artery catheter to measure right-sided heart pressures, cardiac output, and systemic vascular resistance. If severe hypertension is present, AKI may be due to malignant nephrosclerosis (e.g., scleroderma), glomerulonephritis, or atheroembolic disease. Use of recreational drugs, particularly cocaine, should be considered. Cardiac murmurs are associated with endocarditis or atrial myxoma, which can cause AKI due to fulminant glomerulonephritis. A pericardial friction rub in a patient with newly diagnosed renal failure may be a sign of impending cardiac tamponade and is an indication for emergency dialysis. In this situation, progressive hypotension is dramatic but can be temporarily stabilized by a rapid intravenous bolus infusion of fluids.

Abdomen Abdominal examination may reveal a palpable bladder (urinary obstruction). Also, tenderness in the upper quadrants can be associated with ureteral obstruction or renal infarction. Ascites may be observed in fulminant hepatic failure, severe nephrotic syndrome, and Budd-Chiari syndrome, all of which are associated with AKI. An abdominal bruit evokes the diagnosis of severe atherosclerotic disease, which can engender renal failure from renal artery stenosis, thrombosis of the aortorenal bifurcation, or atheroembolic renal disease. A flank mass can be a sign of renal obstruction from tumor or retroperitoneal fibrosis. In addition, a tense distended abdomen in a patient who has just undergone surgery raises the possibility of abdominal compartment syndrome.

Extremities Examination of the extremities for signs of edema, evidence of tissue ischemia, muscle tenderness (e.g., rhabdomyolysis causing myoglobinuric renal failure), and arthritis (e.g., systemic lupus erythematosus, rheumatoid arthritis, infections) may provide clues to the diagnosis of renal failure.

Neuropsychiatric Features Neuropsychiatric abnormalities range from signs of uremic encephalopathy (confusion, somnolence, stupor, coma, seizures) to focal neurologic abnormalities in specific diseases such as the vasculitides. Cranial nerve palsies can be seen in patients with ethylene glycol poisoning or vasculitides. Altered and changing mental status is common in thrombotic microangiopathies and systemic atheroembolism.

9

Urinalysis

Table 1-4

Urine Tests in the Differential Diagnosis of Acute Kidney Injury Urine/ Plasma UNaþ Osmolality (mEq/L)

Fractional Excretion of Naþ

Diagnosis

Urinalysis

Prerenal

Normal

>1

1

Interstitial nephritis

RBCs, WBCs, eosinophils, granular casts

1

>20

>1

GlomeruRBCs, RBC lonephritis casts, marked proteinuria

>1

90 (with CKD risk factors)

Screening CKD risk reduction

1

Kidney damage with normal or increased GFR

90

Diagnose and treat cause, slow progression, evaluate risk of cardiovascular disease

2

Kidney damage with mild decrease in GFR

60–89

Estimate progression

3

Moderate decrease in GFR

30–59

Evaluate and treat complications

4

Severe decrease in GFR

15–29

Prepare for renal replacement therapy

5

Kidney failure

7.0) is suggestive of infection with a urea-splitting organism, such as Proteus mirabilis. Prolonged storage can lead to overgrowth of urea-splitting bacteria and a high urine pH. However, diet (vegetarian), diuretic therapy, vomiting, gastric suction, and alkali therapy can also cause a high urine pH. Low urine pH (pH < 5.0) is seen most commonly in metabolic acidosis. Acidic urine is also associated with the ingestion of large amounts of meat.

Bilirubin and Urobilinogen Only conjugated bilirubin is passed into the urine. Thus, a reagent test for bilirubin is typically positive in patients with obstructive jaundice or jaundice due to hepatocellular injury, whereas it is usually negative in patients with jaundice due to hemolysis. In patients with hemolysis, however, the urine urobilinogen result is often positive. Reagent test strips are very sensitive to bilirubin, detecting as little as 0.05 mg/dL. False-positive test results for urine bilirubin can occur if the urine is contaminated with stool. Prolonged storage and exposure to light can lead to false-negative results.

Leukocyte Esterase and Nitrites Dipstick screening for urinary tract infection has been recommended for high-risk individuals, but the issue is controversial. The esterase method relies on the fact that esterases are released from lysed urine granulocytes, causing a dye change on the strip. The result is usually interpreted as negative, trace, small, moderate, or large. Urine that is allowed to stand indefinitely results in greater lysis of leukocytes and a more intense reaction. False-positive results can occur with vaginal contamination. High levels of glucose, albumin, ascorbic acid, tetracycline, cephalexin, or cephalothin, or large amounts of oxalic acid can inhibit the dye reaction. Urinary bacteria convert nitrates to nitrites. The latter induce a dye change on the strip. Results are usually interpreted as positive or negative. High specific gravity and the presence of ascorbic acid may interfere with the test. False-positive results are common and may be due to low urine nitrates resulting from low dietary intake. It may take up to 4 hours to convert nitrate to nitrite, so inadequate bladder retention time can also give false-negative results. Prolonged storage of the sample can lead to degradation of nitrites, another source of false-negative

Glucose Reagent strip measurement of urine glucose level, once used to monitor diabetic therapy, has been almost completely replaced by more reliable methods that measure finger-stick blood glucose level. Most reagent strips detect levels of glucose as low as 50 mg/dL. Because the renal threshold for glucose is generally 160 to 180 mg/dL, the presence of detectable urine glucose indicates blood glucose values in excess of 210 mg/dL. Large quantities of ketones, ascorbate, and pyridium metabolites may interfere with the color reaction, and urine peroxide contamination can cause false-positive results. Nevertheless, the appearance of glucose in the urine is a specific indicator of high serum glucose levels. Glucosuria due to a low renal threshold for glucose reabsorption is rare.

Ketones Ketones (acetoacetate and acetone) are generally detected with the nitroprusside reaction. Ascorbic acid and phenazopyridine can give false-positive reactions. b-Hydroxybutyrate (often 80% of total serum ketones in ketosis) is not normally detected by the nitroprusside reaction. Ketones can appear in the urine, but not in serum, with prolonged fasting or starvation. Ketones may also be observed in the urine in alcoholic or diabetic ketoacidosis.

Hemoglobin and Myoglobin Hematuria and contamination of the urine with menstrual blood produce a positive reaction on dipstick urinalysis. Myoglobin, oxidizing contaminants, and povidone iodine can cause false-positive reactions. Free hemoglobin is filtered at the renal glomerulus and thus appears in the urine when the capacity for plasma protein binding with haptoglobin is

Laboratory Assessment of Kidney Disease

results. Finally, several potential urinary pathogens such as 29 Streptococcus faecalis, other gram-positive organisms, Neisseria gonorrhoeae, and Mycobacterium tuberculosis do not convert nitrate to nitrite. Restrospective analysis of the available data suggests that the pairing of both tests is the most accurate CH 2 approach to screening for infection. However, when the likelihood of infection is high (e.g., when signs and symptoms are present), negative results of both tests are still insufficient to exclude infection. These tests, in combination with other clinical information, may be more useful in situations in which the likelihood of infection is low.

30 exceeded. Some of the hemoglobin is catabolized by the prox-


imal tubules. The principal cause of increased serum and urine free hemoglobin levels is hemolysis. Rhabdomyolysis, on the other hand, gives rise to myoglobin. A positive dipstick I test result for hemoglobin in the absence of red blood cells in the urine sediment suggests either hemolysis or rhabdomyolysis. Specific assays for hemoglobin and myoglobin can be used to measure urine levels.

Protein Normal Physiology The upper limit of normal total urine protein excretion in healthy adults is 150 to 200 mg/day. The upper limit of normal albumin excretion is 30 mg/day. Most urinary protein consists of Tamm-Horsfall protein, a glycoprotein that is formed on the epithelial surface of the thick ascending limb of the loop of Henle and early distal convoluted tubule. Immunoglobulin A and urokinase are also secreted by the renal tubule and appear in the urine in small amounts. Disruption of the glomerular capillary wall barrier can lead to the filtration of a large amount of high-molecular-weight plasma proteins that overwhelm the limited capacity of tubular reabsorption and cause protein to appear in the urine, resulting in glomerular proteinuria. Tubular damage or dysfunction that inhibits the normal resorptive capacity of the proximal tubule may result in tubular proteinuria that generally consists of lower-molecular-weight proteins. Increased production of normal or abnormal plasma proteins can be filtered at the glomerulus, overwhelming the resorptive capacity of the proximal tubule. Although increased urine protein excretion can also result from increased tubular production of protein, this is rarely the case.

Techniques to Measure Urine Protein Total protein concentration in urine can be rapidly estimated with chemically impregnated plastic strips. Most dipstick reagents contain a pH-sensitive colorimetric indicator that changes color when negatively charged proteins bind to it. However, positively charged proteins are less readily detected. Positively charged immunoglobulin light chains (myeloma), for example, may escape urine dipstick detection even when present in large amounts in the urine. A very high urine pH (>7.0) can also give false-positive results, as can contamination of the urine with blood. The dipstick technique is sensitive to very small urine protein concentrations (the lower limit of detection is 10 to 20 mg/dL). However, at these low levels, the major constituent of urine protein may be Tamm-Horsfall protein, particularly when the urine volume is low and the


concentration is high, and a positive test result may therefore 31 not reflect kidney injury. When urine volume is high and the urine is maximally dilute, however, a relative large amount of protein can go undetected. Indeed, total protein excretion approaching 1 g/day may not be detected if urine output is suf- CH 2 ficiently high. Screening methods have been developed to detect microalbuminuria, levels of albumin excretion that are below the limits of detection achieved by standard reagent strips. In general, these albumin reagent tests are more sensitive than standard dipsticks, but have a high rate of false-positive results. Urine albumin concentrations can be quantified more accurately by a number of techniques including radioimmunoassay, immunoturbimetry, laser nephelometry, enzymelinked immunosorbent assay (ELISA), and HPLC. Protein can be measured in random samples, in timed or untimed overnight samples, or in 24-hour collections. Inaccurate urine collection is probably the greatest source of error in quantifying protein excretion in timed collections, particularly 24-hour collections. The adequacy of collection can be judged by performing a simultaneous measurement of urine creatinine excretion. For men aged 20 to 50 years, the normal range of creatinine excretion is 18.5 to 25 mg/kg/day, and for women of the same age, 16.5 to 22.4 mg/kg/day. These values decline with age so that the normal ranges are approximately 20% to 25% lower in patients over 60 years of age. In an effort to correct for problems arising out of variability in urine volume and concentration, many investigators have used the protein/creatinine or albumin/creatinine ratio in random or timed urine collections. There is a high degree of correlation between 24-hour urine protein excretion and protein/creatinine ratios in random, single-voided urine samples in patients with a variety of kidney diseases, including kidney transplant recipients (i.e., a protein/creatinine ratio of 3 indicates a protein excretion rate of 3 g/24 hours). Protein/creatinine ratios have been shown to be predictive of declining kidney function in patients with nondiabetic CKD, and are useful as both screening devices and as longitudinal tests for following the level of proteinuria. Although protein/creatinine or albumin/creatinine ratios may be more quantitative than a simple dipstick screening procedure, their use has a number of limitations. For example, obtaining protein/creatinine or albumin/creatinine ratios on morning, first-void samples may underestimate 24-hour protein excretion because of the reduction in proteinuria that normally occurs at night. Storage time and temperature may also affect albumin levels in urine, and specimens should be analyzed as soon as possible after collection. Urine creatinine concentration is extremely variable, and very different ratios can be obtained in individuals with similar protein excretion rates. Despite these limitations, the

32 urine protein/creatinine or albumin/creatinine ratio may be

useful, especially in individuals in whom urine collection is difficult.


I

Applications of Urine Protein Measurement

Screening for Kidney Disease. Although urine protein measurement can be used to assist in the diagnosis of kidney disease and to assess disease progression and response to therapy (discussed later), it is most commonly used as a screening test. Microalbuminuria is defined as urine albumin excretion of 30 to 300 mg/day and appears to be an important risk factor for end-organ damage in patients with diabetes or hypertension. Most studies showing a relationship between microalbuminuria and end-organ damage have used 24-hour quantitative techniques to measure urine albumin excretion. As previously discussed, this is cumbersome and prone to error, and an albumin/creatinine ratio in an untimed spot urine specimen can be used instead. Indeed, albumin/creatinine ratios have been shown to predict the subsequent development of overt kidney disease. A value above 30 mg/g (or 0.03 mg/mg) suggests that albumin excretion is above 30 mg/day, consistent with microalbuminuria. The appropriate manner in which to use various tests to screen for kidney disease in the general population has not been extensively investigated. Because the number of falsepositive results of dipstick tests for protein excretion is high, a positive result should probably be followed by tests designed to more accurately quantitate urine protein excretion. However, in some clinical circumstances, the likelihood that a positive dipstick test result for urine protein excretion indicates CKD is so low that the screening test should be repeated at a later date before more costly quantitation procedures are undertaken. Fever can cause tubular and glomerular proteinuria that most often disappears when the fever resolves. Congestive heart failure and seizures can also cause transient proteinuria. Light or strenuous exercise is often associated with urine protein excretion that resolves spontaneously. Posture can cause a rise in urine protein excretion in otherwise normal individuals. Postural proteinuria usually does not exceed 1 g/24 hours. It is usually diagnosed through detection of protein excretion during the day that is absent in a first morning void sample. Patients with postural proteinuria have been shown to have an excellent long-term prognosis. Diagnosis and Prognosis. Once proteinuria has been detected by screening, the degree of protein excretion must be quantified. This may help to distinguish glomerular from tubular proteinuria (see later discussion), and can also provide prognostic information and monitor response to therapy.


Determination of the components of urinary protein may 33 provide diagnostic information. Higher amounts of albumin and high-molecular-weight (HMW) proteins suggest glomerular proteinuria, whereas isolated increases in low-molecularweight (LMW) protein fractions are more suggestive of tubular CH 2 proteinuria. It is unusual for tubular proteinuria to exceed 1 to 2 g/day, and only a small fraction should be albumin. Tubular proteins are heterogeneous, although a2-microglobulin is often a major component. Glomerular proteinuria can be further characterized as selective or nonselective. Patients with a clearance ratio of immunoglobulin G (IgG) to albumin less than 0.1 are said to have selective proteinuria, whereas those with ratios of greater than 0.5 have a nonselective pattern. In general, selective proteinuria is most often seen in patients with minimal change disease, and predicts a good response to treatment with corticosteroids. The sensitivity and specificity of determining the selectivity of glomerular proteinuria have not been systematically examined in large numbers of patients with different kidney diseases, and the cost of performing protein separation procedures has limited their widespread use. Plasma cell dyscrasias can produce monoclonal proteins, immunoglobulin, free light chains, and combinations of these. Light chains are filtered at the glomerulus and may appear in the urine as Bence Jones protein. The detection of urine immunoglobulin light chains can be the first clue to a number of important clinical syndromes associated with plasma cell dyscrasias that involve the kidney. Unfortunately, urine immunoglobulin light chains may not be detected by reagent strip tests for protein. However, plasma cell dyscrasias may also manifest as proteinuria or albuminuria when the glomerular deposition of light chains causes disruption of the normally impermeable capillary wall. The diagnosis of a plasma cell dyscrasia can be suspected when a tall, narrow band on electrophoresis suggests the presence of a monoclonal g-globulin or immunoglobulin light chain. However, monoclonal proteins are best detected with serum and urine immunoelectrophoresis. The amount of urine protein excretion has consistently been shown to predict subsequent disease progression in kidney disease of varying etiology. The clinical course and effect of immunosuppressive therapy can also be monitored with sequential quantitation of urine protein excretion.

Formed Elements Urine Microscopy Methods A midstream, “clean-catch” specimen should be collected when possible; the patient should be instructed to retract the foreskin or labia. A high urine concentration and a low urine

34 pH help preserve formed elements. Thus, a first-void morning


specimen, which is most likely to be acidic and concentrated, should be used whenever possible. Strenuous exercise and bladder catheterization can cause hematuria, and urine speciI mens collected to detect hematuria should not be obtained under these conditions. Urine should be examined as soon as possible after collection to avoid lysis of the formed elements and bacterial overgrowth. The specimen should not be refrigerated because lowering the temperature causes the precipitation of phosphates and urates. It is helpful to first measure the urine specific gravity and pH, so as to judge the density of formed elements according to the concentration and acidity of the specimen. Specimens from concentrated and acidic urine may be expected to have a greater density of formed elements than dilute and alkaline specimens from the same patients. Urine should be centrifuged at approximately 2000 rpm for 5 to 10 minutes. The supernatant should be carefully poured off, the pellet resuspended by gentle agitation, and a drop placed on a slide under a coverslip. Most commonly, urine is examined with an ordinary brightfield microscope. However, polarized light can be used to identify anisotropic crystals, and phase-contrast microscopy can enhance the contrast of cell membranes. Generally, urine is examined unstained; stains may occasionally be helpful in distinguishing cell types.

Hematuria Gross hematuria may first be detected as a change in urine color. Microscopic hematuria can be identified by dipstick methodology, microscopic examination, or both. Even when the urine is red, or when a dipstick screening test result is positive, the sediment should be examined to determine whether red blood cells are present. The presence of other pigments, such as free hemoglobin and myoglobin, can masquerade as hematuria. An occasional red blood cell can be seen in normal individuals, but generally there are only one or two cells per high-power field. The differential diagnosis of hematuria is broad, but for practical purposes can be categorized as originating in either the upper or lower urinary tract. Red blood cells originating in glomeruli have been reported to have a distinctive dysmorphic appearance that is most readily appreciated with phase-contrast microscopy. The differential diagnosis of hematuria is broad (Table 2-2). Kidney vascular causes include arterial and venous thrombosis, arteriovenous malformations, arteriovenous fistula, and the nutcracker syndrome (compression of the left renal vein between the aorta and superior mesenteric artery). Most

Table 2-2

Common Sources of Hematuria

Vascular

Glomerular

IgA nephropathy Thin basement membrane diseases (including Alport’s syndrome) Other causes of primary and secondary glomerulonephritis

Interstitial

Allergic interstitial nephritis Analgesic nephropathy Renal cystic diseases Acute pyelonephritis Tuberculosis Renal allograft rejection

Uroepithelium

Malignancy Vigorous exercise Trauma Papillary necrosis Cystitis/urethritis/prostatitis (usually caused by infection) Parasitic diseases (e.g., schistosomiasis) Nephrolithiasis or bladder calculi

Multiple sites or source unknown

Hypercalciuria Hyperuricosuria Sickle cell disease

patients undergoing anticoagulant therapy who have hematuria can be found to have an underlying cause, especially if the hematuria is macroscopic. However, excessive anticoagulation or other coagulopathies can themselves be associated with hematuria. A reasonable approach to the patient with asymptomatic hematuria is to first obtain a thorough history and perform a complete physical examination. The presence of RBC casts, significant proteinuria, or both suggests a glomerular source for the hematuria. For the patient in whom glomerular proteinuria is likely, a kidney biopsy may yield the diagnosis. If the source of proteinuria is not evident from the history, physical examination, or urinalysis, renal ultrasonography is probably a reasonable next step. In the young patient (e.g.,

CH 2


Coagulation abnormalities Excessive anticoagulation Arterial emboli or thrombosis Arteriovenous fistula Nutcracker syndrome Renal vein thrombosis Loin-pain hematuria syndrome (? vascular)

35

36 3 L/day) and water and salt repletion is not appropriate, then volume depletion can ensue. Transdermal volume losses are markedly increased in the setting of burns and require substantial and meticulous fluid and electrolyte repletion.

Clinical Manifestations of Volume Depletion Historical enquiry should focus on potential causes of volume depletion including diuretic use, vomiting, diarrhea, and polyuria. The symptoms of volume contraction are typically nonspecific but can include postural dizziness, thirst, or salt craving. Despite the frequency of this clinical presentation, the diagnosis of volume depletion by physical examination can be difficult even for the experienced clinician. The physical manifestations of volume depletion are variable, and the absence of physical findings does not preclude the diagnosis.

Body Weight A rapid decline in body weight is a key finding in the evaluation of the patient with volume contraction, particularly in the elderly patient in whom other physical signs are often highly unreliable. The change in body weight not only aids in the diagnosis of volume depletion, but can also help guide therapy.

Skin and Mucous Membranes Volume depletion is classically associated with a loss of normal skin turgor over the forearm or thigh. However, because of loss of the inherent elastic tone of skin with aging, decreased skin turgor is an unreliable clinical sign in older subjects. Dryness of the mucous membranes is also associated with ECF volume contraction but can result from mouth breathing.

Jugular Venous Pressure When hypovolemia is suspected, the jugular venous pulse (JVP) is best assessed with the patient lying recumbent at a lower angle than normal (20–35 degrees) with the head tilted away from the examiner. At this angle, the JVP should be visible in the euvolemic patient, arising between the two heads of

the sternocleidomastoid muscle. If the pulse is absent, this is 77 suggestive of low right-sided filling pressures consistent with ECF contraction.

Arterial Blood Pressure

Diagnosis of Volume Depletion Hemodynamic Monitoring Intravascular hemodynamic monitoring is often required in the critically ill patient in whom clinical clues of volume status may be conflicting. Measurements of intravascular volume status include the central venous pressure (CVP), which reflects right-sided heart filling pressures, and the pulmonary capillary wedge pressure (PCWP), which reflects left ventricular filling pressures. Measurement of the latter is not usually performed unless other hemodynamic parameters are required (cardiac output, systemic vascular resistance). Under normal circumstances the CVP reflects the PCWP and can be used as a surrogate marker of left-sided filling pressures. When the CVP is in the low-normal range the response to a fluid volume challenge can further help define the intravascular volume status. Conditions for which the CVP does not reflect the PCWP include isolated right-sided heart failure (cor pulmonale) or pure left-sided heart failure. In these settings, measurement of the PCWP may provide a more accurate index of the optimal left ventricular filling pressure.

Serum Indices Analysis of blood biochemistry is useful in the determination of ECF volume status based on knowledge of the normal physiologic response to volume contraction outlined earlier. Volume depletion leads to enhanced proximal tubule salt and water retention, thereby increasing the passive reabsorption of urea, leading to a rise in the normal blood urea nitrogen (BUN) to creatinine ratio from the normal level of 10:1 to over 20:1. Factors that alter urea generation independent of renal clearance (e.g., corticosteroid use) can affect the reliability of this index. The nonosmotic release of vasopressin can trigger a modest decrement in the serum Naþ concentration, while hemoconcentration (high hematocrit) may result from plasma volume contraction. Analysis of the acid-base status can further elucidate the underlying cause of the volume-contracted state. A hypochloremic metabolic alkalosis is characteristic

CH 4

Control of Extracellular Fluid Volume and the Pathophysiology of Edema Formation

Overt hypotension is typically observed only in severe volume depletion and may be associated with signs and symptoms of peripheral hypoperfusion such as oliguria, clammy extremities, and confusion. Less profound ECF volume deficits may be demonstrated by checking for postural hypotension.

78 of volume depletion due to diuretic use, vomiting, or nasogastric suctioning. In contrast, diarrhea can lead to heavy losses of bicarbonate-rich fluids with secondary NaCl retention by the kidney, giving rise to a hyperchloremic metabolic acidosis.

Disturbances in Control of Body Fluid Volume and Composition

II

Urine Indices Volume-depleted patients typically reabsorb sodium avidly in the renal tubule and excrete urine with a Naþ concentration less than 20 mEq/L and a high specific gravity. The fractional excretion of Naþ (FENa), which relates Naþ clearance to creatinine clearance, is more sensitive in diagnosing ECF volume depletion. Creatinine is reabsorbed to a much smaller extent than Naþ in volume depletion. Consequently, patients with volume depletion typically have a FENa below 1% (frequently < 0.01%), whereas the FENa is usually above 1% in euvolemic patients. The FENa may be greater than 1% in prerenal azotemia in patients receiving diuretics or in those with a metabolic alkalosis (in which Naþ is excreted with HCO3 to maintain electroneutrality). In the latter case the urine Cl is a better index of intravascular volume status, with a level less than 20 mEq/L suggesting chloride depletion and ECF volume contraction. In a patient receiving diuretics, the fractional excretion of urate may be used as a surrogate marker of the FENa, with a value less than 35% considered indicative of volume depletion.

Management of Volume Depletion The management of volume depletion is discussed in Chapter 10, Acute Kidney Injury.

PATHOPHYSIOLOGY OF EDEMA FORMATION Generalized edema formation, the clinical hallmark of ECF volume expansion, represents the accumulation of excessive fluid in the interstitial compartment and is invariably associated with renal Naþ retention. It occurs most commonly in response to congestive heart failure (CHF), cirrhosis with ascites, and the nephrotic syndrome.

Local Mechanisms in Interstitial Fluid Accumulation The balance of Starling forces prevailing at the arteriolar end of the capillary (△ hydraulic pressure > △ oncotic pressure) favors the net filtration of fluid into the interstitium. Net outward movement of fluid along the length of the capillary is

Renal Sodium Retention and Edema Formation in Congestive Heart Failure CHF is a clinical syndrome in which the heart is unable to satisfy the requirements of peripheral tissues for oxygen and other nutrients. This happens most commonly in the setting of a decrease in cardiac output (low-output CHF), but it may also occur when cardiac output is increased, such as in patients with arteriovenous fistula, hyperthyroidism, or beriberi (highoutput CHF). In both situations, the kidney responds in a similar manner, by avidly retaining Naþ and water despite ECF volume expansion. The syndrome of CHF encompasses a series of compensatory circulatory and neurohumoral mechanisms which occur in response to reduction of the distending pressure within the arterial circuit and to an increase in the filling pressures in the atria and great veins, behind the failing ventricle. As long as these adaptations are able to maintain their compensatory role, they may prove to be beneficial (compensated CHF). However, excessive activation of these systems may become detrimental by further promoting peripheral vasoconstriction


associated with decreased capillary hydraulic pressure and an 79 increase in plasma colloid osmotic pressure, such that the net balance of forces favors fluid movement back into the capillary at the distal end of the capillary bed. In several tissues, the local transcapillary hydraulic pressure gradient continues CH 4 to exceed the opposing colloid osmotic gradient throughout the length of the capillary bed, so that filtration occurs along its entire length. In such capillary beds, a substantial volume of filtered fluid must return to the circulation via lymphatics. The appearance of generalized edema implies one or more disturbances in microcirculatory hemodynamics associated with expansion of the ECF volume: increased venous pressure transmitted to the capillary, unfavorable adjustments in precapillary and postcapillary resistance, or lymphatic flow inadequate to drain the interstitial compartment and replenish the intravascular compartment. Generalized edema implies substantial renal Naþ retention, as the continued net accumulation of interstitial fluid in the absence of renal Naþ retention might result in prohibitive intravascular volume contraction and the cessation of interstitial fluid formation. Indeed, the volume of accumulated interstitial fluid required for clinical detection of generalized edema (>2–3 L) necessitates that all states of generalized edema are associated with expansion of ECF volume and hence with body-exchangeable sodium content. Therefore, it can be concluded that all states of generalized edema reflect past or ongoing renal Naþ retention.

80 and increasing the abnormal loading conditions in the failing


heart. At this critical point, a vicious circle is created (decompensated CHF), in which the “compensatory” mechanisms themselves contribute to further deterioration of the cardioII vascular system. From the standpoint of ECF volume homeostasis, there are two key abnormalities in CHF: • The perception of an inadequate circulating volume by various sensors within the circulation • A disturbance in the effector arm of volume control, with excessive activation of antinatriuretic vasoconstrictor systems and failure of natriuretic vasodilatory mechanisms, promoting Naþ and water retention by the kidney The observation that the kidney is intrinsically normal in CHF but continues to retain Naþ and water avidly, despite ECF volume expansion, indicates that it must be responding to “inadequate” signals from the volume regulatory system, which suggests “underfilling” of a critical sensing area in the vascular tree or failure of the normal volume-sensing mechanisms. The disturbances in the sensing mechanisms that initiate and maintain renal Naþ retention in CHF include elevated cardiac atrial pressure, which increases capillary hydraulic pressure leading to transudation of fluid and Naþ into the interstitium with edema formation and depletion of plasma volume: “backward failure.” The decrease in plasma volume then initiates renal Naþ and water retention, perpetuating a maladaptive cycle. In contrast, the concept of “forward failure” emphasizes the importance of the failure of the heart as a pump in supplying adequate blood flow to the tissues, similar to the mechanism of acute circulatory failure (shock), such that the kidneys are no longer able to excrete salt in a normal manner. Other factors perpetuating the maladaptive responses in CHF include chronic dilatation of the cardiac atria with blunting of the normal natriuretic response to central venous congestion. This attenuation is manifested predominantly as diminished neural tonic inhibitory response to atrial stretch, which triggers unopposed increased sympathetic nerve activity and augmented release of renin and AVP. Experimental evidence suggests that high endogenous levels of A-II in CHF may contribute to the depression of baroreflex sensitivity seen in the syndrome; use of AT-receptor antagonists and angiotensinconverting enzyme (ACE) inhibitors in animal studies has been shown to augment arterial and cardiopulmonary baroreflex control of renal sympathetic activity. Alterations in the efferent limb of volume regulation include enhanced activities of both the vasoconstrictor/Naþ-retaining systems, as well as activation of counterregulatory vasodilatory/natriuretic systems. The magnitude of Naþ excretion by the kidney, and therefore the disturbance of volume homeostasis in

Renal Sodium Retention and Edema Formation in Cirrhosis with Ascites Abnormalities in renal Naþ and water excretion are commonly found in cirrhosis. These abnormalities lead eventually to ascites, a common complication of cirrhosis and a major cause of morbidity and death, with the potential occurrence of spontaneous bacterial peritonitis, variceal bleeding, and development of the hepatorenal syndrome. Similarly to CHF, the pathogenesis of the renal water and Naþ retention in cirrhosis is not related to an intrinsic abnormality of the kidney but to extrarenal mechanisms that regulate renal Naþ and water handling. The transplantation of kidneys from cirrhotic patients into persons with normal liver function results in normal excretion of Naþ and water. Two general explanations of Naþ retention complicating cirrhosis have been proposed. The “underfilling” theory postulates “effective” vascular volume depletion. In this hypothesis, peripheral arterial vasodilation leads to relative underfilling of the arterial vascular compartment, which leads to the same neurohumoral responses that occur in low cardiac output. These include activation of the RAAS and the sympathetic nervous system, as well as nonosmotic release of vasopressin resulting in renal water and Naþ retention. The retained fluid extravasates from the expanded splanchnic venous circulation, preventing arterial repletion, and propagating Naþ retention and ascites formation. The alternate “overflow” theory of ascites formation in cirrhosis envisions a volume-independent stimulus for renal Naþ retention. Possible mediators include adrenergic reflexes activated by hepatic sinusoidal hypertension and increased systemic concentrations of an unidentified antinatriuretic factor due to impaired liver metabolism. It is likely that neither the “underfilling” nor the “overflow” theory can account exclusively for all the observed derangements in volume regulation in cirrhosis. Rather, it is probable that elements of the two concepts may occur simultaneously or sequentially in patients with cirrhosis. There is evidence to suggest that, early in cirrhosis, intrahepatic hypertension


CHF, is largely determined by the balance between these antag- 81 onistic systems. In the early stages, the vasodilatory/natriuretic systems are important in maintaining circulatory and renal function; however, as CHF progresses, dysfunction of the vasodilatory/natriuretic systems occurs, with marked activation of CH 4 the vasoconstrictor/antinatriuretic systems. This results in avid retention of salt and water, leading to edema formation and the dilutional hyponatremia observed in decompensated CHF. For a further discussion of the clinical aspects of diuretic use in CHF, see Chapter 26, Diuretics.

82 caused by hepatic venous outflow obstruction signals primary


renal Naþ retention with consequent intravascular volume expansion. It is unclear if arterial circuit underfilling consequent to vasodilatation is also operational at this stage. Plasma II ANP levels rise consequent to intrathoracic venous compartment expansion. The rise in ANP levels is sufficient to counterbalance the renal Naþ-retaining forces but does so at the expense of an expanded intravascular volume with the potential for overflow ascites. The propensity for accumulation of volume in the peritoneal compartment and in the splanchnic bed results from altered intrahepatic hemodynamics. Current evidence suggests that the increase in intrahepatic vascular resistance is not merely due to mechanical distortion of the vasculature by fibrosis, but rather a dynamic process due to contraction of myofibroblasts and stellate cells, in conjunction with altered NO production due to endothelial dysfunction, leading to a balance shift in favor of vasoconstrictor mechanisms. With disease progression, disruptions of intrasinusoidal Starling forces and loss of volume from the vascular compartment into the peritoneal compartment occur. These events, coupled with other factors such as portosystemic shunting, hypoalbuminemia, and vascular refractoriness to pressor hormones, lead to underfilling of the arterial circuit, even in the absence of measurable underfilling of the venous compartment. This may attenuate further increases in ANP levels and promote the activation of antinatriuretic factors. Whether the antinatriuretic factors activated by underfilling are the same as or different from those which promote primary renal Naþ retention in early disease remains to be determined. At this later stage of disease, increased levels of ANP may not be sufficient to counterbalance antinatriuretic influences. In early cirrhosis salt retention is isotonic and is accompanied by ECF expansion and normonatremia. However, with advancing cirrhosis, defective water excretion supervenes, resulting in hyponatremia, reflecting combined ECF and intracellular fluid space expansion, primarily due to nonosmotic stimuli for release of vasopressin, acting with additional factors such as renal prostaglandins and impaired distal sodium delivery. This reflects the severity of the attendant hemodynamic abnormalities that initiate Naþ retention and eventuate in hepatorenal failure. For a discussion of the clinical aspects of diuretic use in cirrhosis, see Chapter 26, Diuretics.

Renal Sodium Retention and Edema Formation in the Nephrotic Syndrome Edema is the most common presenting symptom of the nephrotic syndrome. Various theories for the cause of nephrotic edema have been proposed. The “underfilling” theory suggests


that hypovolemia consequent to reduced plasma oncotic pres- 83 sure is the primary stimulus for salt and water retention by the kidney. Enhanced tubular sodium reabsorption is considered a function of multiple mediator systems responding to the “perceived volume depletion” with activation of the RAAS, CH 4 sympathetic nervous system, and vasopressor system. However, the literature is conflicting with regard to the prevailing plasma volume in nephrotic syndrome; some studies have been unable to consistently detail hormonal modulations consistent with hypovolemia or indeed document hypovolemia by direct measurements, whereas others have data to suggest hypovolemia, with a natriuretic response to maneuvers designed to expand plasma volume. It is reasonable to assert that hypoproteinuria results in a fall in the plasma oncotic pressure and the movement of fluid into the interstitial space. Ongoing edema accumulation is normally mitigated by several factors: expansion of the lymphatic system resulting in increased lymphatic flow; transudation of protein-free fluid into the interstitium, reducing the transcapillary oncotic pressure gradient (plasma oncotic pressure minus interstitial oncotic pressure); and fluid flux increasing interstitial hydrostatic pressure, reducing the transcapillary pressure gradient. Furthermore, the compliance characteristics of the interstitium resist fluid accumulation. In normal patients, colloid osmotic pressure in the plasma is approximately 26 mm Hg. The interstitial oncotic pressure may be as high as 10 to 15 mm Hg due to filtration of albumin across the capillary wall. In nephrotic patients, the interstitial oncotic pressure may fall as low as 2.6 mm Hg in the lower leg. The fall in interstitial oncotic pressure may parallel the decline in plasma oncotic pressure, and is a protective mechanism in hypoproteinemic patients, acting to minimize the change in the transcapillary gradient and reduce the fluid shift from the vascular compartment to the interstitium. Excessive dietary salt ingestion or the administration of saline to hypoproteinemic patients results in a rapid fall in the transcapillary oncotic pressure gradient and subsequent substantial edema. Although some evidence supports the “underfilling” hypothesis of edema formation, recent studies suggest that the salt and water retention characteristic of the nephrotic syndrome occurs as a primary renal phenomenon (the “overfill” hypothesis) rather than as a response to perceived intravascular volume depletion. As discussed earlier, multiple studies have shown the plasma volume to be expanded in nephrotic syndrome, which is consistent with the finding that many adult nephrotics are hypertensive. Other persuasive evidence is the finding that levels of ANP and plasma renin activity in patients with the nephrotic syndrome are equivalent to normal subjects ingesting a usual amount of sodium, suggesting that renal

84 sodium retention in nephrosis is probably a consequence of pri-


mary renal sodium retention rather than a consequence of plasma hormone effects on the kidney. Clinical and experimental data have noted renal resistance to ANP, with either blunted þ II or absent natriuretic response. Animal data suggest that Na retention in the cortical collecting duct is due, at least in part, to coordinated overactivity of the Naþ/Kþ-ATPase and ENaC sodium transporters. Certain important issues should be considered when making decisions about management of edema in the nephrotic syndrome. In some patients, the edema is only of minimal discomfort, but in others it causes substantial morbidity. The goal should be a slow resolution of edema. In all instances, the institution of rapid diuresis resulting in hypovolemia and hypotension must be avoided. The mainstay of therapy remains dietary restriction of sodium intake. Patients with nephrosis have marked sodium avidity and the amount of sodium in the urine may be as low as 10 mmol/day. It is virtually impossible to lower the sodium intake to these levels, however, and it is more useful to suggest and achieve a mild-moderate sodium restriction. Thiazide diuretics may be sufficient in patients with mild edema. Potassium-sparing diuretics, such as triamterene, amiloride, or spironolactone, are useful in those patients in whom hypokalemia becomes a clinical problem. However, their use is limited in those patients with renal insufficiency. Furosemide and other loop diuretics are typically used for moderate to severe nephrotic edema. While the high-protein content of tubular fluid was once thought to inhibit furosemide and other loop diuretics by binding to them, new data suggest that urinary protein binding does not affect the response to furosemide. Metolazone may be effective when used alone or in combination with loop diuretics (i.e., furosemide) in patients with refractory nephrotic edema. In patients treated with diuretics, episodes of profound volume depletion may occur. The resultant peripheral vasoconstriction, tachycardia, orthostatic hypotension, and, at times, oliguria and renal insufficiency are usually amenable to cessation of the diuretic and rehydration. Albumin infusions transiently increase plasma volume and are most useful in patients with profound volume depletion. Unfortunately, because of the rapid excretion of infused albumin within 48 hours, the utility of this approach is short-lived and may result in transient development of pulmonary edema. In extreme cases of marked edema and especially pulmonary edema, usually in the setting of reduced GFR, filtration using either intermittent or continuous extracorporeal dialysis is useful. For a further discussion of the clinical aspects of diuretic use in the nephrotic syndrome, see Chapter 26, Diuretics.

Idiopathic Edema and Capillary Leak

85


Idiopathic edema is a disorder characterized by fluid retention that cannot be attributed to the known causes or pathogenic mechanisms of edema formation. Although the etiology of this CH 4 syndrome has not yet been clarified, it is known that it is overwhelmingly more common in women. It is important to distinguish this disorder from excessive estrogen-stimulated Naþ and fluid retention associated with the premenstrual state (cyclic or premenstrual edema), diabetes mellitus, or hypothyroidism. A hallmark of idiopathic edema is the observation that most of the affected patients retain Naþ and water in the upright posture but diurese in the recumbent position. There is considerable evidence that affected patients have a decreased plasma volume, which declares itself with stimulation of antinatriuretic and antidiuretic effector mechanisms in the upright position. The relative importance of secondary hyperaldosteronism in sustaining the progressive weight gain in this disorder is highlighted by the observation that treatment with ACE inhibitors often results in weight loss and symptomatic improvement. A subpopulation of patients with idiopathic edema has been reported to develop edema while receiving diuretic agents. It is assumed that in these patients saltretaining mechanisms overcompensate for the direct effects of the drug. However, it is possible that Kþ depletion, a common complication of chronic diuretic therapy, in itself contributes to edema formation. Overall, the effects of diuretic therapy in this setting are unclear and patients are best treated by salt restriction.

Chapter 5

Disorders of Water Balance Disorders of body fluids are among the most commonly encountered problems in the practice of clinical medicine, largely because many different disease states can potentially disrupt the finely balanced mechanisms that control the intake and output of water and solute. As body water is the primary determinant of the osmolality of the extracellular fluid (ECF), disorders of water metabolism can be broadly divided into hyperosmolar disorders, in which there is a deficiency of body water relative to body solute, and hypo-osmolar disorders, in which there is an excess of body water relative to body solute. Because sodium is the main constituent of plasma osmolality, these disorders are typically characterized by hypernatremia and hyponatremia, respectively. Water constitutes approximately 55% to 65% of body weight, varying with age, sex, and body fat. Total body water (TBW) is distributed between the intracellular fluid (ICF) and ECF compartments, with approximately 55% to 65% in the ICF and 35% to 45% in the ECF; approximately 75% of the ECF compartment is interstitial. Osmolality is defined as the concentration of all solutes in a given weight of water and is expressed as units of either osmolality (milliosmoles of solute per kilogram of water, mOsm/kg H2O) or osmolarity (milliosmoles of solute per liter of water, mOsm/L H2O). Total solute concentration can be estimated by adding the concentrations of all individual ions and other solutes. Plasma osmolality (Posm) can be measured directly (freezing point) or calculated using the following formula: Posm ðmOsm=kg H2OÞ ¼ 2 plasma½Naþ þ Kþ ðmEq=LÞ þ glucoseðmg=dLÞ=18 þ BUNðmg=dLÞ=2:8 where BUN ¼ blood urea nitrogen. The total osmolality of plasma is not always equivalent to the “effective” osmolality, because the latter is a function of the relative solute permeability properties of the membranes separating the ICF and ECF compartments. Solutes that cannot freely traverse cell membranes (Naþ, mannitol) are restricted to the ECF compartment and are effective solutes because they create osmotic pressure gradients across cell membranes, leading to osmotic movement of water from the ICF to the ECF

87

88 compartments. Solutes that traverse cell membranes (urea,


ethanol, methanol) are ineffective solutes, because they do not create such osmotic pressure gradients with the attendant water shifts. At normal physiologic plasma concentrations, II glucose is an ineffective solute as it is taken up by cells via active transport mechanisms; however, under conditions of impaired cellular uptake (e.g., insulin deficiency) it becomes an effective extracellular solute. The importance of this distinction between total and effective osmolality lies in the fact that only the effective solutes in plasma are determinants of whether clinically significant hyperosmolality or hypo-osmolality is present. An example of this is uremia: a patient with a urea concentration that has increased by 56 mg/dL will have a corresponding 20 mOsm/kg H2O elevation in plasma osmolality, but the effective osmolality will remain normal because the increased urea is proportionally distributed across both the ECF and the ICF compartments. In contrast, a patient whose plasma [Naþ] has increased by 10 mEq/L will also have a 20 mOsm/kg H2O elevation of plasma osmolality, because the increased cation must be balanced by an equivalent increase in plasma anions. However, in this case, the effective osmolality will also be elevated by 20 mOsm/kg H2O as the Naþ and accompanying anions will largely remain restricted to the ECF. Thus, elevations of solutes such as urea, unlike elevations in plasma Naþ concentration, do not cause cellular dehydration, and consequently do not activate mechanisms that defend body fluid homeostasis by acting to increase body water stores.

CONTROL OF PLASMA OSMOLALITY Arginine Vasopressin Synthesis and Secretion Arginine vasopressin (AVP) is a nonapeptide that is synthesized in the hypothalamus. As its name suggests, arginine vasopressin causes constriction of blood vessels, but the pressor effect occurs only at a much higher concentration than that required to produce antidiuresis and is probably of no physiologic or pathologic importance in humans except under conditions of severe hypotension and hypovolemia, in which it acts to supplement the vasoconstrictive actions of angiotensin II (A-II) and the sympathetic nervous system. AVP is produced by the posterior pituitary gland or neurohypophysis in response to a rise in serum osmolality. It affects antidiuresis via binding to AVP V2 receptors in the collecting duct of the kidney, which causes increased water permeability through the insertion of the aquaporin-2 (AQP-2) water channel into

Disorders of Water Balance

the apical membranes of collecting tubule principal cells. 89 Water reabsorption is enhanced, thereby lowering the plasma osmolality toward the normal range. In healthy adults, the osmotic threshold for AVP secretion ranges from 275 to 290 mOsm/kg H2O (averaging 280–285 mOsm/kg H2O). CH 5 A rise in plasma osmolality of as little as 1% is sufficient to trigger AVP release with proportional increases in urine concentration, and maximal antidiuresis is achieved after increases in plasma osmolality of only 5 to 10 mOsm/kg H2O above the threshold for AVP secretion. However, multiple factors, in addition to genetic influences, can alter either the sensitivity or the set-point of the osmoregulatory system for AVP secretion. Other nonosmotic causes of AVP release include actual or “effective” circulating blood volume, nausea, hypoglycemia, stress, and a variety of drugs (Table 5-1). Aging has been associated with increased sensitivity of the osmoregulatory system, and pregnancy reliably decreases the osmostat for AVP secretion.

Thirst Thirst is the body’s defense mechanism to increase water consumption in response to a perceived water deficit. However, the vast majority of fluid ingested is determined by influences

Table 5-1

Drugs and Hormones That Affect Vasopressin Secretion

Stimulatory Acetylcholine Nicotine Apomorphine Morphine (high doses) Epinephrine Isoproterenol Histamine Bradykinin Prostaglandin b-Endorphin Cyclophosphamide IV Vincristine Insulin 2-Deoxyglucose Angiotensin II Lithium Corticotropin-releasing factor Naloxone Cholecystokinin

Inhibitory Norepinephrine Fluphenazine Haloperidol Promethazine Oxilorphan Butorphanol Opioid agonists Morphine (low doses) Alcohol Carbamazepine Glucocorticoids Clonidine Muscimol Phencyclidine Phenytoin

90 such as meal-associated fluid intake, taste, or psychosocial


factors rather than true thirst. In healthy adults, an increase in effective plasma osmolality of only 2% to 3% above basal levels produces a strong desire to drink, and is not dependent II on changes in ECF or plasma volume. The absolute level of plasma osmolality at which a person develops a conscious urge to seek and drink water is called the osmotic thirst threshold. It varies appreciably among individuals but averages approximately 295 mOsm/kg H2O. Of physiologic significance is the fact that this level is above the osmotic threshold for AVP release and approximates the plasma osmolality at which maximal concentration of the urine is normally achieved. Thirst can also be stimulated by intravascular hypovolemia, via activation of low or high baroreceptors and circulating A-II, in contrast to the hypothalamic osmoreceptormediated osmotic thirst, although the threshold for stimulation of hypovolemic thirst appears to be significantly higher than that of osmotic thirst.

HYPERNATREMIA Hypernatremia, defined as plasma Naþ level greater than 146 mEq/L, implies a deficiency of total body water relative to total body sodium rather than total body Naþ overload. When approaching a patient with either hypo- or hypernatremia, it is important to understand the following key concept: Total body Naþ stores are a major factor determining ECF volume status; however, the measured serum Naþ reflects only the concentration of sodium within the ECF. Analysis of the serum Naþ without reference to the physical examination or other laboratory indices of volume status gives no information regarding a patient’s ECF volume status. The patient with hypernatremia may be hypovolemic, euvolemic, or hypervolemic, and clinical determination of the volume status is attained by evaluating several factors including the physical examination findings (e.g., blood pressure, skin turgor), laboratory findings (e.g., BUN/creatinine ratio) and hemodynamic parameters (e.g., central venous pressure). Hypernatremia rarely develops in patients who have free access to water because the hyperosmolar-induced thirst sensation triggers avid water ingestion that returns the serum osmolality to normal or near normal. When access to free water is limited, such as may occur in critically ill patients, infants, and patients with dementia, then either free water losses in excess of Naþ losses (diarrhea, osmotic diuresis), free water losses alone (diabetes insipidus), or augmented Naþ intake without sufficient free water (hypertonic feeds, NaHCO3 administration) can lead to the development of hypernatremia. As Naþ is

Management of the Patient with Hypernatremia The approach to the patient with documented hypernatremia includes the following key steps: • Determination of total body Naþ stores (i.e., ECF volume status) • Identification of the underlying cause of the water deficit • Calculation of total body water deficit and ongoing free water losses • Correction of volume disturbance, if present • Correction of the water deficit with specific regard to the risk of cerebral edema from overly rapid correction

Hypovolemic Hypernatremia Hypovolemic hypernatremia implies renal or extrarenal losses of sodium that are exceeded by the loss of free water. Extrarenal losses can be due to increased dermal losses (e.g., burns, sweating) or more commonly diarrhea (e.g., lactulose administration). An assessment of the urinary biochemistry can help to distinguish renal from extrarenal losses. In the latter setting, the kidney avidly reabsorbs Naþ and water leading to the excretion of concentrated urine with a urine Naþ concentration, [UNaþ], usually less than 20 mEq/L. In contrast, primary renal salt and water losses (water > salt losses), as may occur secondary to an osmotic diuresis (mannitol, postobstruction, hyperglycemia), are characterized by the excretion of an isotonic or hypotonic urine (Uosm < 300 mOsm/L) and a UNaþ greater than 20 mEq/L.

Euvolemic Hypernatremia Euvolemic hypernatremia implies a disorder of urinary concentration related to either the absence of AVP or a resistance to the actions of AVP within the principal cells in the distal tubule. The common causes of euvolemic hypernatremia are discussed in the following sections.


the principal determinant of serum osmolality, hypernatremia is 91 associated with a rise in serum osmolality, which causes fluid to exit brain cells, causing cell shrinkage and a variety of neurologic sequelae. Depending on the speed of onset of the hypernatremia, these sequelae include restlessness, anxiety, confusion, coma, CH 5 seizures, and most dramatically, central pontine myelinolysis (see later discussion in this chapter).

92 Central Diabetes Insipidus


Central diabetes insipidus (CDI) is caused by inadequate secretion of AVP from the posterior pituitary in response to osmotic stimulation. In most cases, this is due to destruction of the neuII rohypophysis by a variety of acquired or congenital anatomic lesions, which damage the neurohypophysis by either direct pressure or by infiltrative mechanisms (Table 5-2). Familial CDI, an autosomal dominant disorder, is caused by diverse mutations in the gene that encodes the AVPneurophysin precursor. Idiopathic forms of AVP deficiency may represent autoimmune destruction of the neurohypophysis, and account for a large proportion of cases of CDI. AVP antibodies have been found in the serum of as many as one third of patients with idiopathic diabetes insipidus (DI) and two thirds of those with Langerhans cell histiocytosis X, but not in patients with DI caused by tumors. Lymphocytic infundibuloneurohypophysitis has been demonstrated to be present in a subset of patients with idiopathic CDI, similar to the wellrecognized lymphocytic infiltration of the anterior pituitary gland (lymphocytic hypophysitis) shown to cause anterior pituitary deficiency. The magnetic resonance imaging (MRI) appearance of lymphocytic infundibuloneurohypophysitis is characterized by a thickened stalk and enlargement of the posterior pituitary mimicking a pituitary tumor. CDI is also associated with changes in the renal response to AVP, the most notable of which is a reduction in the maximal concentrating ability, which has been attributed to washout of the medullary concentrating gradient due to chronic polyuria. The severity of this change is proportional to the degree of polyuria, and is independent of its cause. In CDI, this is balanced to some extent by an apparent increase in renal sensitivity to low levels of plasma AVP, thought to be via upregulation of AVP V2 receptor expression or function.

Osmoreceptor Dysfunction The primary osmoreceptors that control AVP secretion and thirst are located in the anterior hypothalamus. Lesions of this region result in hyperosmolality through a combination of impaired thirst and osmotically stimulated AVP secretion, known as “adipsic hypernatremia” in recognition of the profound thirst deficits found in most patients. All cases of osmoreceptor dysfunction reported to date have been due to variable degrees of osmoreceptor destruction caused by the same types of lesions that can cause classic CDI, but in contrast, they are located, or extend, more anteriorly in the hypothalamus. One lesion unique to this disorder is an anterior communicating cerebral artery aneurysm, which is associated with spontaneous or postsurgical infarction of the osmoreceptive region of the hypothalamus. Several patterns of

Table 5-2

Etiology of Hypotonic Polyuria

93

Central Diabetes Insipidus Congenital (congenital malformations, autosomal dominant, AVPneurophysin gene mutations) Granulomatous (histiocytosis, sarcoidosis) Neoplastic (craniopharyngioma, germinoma, lymphoma, leukemia, meningioma, pituitary tumor, metastases) Infectious (meningitis, tuberculosis, encephalitis) Inflammatory/autoimmune (lymphocytic infundibuloneurohypophysitis) Trauma (neurosurgery, deceleration injury) Vascular (cerebral hemorrhage/infarction, brain death) Idiopathic Osmoreceptor Dysfunction Granulomatous (histiocytosis, sarcoidosis) Neoplastic (as above) Vascular (anterior communicating artery aneurysm/ligation, intrahypothalamic hemorrhage) Idiopathic Increased AVP Metabolism Pregnancy Nephrogenic Diabetes Insipidus Congenital (X-linked recessive, AVP-V2 receptor gene mutations, aquaporin-2 water channel mutations) Drug-induced (demeclocycline, lithium, cisplatin, methoxyflurane) Hypercalcemia Hypokalemia Infiltrating lesions (sarcoidosis, amyloidosis) Vascular (sickle cell anemia) Mechanical (polycystic kidney disease, bilateral ureteral obstruction) Solute diuresis (glucose, mannitol, sodium, radiocontrast dyes) Idiopathic Primary Polydipsia Psychogenic (schizophrenia, obsessive-compulsive behavior) Dipsogenic (downward-resetting of thirst threshold: idiopathic, or lesions similar to those for central diabetes insipidus) AVP, arginine vasopressin.

CH 5


Drug/toxin-induced (ethanol, diphenylhydantoin, snake venom)

94 osmoreceptor dysfunction have been described, ranging from


normal thirst and AVP responses but at an abnormally high osmostat, to blunting of thirst and AVP response at all osmolalities and complete absence of thirst and AVP response II regardless of the plasma osmolality. The hallmark of this disorder, regardless of the actual disease pattern, is an abnormal thirst response, in addition to variable defects in AVP secretion, such that plasma osmolality rises far above the normal thirst threshold, typically in the range of 300 to 340 mOsm/kg H2O. Despite the impaired osmotic release of AVP, these patients usually have normal AVP and renal concentrating responses to baroreceptor-mediated stimuli such as hypovolemia and hypotension, or to other nonosmotic stimuli such as nausea.

Gestational Diabetes Insipidus A relative deficiency of plasma AVP due to the action of the circulating enzyme oxytocinase/vasopressinase, normally produced by the placenta to degrade circulating oxytocin, can trigger gestational diabetes insipidus, via degradation of the structurally similar AVP. Marked variability in the plasma levels of oxytocinase/vasopressinase has been demonstrated, such that some patients have levels far in excess of those normally seen in pregnancy, and some have relatively normal levels. Coexistent preeclampsia, acute fatty liver, and coagulopathies have been described, although a unifying causal relationship has not been indentified.

Nephrogenic Diabetes Insipidus Resistance to the antidiuretic action of AVP due to a defect within the kidney is commonly referred to as nephrogenic DI (NDI). NDI may be congenital or caused by a variety of drugs, diseases, and metabolic disturbances, among them lithium, hypokalemia, and hypercalcemia, all thought to cause NDI via effects on the expression of AQP2, the protein that forms water channels in renal medullary collecting tubules (see Table 5-2). Inherited causes of nephrogenic DI are discussed in Chapter 20, Inherited Disorders of the Kidney.

Clinical Manifestations of Diabetes Insipidus The cardinal clinical symptoms of DI are polyuria and polydipsia. Clinical manifestations of hyperosmolality can be divided into the signs and symptoms produced by dehydration, which are largely cardiovascular, and those caused by the hyperosmolality itself, which are predominantly neurologic and reflect brain dehydration as a result of osmotic water shifts out of the central nervous system (CNS). Cardiovascular manifestations

Hypervolemic Hypernatremia Patients with hypervolemic hypernatremia typically have received an exogenous Naþ load. Examples include the administration of hypertonic intravenous sodium bicarbonate to a patient with a metabolic acidosis or the administration of excess NaCl to an infant.

Treatment of Hypernatremia To reduce the risk of CNS damage from protracted exposure to severe hyperosmolality, in most cases the plasma osmolality should be lowered relatively rapidly within the first 24 hours, to a range of 320 to 330 mOsm/kg H2O or by replacing approximately 50% of the free water deficit (see later discussion). In chronic hypernatremia and sustained hyperosmolality the brain counteracts osmotic shrinkage by increasing the intracellular content of solutes. However, once the brain has adapted by increasing its solute content, rapid correction of the hyperosmolality can trigger cerebral edema and neurologic injury. Therefore, further correction to a normal plasma osmolality should be extended over the next 24 to 72 hours to avoid triggering cerebral edema. This slower correction is especially important in children, where several studies have indicated that limiting correction of hypernatremia to a maximal rate of 0.5 mmol/L/hour prevents the occurrence of symptomatic cerebral edema with seizures. In addition, the possibility of associated thyroid or adrenal insufficiency should also be considered because patients with CDI caused by hypothalamic masses may have associated anterior pituitary function deficiency. Acute hypernatremia with associated neurologic signs can be corrected over a shorter period ( 20

U[Na] < 20

U[Na] > 20

U[Na] > 20

U[Na] < 20

Renal losses Diuretic excess Mineralocorticoid deficiency Salt-losing nephropathy Bicarbonaturia with RTA and metabolic alkalosis Cerebral salt wasting

Extrarenal losses Vomiting Diarrhea Third spacing of fluids Burns Pancreatitis Trauma

Glucocorticoid deficiency Hypothyroidism Stress Drugs SIADH

Acute or chronic renal failure

Nephrotic syndrome Cirrhosis Cardiac failure

Figure 5-1. Diagnostic approach to the hyponatremic patient. RTA, renal tumor acidosis; SIADH, syndrome of inappropriate secretion of antidiuretic hormone. (Modified from Halterman R, Berl T: Therapy of dysnatremic disorders. In Brady H, Wilcox C [eds]: Therapy in Nephrology and Hypertension. Philadelphia, WB Saunders, 1999, p 256.)

1. Hyponatremia with ECF volume depletion 2. Hyponatremia with excess ECF volume 3. Hyponatremia with normal ECF volume

Hyponatremic patients with ECF volume depletion have sustained a deficit in total body Naþ that exceeds their water deficit. Volume depletion, if sufficiently severe, is a potent stimulus to AVP release. Although the hyponatremia in this setting clearly involves depletion of body solutes, a concomitant failure to excrete water is critical to the process. An examination of the urinary Naþ concentration, [UNaþ], is helpful in assessing whether the fluid losses are renal or extrarenal in origin. A [UNaþ] less than 20 mEq/L reflects the normal renal response to volume depletion and suggests an extrarenal source of fluid loss (gastrointestinal, burns, sequestration). Hypovolemic hyponatremia in patients with a [UNaþ] above 20 mEq/L suggests the kidney as the source of fluid loss. Diuretic-induced hyponatremia accounts for a significant proportion of symptomatic hyponatremia in hospitalized patients and occurs almost exclusively with thiazide rather than loop diuretics, owing to the lack of effect of thiazides on urine concentrating ability. Risk factors include female sex, low body weight, and older age. Diuretics can cause hyponatremia by a variety of mechanisms: (1) volume depletion, which enhances AVP release and decreases fluid delivery to the diluting segment; (2) direct effect of diuretics on the diluting segment; and (3) Kþ depletion causing a decrease in the water permeability of the collecting duct, as well as an increase in water intake. Salt-losing nephropathy with hypovolemic hyponatremia may occur in the following settings: advanced kidney disease, interstitial nephropathy, medullary cystic disease, polycystic kidney disease, and partial urinary obstruction. Patients with proximal renal tubular acidosis exhibit renal sodium and potassium wasting despite modest renal insufficiency because bicarbonaturia obligates these cation losses. Adrenal insufficiency has long been associated with impaired renal water excretion and hyponatremia. This diagnosis should be considered in the volume-contracted hyponatremic patient whose urinary Naþ concentration is not low, particularly when the serum Kþ, BUN, and creatinine levels are elevated. Cerebral salt wasting is a rare syndrome described primarily in patients with subarachnoid hemorrhage; it leads to renal salt wasting and volume contraction. The mechanism is thought to involve increased release of natriuretic peptides.

CH 5


Hyponatremia with Extracellular Fluid Volume Depletion

101

102 Hyponatremia with Excess Extracellular Fluid

Volume


In the advanced stages, the edematous states discussed in this II section are associated with hyponatremia. These patients have an increase in total body Naþ content, but the rise in TBW exceeds that of Naþ. With the exception of renal failure and ongoing diuretic use, these states are characterized by avid Naþ retention (UNaþ < 10 mEq/L).

Congestive Heart Failure Advanced congestive heart failure is associated with hyponatremia due to excess water retention. This is mediated by a combination of decreased delivery of tubule fluid (i.e., Naþ) to the distal nephron and increased release of AVP in response to the decrement in “effective” blood volume and decreased arterial filling sensed by aortic and carotid sinus baroreceptors. Although acute atrial distention is associated with inhibition of AVP, there is evidence that chronic atrial distention blunts the receptor sensitivity, allowing unopposed stimulation of AVP release. The degree of neurohumoral activation correlates with the clinical severity of left ventricular dysfunction, and the degree of hyponatremia has been shown to be a significant prognostic factor in these patients.

Hepatic Failure Patients with advanced cirrhosis and ascites frequently present with hyponatremia consequent to their inability to excrete a water load. This process results from a decrement in effective arterial volume (splanchnic venous pooling, decreased plasma oncotic pressure due to hypoalbuminemia, peripheral vasodilatation) leading to avid Naþ and water retention, again thought to be via baroreceptor-mediated AVP release.

Nephrotic Syndrome The incidence of hyponatremia in the nephrotic syndrome is lower than in either congestive heart failure or cirrhosis, most likely consequent to the higher blood pressure, higher glomerular filtration rate (GFR), and more modest impairment in Naþ and water excretion than in the other groups of patients. As lipids are frequently elevated, a direct measurement of plasma osmolality should be performed.

Renal Failure Hyponatremia with edema can occur with either acute or chronic renal failure owing to an inability to excrete an ingested water load, often combined with an increased sensation of thirst.

Hyponatremia with Normal Extracellular Fluid Volume Syndrome of Inappropriate Antidiuretic Hormone Secretion

Table 5-4

Disorders Associated with SIADH

Carcinomas Bronchogenic Gastric Pancreas Lymphoma Pulmonary Pneumonia Tuberculosis Pulmonary abscess Asthma Aspergillosis Asthma Pneumothorax

CNS Meningitis Encephalitis Brain abscess Guillain-Barre´ syndrome Multiple sclerosis Cerebrovascular accident Subarachnoid/subdural hemorrhage Alcohol withdrawal Other HIV infection

SIADH, syndrome of inappropriate antidiuretic hormone.

CH 5


Patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) are hypo-osmolar while excreting urine that is less than maximally dilute (>50 mOsm/kg H2O). However, the development of hyponatremia accompanied by a dilute urine ( DAG suggests the presence of combined hyperchloremic and high-AG acidosis. It must then be established if the acid anion in serum is metabolizable (i.e., b-hydroxybutyrate, acetoacetate, lactate) or nonmetabolizable (anions that accumulate in chronic kidney disease). The latter variety

132 requires normal renal function and renal ammoniagenesis to

Distrurbances in Control of Body Fluid Volume and Composition

replenish the HCO3 deficit, a slow and often unpredictable process. Therefore, patients with a normal AG (hyperchloremic acidosis), a small AG (mixed hyperchloremic and AG II acidosis), or a high AG attributable to a nonmetabolizable anion in the setting of renal insufficiency should receive alkali therapy to increase the serum HCO3 concentration slowly into the range of 20 to 22 mEq/L. In acute lifethreatening metabolic acidosis once the blood pH falls below 7.2, the decrease in myocardial contractility predisposes to congestive heart failure; therefore, a pH of 7.2 is a reasonable therapeutic end point. Intravenous HCO3 should be given in amounts that increase the pH to this value. There is no fixed dose to achieve this goal and a reasonable estimated starting dose is determined as follows: Serum ½HCO3 > 10 mEq=L : Dose in mEq ¼ Desired DHCO3 ½body weight ðkgÞ 0:5 or Serum ½HCO3 < 10 mEq=L : Dose in mEq ¼ Desired DHCO3 ½body weight ðkgÞ 0:8 The need for the two equations is due to the increasing volume of distribution of HCO3 as acidemia worsens. Serum electrolytes should be monitored hourly during the course of therapy to facilitate timely modification of treatment, with particular regard to the serum Kþ, which may decline precipitously as the pH increases.

Treatment of Lactic Acidosis The basic principle (and only effective form) of therapy for lactic acidosis is the correction of the underlying condition initiating the derangement in normal lactate metabolism. In type A lactic acidosis, cessation of acid production through improved tissue oxygenation, restoration of the circulating fluid volume, improvement or augmentation of cardiac function, resection of ischemic tissue, or treatment of sepsis is necessary in many cases. Alkali therapy is generally advocated for acute, severe acidemia (pH < 7.1), to improve inotropy and lactate utilization. However, NaHCO3 therapy in large amounts may depress cardiac performance and paradoxically exacerbate acidemia. The accumulation of lactic acid may be relentless and may necessitate use of renal replacement therapy, which can simultaneously deliver HCO3, remove lactate, and correct fluid and electrolyte abnormalities. If the underlying cause can be remedied, blood lactate will be reconverted to HCO3.

HCO3 derived from lactate conversion and any new HCO3 133 generated by renal mechanisms during acidosis, or from exogenous alkali therapy, are additive, and may result in an overshoot alkalosis. CH 6

The administration of insulin, with simultaneous correction of extracellular volume and Kþ deficits, is the cornerstone of treatment of DKA. Administration of alkali is not usually required except in cases of severe acidemia (1000 mEq), Mg2þ deficiency, Gitelman syndrome, Bartter syndrome, or primary autonomous mineralocorticoid states, as listed in Table 6-6. Therapy in these cases must be directed toward the underlying pathophysiology. If infusion of saline is precluded by associated conditions (such as a mixed metabolic alkalosis and respiratory acidosis in chronic obstructive pulmonary disease/congestive heart failure), accelerated renal HCO3 loss can be achieved by the administration of the carbonic anhydrase inhibitor acetazolamide (250 mg twice a day), which is usually very effective in patients with adequate renal function, but may exacerbate

urinary Kþ losses. Dilute hydrochloric acid (0.1 N HCl), 135 although effective, can be dangerous and can result in brisk hemolysis. Finally, if renal replacement therapy is required, a custom dialysate lower in HCO3 and higher in Cl should be utilized. CH 6

The treatment of respiratory acidosis depends on its severity and rate of onset. Acute respiratory acidosis can be lifethreatening, and measures to reverse the underlying cause should be made simultaneously with restoration of adequate alveolar ventilation to relieve severe hypoxemia and acidemia. Temporarily, this may necessitate assisted noninvasive or invasive mechanical ventilation. Oxygen should be carefully titrated in patients with severe chronic obstructive pulmonary disease and chronic CO2 retention who are breathing spontaneously. Injudicious use of oxygen may exacerbate the respiratory acidosis. Aggressive and rapid correction of hypercapnia should be avoided, because the falling PaCO2 may provoke the same complications noted with acute respiratory alkalosis (i.e., cardiac arrhythmias, reduced cerebral perfusion, and seizures). It is advisable to lower the PaCO2 gradually in chronic respiratory acidosis, aiming to restore the PaCO2 to baseline levels while at the same time providing sufficient chloride and potassium to enhance the renal excretion of bicarbonate. Chronic respiratory acidosis is frequently difficult to correct, but general measures aimed at maximizing lung function, cessation of smoking, use of oxygen, bronchodilators, corticosteroids, diuretics, and physiotherapy can help some patients and can forestall further deterioration. Respiratory stimulants may prove useful in selected cases, particularly if the patient appears to have hypercapnia disproportionate to the level of lung function. The treatment of respiratory alkalosis is primarily directed toward alleviation of the underlying disorder. Respiratory alkalosis is rarely life-threatening, and direct measures to correct it will be unsuccessful if the stimulus remains unchecked.

Disorders of Acid-Base Balance

Treatment of Respiratory Acid-Base Disorders

the addition of sequential agents only when the patient has been 157 demonstrated to tolerate such medications.

The Clinical Approach to Hyperkalemia

Treatment of Hyperkalemia Most cases of hyperkalemia result from Kþ accumulation due to a combination of renal insufficiency and impaired distal Kþ excretion; Kþ elimination is therefore the aim of treatment. However, occasionally, hyperkalemia may be due to Kþ redistribution, and the clinical approach is addressed at achieving intracellular translocation of Kþ rather than Kþ loss, as this may result in rebound hypokalemia (e.g., diabetic ketoacidosis). The management of hyperkalemia is based on a combination of factors, including the severity of the hyperkalemia, the presence of ECG evidence of cardiac toxicity, and clinical signs of hyperkalemia, which are also influenced by other electrolyte abnormalities, acid-base status, and chronicity. Severe hyperkalemia (serum Kþ 8 mmol/L or serum Kþ > 6.5 mmol/L with ECG changes other than peaked T waves) is a medical emergency and requires urgent intervention (Table 7-3). Given the limitations of ECG changes as a predictor of cardiac toxicity, patients with moderate hyperkalemia (Kþ 6.5 mmol/L) in the absence of ECG changes or symptomatic patients (muscle weakness) should also receive prompt medical intervention. Urgent management of severe hyperkalemia includes a 12-lead electrocardiogram, admission to the hospital, continuous ECG monitoring, and immediate treatment. The treatment of hyperkalemia is generally divided into three categories: 1. Antagonism of the cardiac effects of hyperkalemia 2. Rapid reduction in Kþ by redistribution into cells 3. Removal of Kþ from the body The necessary measures to treat the underlying conditions causing hyperkalemia should be undertaken to minimize the

Disorders of Potassium Metabolism

As for hypokalemia, the priority in the initial management of hyperkalemia is to assess the requirement for emergency treatment. Thereafter, a comprehensive investigation into the underlying etiology should be undertaken, with particular focus on medication history, diet (including supplements), risk factors for kidney disease, and volume status (Fig. 7-2). Initial laboratory tests should include a full electrolyte screen, blood urea nitrogen (BUN), creatinine, serum osmolality, complete blood count, and urinary pH, osmolality, creatinine, and electrolytes, with calculation of the TTKG.

CH 7

158 Emergency therapy

Yes

K+ ≥ 6 or ECG changes

Hypokalemia (serum K+ ≥ 5.5 mmol/L)

Yes

Evidence of increased potassium load

History, physical examination and basic laboratory tests

Evidence of transcellular shift

No

Yes

Treat accordingly and re-evaluate

No Decreased urinary K+ excretion (7

20 mL/min)

• Hypertonicity (e.g., mannitol) • Hyperglycemia • Succinylcholine • ε-Aminocaproic acid • Digoxin • β-Blockers • Metabolic acidosis (nonorganic) • Arginine infusion • Hyperkalemic periodic paralysis • ↓ Insulin • Exercise

Advanced kidney failure (GFR ≤ 20 mL/min)

Reduced ECV

Administer 9α-fludrocortisone

TTKG ≥ 7

TTKG < 7 (tubular resistance)

Low aldosterone Drugs • Amiloride • Spironolactone • Triamterene • Trimethoprim • Pentamidine • Eplerenone • Calcineurin inhibitors

Other causes • Tubulointerstitial diseases • Urinary tract obstruction • PHA type I • PHA type II • Sickle cell disease • Renal transplant • SLE

Renin High • Primary adrenal insufficiency • Isolated aldosterone deficiency • Heparin/LMW heparin • ACE-I/ARB • Ketoconazole

Low • Diabetes mellitus • Acute GN • Tubulointerstitial diseases • PHA type II • NSAIDs • β-Blockers

Figure 7-2. The diagnostic approach to hyperkalemia. ACE-I, angiotensin-converting enzyme inhibitor; acute GN, acute glomerulonephritis; ARB, angiotensin II receptor blocker; CCD, cortical collecting duct; ECG, electrocardiogram; ECV, effective circulatory volume; GFR, glomerular filtration rate; LMW heparin, low-molecular-weight heparin; PHA, pseudohypoaldosteronism; SLE, systemic lupus erythematosus; TTKG, transtubular potassium gradient. (From Mount DB, Zandi-Nejad K: Disorders of potassium balance. In Brenner & Rector’s The Kidney, 8th ed. Philadelphia, WB Saunders, 2005, pp 547–588.)

159

160

Table 7-3

Acute Management of Severe Hyperkalemia

Stabilize myocardium with calcium salts Calcium gluconate 10% 10 mL as IV bolus


II

Shift potassium into cells Intravenous glucose (50 mL of 50%) with 5–10 IU of insulin and 10–20 mg nebulized albuterol over 10 min (2–4 mL of 5 mg/mL albuterol solution) or Subcutaneous terbutaline injection (7 mg/kg) Potassium removal with dialysis (in patients with ESRD, or when conservative measures are unsuccessful in the non-ESRD population) ESRD, end-stage renal disease. From Putcha N, Allon M: Management of hyperkalemia in dialysis patients. Semin Dial 20:431–439, 2007.

factors that are contributing to hyperkalemia and to prevent future episodes. Dietary restriction (usually 60 mEq/day) with emphasis on the Kþ content of total parenteral nutrition solutions and enteral feeding products (typically 25–50 mmol/L) and adjustment of medications and intravenous fluids are necessary; hidden sources of Kþ, such as intravenous antibiotics, should not be overlooked.

Antagonism of Cardiac Effects Intravenous calcium raises the action potential threshold and reduces excitability without changing the resting membrane potential, and reverses the depolarization blockade that occurs with hyperkalemia. Calcium is available as calcium chloride or calcium gluconate (10-mL ampules of 10% solutions) for intravenous infusion. Calcium gluconate is less irritating to the veins and can be used through a peripheral intravenous line; calcium chloride can cause tissue necrosis if it extravasates and it requires a central line. The recommended dose is 10 mL of 10% calcium gluconate (3–4 mL of calcium chloride), infused intravenously over 2 to 3 minutes and under continuous ECG monitoring. The effect of the infusion starts in 1 to 3 minutes and lasts 30 to 60 minutes. The dose should be repeated if there is no change in ECG findings or if they recur after initial improvement. Of note, calcium should be used with extreme caution in patients taking digoxin, because hypercalcemia potentiates the cardiotoxic effects of digoxin. In such cases, 10 mL of 10% calcium gluconate should be added to 100 mL of 5% dextrose in water and infused over 20 to 30 minutes to avoid hypercalcemia. To prevent the precipitation of calcium carbonate, calcium should not be administered in solutions containing bicarbonate. Intravenous calcium should be administered to all

patients with ECG changes; some authors advocate its use 161 in patients with serum potassium greater than 6 to 6.5 mmol/L, even in the absence of ECG changes.

Redistribution of Potassium into Cells

CH 7


Insulin and Glucose. Insulin lowers the serum Kþ concentration by shifting Kþ into cells. The effect is reliable, dose dependent, and effective, even in patients with chronic kidney disease and ESRD. The recommended dose is 5 to 10 units of regular insulin administered intravenously, followed by 50 mL of 50% dextrose. The effect of insulin on the Kþ level begins in 10 to 20 minutes, peaks at 30 to 60 minutes, and lasts for 4 to 6 hours. The expected fall in serum Kþ concentration should be 0.5 to 1.2 mmol/L and the dose can be repeated as necessary. Hypoglycemia may occur in up to 75% of patients. Therefore, a continuous infusion of 10% dextrose at 50 to 75 mL/hour and close monitoring of the blood glucose levels is recommended following administration of the bolus insulin/dextrose dose. Administration of glucose without supplemental insulin is not recommended because the endogenous insulin response to such a glucose load may be variable, and glucose, in the absence of insulin, may in fact increase serum Kþ, by increasing plasma osmolality. In hyperglycemic patients with glucose levels of 200 to 250 mg/dL, insulin should be administered without glucose, but should be followed by close monitoring of the serum glucose. b2-Adrenergic Agonists. b2-Agonists are important, but underutilized, agents for the acute management of hyperkalemia. They exert their effect by activating Naþ/Kþ-ATPase and the NKCC1 Naþ-Kþ-2Cl cotransporter, shifting Kþ into hepatocytes and skeletal myocytes. Albuterol (Salbutamol), a selective b2-agonist, is the most widely used agent; both intravenous and nebulized forms are effective. The recommended dose for intravenous administration is 0.5 mg of albuterol in 100 mL of 5% dextrose, given over 10 to 15 minutes. The Kþ-lowering effect starts in few minutes, is maximal at about 30 to 40 minutes, and lasts for 2 to 6 hours. It reduces serum Kþ levels by approximately 0.9 to 1.4 mmol/L. The recommended dose for inhaled albuterol is 10 to 20 mg of nebulized albuterol in 4 mL of normal saline, inhaled over 10 minutes. Its effects start at 30 minutes, peaks at 90 minutes, and last for 2 to 6 hours. Inhaled albuterol reduces serum Kþ levels by approximately 0.5 to 1 mmol/L. Administration of inhaled or parenteral albuterol has an additive effect when given with glucose/insulin in reducing serum Kþ levels, by approximately 1.2 to 1.5 mmol/L in total. Treatment with albuterol may result in increased heart rate, an effect seen more prominently with intravenous administration, and it should be used with caution in patients with ischemic heart disease. Importantly, up to 40% of patients with ESRD are not

162 responsive to Kþ-lowering effect of albuterol; it should not


therefore be used as a single agent in this population. In an attempt to reduce pharmacokinetic variability, a weight-based regimen of subcutaneous terbutaline (7 mg/kg) was recently of ESRD patients, and effected a II given a trial in a small group mean reduction in serum Kþ levels of 1.3 mmol/L in 30 to 90 minutes, suggesting promise as an alternate approach, characterized by simplicity of administration and speed of onset. Sodium Bicarbonate. The role of bicarbonate in the acute treatment of hyperkalemia is increasingly being challenged. The effect of combining bicarbonate with either insulin-glucose or with albuterol has been studied, with no convincing benefit demonstrated in terms of lowering of the serum Kþ. Potential adverse effects include a reduction in ionized calcium levels and volume overload. Indeed some studies utilizing hypertonic bicarbonate have shown an increase in the serum Kþ level, thought to be due to increased plasma osmolality, promoting Kþ shift out of cells. As a result the routine administration of bicarbonate, especially as a single agent, has no role in the acute treatment of hyperkalemia. One exception may be the management of severely acidemic patients.

Removal of Potassium

Diuretics. Diuretics have a relatively modest effect on urinary Kþ excretion in patients with chronic kidney disease. However, they are useful in correcting chronic hyperkalemia in patients with the syndrome of hyporeninemic hypoaldosteronism and selective renal Kþ secretory problems (e.g., post-transplantation or trimethoprim administration). In patients with impaired renal function, the following are recommended: • Oral diuretics with the highest bioavailability and the least renal metabolism (e.g., torsemide, bumetanide) to minimize the chance of accumulation and toxicity • Intravenous agents (short-term) with the least hepatic metabolism (e.g., furosemide rather than bumetanide) • Combination loop-thiazide therapy, although this may activate tubuloglomerular feedback and decrease GFR • Use of the maximal effective “ceiling” dose Mineralocorticoids. Fludrocortisone may be useful in treating chronic hyperkalemia in patients with hypoaldosteronism with or without hyporeninism, those with SLE, kidney transplant recipients on cyclosporine, and as a preventive agent in ESRD patients on hemodialysis with interdialytic hyperkalemia, although the available data are limited. Mineralocorticoids are thought to lower potassium by two mechanisms: (1) augmentation of colonic potassium excretion, and (2) stimulation of Naþ/Kþ-ATPase on the cell membrane to enhance


extrarenal potassium excretion. The recommended dose is 0.1 163 to 0.3 mg/day. In patients with ESRD on hemodialysis, this regimen reduces serum Kþ by up to 0.5 to 0.7 mmol/L. Close monitoring of blood pressure and weight after initiation of these medications is prudent, especially in patients without CH 7 ESRD. Cation Exchange Resins. Sodium polystyrene sulfonate (SPS, Kayexalate) exchanges Naþ for Kþ in the gastrointestinal tract. To prevent constipation and to facilitate the passage of the resin through the gastrointestinal tract, sorbitol may be added. The current recommended dose is 15 to 30 g of powder in water or, preferably, 70% sorbitol, one to four times daily. It can take from 4 to 24 hours for the full effect to occur. Therefore, this approach should be used only in conjunction with other measures in the treatment of acute hyperkalemia. Each gram of resin binds 0.5 to 1.2 mEq of Kþ in exchange for 2 to 3 mEq of Naþ. It is worth noting that a recent, albeit small, study failed to demonstrate any potassium-lowering effect when examining the use of single-dose resins in ESRD patients on hemodialysis. Kayexalate can also be administered rectally as a retention enema in patients unable to take or tolerate the oral form. The recommended dose is 30 to 50 g of resin every 6 hours administered as a warm (i.e., body temperature) emulsion in 100 mL 20% dextrose in water after an initial cleansing enema (i.e., body temperature tap water) and through a rubber tube secured at about 20 cm from the rectum and well into the sigmoid colon. The emulsion should be introduced by gravity, flushed with an additional 50 to 100 mL of non–sodiumcontaining fluid, retained for at least 30 to 60 minutes, and followed by a cleansing enema (250 to 1000 mL of body temperature tap water). The use of sorbitol in the enema preparation is not recommended due to multiple reported cases of colonic necrosis, ischemic colitis, and perforation secondary to SPS-sorbitol. This complication can also occur with oral administration of SPS in sorbitol, although the incidence tends to be much lower. Other potential complications, although rare, include reduction of serum calcium, volume overload, interference with lithium absorption, and iatrogenic hypokalemia. Given the slow onset of action and limited potassium-lowering effect of resins, their use in the acute treatment of hyperkalemia is of limited benefit. Dialysis. Dialysis is the definitive treatment for severe hyperkalemia in ESRD patients, and may also be required following failure of conservative measures to control severe hyperkalemia and in settings of massive Kþ release (e.g., rhabdomyolysis). Continuous hemodiafiltration is increasingly used for the management of critically ill and hemodynamically unstable patients; peritoneal dialysis, although

164 less effective in an acute setting, can remove significant


amounts of Kþ over a 24-hour period using multiple exchanges. However, hemodialysis is the preferred mode when rapid correction of an acute hyperkalemic episode is II desired in patients. An average 3- to 5-hour hemodialysis session removes approximately 40 to 120 mmol of Kþ, with the greatest decline in serum Kþ levels (1.2–1.5 mmol/L) occurring during the first hour. The amount of potassium removed depends primarily on the type and surface area of the dialyzer used, blood flow rate, duration, and serum to dialysate Kþ gradient. Other factors include the dialysate concentration of bicarbonate and glucose. Dialysates with a lower Kþ concentration are more effective in reducing serum Kþ levels. However, a rapid decline in serum Kþ is associated with an increased incidence of cardiac arrhythmias, and may also be associated with rebound hypertension. Therefore, dialysates with a very low Kþ concentration (0 or 1 mmol/L) should be used cautiously, particularly in high-risk patients (digoxin use, history of arrhythmia, coronary artery disease, left ventricular hypertrophy, hypertension, older age). Continuous cardiac monitoring is recommended for all patients dialyzed against a 0- or 1-mmol/L Kþ bath. A graded reduction in the dialysate Kþ concentration over the course of the dialysis session may be used, particularly in high-risk patients. Glucose-free dialysates are more efficient in removing Kþ, thought to be due to alterations in endogenous insulin levels and associated Kþ shifts. The bicarbonate concentration of dialysate has also been shown to influence Kþ removal: the use of high concentration (39 mmol/L) bicarbonate dialysate is associated with a more rapid reduction in serum Kþ, although the total amount of Kþ removal is greater with low concentration (27 mmol/L) dialysate. A rebound increase in serum Kþ can occur after hemodialysis. This phenomenon can be especially marked in cases of massive release from devitalized tissues (e.g., tumor lysis, rhabdomyolysis). Other factors attenuating Kþ removal and thus increasing the risk and magnitude of post-dialysis rebound include pretreatment with b2-agonists, insulin and glucose, eating early during the dialysis treatment, a high predialysis serum Kþ, and higher dialysate Naþ concentrations.

Other Therapeutic Options for Prevention of Hyperkalemia in ESRD Strategies to prevent hyperkalemia in the ESRD population are critically important (Table 7-4) and include dietary restriction of potassium, and use of b2-agonists and glucose with or without insulin in the prolonged fasting situation (e.g., presurgery).

Table 7-4

Strategies to Prevent Hyperkalemia in the ESRD Population

165

Restriction of dietary potassium

Avoidance of medications that may increase serum potassium, including Kþ-sparing diuretics, ACE inhibitors, heparin, NSAIDs, and nonselective b-blockers Potential therapies requiring further study Mineralocorticoids, such as fludrocortisone Bisacodyl Fosinopril ACE, angiotensin-converting enzyme; ESRD, end-stage renal disease. From Putcha N, Allon M: Management of hyperkalemia in dialysis patients. Semin Dial 20:431–439, 2007.

Use of the ACE inhibitor fosinopril in a group of hemodialysis patients was shown to result in a significant reduction in predialysis serum potassium levels. Fosinopril is excreted by both renal and biliary pathways, and it is thought that fosinopril may increase potassium secretion via the biliary system, thereby decreasing interdialytic hyperkalemia. Daily administration of the laxative bisacodyl has also undergone trial as a modality for the reduction of interdialytic potassium. Daily use of 5 to 10 mg of bisacodyl in hemodialysis patients was shown to reduce serum potassium levels, and although it increased stool frequency, it did not cause overt diarrhea. Bisacodyl is thought to stimulate cAMP, thereby activating potassium secretion in the gut.

CH 7


Administration of nebulized albuterol and/or 10% dextrose at 50 mL/hour (add 10 IU insulin per liter if patient is diabetic) during prolonged fasting

Chapter 8

Disorders of Calcium, Magnesium, and Phosphate Balance DISORDERS OF CALCIUM METABOLISM The extracellular calcium concentration is tightly maintained, reflecting the actions of multiple hormones (parathyroid hormone [PTH], calcitonin, and vitamin D) on bone, intestine, kidney, and parathyroid tissue. This homeostatic system is modulated by dietary and environmental factors (including vitamins, hormones, medications, and mobility). The normal total extracellular calcium concentration is 9 to 10.5 mg/dL (2.25–2.65 mmol/L) of which approximately 50% is bound to serum proteins, the remainder existing as free ionized calcium (pathophysiologically relevant fraction). Alterations in the serum pH can alter the fraction of ionized calcium: alkalosis promotes the binding of serum free Ca2þ to albumin; the converse is true in the setting of acidosis. Although an alteration in ionized calcium is usually reflected by altered total calcium, this may not be the case if the serum protein concentrations are abnormal. A useful rule is to add 0.8 mg/dL for every 1-mg depression in serum albumin below 4 mg/dL to “correct” for hypoalbuminemia.

Hypercalcemia Signs and Symptoms The clinical manifestations of hypercalcemia reflect both the degree of hypercalcemia and rate of increase. Neuromuscular sequelae are common, and include altered mental status, depression, fatigue, and muscle weakness. Frequent gastrointestinal complications include constipation, nausea, and vomiting; peptic ulcer disease is rare, pancreatitis exceedingly so. Hypercalcemia causes polyuria and polydipsia; significant hypercalcemia can lead to severe dehydration. Nephrolithiasis and nephrocalcinosis are seen in 15% to 20% of cases of primary hyperparathyroidism (HPT). Hypercalcemia causes a shortened QT interval on electrocardiograms due to an increased rate of cardiac repolarization. Heart block and other

166

arrhythmias also may be observed. Even mild hypercalcemia 167 may be of clinical significance, as some studies have suggested an increased cardiovascular risk from relatively mild, although prolonged, elevation in serum calcium. CH 8

Primary HPT and malignancy-associated hypercalcemia are responsible for the vast majority of cases of hypercalcemia. In primary HPT, the serum PTH is usually frankly elevated; in malignancy-associated hypercalcemia and in most other causes, PTH levels are low. An elevated parathyroid hormone–related protein (PTHrP) level indicates humoral hypercalcemia of malignancy (although some forms of malignancyassociated hypercalcemia are not mediated by this circulating hormone). Approximately 10% of cases of hypercalcemia are due to other causes. Of particular importance in the evaluation of a hypercalcemic patient are the family history (familial syndromes including multiple endocrine neoplasia [MEN] types I and II, and familial hypocalciuric hypercalcemia), medication history (several medication-induced forms of hypercalcemia), and the presence of other disease (e.g., granulomatous or malignant disease).

Causes of Hypercalcemia (Tables 8-1 and 8-2)

Primary Hyperparathyroidism. Primary HPT is caused by excess PTH secretion and accounts for 50% of cases of hypercalcemia. Incidental detection of hypercalcemia is the usual presentation and the degree of hypercalcemia may be mild and

Table 8-1

Causes of Hypercalcemia

Common Primary hyperparathyroidism Adenoma Carcinoma Hyperplasia Malignancy Humoral hypercalcemia Lytic bone disease Ectopic 1,25(OH)2vitamin D Less Common Inherited disease Multiple endocrine neoplasia type I, II Familial hypocalciuric hypercalcemia Other

Drug-induced Lithium Aminophylline Vitamin D Estrogens Thiazides Vitamin A Milk-alkali syndrome Granulomatous disease Nonparathyroid endocrinopathies Immobilization Chronic kidney disease Neonatal hypercalcemia

Disorders of Calcium, Magnesium, and Phosphate Balance

Diagnosis

168


II

Table 8-2

Causes of Chronic Hypocalcemia

Hypoparathyroidism Altered Ca2þ/PTH setpoint PTH gene defects Postsurgical Neck irradiation Infiltrative disease Hypo/hypermagnesemia Autoimmune disease

PTH Resistance Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Hypomagnesemia Other Vitamin D deficiency Altered vitamin D metabolism Drug induced

PTH, parathyroid hormone.

intermittent. The estimated prevalence of primary HPT is approximately 1%, rising to 2% in postmenopausal women. A single enlarged gland is causative in 80% to 90% of cases, usually due to a single benign adenoma; carcinoma is rare. In approximately 15% of cases, HPT is due to four-gland hyperplasia. The disease is about three times more common in women than in men. Primary HPT rarely causes life-threatening hypercalcemia; however, some data suggest that primary HPT may be associated with hypertension, dyslipidemia, diabetes, arterial thickening, and increased mortality rate, primarily due to cardiovascular disease. The classic bony lesion of HPT, osteitis fibrosa cystica, is now rarely seen; diffuse osteopenia is a more common finding. Standard therapy for primary HPT remains parathyroidectomy. Indications include serum calcium levels greater than 1 mg/dL above normal, a history of life-threatening hypercalcemia, renal insufficiency, kidney stones, reduced bone mass, or hypercalciuria (>400 mg calcium per 24 hours). Medical surveillance is considered a reasonable alternative for individuals older than 50 years with no obvious symptoms and normal bone density. Such patients should receive close follow-up, including periodic measurements of bone density, renal function, and serum calcium. Preoperative localization of parathyroid adenomas is increasingly performed by means of a technetium-99 sestamibi scan. If a single adenoma is identified, minimally invasive parathyroidectomy may be a viable option; this requires intraoperative visualization of only the culpable gland, as long as resection results in a substantial intraoperative decline in PTH. Otherwise, all four glands should be surgically identified. Although excision of a single enlarged gland is curative, the presence of more than one enlarged gland raises the possibility of diffuse parathyroid hyperplasia and the syndrome of multiple endocrine neoplasia (MEN). When all glands are enlarged, removal of 3½ glands or all 4 glands with forearm autotransplantation of a portion of the gland is advocated.


Parathyroid Carcinoma. Parathyroid carcinoma accounts for 169 less than 1% of primary HPT. The diagnosis of parathyroid carcinoma may be difficult to make in the absence of metastases because the histologic appearance may be similar to that of atypical adenomas. In general, parathyroid carcinoma is not aggres- CH 8 sive, and survival is common if the entire gland can be removed. Malignancy. Humoral hypercalcemia of malignancy (HHM) generally refers to the syndrome of malignancy-associated hypercalcemia caused by secretion of PTHrP (approximately 80% of malignancy-associated hypercalcemia). PTHrP is widely expressed in a variety of tissues, but normal circulating levels are negligible. PTHrP and PTH interact with the PTH receptor with equal affinity. Malignancies associated with HHM include squamous cell, renal cell, breast, and ovarian carcinomas. Lymphomas associated with human T-lymphotropic virus type 1 (HTLV-1), and other non-Hodgkin lymphomas, may also cause PTHrP-mediated HHM. Patients are hypercalcemic, hypophosphatemic, and hypercalciuric. Malignant lymphomas have been reported to produce 1,25(OH)2D in sufficient quantity to cause hypercalcemia due to increased bone and calcium reabsorption. Rarely, ectopic production of PTH by a nonparathyroid tumor may occur. Osteolytic metastases may produce severe pain, pathologic fractures, and hypercalcemia. Extensive bone destruction is seen in patients with multiple myeloma. Although bony lesions are nearly universal, hypercalcemia is not noted with the same frequency; the degree of hypercalcemia does not correlate well with the extent of bone destruction. Inherited Disease Multiple Endocrine Neoplasias. Multiple endocrine neoplasia type I (MEN-I), an autosomal dominant disorder characterized by tumors of the parathyroid gland, pituitary, and pancreas, is the most common form of familial HPT, usually due to diffuse four-gland-hyperplasia. The gene defect in MEN-I is the menin gene, a possible tumor suppressor gene found on chromosome 11q13. MEN-IIA is also characterized by parathyroid hyperplasia and autosomal dominant inheritance. Medullary thyroid carcinoma and pheochromocytoma are associated findings. The MEN-IIA gene defect is on chromosome 10 within the RET proto-oncogene. Treatment of the HPT is surgical: subtotal parathyroidectomy or total parathyroidectomy with autotransplantation of a portion of the excised parathyroid gland in the forearm. Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism. Familial hypocalciuric hypercalcemia (FHH), or familial benign hypercalcemia, is a rare autosomal dominant condition, the majority of cases due to inactivating defects in the extracellular calcium receptor (CaR) located on chromosome 3q. The hypercalcemia is typically mild to

170 moderate (10.5–12 mg/dL) and asymptomatic. Both total and


ionized calcium levels are elevated, and the PTH level is generally “inappropriately normal” in the presence of hypercalcemia. Urinary calcium excretion is not elevated, as would be II expected in hypercalcemia of other causes. Relative hypocalciuria persists even after parathyroidectomy in FHH, confirming the role of CaR in regulating renal calcium handling. Differentiating primary HPT from FHH is critical, because the hypercalcemia in FHH is benign and does not respond to subtotal parathyroidectomy. Two copies of CaR alleles bearing inactivating mutations cause neonatal severe hyperparathyroidism (NSHPT). This rare disorder, most often reported in the offspring of consanguineous FHH parents, is characterized by severe hyperparathyroid hyperplasia, PTH elevation, and elevated extracellular calcium. Treatment is total parathyroidectomy followed by vitamin D and calcium supplementation. This disease is usually lethal without surgical intervention. Medications. Hypercalcemia, often with elevated PTH levels, affects 5% to 10% of patients treated with lithium, likely mediated by interaction with the extracellular CaR to alter the calcium set-point for PTH secretion. The hypercalcemia is typically reversible, although lithium-independent HPT may develop after prolonged treatment. Vitamin A intoxication (in the order of 100,000 U/day) may cause hypercalcemia, presumably from increased osteoclast-mediated bone resorption. Hypercalcemia has also been reported to be due to use of vitamin A analogs, used in the treatment of dermatologic and hematologic malignancy. Hypercalcemia is a wellrecognized complication of thiazide diuretics, although it is unclear whether their hypocalciuric effect alone is responsible for the observed hypercalcemia. Because thiazides may exacerbate borderline hypercalcemia of other causes, severe hypercalcemia in a thiazide-treated patient should prompt further investigation. Milk-Alkali Syndrome. The syndrome of hypercalcemia, alkalosis, and renal insufficiency caused by the ingestion of large amounts of calcium and antacids is known as the milkalkali syndrome. Reduction in the use of antacids had resulted in a decline in the incidence of this syndrome, but the popularity of calcium supplementation in the form of calcium carbonate has resulted in a recent upsurge in cases, such that some reports suggest it is the underlying cause of hypercalcemia in up to 12% of cases. The pathogenesis of the syndrome is unclear, and requires the ingestion of calcium of significantly greater quantities than that contained within a normal calcium-supplemented diet, in the order of 5 g/day. In susceptible individuals, increased alkali intake, hypercalcemia, and a concomitant reduction in glomerular filtration rate (GFR)


engender a metabolic alkalosis that inhibits calcium excretion 171 and further perpetuates the syndrome. Vitamin D Intoxication. Hypercalcemia may develop in individuals ingesting vitamin D or vitamin D analogs, including 1,25(OH)2D. Serum 25(OH)D is elevated and immunoreacCH 8 tive PTH (iPTH) is depressed. The diagnosis is made by the history and detection of elevated 25(OH)D levels. Immobilization. Immobilization can produce increased rates of bone resorption, decreased rates of bone formation, and hypercalcemia days to weeks after start of complete bed rest. The hypercalcemia is reversible with resumption of activity. Low PTH and 1,25(OH)2D levels are characteristically seen. Granulomatous Disease. Hypercalcemia is observed in 10% of cases of sarcoidosis due to increased production of 1,25(OH)2D from nonrenal sites; hypercalciuria is more common, seen in up to 50% of patients, and may precede the development of hypercalcemia. Macrophages in sarcoid granulomata produce calcitriol. Other granulomatous disorders, including leprosy, Wegener granulomatosis, and AIDS with pulmonary Pneumocystis carinii (PCP) infection, have rarely been associated with altered vitamin D metabolism and hypercalcemia. Nonparathyroid Endocrinopathies. Mild hypercalcemia is common in thyrotoxicosis. Bone turnover is increased, and PTH and 1,25(OH)2D levels are decreased. Pheochromocytoma may be associated with hypercalcemia, usually due to coincident HPT and MEN-IIA. Adrenal insufficiency, pancreatic islet cell tumors, growth hormone administration, and acromegaly have all been associated with hypercalcemia.

Management of Hypercalcemia The treatment of mild chronic hypercalcemia should be directed at the underlying cause. However, immediate therapy is required for patients with acute severe hypercalcemia (>14 mg/dL/3.5 mmol/L). Volume depletion is almost universal in severe hypercalcemia. Volume repletion and induction of saline diuresis prompt a calciuresis and are central to successful therapy. Patients should be initially administered 200 to 300 mL/hour of 0.9% NaCl; tapering thereafter to 100 to 200 mL/hour at the clinical discretion of the treating physician. Once volume is replete, loop diuretics may be administered to augment the urinary calcium losses. Care should be taken not to use loop diuretics prior to volume expansion as this may trigger prerenal acute kidney injury (AKI). The patient’s volume status must be closely monitored during the administration of large amounts of saline and diuretic, particularly in hospitalized patients with cardiac or pulmonary disease. Bisphosphonates such as pamidronate (30–90 mg IV over 2 hours) and zoledronate (4 mg IV over 15 minutes) are highly

172 effective at lowering the serum calcium; a single dose may


control the serum calcium for several weeks. They act via inhibition of osteoclast function in areas of high bone turnover and appear to be particularly efficacious in patients with II malignancy. Calcitonin, an effective inhibitor of osteoclast bone resorption, is of limited use as sole therapy for hypercalcemia. Other therapies, including plicamycin, chelation with EDTA, and intravenous phosphate, have adverse side effect profiles, and are no longer recommended. Glucocorticoids are most effective in the hematologic malignancies (multiple myeloma, Hodgkin disease) and disorders of vitamin D metabolism (granulomatous disease, vitamin D toxicity). In severely hypercalcemic patients (>18 mg/dL/ 4.5 mmol/L), hemodialysis with a low- or no-calcium dialysate is an effective treatment. Newer therapies for the management of hypercalcemia continue to evolve. Noncalcemic analogs of calcitriol, such as 22-oxacalcitriol, may reduce the release of PTHrP in patients with HHM. Manipulation of the Ca2þ/PTH response with calcimimetic agents such as cinacalcet has revolutionized the management of secondary HPT, and may hold promise for the treatment of primary HPT.

Hypocalcemia The clinical manifestations of hypocalcemia vary greatly and, when present, are predominantly neurologic and neuromuscular. The most common clinical manifestations are muscle cramps and numbness in the digits. Severe hypocalcemia can cause laryngeal spasm, carpopedal spasm, bronchospasm, seizures, and even respiratory arrest. Mental changes include irritability, depression, and decreased cognitive capacity. Bedside signs of hypocalcemia include ipsilateral facial muscle twitching in response to tapping the facial nerve (Chvostek sign) and carpal spasm induced by brachial artery occlusion (Trousseau sign). Electrocardiographic (ECG) changes include prolongation of the QT interval. Long-standing hypocalcemia may result in dry skin, coarse hair, alopecia, and brittle nails. Teeth may be absent or hypoplastic. Calcification of the basal ganglia and cerebral cortex may be detected by computed tomography (CT) in chronic hypocalcemia. Although the total calcium concentration generally reflects the physiologically relevant ionized fraction, hypoalbuminemia affects the total calcium measurement, without affecting the ionized level. Pseudohypocalcemia may also occur due to interference with colorimetric calcium assays by some gadolinium-based contrast agents commonly used in magnetic resonance imaging. The most common causes of hypocalcemia in the nonacute setting are hypoparathyroidism, hypomagnesemia, renal failure, and vitamin D deficiencies.

Acquired Hypoparathyroidism

173

Magnesium-Related Disorders Both hypomagnesemia and hypermagnesemia are associated with hypocalcemia. Mg2þ is an extracellular CaR agonist and infusion of Mg or hypermagnesemia inhibits PTH secretion. Chronic severe hypomagnesemia results in hypocalcemia, via intracellular Mg2þ depletion and its effect on PTH gland function. Hypomagnesemia also alters end-organ responsiveness to PTH. Typically, these patients have low or inappropriately normal PTH levels for the degree of hypocalcemia observed. The appropriate therapy is Mg2þ repletion; in the absence of adequate Mg repletion, the hypocalcemia is resistant to PTH or to vitamin D therapy. Hypoparathyroidism can also occur acutely due to hypermagnesemia (e.g., high doses of magnesium sulfate used in the obstetric setting), likely via CaR-mediated inhibition of PTH secretion.

Autoimmune Disease Type I polyglandular autoimmune syndrome, also referred to as APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome), is a recessive disorder. Its cardinal features are childhood onset of hypoparathyroidism in association with adrenal insufficiency and mucocutaneous candidiasis. The gene for APECED has been localized to chromosome 21q, and is termed AIRE (autoimmune regulator). Autoantibodies against parathyroid tissue have been reported in a significant percentage of cases of hypoparathyroidism, but the causative role of these antibodies is unclear. CaR has been identified as a possible autoantigen in some cases of autoimmune hypoparathyroidism (either isolated or polyglandular).

Vitamin D–Related Disorders Vitamin D3 is normally produced by the skin from 7-dehydrocholesterol in the presence of sunlight; vitamin D deficiency therefore requires both dietary deficiency and lack of exposure


Surgical hypoparathyroidism is the most common cause of acquired hypoparathyroidism. It is observed after total thyroidectomy, radical neck dissection, and repeated operations for parathyroid adenoma. Hypoparathyroidism may result CH 8 from inadvertent removal of the parathyroid glands or vascular damage, including devascularization. Transient hypoparathyroidism and hypocalcemia are quite common after total thyroidectomy, and may result from a rapid reduction in thyroid-mediated bone resorption, or from temporary insult to the parathyroid gland. Removal of a single hyperfunctioning parathyroid adenoma can result in transient hypocalcemia because of hypercalcemia-induced suppression of PTH secretion from the normal glands.

174 to the sun. Prolonged vitamin D deficiency causes rickets (a dis-


order of mineralization of growing bone) and osteomalacia (a disorder of mineralization of formed bone). Elevation of PTH levels is generally observed. The diagnosis is confirmed by meaII surement of serum 25(OH)D levels. Populations at risk include hospitalized patients, nursing home residents, and breastfeeding infants of mothers with diets low in vitamin D. In urban populations with low exposure to sunlight, vitamin D deficiency is common. Vitamin D deficiency may also be seen following gastrectomy, in Crohn disease, in celiac sprue, and following intestinal resection due to altered enterohepatic circulation and malabsorption of vitamin D. Vitamin D deficiency with hypocalcemia is commonly seen in patients with renal insufficiency and is due in part to impaired 1a-hydroxylation of vitamin D. Disorders of altered vitamin D metabolism represent a second group of vitamin D–related hypocalcemias. They may be acquired or inherited. Medications, most notably the anticonvulsants phenytoin and phenobarbital, can increase the rate of hepatic metabolism of 25(OH)D to inactive metabolites.

Medications Bisphosphonates, mithramycin, and calcitonin, all of which inhibit bone resorption, may depress serum calcium to subnormal levels. Administration of citrated blood during massive transfusion can cause hypocalcemia. Similarly, significant hypocalcemia may occur after plasmapheresis. Foscarnet (trisodium phosphoformate) can cause hypocalcemia through the chelation of extracellular calcium ions; normal total calcium measurements may not reflect ionized hypocalcemia. Other drugs associated with hypocalcemia include antimicrobial agents (pentamidine, ketoconazole) and chemotherapeutic drugs (asparaginase, cisplatin, and doxorubicin).

Critical Illness In critically ill patients, total calcium measurements may be poor indicators of the ionized calcium concentration (hypoproteinemia, acid-base disturbances, dialysis therapy). Thus, it is particularly important to measure ionized calcium in this setting. Hypocalcemia has been reported to be present in 70% of intensive care unit patients. Hypocalcemia is frequently noted in gram-negative sepsis and toxic shock syndrome, the mechanism of which is unknown, but which may involve direct effects of interleukin-1 on parathyroid function.

Miscellaneous Hypocalcemia is commonly seen in acute pancreatitis, and is a poor prognostic factor. It is probably due to calcium chelation by free fatty acids generated by the action of pancreatic lipase. Severe hyperphosphatemia may cause hypocalcemia,

particularly in patients with renal failure. The use of phosphate 175 enemas and phosphate-supplemented infant formula has been reported to cause hypocalcemia. Hypophosphatemia may also be associated with massive tumor lysis and the early phase of rhabdomyolysis. CH 8

A variety of inherited or genetic disorders give rise to hypocalcemia, including DiGeorge syndrome and pseudohypoparathyroidism. For a more detailed discussion of these conditions, see Chapter 16, Disorders of Calcium, Magnesium and Phosphate Balance, in Brenner and Rector’s The Kidney.

Treatment of Hypocalcemia Treatment of acute hypocalcemia depends on the severity of the depression in serum calcium and the presence of clinical manifestations. Oral calcium supplementation may be sufficient treatment for mild hypocalcemia; severe hypocalcemia with evidence of neuromuscular effects or tetany requires intravenous calcium. Typically, 1 to 3 g of intravenous calcium gluconate is given over a period of 10 to 20 minutes, followed by slow intravenous infusion. Dialysis (with a high calcium dialysate) may be the appropriate treatment if severe hyperphosphatemia is also present. Correction of hypomagnesemia and hyperphosphatemia should also be undertaken when present. Treatment of chronic hypocalcemia depends on the underlying cause. The principal therapy for primary disorders of parathyroid dysfunction or PTH resistance is dietary calcium supplementation and vitamin D therapy. Correction of serum calcium to the low-normal range is generally advised; correction to normal levels may lead to frank hypercalciuria.

DISORDERS OF MAGNESIUM HOMEOSTASIS Hypomagnesemia and Magnesium Deficiency Extracellular fluid Mg2þ accounts for only 1% of total body Mg2þ, and serum Mg2þ concentrations therefore correlate poorly with overall Mg2þ status. The incidence of hypomagnesemia ranges from 11% in the general inpatient population to 60% of patients admitted to intensive care units, where it is associated with increased mortality rate.

Etiology and Diagnosis

Mg2þ deficiency may be caused by decreased intake or intestinal absorption; increased losses via the gastrointestinal tract, kidneys, or skin; or rarely, sequestration in the bone compartment. Urinary Mg2þ excretion distinguishes between renal


Genetic Disorders of Parathyroid Hormone Dysfunction or Altered Responsiveness

176 Mg2þ wasting and extrarenal causes of Mg2þ loss. The frac-


tional excretion of magnesium (FeMg2þ) should be estimated, and is calculated in the standard fashion after multiplication of the serum Mg2þ concentration by 0.7, as approximately is protein bound, and remains II 30% of circulating magnesium unfiltered. A FeMg2þ greater than 3% in an individual with normal GFR in the setting of Mg2þ deficiency is indicative of inappropriate urinary magnesium loss. The FeMg2þ is thought to be superior to the urinary magnesium/creatinine molar ratio for this purpose. If renal Mg2þ wasting has been excluded, the etiology of the extrarenal losses can usually be identified from the case history.

Extrarenal Causes

Nutritional Deficiency. Induction of magnesium deficiency by dietary means in normal individuals is surprisingly difficult, as the majority of foods contain significant amounts of magnesium, and the renal adaptation to conserve Mg2þ is very efficient. Nonetheless, magnesium deficiency of nutritional origin is characteristically seen in two clinical settings: alcoholism and parenteral feeding. Approximately 20% to 25% of alcoholics are frankly hypomagnesemic. Some evidence suggests that alcohol may also impair renal magnesium conservation. Patients receiving parenteral nutrition have a high incidence of hypomagnesemia due to associated medical conditions, a poorly understood increase in daily Mg2þ requirements, and the refeeding syndrome, whereby overzealous parenteral feeding of severely malnourished patients causes hyperinsulinemia and a rapid cellular uptake of Mg2þ. Intestinal Malabsorption. Generalized malabsorption syndromes caused by conditions such as celiac disease, Whipple disease, and inflammatory bowel disease are frequently associated with intestinal Mg2þ wasting and Mg2þ deficiency. In fat malabsorption with concomitant steatorrhea, free fatty acids in the intestinal lumen may combine with Mg2þ to form nonabsorbable soaps; in rare patients reduction of dietary fat intake, which reduces steatorrhea, can correct the hypomagnesemia. Previous intestinal resection, particularly of the distal part of the small intestine, is also an important cause of Mg2þ malabsorption. Similarly, Mg2þ deficiency can be a late complication of jejunoileal bypass surgery performed for the treatment of obesity. Cutaneous Losses. Hypomagnesemia may be observed after prolonged intense exertion. About a quarter of the decrement in serum Mg2þ can be accounted for by losses in sweat, with the remainder most likely being due to transient redistribution into the intracellular space. Hypomagnesemia occurs in 40% of patients with severe burn injuries during the early period of recovery due to cutaneous losses, which can exceed 1 g/day.

Renal Magnesium Wasting

Polyuria. Renal Mg2þ wasting occurs with osmotic diuresis, during recovery from ischemic injury in the transplanted kidney, and during postobstructive diuresis. In the latter cases, it is likely that residual tubule reabsorptive defects persisting from the primary renal injury play as important a role as polyuria itself in inducing renal Mg2þ wasting. Extracellular Fluid Volume Expansion. Chronic therapy with Mg2þ-free parenteral fluids, either crystalloid or hyperalimentation, can cause renal Mg2þ wasting, partly due to extracellular fluid volume expansion. Renal Mg2þ wasting is also characteristic of hyperaldosteronism. Defective Naþ Reabsorption in Distal Nephron. Loop diuretics inhibit paracellular Mg2þ reabsorption via inhibition of the Naþ-Kþ-2Cl cotransporter of the thick ascending loop of Henle (TAL) and abolition of the transepithelial potential difference. Hypomagnesemia is therefore a frequent finding in patients receiving chronic loop diuretic therapy. Thiazides also inhibit renal Mg2þ reabsorption by an incompletely understood mechanism. Hypercalcemia. Elevated serum ionized Ca2þ levels directly induce renal Mg2þ wasting and hypomagnesemia. In HPT, the hypercalcemia-induced tendency to Mg2þ wasting is counteracted by the action of PTH, which stimulates Mg2þ reabsorption, so renal Mg2þ handling is usually normal and Mg2þ deficiency is therefore rare. Tubule Nephrotoxins. Multiple tubulotoxins are associated with hypermagnesuria. The most commonly implicated drugs include cisplatin, aminoglycosides, amphotericin B, pentamidine, foscarnet, and cyclosporine. As with aminoglycosides and pentamidine, foscarnet-induced hypomagnesemia is often associated with significant hypocalcemia. In contrast, the hypomagnesemia seen with cisplatin and amphotericin B is accompanied by hypocalciuria, suggesting a distal convoluted tubule defect, as with Gitelman syndrome. The hypomagnesemia associated with cisplatin is dose-related and may persist for months, even years, following cessation of therapy. Cyclosporine causes renal Mg2þ wasting and hypomagnesemia in patients after renal and bone marrow transplantation.


Redistribution to Bone Compartment. Hypomagnesemia 177 may occasionally accompany the profound hypocalcemia of hungry bone syndrome, observed in some patients with HPT and severe bone disease immediately after parathyroidectomy, when the sudden removal of excess PTH results in an immedi- CH 8 ate cessation of bone resorption, but continued high rate of bone formation and consequent sequestration of both Ca2þ and Mg2þ into bone mineral.

2þ 178 Inherited Renal Mg -Wasting Disorders. Other rare causes


of Mg2þ wasting include isolated familial hypomagnesemia, familial hypomagnesemia, and primary hypomagnesemia with hypocalcemia. Bartter and Gitelman syndromes are disII cussed at further length in Chapter 20, Inherited Disorders of the Kidney.

Clinical Manifestations (Table 8-3) Hypomagnesemia may cause symptoms and signs of disordered cardiac, neuromuscular, and central nervous system function, although most patients are completely asymptomatic. Thus, the clinical importance of hypomagnesemia remains controversial. Moreover, the frequent coexistence of hypokalemia and hypocalcemia may explain many of the cardiac and neurologic manifestations attributed to Mg2þ deficiency.

Treatment Given the clinical manifestations outlined earlier, it seems prudent to replete all Mg2þ-deficient patients with a significant underlying cardiac or seizure disorder, patients with concurrent severe hypocalcemia or hypokalemia, and patients with isolated asymptomatic hypomagnesemia if severe (2 mg/dL), oral repletion with low-fat milk (containing 0.9 mg phosphorus per milliliter) is effective. In individuals intolerant of milk, potassium phosphate or sodium phosphate preparations can be used (up to 3.5 g/day in divided doses). Intravenous phosphorus repletion is generally reserved for individuals with severe (90

2

Kidney damage with mild # GFR

60–89

3

Moderate # GFR

30–59

4

Severe # GFR

15–29

5

Kidney failure

4 mg/dL

Anuria 12 hr

Loss

Dialysis dependent AKI > 4 wk

ESKD

Dialysis dependent AKI > 3 mo

AKI, acute kidney injury; Cr, creatinine; ESKD, end-stage kidney disease; GFR, glomerular filtration rate.

creatinine must take into account differences in creatinine generation rates. As a result, definitions of AKI that are based on a fixed increment in serum creatinine would be expected to be biased toward making an early diagnosis in well-muscled (as compared with malnourished) subjects and in men rather than women. Creatinine clearances, especially when measured over a short time frame such as 2 to 4 hours, have some utility but may substantially overestimate GFR at low levels of renal function, owing to a relatively high proportion of tubular secretion.

ETIOLOGY OF ACUTE KIDNEY INJURY Prerenal Azotemia Prerenal azotemia is the most common cause of AKI. By definition, the integrity of renal parenchymal tissue is maintained and GFR is corrected rapidly with restoration of renal perfusion. Untreated, severe renal hypoperfusion may contribute to the development of ischemic ATN; in practice the two syndromes frequently coexist. Prerenal azotemia can complicate any disease characterized by hypovolemia, low cardiac output, systemic vasodilatation, or intrarenal vasoconstriction (Table 10-2). Glomerular filtration is preserved during mild hypoperfusion (mean systemic blood pressure > 80 mm Hg) through several compensatory mechanisms (see Chapter 4, Control of Extracellular Fluid Volume and Pathophysiology of Edema Formation). These compensatory renal responses are blunted by a variety of drugs including ACE (angiotensinconverting enzyme) inhibitors, angiotensin receptor antagonists, and NSAIDs. The use of these agents can trigger prerenal AKI in the setting of relatively modest falls in renal perfusion pressure if administered to high-risk individuals, including those

Table 10-2

Major Causes of Prerenal Azotemia

203

Intravascular Volume Depletion Hemorrhage Gastrointestinal losses

Increased insensible losses “Third-space” losses (pancreatitis, crush syndrome) Decreased Cardiac Output Cardiac failure Systemic vasodilatation Drugs: antihypertensives, afterload reduction, anesthetics, drug overdoses Sepsis, liver failure, anaphylaxis Renal Vasoconstriction Norepinephrine, ergotamine, liver disease, sepsis, hypercalcemia Pharmacologic Agents That Acutely Impair Autoregulation and Glomerular Filtration Rate in Specific Settings Angiotensin-converting enzyme inhibitors in renal artery stenosis or severe renal hypoperfusion Nonsteroidal anti-inflammatory drugs during renal hypoperfusion

with preexisting renal disease and the elderly. Occasionally prerenal AKI can be triggered by direct renal vasoconstriction without overt systemic hypotension, as occurs in the setting of hypercalcemia, vasoconstrictor administration, or the use of a calcineurin inhibitor (cyclosporine/tacrolimus).

Intrinsic Renal Azotemia From a clinicopathologic viewpoint, it is helpful to categorize intrinsic renal failure as follows: • • • •

Diseases involving large renal vessels Diseases of the renal microvasculature and glomeruli Ischemic and nephrotoxic ATN Tubulointerstitial diseases

Diseases of Large Renal Vessels, Microvasculature, and Tubulointerstitium Bilateral occlusion of the large renal vessels or unilateral occlusion in a single functioning kidney is a rare cause of AKI. Acute renal artery occlusion is usually caused by atheroemboli that are dislodged from an atheromatous aorta during

Acute Kidney Injury

Renal losses (overzealous diuresis, osmotic diuresis, diabetes insipidus)

CH 10

204 arteriography, angioplasty, or aortic surgery. Outside the

Pathogenesis of Renal Disease

immediate post-transplantation period, renal vein thrombosis is an exceedingly rare cause of AKI and is usually encountered only as a complication of the nephrotic syndrome in IV adults or of severe dehydration in children. Virtually any disease that compromises blood flow within the renal microvasculature may induce AKI. These disorders include inflammatory (e.g., glomerulonephritis, vasculitis) and noninflammatory (e.g., malignant hypertension) diseases of the vessel wall, thrombotic microangiopathies, and hyperviscosity syndromes. Disorders of the tubulointerstitium that induce AKI, other than ischemia or tubule cell toxins, include allergic interstitial nephritis, bilateral pyelonephritis, allograft rejection, and, rarely, infiltrative disorders such as sarcoid, lymphoma, or leukemia.

Acute Tubule Necrosis The pathologic term ATN and the clinical term AKI are often used interchangeably when referring to ischemic and nephrotoxic renal injury. The clinical course of ATN can be divided into three phases: the initiation phase, the maintenance phase, and the recovery phase. The initiation phase is the period during which patients are exposed to the ischemia or toxin and parenchymal renal injury is evolving but not yet established. ATN is potentially preventable during this period, which may last hours to days. This is followed by a maintenance phase, during which parenchymal injury is established and GFR stabilizes at a value of 5 to 10 mL/min. The maintenance phase typically lasts 1 to 2 weeks but may be prolonged for 1 to 12 months before the recovery phase, the period during which patients recover renal function through repair and regeneration of renal tissue. Its onset is typically heralded by a gradual increase in urine output and a fall in serum creatinine, although the latter may lag behind the onset of diuresis by several days. This “post-ATN” diuresis may reflect appropriate excretion of salt and water accumulated during the maintenance phase, osmotic diuresis induced by filtered urea and other retained solutes, and the actions of diuretics administered to hasten salt and water excretion. Occasionally, diuresis may be inappropriate and excessive if recovery of tubule reabsorptive processes lags behind glomerular filtration, although this phenomenon is more common after relief of urinary tract obstruction. Ischemic ATN and prerenal azotemia are part of a spectrum of manifestations of renal hypoperfusion, with prerenal azotemia being a response to mild or moderate hypoperfusion and ischemic ATN being the result of more severe or prolonged hypoperfusion, usually coexistent with other renal insults (vasoactive drugs, nephrotoxins). In its more extreme form,

Table 10-3

Exogenous Nephrotoxins Associated with Development of Acute Tubular Necrosis

Chemotherapeutic agents Cisplatin Ifosfamide Anti-inflammatory and immunosuppressive agents NSAIDs (including COX-2 inhibitors) Cyclosporine/tacrolimus Radiocontrast agents Organic solvents Ethylene glycol Toluene Poisons Paraquat COX-2, cyclooxygenase-2.

renal hypoperfusion may result in bilateral renal cortical necrosis and irreversible renal failure ( 2 mg/dL, 176 mmol/L), diabetic nephropathy, cardiac failure, jaundice, volume depletion, large contrast volumes, and the coincident use of ACE inhibitors or NSAIDs. Creatinine levels usually peak after 3 to 5 days in contrast nephropathy and return to the normal range within 5 to 7 days. In atheroembolic renal disease the initial rise occurs over a similar time frame; however, the renal failure is typically irreversible. Patients with contrast nephropathy usually present with benign urine sediment, concentrated urine, and low fractional excretion of Naþ. Acute Kidney Injury in a Patient with Cancer. Most AKI in patients with cancer is caused either by prerenal azotemia induced by vomiting, often in the presence of NSAIDs, or by intrinsic renal azotemia triggered by chemotherapeutic drugs or the products of tumor lysis. Rarer causes include hypercalcemia of malignancy, tumor-associated glomerulonephritis, hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) induced by drugs or irradiation, or infiltration of the renal vessels or urinary collecting system by tumor. The leukemias have long been associated with

Acute Kidney Injury

infiltration of the ureteric wall (e.g., neoplasia), or external 207 compression (e.g., retroperitoneal fibrosis, neoplasia, or abscess, inadvertent surgical ligature). During the early stages of obstruction (hours to days), continued glomerular filtration leads to increased intraluminal pressure upstream of the site CH 10 of obstruction. This results in gradual distention of the proximal ureter, renal pelvis, and calyces and a fall in GFR.

208 the development of AKI, usually as a result of tumor lysis syn-


drome or acute urate nephropathy, which can sometimes develop before the administration of chemotherapeutic agents. AKI in association with multiple myeloma carries a wide difIV ferential diagnosis that includes hypovolemic prerenal AKI, hypercalcemia, cryoglobulinemia, hyperviscosity syndrome, contrast nephropathy, myeloma cast nephropathy, light-chain deposition disease, plasma cell infiltration, vascular amyloidosis, sepsis caused by immunocompromise, and ATN induced by drugs or tumor lysis syndrome. Acute Kidney Injury after a Solid Organ or Bone Marrow Transplant. Nonrenal solid organ transplant recipients have a notably high risk of developing AKI from cardiopulmonary disease, hepatic failure, sepsis, and the nephrotoxic effects of antimicrobial and immunosuppressive agents. AKI has been shown to occur in 35% of heart transplants, 15% of lung transplants, and 20% to 30% of liver transplants. The incidence of AKI following myeloablative hematopoietic cell transplantation (HCT) is as high as 50%, with 20% to 31% of patients requiring hemodialysis. Causes of AKI in this setting include hypovolemia, sepsis, tumor lysis syndrome, direct tubular toxicity from cytoreductive therapy, antibiotics, and calcineurin inhibitors. The prognosis is grave, particularly for patients requiring dialysis (>80% mortality rate). The most common cause of severe AKI complicating myeloablative HCT is the hepatorenal syndrome (HRS) complicating the development of veno-occlusive disease (VOD) of the liver. The syndrome is characterized clinically by profound jaundice and avid salt retention with edema and ascites within the first month after engraftment. The mortality rate approaches 100% for severe VOD. Acute Kidney Injury in Pregnancy. Ischemic ATN may be provoked by postpartum hemorrhage or abruptio placentae and less commonly by amniotic fluid embolism or sepsis. Glomerular filtration is usually normal in mild or moderate preeclampsia; however, AKI may complicate severe disease. In this setting, AKI is typically transient and found in association with intrarenal vasospasm, marked hypertension, neurologic abnormalities, and laboratory evidence of abnormal liver function, thrombocytopenia, and coagulation abnormalities. A distinct variant of preeclampsia, the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), is characterized by an initial benign course that can rapidly deteriorate with marked hemolysis and derangement of coagulation and hepatic and renal function. This presentation contrasts with that of postpartum HUS or TTP, which typically occurs against a background of normal pregnancy, is characterized by thrombocytopenia, microangiopathic anemia, normal prothrombin and partial thromboplastin times, and frequently causes long-term impairment of renal function.

Acute Kidney Injury

Acute Kidney Injury after Cardiovascular Surgery. AKI 209 requiring dialytic support is seen in 1% to 5% of patients undergoing coronary bypass grafting procedures. AKI in this setting can usually be attributed to prerenal azotemia, ischemic ATN, atheroembolic disease, or the effects of radiocon- CH 10 trast material administered perioperatively. The pattern of rise in serum creatinine may be extremely helpful in the differential diagnosis of AKI in this setting. As noted earlier, prerenal azotemia is typified by rapid fluctuations in serum creatinine values that usually precede surgery and mirror changes in systemic hemodynamics and renal perfusion. In ischemic ATN the rise in serum creatinine postoperatively is sustained and returns to baseline over days to weeks. Independent preoperative risk factors for the development of ATN after cardiovascular surgery include advanced age, creatinine clearance less than 60 mL/min, peripheral vascular disease, cardiomegaly, and a left ventricular ejection fraction of less than 35%. Intraoperative risk factors include emergency surgery, bypass time greater than 100 minutes, intra-aortic balloon pump insertion, and combined valvular and coronary revascularization procedures. Acute Kidney Injury in Association with Pulmonary Disease. The coexistence of AKI and pulmonary disease (pulmonary renal syndrome) classically suggests a diagnosis of Goodpasture syndrome, Wegener granulomatosis, or another vasculitis. The detection of circulating antineutrophil cytoplasmic antibodies, anti-glomerular basement membrane antibodies, or hypocomplementemia can be useful in the differentiation of these diseases, although the urgent need for definitive diagnosis and treatment may mandate a lung or renal biopsy. More commonly, AKI and pulmonary disease coexist due to volume overload or pulmonary infection in the critically ill patient. Acute Kidney Injury in Association with Liver Disease. The term hepatorenal syndrome (HRS) is widely misused. It should be reserved for a syndrome of irreversible AKI that complicates advanced liver disease, hepatic failure, or portal hypertension. Two subtypes of HRS have been described. Type 1 is characterized by a rapid onset of renal failure with a doubling of serum creatinine to greater than 2.5 mg/dL or a 50% reduction in GFR to less than 20 mL/min over a 2-week period. This subtype is characterized by a fulminant course with oliguria, encephalopathy, marked hyperbilirubinemia, and death usually within 1 month of presentation. Type 2 HRS is typified by a more indolent course with a stable reduction in GFR accompanying diuretic-resistant ascites and avid sodium retention. The diagnosis of HRS is one of exclusion. Other diagnoses that must be entertained in the patient with AKI and liver disease are prerenal AKI due to

210 gastrointestinal losses, drug toxicity, combined hepatitis and


tubulointerstitial nephritis induced by drugs or infectious agents, and multiorgan involvement in vasculitides (e.g., hepatitis C–induced cryoglobulinemia). The BUN and serum IV creatinine values are characteristically deceptively low, despite marked impairment of GFR, because of impaired urea generation and coexisting muscle wasting. The urinary findings include a benign sediment and a low fractional excretion of sodium (FENa). The most common precipitant of the HRS in patients with compensated cirrhosis is spontaneous bacterial peritonitis. Other trigger factors include vigorous diuresis, paracentesis, gastrointestinal bleeding, infections, minor surgery, or the use of NSAIDs and other drugs. Death is almost invariable in true HRS and is usually caused by hepatic failure, infection, hemorrhage, or circulatory failure.

COMPLICATIONS OF ACUTE KIDNEY INJURY Intravascular Volume Disturbance Intravascular volume overload is a common consequence of AKI and manifests clinically as mild hypertension, increased jugular venous pressure, bibasilar lung crackles, pleural effusions or ascites, peripheral edema, increased body weight, and life-threatening pulmonary edema. Hypervolemia may be particularly troublesome in patients receiving multiple intravenous medications, sodium bicarbonate for correction of acidosis, or enteral or parenteral nutrition. Moderate to severe hypertension is unusual in ATN and should suggest other diagnoses, such as malignant hypertension, scleroderma, renal crisis, or primary glomerular disease. A vigorous osmotic diuresis may complicate the recovery phase of AKI and precipitate intravascular volume depletion and a delay in recovery of renal function.

Electrolyte Disturbances Hyponatremia due to a combination of impaired free-water clearance and the ingestion of water or administration of hypotonic intravenous solutions can cause hyponatremia, which can be severe. Hyperkalemia is a common and potentially life-threatening complication. The serum potassium typically rises by 0.5 to 1 mEq/L/day in oligoanuric patients but the rate of rise may be higher in rhabdomyolysis or the tumor lysis syndrome. Mild hyperkalemia ( 2 mEq/L) if the generation of Hþ is increased by additional mechanisms (e.g., diabetic or fasting ketoacidosis; lactic acidosis complicating generalized tissue hypoperfusion, liver disease, or sepsis; metabolism of ethylene glycol). Metabolic alkalosis is an infrequent finding but may complicate overzealous correction of acidosis with bicarbonate or prerenal AKI triggered by loss of gastric secretions by vomiting or nasogastric aspiration.

Uremic Syndrome Protracted periods of severe AKI or short periods of catabolic, anuric azotemia often lead to the development of the uremic syndrome. Clinical manifestations of the uremic syndrome include pericarditis, pericardial effusion, and cardiac tamponade; gastrointestinal complications such as anorexia, nausea, vomiting, and ileus; and neuropsychiatric disturbances

212 including lethargy, confusion, stupor, coma, agitation, psychosis, asterixis, myoclonus, hyperreflexia, restless leg syndrome, focal neurologic deficit, and seizures.


IV

MANAGEMENT OF ACUTE KIDNEY INJURY Prerenal Azotemia By definition, prerenal azotemia is rapidly reversible on restoration of renal perfusion. Hypovolemia caused by hemorrhage is ideally corrected with packed red blood cells if the patient is hemodynamically unstable or if the hematocrit is dangerously low. In the absence of active bleeding or hemodynamic instability, isotonic saline may suffice. Isotonic saline is the appropriate replacement fluid for plasma losses (e.g., burns, pancreatitis). Urinary or gastrointestinal fluids vary greatly in composition but are usually hypotonic and, accordingly, initial replacement is best achieved with hypotonic solutions (e.g., 0.45% saline). Colloid solutions should be used sparingly in prerenal AKI with regular monitoring of renal function, and the risk of hyperoncotic renal failure minimized by concomitant use of appropriate crystalloid solutions. Cardiac failure may require aggressive management with loop diuretics, antiarrhythmic drugs, positive inotropes, and preloador afterload-reducing agents. Fluid management may be particularly challenging in patients with prerenal AKI and cirrhosis. These subjects typically have intense intrarenal vasoconstriction and expanded total plasma volume because of pooling of blood in the splanchnic circulation; the relative contribution of hypovolemia to AKI in this setting can be determined only by administration of a fluid challenge. Fluids should be administered slowly, because nonresponders may suffer an increase in ascites formation or pulmonary edema, or both. Spontaneous bacterial peritonitis is a common trigger factor for HRS in patients with advanced cirrhosis and ascites. The administration of albumin (1.5 g/kg on diagnosis and 1 g/kg on day 3) in combination with standard antibiotic therapy in this setting has been demonstrated to reduce the incidence of HRS and improve patient survival. Paracentesis can be employed to remove large volumes of ascitic fluid. Although it is controversial, simultaneous administration of albumin intravenously is thought by some investigators to minimize the risk of prerenal AKI and full-blown HRS during large-volume paracentesis. Indeed, large-volume paracentesis may occasionally improve GFR, possibly by lowering intra-abdominal pressure and promoting blood flow in renal veins. Vasopressin (V1) receptor agonists, either alone or in combination

Intrinsic Renal Azotemia Prevention Optimization of cardiovascular function and intravascular volume is the single most important maneuver in the management of acute intrinsic azotemia. There is compelling evidence that aggressive restoration of intravascular volume dramatically reduces the incidence of ATN after major surgery, trauma, and burns. Recent studies have emphasized two salient features of successful management of sepsis that may be of importance in the prevention of AKI. Early goal-directed resuscitation to defined hemodymanic targets (mean arterial pressure > 65 mm Hg, central venous pressure 10–12, urine output > 0.5 mL/kg/hour, SCVO2 > 70%) using a combination of crystalloid solutions, red blood cell transfusion, and vasopressors results in a significant reduction in organ dysfunction and mortality rate in patients with the sepsis syndrome. The importance of maintaining euvolemia in high-risk clinical situations has been demonstrated most convincingly with contrast nephropathy. Prophylactic infusion of half-normal saline (1 mL/kg for 12 hours before and after procedure) appears to be more effective in preventing AKI than other commonly used agents such as mannitol and furosemide. Prophylactic administration of oral acetylcysteine (600 mg twice daily, 24 hours before and 24 hours after the procedure), in combination with hydration, reduced the incidence of contrast nephropathy in patients with moderate renal insufficiency in several trials. Diuretics, NSAIDs (including COX-2 inhibitors), ACE inhibitors, and other vasodilators should be avoided in patients with suspected true or effective hypovolemia, because they may convert prerenal azotemia to ischemic ATN. Careful monitoring of circulating drug levels appears to reduce the incidence of AKI associated with aminoglycoside antibiotics. There is convincing evidence that once-daily dosing with these agents affords equal antimicrobial activity and less nephrotoxicity than do conventional regimens. The use of lipid-encapsulated formulations of amphotericin B may offer some protection against renal injury. Several other agents are commonly employed to prevent AKI in specific clinical

Acute Kidney Injury

with the a-agonist midodrine, have shown promise in the rever- 213 sal of established HRS. In a small randomized trial, terlipressin (1 mg IV twice daily) combined with albumin resuscitation (goal, central venous pressure 10–12 mm Hg) resulted in 5 of 12 patients surviving 15 days as opposed to none of the placebo CH 10 group. Predictors of nonresponse include older age and more severe liver failure (Child-Pugh score > 13).

214 settings. Allopurinol is useful for limiting uric acid generation


in patients at high risk for acute urate nephropathy; Amifostine, an organic thiophosphate, has been demonstrated to ameliorate cisplatin nephrotoxicity in patients with solid organ or hematoIV logic malignancies. Forced diuresis and alkalinization of urine may attenuate renal injury caused by uric acid or methotrexate. N-Acetylcysteine limits acetaminophen-induced renal injury if given within 24 hours of ingestion, and dimercaprol, a chelating agent, may prevent heavy metal nephrotoxicity. Both ethanol or fomepizole inhibit ethylene glycol metabolism to oxalic acid and other toxic metabolites and can prevent the development of ATN following toxic ingestion.

Specific Therapies Despite intensive investigation no specific therapy exists that accelerates recovery from ATN. Judicious volume management, treatment of complications, and avoidance of further injury are the mainstays of therapy. “Renal dose dopamine” (1–3 mg/kg/min) has been widely advocated for the management of oliguric AKI; however, it has not been demonstrated to prevent or alter the course of ischemic or nephrotoxic ATN in prospective, controlled clinical trials. The administration of high-dose intravenous diuretics to individuals with oliguric AKI is commonly practiced. Although this strategy may minimize fluid overload, there is no evidence that it alters the mortality rate or the dialysis-free survival rate. Similarly, no adequate data exist to support the routine administration of mannitol, fenoldopam, or natriuretic peptides to oliguric patients. AKI caused by other intrinsic renal diseases, such as acute glomerulonephritis or vasculitis, may respond to corticosteroids, alkylating agents, or plasmapheresis, depending on the primary disease.

Management of Complications Metabolic complications such as intravascular volume overload, hyperkalemia, hyperphosphatemia, and metabolic acidosis are almost invariable in oliguric AKI, and preventive measures should be taken from the time of diagnosis. Prescription of nutrition should be designed to meet caloric requirements and minimize catabolism. In addition, doses of drugs excreted via the kidney must be adjusted for the degree of renal impairment. Intravascular Volume Management. After correction of intravascular volume deficits, salt and water intake should be adjusted to match losses (urinary, gastrointestinal, drainage sites, insensible losses). Intravascular volume overload can usually be managed by restriction of salt and water intake and the use of diuretics. In the volume-overloaded patient, high doses of loop diuretics such as furosemide (bolus doses

Acute Kidney Injury

of up to 200 mg or up to 20 mg/hour as an intravenous infu- 215 sion) or sequential thiazide and loop diuretic administration may be required if there is no response to conventional doses. Diuretic therapy should be discontinued in resistant patients to avoid complications such as ototoxicity. Ultrafiltration or CH 10 dialysis may be required for removal of volume if conservative measures fail. Hyponatremia associated with a fall in effective serum osmolality can usually be corrected by restriction of water intake. Electrolyte Disturbances. Mild hyperkalemia (10 g/day). Hematuria, which can be gross, occurs in over half of FSGS patients, and approximately one third of patients present with some degree of renal insufficiency. Hypertension is found as a presenting feature in one third of patients. Patients with a variant of FSGS known as “collapsing FSGS” typically have more severe proteinuria and renal insufficiency. The rapidity of onset of FSGS is similar to the clinical presentation of minimal change glomerulopathy. Predictors of a poor outcome in primary FSGS include nephrotic range proteinuria, renal insufficiency, and failure to respond to corticosteroid therapy. Neither the degree of scarring within the glomerulus nor the number of glomeruli that are totally obsolescent is predictive of long-term renal outcome; however, significant interstitial fibrosis and tubular atrophy correlate with poor prognosis.

Laboratory Findings Hypoproteinemia is common in patients with FSGS and the serum albumin concentration may fall to below 2 g/dL, especially in patients with the collapsing variant. Hypogammaglobulinema and hyperlipidemia are typical; serum complement components are generally in the normal range. Serologic testing for HIV infection should be obtained for all patients with FSGS, especially those with the collapsing pattern.

Treatment

231

Primary Glomerular Disease

Angiotensin-converting enzyme (ACE) inhibitors decrease proteinuria and the rate of progression to end-stage renal disease in proteinuric renal disease including FSGS. ACE inhibition may provide a substantial reduction in proteinuria CH 11 and a long-term renoprotective effect that may be equal to, or greater than, that of immunosuppressive therapy. In patients who have proteinuria of less than 3 g/day, a trial of ACE inhibition without recourse to immunosuppression may be warranted as first-line therapy. Response rates to immunosuppressive therapy in primary FSGS are approximately 45% for complete remission, 10% for partial remission, and 45% for no response. In children, the initial treatment of FSGS is similar to that of minimal change glomerulopathy. In adults with nephrotic range proteinuria, the recommended dose of prednisone is 1 mg/kg/day, up to 80 mg/day, for up to 16 weeks. The prolonged course is based on the finding that the median time for complete remission in adults is 3 to 4 months. Among adult patients who relapse following a prolonged remission (>6 months), a repeat course of corticosteroid therapy may again induce a remission. In steroid-dependent patients who develop frequent relapses, alternative strategies include the introduction of cyclosporine (5 mg/kg/day). The practice of using higher doses of corticosteroids to reach remission has resulted in alternative therapeutic approaches, including the administration of methylprednisolone boluses of 30 mg/kg/day to a maximum of 1 g given every other day for six doses, followed by this same dose on a weekly basis for 10 weeks; subsequently, similar doses are given on a tapering schedule. These very high doses of corticosteroids are not without significant short- and long-term side effects.

Alternatives to Corticosteroid Therapy Patients resistant to prednisone may be induced into remission with cyclosporine. In steroid-resistant FSGS patients treated with cyclosporine, complete remission rates approximate 20% and partial remission rates are in the 40% to 70% range. However, as with minimal change disease the withdrawal of treatment results in relapse in over 75% of patients. Relapse rates may be minimized by maintaining therapy for 12 months following induction of remission followed by a slow taper. However, long-term treatment with cyclosporine is associated with the development of tubular atrophy, tubulointerstitial fibrosis, and renal insufficiency. Clinical studies have failed to convincingly demonstrate the effectiveness of cytotoxic drugs, including cyclophosphamide, or plasmapheresis in the treatment of FSGS in both adults and children.

232 C1q Nephropathy


C1q nephropathy is a relatively rare cause of proteinuria and nephrotic syndrome that can mimic FSGS clinically and histoIV logically. The diagnosis is based on the presence of mesangial immune complex deposits that have conspicuous staining for C1q accompanied by staining for IgG, IgM, and C3. Patients with C1q nephropathy are predominantly black, male, and between 15 and 30 years of age. Many are asymptomatic, but 50% present with edema, 40% with hypertension, and 30% with hematuria. Renal survival rate at 3 years is 84% and treatment with corticosteroids does not yield any improvement in proteinuria or preservation of renal function.

Membranous Glomerulopathy Idiopathic membranous glomerulopathy is the most common cause of nephrotic syndrome in adults (25% of adult cases) and can occur as an idiopathic (primary) or secondary disease. Secondary membranous glomerulopathy is caused by autoimmune diseases (e.g., lupus erythematosus, autoimmune thyroiditis), infection (e.g., hepatitis B, hepatitis C), drugs (e.g., penicillamine, gold), and malignancies (e.g., colon cancer, lung cancer). In patients over the age of 60, membranous glomerulopathy is associated with a malignancy in 20% to 30% of patients. The peak incidence of membranous glomerulopathy is in the fourth or fifth decade of life. Although most patients with membranous glomerulopathy present with the nephrotic syndrome, 10% to 20% of patients have less than 2 g/day proteinuria.

Pathology The characteristic histologic abnormality in membranous glomerulopathy is diffuse global capillary wall thickening and the presence of subepithelial immune complex deposits.

Clinical Features and Natural History Patients with membranous glomerulopathy usually present with the nephrotic syndrome. The onset is usually not associated with any prodromal disease process or other antecedent infections. Hypertension early in the disease process is variable. Most patients present with normal or slightly decreased renal function, and if progressive renal insufficiency develops, it is usually relatively indolent. Causes of an abrupt decline in renal function include overzealous diuresis, crecentic transformation (ANCA/anti-GBM associated), or acute bilateral renal vein thrombosis. Patients with membranous nephropathy are hypercoagulable to a greater extent than other nephrotic patients. Consequently, venous thrombosis,


including renal vein thrombosis, is reported more frequently 233 in patients with membranous glomerulopathy than other nephrotic glomerulopathies. The high prevalence of deep vein thrombosis in patients with membranous glomerulopathy (up to 45%) has led to the use of prophylactic anticoagulation for CH 11 patients with proteinuria greater than 10 g/day. Approximately 35% of patients progress to end-stage renal disease by 10 years, while 25% can expect a complete spontaneous remission of proteinuria within 5 years. Spontaneous remission may take 36 to 48 months to develop. Risk factors for progression include renal insufficiency at presentation, persistent proteinuria, male sex, advanced age (>50 years), and poorly controlled hypertension. In addition to the clinical prognostic features, the presence of advanced membranous glomerulopathy on renal biopsy, tubular atrophy, and interstitial fibrosis are also associated with a poor outcome.

Laboratory Findings Proteinuria is usually more than 3 g of protein per 24 hours and may exceed 10 g/day in 30% of patients. Microscopic hematuria is present in 30% to 50% of patients, while macroscopic hematuria is distinctly uncommon. Renal function is typically preserved at presentation. Hypoalbuminemia is observed if proteinuria is severe. Complement levels are normal; however, the complex of terminal complement components known as C5b-9 is found in the urine in some patients. Tests for hepatitis B, hepatitis C, syphilis, and immunologic disorders such as lupus, mixed connective tissue disease, and cryoglobulinemia should be obtained to exclude secondary causes.

Treatment The management of primary membranous glomerulopathy is controversial. Common therapeutic approaches include the following: • Supportive care including ACE inhibition, lipid-lowering therapy, and anticoagulation, if required • Corticosteroids (usually prednisone or methylprednisolone) • Alkylating agents, such as chlorambucil or cyclophosphamide, with or without concurrent corticosteroid treatment • Cyclosporine All patients should receive supportive care, including the use of ACE inhibitors or adrenergic receptor blockers, lipid-lowering agents, and consideration of the use of prophylactic anticoagulation. Corticosteroids. There have been three large, prospective, randomized trials examining the efficacy of oral corticosteroid therapy in adult patients, but they have differed in outcome. A pooled analysis of randomized trials and prospective

234 studies has suggested a lack of benefit of corticosteroid ther-


apy in inducing a remission of the nephrotic syndrome. It has been argued that higher does (60–200 mg every other day) of prednisone and longer course of therapy (up to 1 year) IV are required to effect a response. However, the side effects of extended high-dose corticosteroid therapy are substantial and the risk-benefit ratio may not favor corticosteroid therapy in most, if not all, patients. Cyclophosphamide. Cytotoxic drugs have been used in the treatment of idiopathic membranous glomerulopathy, including cyclophosphamide and chlorambucil. Chlorambucil (0.2 mg/kg/day), alternating monthly with daily prednisone (0.5 mg/kg/day), in combination with intravenous pulse methylprednisolone (1 g/day) for the first 3 days of each month, has been demonstrated to lead to a higher and more rapid rate of remission in addition to stabilizing renal function. Cyclophosphamide may be at least as effective as chlorambucil when used in a similar dosing protocol. The risk-benefit ratio of these aggressive treatment protocols must be acceptable to the patient, who must be informed of the heightened longterm risk of transitional cell carcinoma of the bladder and of lymphoma. Thus, these more aggressive strategies for membranous glomerulopathy should probably only be considered for patients with evidence of progressive deterioration of renal function or adverse prognostic features. Other Forms of Immunosuppressive Therapy. Cyclosporine given in doses of 4 to 5 mg/kg/day has resulted in improvement in proteinuria and stability of renal function in many patients with membranous glomerulopathy. However, relapse of proteinuria occurs in the majority of patients soon after the cessation of cyclosporine therapy, and biopsy studies have documented persistent deposition of immunoglobulin and complement in cyclosporine-treated patients. The role of agents such as mycophenolate mofetil and rituximab in the treatment of membranous nephropathy remains to be elucidated. In summary, most patients should be observed for the development of adverse prognostic factors or the development of spontaneous remissions. Adult patients with good prognostic features, with less than 4 g/day proteinuria and normal renal function, should be managed conservatively. Patients at moderate risk (persistent proteinuria between 4 and 6 g/day after 6 months of conservative therapy and normal renal function) or high risk of progression (persistent proteinuria greater than 8 g/day with or without renal insufficiency) should be considered for immunosuppressive therapy, with either the combination of glucocorticoids and cyclophosphamide (or chlorambucil) in alternating monthly pulses or a regimen consisting of cyclosporine with low-dose glucocorticoids. Individuals who have advanced chronic kidney disease and in

whom serum creatinine exceeds 3 to 4 mg/dL are best treated by 235 supportive care awaiting dialysis and renal transplantation.

MPGN is characterized by diffuse global capillary wall thickening, frequently with a double contoured appearance and either subendothelial deposits (type I MPGN) or deposits within the mesangium and basement membrane (type II MPGN). The majority of patients with idiopathic MPGN are children with an equal proportion of males to females in both type I and type II disease. Although the pathologic findings indicate that type I MPGN is an immune complex disease, the identity of the nephritogenic antigen is unknown in most patients. In type II MPGN, an autoantibody, C3 nephritic factor, that triggers persistent activation of the complement cascade occurs in over 60% of patients, and may be responsible for disease in these patients.

Clinical Features and Natural History The clinical presentations of MPGN are as follows: • Nephrotic syndrome (50%) • Combination of asymptomatic hematuria and proteinuria (25%) • Acute nephritic syndrome (25%) Hypertension is typically mild and renal dysfunction occurs in at least half of cases. When present at the outset of disease, renal dysfunction portends a poor prognosis. Membranoproliferative glomerular diseases are also associated with a number of other disease processes (Table 11-3). A wide variety of infectious and autoimmune conditions are associated with MPGN, suggesting that, in addition to the known association with hepatitis, infections may themselves present with MPGN. A small number of patients have an X-linked deficiency of C2 or C3 with or without partial lipodystrophy. In addition to partial lipodystrophy, congenital complement deficiency states and deficiency of a1-antitrypsin also predispose to MPGN type I. In general, one third of patients with type I MPGN will have a spontaneous remission, one third will have progressive disease, and one third will have a disease process that waxes and wanes but never completely disappears. The 10-year renal survival rate is 40% to 60%; however, non-nephrotic patients have a 10-year survival rate of over 80%. The parameters suggestive of poor prognosis in idiopathic MPGN type I include hypertension, renal insufficiency, nephritic syndrome, and cellular crescents on biopsy. The prognosis for type II disease is worse than that for type I, as it is associated with a higher rate of crescentic

CH 11


Membranoproliferative Glomerulonephritis (Mesangial Capillary Glomerulonephritis)

236 Table 11-3

Classification of Membranoproliferative Glomerulonephritis

Idiopathic


IV

Type I Type II Type III Secondary Infections Hepatitis B and C Visceral abscesses Infective endocarditis Shunt nephritis Quartan malaria Schistosoma nephropathy Mycoplasma infection Rheumatologic Diseases Systemic lupus erythematosus Scleroderma Sjo¨gren syndrome Sarcoidosis Mixed essential cryoglobulinemia with or without hepatitis C infection Anti–smooth muscle syndrome Malignancy Carcinoma Lymphoma Leukemia Inherited a1-Antitrypsin deficiency Complement deficiency (C2 or C3), with or without partial lipodystrophy

glomerulonephritis and chronic tubulointerstitial nephritis at the time of biopsy. Clinical remissions of type II MPGN are rare and recurrence in the transplanted kidney occurs much more regularly than type I. Type III MPGN occurs in a very small number of children and young adults. These patients may have clinical features and outcomes quite similar to that of MPGN type I.

Laboratory Findings Hematuria is the hallmark of patients presenting with MGPN, and may be microscopic or macroscopic. The degree of proteinuria varies widely. Renal insufficiency occurs in a variable number of cases, but it is the most ominous feature of the acute nephritic syndrome. Serologic and clinical evidence of cryoglobulinemia, hepatitis C, hepatitis B, osteomyelitis, subacute bacterial endocarditis, or infected ventriculoatrial shunt should

be sought in type I MGPN. C3 is persistently depressed in 237 approximately 75% to 90% of MPGN patients. C3 nephritic factor is found in 60% of cases of type II MPGN.

Treatment

GLOMERULONEPHRITIS The syndrome of glomerulonephritis is characterized as follows: • • • •

Hematuria with or without red blood cell casts Proteinuria Hypertension Renal insufficiency

The spectrum of clinical presentation ranges from asymptomatic hematuria to the acute nephritic syndrome. A diagnostic algorithm is outlined in Figure 11-1.

Acute Poststreptococcal Glomerulonephritis Acute poststreptococcal glomerulonephritis (PSGN) is a disease that affects primarily children, with peak incidence between the ages of 2 and 6 years. It may occur as part of an epidemic or sporadic disease, and only rarely do PSGN and rheumatic fever occur concomitantly. The incidence of acute PSGN is on the decline in developed countries, but it remains

CH 11


The treatment of type I MPGN is based on the underlying cause of the disease process. Thus, the therapy for MPGN associated with cryoglobulinemia and hepatitis C should be aimed at treating hepatitis C virus infection (interferon/ribavirin), whereas the treatment of MPGN associated with lupus or with scleroderma should be based on the principles of care of those rheumatologic conditions. Most recommendations for the treatment of idiopathic type I MPGN are limited to studies in children where low-dose prednisone therapy improves renal survival. Whether similar effects are achieved in adults has never been subjected to a prospective randomized trial. In addition to glucocorticoids, numerous other forms of immunosuppressive and anticoagulant treatment have been used in the treatment of type I MPGN including dipyridamole, aspirin, and warfarin, with and without cyclophosphamide. However, definitive prospective data are lacking. Unfortunately, there is no effective therapy for MPGN type II. This problem is compounded by the fact that MPGN type II recurs almost invariably in renal transplant patients, especially if crescentic disease was present in the native renal biopsy.

238 static in developing countries. Epidemic PSGN is frequently


associated with skin infections rather than pharyngitides in developed countries. Overt glomerulonephritis is found in about 10% of children at risk, but when one includes subclinIV ical disease as evidenced by microscopic hematuria, about 25% of children at risk are affected. In some developing countries, acute PSGN remains the most common form of acute nephritic syndrome among children.

Clinical Features and Natural History The syndrome of acute PSGN can present with a spectrum of severity ranging from asymptomatic to oliguric acute kidney injury. A latent period is present (7–21 days) from the onset of pharyngitis to that of nephritis. The hematuria is microscopic in more than two thirds of cases. Hypertension occurs in more than 75% of patients and is usually mild to moderate in severity. It is most evident at the onset of nephritis and typically subsides promptly after diuresis. Antihypertensive treatment is necessary in only about one half of patients. Signs and symptoms of congestive heart failure may occur in as many of 40% of elderly patients with PSGN. Edema may be the presenting symptom in two thirds of patients, and is present in up to 90% of patients. Ascites and anasarca may occur in children. Encephalopathy is not seen frequently but affects children more often than adults. This encephalopathy is not always attributable to severe hypertension, but may be the result of central nervous system (CNS) vasculitis. The clinical manifestations of acute PSGN typically resolve in 1 to 2 weeks as the edema and hypertension disappear after diuresis. Both the hematuria and proteinuria may persist for several months, but are usually resolved within a year. The long-term persistence of proteinuria, and especially albuminuria, may indicate the persistence of a proliferative glomerulonephritis. The differential diagnosis of acute PSGN includes IgA nephropathy/Henoch-Scho¨nlein purpura, MPGN, or acute crescentic glomerulonephritis. The occurrence of an acute nephritis in the setting of persistent fever should raise the suspicion of a peri-infectious glomerulonephritis, such as may occur with an occult abscess or infective endocarditis.

Laboratory Findings Hematuria, microscopic or gross, is nearly always present in acute PSGN. Microscopic examination of urine typically reveals the presence of dysmorphic red blood cells or red blood cell casts. Proteinuria is nearly always present, typically in the subnephrotic range. Nephrotic-range proteinuria may occur in as many as 20% of patients and is more frequent in adults than in children. A pronounced decline in the GFR is unusual in children and more common in the elderly


population. Throat or skin cultures may reveal group A strepto- 239 cocci, but serologic studies to evaluate the presence of recent streptococcal infection are superior. The antibodies most commonly studied for the detection of a recent streptococcal infection are antistreptolysin O (ASO), antistreptokinase, anti- CH 11 hyaluronidase, antideoxyribonuclease B, and antinicotinyladenine dinucleotidase. An elevated ASO titer above 200 units may be found in 90% of patients; however, a rise in titer is more specific than the absolute level of an individual titer. Serial ASO titer measurements with a twofold or greater rise in titer are highly indicative of a recent infection. The serial estimation of complement components is important in the diagnosis of PSGN. Early in the acute phase, the levels of hemolytic complement activity (CH50 and C3) are reduced. These levels return to normal, usually within 8 weeks, and the presence of persistent depression of C3 levels suggests an alternate diagnosis such as MPGN or systemic lupus erythematosus (SLE).

Treatment Treatment of acute PSGN is largely that of supportive care. Children almost invariably recover from the initial episode. Indeed, even the presence of acute kidney injury in adults is not necessarily associated with a poor prognosis. Thus, there is little evidence to suggest the need for any form of immunosuppressive therapy. Supportive therapy may require the use of loop diuretics such as furosemide to ameliorate volume expansion and hypertension. In patients with substantial volume expansion and marked pulmonary congestion who do not respond to diuretics, dialytic support may be appropriate. Importantly, potassium-sparing agents, including triamterene, spironolactone, and amiloride, should not be used in this disease state as patients can develop substantial hyperkalemia. Usually, patients undergo a spontaneous diuresis within 7 to 10 days after onset of their illness and no longer require supportive care. There is no evidence to date that the early treatment of streptococcal disease, either pharyngitic or cellulitic, alters the risk of developing PSGN. The long-term prognosis of patients with PSGN is not as benign as was previously considered. Widespread crescentic glomerulonephritis results in an increased number of obsolescent glomeruli associated with tubulointerstitial disease and may herald a progressive loss of functional renal mass over time.

IgA Nephropathy IgA nephropathy is one of the most common forms of glomerulonephritis, if not the most common. The disease process was initially considered a benign form of hematuria. It is most

240 common in the second and third decades of life, and is much more


common in males than females. IgA nephropathy can only be definitively diagnosed by the immunohistologic demonstration of mesangial immune deposits that stain dominantly or codomiIV nantly for IgA. The mechanisms responsible for the glomerular injury in IgA nephropathy are poorly understood but may involve the synthesis of structurally abnormal IgA molecules.

Clinical Features and Natural History The typical presenting features of IgA nephropathy are as follows: • • • •

Macroscopic hematuria (40–50%) Microscopic hematuria (40%) Nephritic syndrome (10%) Malignant hypertension (90% globally sclerosed glomeruli without residual activity)

*Class V may occur in combination with class III or IV, in which case both will be diagnosed. EM, electron microscopy; IF, immunofluorescence; LM, light microscopy; LN, lupus nephritis.

protracted course with periods of remissions and exacerbations. Patients with WHO class I often have no, or at most mild, evidence of clinical renal disease. Likewise, most patients with disease confined to the mesangial regions of the glomeruli (WHO class II) have minimal clinical renal findings including an inactive urinary sediment, proteinuria below 1 g daily, and a normal serum creatinine. WHO class III, focal proliferative LN, is often associated with active lupus serology, although the degree of serologic activity does not correlate with the severity or extent of the histologic damage. Hypertension and active urinary sediment are commonly present and proteinuria is usually greater than 1 g daily. Up to 25% of these patients will have an elevated serum creatinine level at presentation. Patients with class IV disease typically have high anti-DNA antibody titers, renal dysfunction, hypertension, low serum complement levels, and a very active urinary sediment, with erythrocytes and RBC casts on urinalysis. Virtually all patients have proteinuria, and up to 50% present with the nephrotic syndrome. Patients with lupus membranous nephropathy, WHO class V, typically present with proteinuria, edema, and other manifestations of the nephrotic syndrome. Although serologic activity is often mild, up to 60% of membranous patients have a low serum

251

CH 12

Secondary Glomerular Disease

Table 12-1

252 complement and an elevated anti-DNA antibody titer. End-

stage LN, WHO class VI, is usually the result of “burned out” LN of long duration. It is often the end result of years of lupus flares alternating with periods of inactivity.

Pathogonesis of Renal Disease

IV

Serologic Tests Abnormal autoantibody production is the hallmark of SLE. The presence of antibodies directed against nuclear antigens (antinuclear antibodies [ANAs]), and especially against DNA (anti-DNA), are included in the American Rheumatism Association’s diagnostic criteria for SLE, and are commonly used to monitor the course of patients with SLE. However, the ANA titer does not correlate well with the severity of renal involvement in SLE. Autoantibodies directed against doublestranded DNA (anti-dsDNA) are a more specific but less sensitive marker of SLE. A variety of other autoantibodies are commonly present in lupus patients including anti-Sm, antinRNP, anti-Ro/serum amyloid A, and anti-La/SSB, but are not predictive of renal involvement. Levels of total hemolytic complement (CH50) and complement components are usually decreased during active renal disease and this decrease may precede a clinical flare. Other immunologic abnormalities commonly detected in lupus patients include elevated levels of circulating immune complexes, a positive lupus band test, and the presence of cryoglobulins. Mixed IgG-IgM cryoglobulins may be found in patients with SLE and active renal disease. A false-positive Venereal Disease Research Laboratory (VDRL) test due to the presence of APL antibodies is also common.

Monitoring Clinical Disease LN is typically a chronic disease with relapses and remissions. It is important in the management of lupus patients to be able to predict clinical and renal relapses and prevent their occurrence through the judicious use of immunosuppressive agents. Serial measurements of serologic tests of clinical activity have been used to predict flares of lupus activity. Circulating serum levels of anti-dsDNA typically rise as the clinical activity of SLE increases and usually before there is a clinical renal deterioration. Likewise, serum total hemolytic complement levels typically decline prior to or concurrent with the onset of active clinical disease. An increase in proteinuria from levels of less than 1 g daily to over this amount, and certainly from low levels to nephrotic levels, is a clear indication of either increased activity or a change in renal histologic class.

Drug-Induced Lupus

253

Pregnancy and Systemic Lupus Erythematosus Pregnancy in patients with LN has also been associated with worsening of renal function. Risk factors for loss of renal function include active disease within the previous 6 months, coexistent hypertension, proteinuria, and renal impairment at baseline. Patients with elevated serum creatinine levels are most likely to suffer worsening of renal function and are at highest risk for fetal loss (which may exceed 50%). Both high-dose corticosteroids and azathioprine have been used in pregnant lupus patients, but mycophenolate and cyclophosphamide are contraindicated. Other risk factors for fetal loss include the presence of anticardiolipin antibodies, hypertension, or heavy proteinuria.

Dialysis and Transplantation The percentage of patients with LN who progress to end-stage renal disease (ESRD) ranges from 10% to 30%. Most patients who develop ESRD have a resolution of their extrarenal manifestations of disease and serologic activity. In general, most renal transplant programs allow patients with active SLE to undergo a period of dialysis for 3 to 12 months to allow clinical and serologic disease activity to become quiescent. Allograft survival rates in patients with ESRD due to LN are comparable to the rest of the ESRD population. The rate of recurrent SLE in the allograft is less than 5%.

Course and Prognosis of Lupus Nephritis The prognosis is defined in part by the initial pattern and severity of renal involvement. However, the outcome is ultimately modified by therapy, exacerbations of the disease, and complications of treatment. Patients with lesions limited


A variety of medications may induce a lupus-like syndrome or exacerbate an underlying predisposition to SLE. Although a number of drugs have produced this entity, those metabolized CH 12 by acetylation such as procainamide and hydralazine are common causes. This occurs more commonly in patients with a genetic decrease in hepatic N-acyltransferase activity—“slow acetylators.” Clinical manifestations of drug-induced lupus include fever, rash, myalgias, arthralgias and arthritis, and serositis. Renal involvement is relatively uncommon in druginduced disease.

254 to the renal mesangium generally have an excellent course and


prognosis. Patients with mild WHO class III disease typically respond well to therapy, and fewer than 5% progress to renal failure during 5-year follow-up. Patients with diffuse proliferative IV disease have the least favorable prognosis. Nevertheless, the prognosis for this group has markedly improved in recent years and the 5-year renal survival rate is higher than 90% in some series of patients treated with modern immunosuppressive therapy. Clinical risk factors for a poor outcome in diffuse proliferative disease include age over 30, male sex, African-American race, nephrotic range proteinuria, disease relapse, and elevated creatinine. Patients with combined severe activity and chronicity, as well as those with the combination of cellular crescents and interstitial fibrosis, appear to have a worse prognosis.

Treatment of Lupus Nephritis Class I and II Lupus Nephritis WHO class I and II do not merit renal-specific therapy and patients should be treated only for extrarenal manifestations of SLE.

Class III Lupus Nephritis There is no general consensus on the treatment of patients with focal proliferative LN. Patients with only moderate proliferative lesions involving only a few glomeruli, with no necrotizing features and no crescent formation, have a good prognosis and respond often to a short course of high-dose corticosteroid therapy. Patients with larger amounts of the glomerular surface area involved, with necrotizing features and crescent formation, require more vigorous therapy similar to patients with WHO class IV lesions.

Class IV Lupus Nephritis The most appropriate form of treatment regimen for patients with diffuse proliferative LN is still widely debated. Currently widely used agents include high-dose daily or alternate-day corticosteroids, azathioprine, intravenous pulse methylprednisolone, oral or intravenous cyclophosphamide, cyclosporine, rituximab, and mycophenolate mofetil (MMF). None of the current regimens of immunosuppressive therapy is without major potential side effects and no agent is universally effective. Higher doses of corticosteroids during the early treatment period appear to be more effective when compared to lowdose therapy ( 3) has proved more effective than no therapy, aspirin alone, or low-dose anticoagulation in preventing recurrent thromboses. The role of immunosuppressive agents has yet to be defined. In rare patients who cannot tolerate anticoagulation due to recent bleeding, who have thromboembolic events despite adequate anticoagulation, or who are pregnant, plasmapheresis with corticosteroids and other immunosuppressive drugs have been used with some success.

MIXED CONNECTIVE TISSUE DISEASE Patients with mixed connective tissue disease (MCTD) share many overlapping features with patients with SLE, scleroderma, and polymyositis. They typically have a distinct serologic profile characterized by a very high ANA titer, often with a speckled pattern, and antibodies directed against a specific ribonuclease-sensitive extractable nuclear antigen (ENA), U1RNP. The incidence of renal disease has been reported to vary from 10% to 26% of adults and from 33% to 50% of children with MCTD. Most patients with renal involvement have mild or minimal clinical manifestations, with only microhematuria and less than 500 mg proteinuria daily. However, heavier proteinuria and the nephrotic syndrome occur in up to one third of patients. Other patients have severe hypertension and acute kidney injury reminiscent of “scleroderma renal crisis” (see later discussion). In general, the glomerular lesions resemble the spectrum found in SLE, whereas vascular lesions, when present, resemble those found in scleroderma. Corticosteroid therapy in MCTD is effective in treating the inflammatory features of joint disease and serositis. Glomerular involvement can vary as in SLE, and treatment is generally directed at the glomerular lesion in a similar fashion to treating active LN.


Treatment

258

POLYARTERITIS NODOSA Polyarteritis nodosa (PAN) has been divided into two patterns:


IV

• “Classic” PAN is a systemic necrotizing vasculitis primarily affecting muscular arteries, often at branch points, producing lesions of varying ages with focal aneurysm formation. • “Microscopic” polyangiitis is a necrotizing vasculitis affecting small arteries, veins, and capillaries involving multiple viscera, including lung and dermis, and producing lesions of similar age, usually without aneurysms. Many patients have overlapping features of both patterns. Moreover, both presentations of polyarteritis may be associated with circulating antineutrophilic cytoplasmic antibody (ANCA) and histologic evidence of a pauci-immune segmental necrotizing and crescentic glomerulonephritis similar to patients with isolated pauci-immune idiopathic rapidly progressive glomerulonephritis. Polyarteritis is more common in males than females and occurs most often in the fifth and sixth decades of life. Although a number of diseases have been associated with glomerular disease and a systemic or renal vasculitis, true idiopathic polyarteritis is a primary vasculitis. “Secondary” vasculitis associated with hepatitis B or C infection, cryoglobulinemia, systemic lupus, and Henoch-Scho¨nlein purpura is usually readily distinguished.

Pathogenesis The vasculitis of polyarteritis may be mediated by a number of diverse pathogenetic factors including humoral vascular immune deposits, cellular immunity, endothelial cytopathic factors, and ANCAs. ANCA may play a pathogenetic role in a manner similar to in Wegener granulomatosis.

Renal Features In the microscopic form of the disease, features of vasculitis and glomerulonephritis manifest, whereas in the classic pattern, features of renal ischemia and infarction predominate due to larger vessel disease. Hypertension is common in polyarteritis (50%) and most patients have laboratory evidence of their renal involvement at presentation. The majority of cases have urinary sediment changes with microscopic hematuria and often RBC casts. Proteinuria is found in most patients, but the nephrotic syndrome is rarely present. In microscopic polyarteritis, the severity of the clinical renal findings correlates with the degree of glomerular involvement. Patients with a normal creatinine clearance are likely to have normal

Laboratory Tests The erythrocyte sedimentation rate (ESR) is elevated in almost all patients and is usually associated with anemia, leukocytosis, eosinophilia, and thrombocytosis. Most patients are ANA negative and have normal serum complement levels. Tests for circulating immune complexes and rheumatoid factor are often positive. Cryoglobulins may reflect associated hepatitis B infection (95% of cases), an allergic diathesis, allergic rhinitis, and peripheral eosinophilia. Asthmatic disease typically precedes the onset of the vasculitis by years, but it may occur simultaneously and the severity of the asthma does not necessarily parallel the severity of the vasculitis. Chest radiograph may show patchy infiltrates, nodules, diffuse interstitial disease, and even pleural effusion. This multisystem disease can affect the heart with pericarditis, heart failure, and ischemic disease; the gastrointestinal tract with abdominal pain, ulceration, diarrhea, or bowel disease; and the skin with subcutaneous nodules, petechiae, and purpuric lesions. Mononeuritis multiplex is common, but migrating polyarthralgias and arthritis occur less frequently. Laboratory evaluation typically reveals anemia, leukocytosis, and an elevated ESR. Eosinophilia is universally present and may reach 50% of the total peripheral count. The degree of eosinophilia and the ESR may correlate with disease activity. Rheumatoid factor is often positive and C-reactive protein levels are increased, whereas serum complement, hepatitis markers, circulating immune complexes, ANAs, and cryoglobulins are usually negative. ANCA levels have been elevated in 40% to 80% patients with Churg-Strauss syndrome. Usually patients are P-ANCA positive, but some are positive for C-ANCA. The clinical renal findings in Churg-Strauss syndrome are also quite

diverse, but renal involvement rarely predominates. Micro- 261 scopic hematuria and mild proteinuria are common, but nephrotic-range proteinuria is rare. In pure Churg-Strauss syndrome, renal failure is uncommon, although it occurs in patients with overlap syndromes. CH 12

Patients may have several phases of the syndrome over many months or years. There may be a prodromal phase of asthma or allergic rhinitis, followed by a phase of peripheral blood and tissue eosinophilia remitting and relapsing over months to years before development of systemic vasculitis. A shorter duration of asthma before the onset of vasculitis has been associated with a worse prognosis. Survival rates in treated patients are approximately 90% at 1 year and 70% at 5 years. Patients with significant cardiac or gastrointestinal involvement have a worse prognosis. Corticosteroid therapy is successful in most patients with Churg-Strauss syndrome. Patients respond rapidly to high-dose daily oral prednisone therapy, and even relapses respond to re-treatment. Resistant cases may benefit from concomitant treatment with other immunosuppressive agents, such as azathioprine and cyclophosphamide.

GLOMERULAR INVOLVEMENT IN OTHER VASCULITIDES (TEMPORAL ARTERITIS, TAKAYASU DISEASE) Temporal Arteritis Temporal arteritis, or giant cell arteritis, is a systemic vasculitis with a characteristic giant cell vasculitis of medium-sized and large arteries. The disease is the most common form of arteritis in Western countries. It is primarily a disease of the elderly, with an average age of onset of symptoms of 72 years. Extracranial vascular involvement occurs in 10% to 15% of patients. Renal manifestations are rare and generally mild, consisting of mild hematuria and proteinuria, without renal functional impairment. Abnormal urinary sediment changes disappear with standard corticosteroid therapy.

Takayasu Arteritis Takayasu arteritis is a rare vasculitic disease of unknown pathogenesis characterized by inflammation and stenosis of medium-sized and large arteries, with a predilection for the


Prognosis, Course, and Treatment

262 aortic arch and its branches. The disease most commonly


affects young women between 10 and 40 years of age, and Asians are much more commonly affected. Renal involvement is characterized by an obliterative arteritis of the main renal IV artery or narrowing of the renal ostia by abdominal aortitis leading to renovascular hypertension. Arteriography is most often used to make the diagnosis of Takayasu arteritis, although CT and MR imaging have been used as well. Laboratory abnormalities reveal mild anemia, elevated ESR, increased levels of C-reactive protein, and elevated gamma globulin levels but other serologic tests are normal. Hypertension may be severe and occurs in 40% to 60% of patients; however, renal failure is uncommon.

Treatment In most patients, corticosteroids are effective therapy for the vasculitis and systemic symptoms and further vascular deterioration is suppressed. Other immunosuppressive agents including methotrexate, cyclophosphamide, and mycophenolate have also been used successfully.

¨ NLEIN PURPURA HENOCH-SCHO Henoch-Scho¨nlein purpura (HSP) is a systemic vasculitis syndrome with involvement of the skin, gastrointestinal tract, and joints in association with a glomerulonephritis characterized by prominent IgA deposition. IgA immune complexes deposit in the skin, kidney, and other organs in association with an inflammatory reaction of the vessels. Children are far more commonly affected than adults, although the disease can occur at any age. More severe renal disease occurs in older children and adults.

Clinical Findings The classic tetrad in HSP includes dermal involvement, gastrointestinal disease, joint involvement, and glomerulonephritis. Constitutional symptoms such as fever, malaise, fatigue, and weakness may be associated with active isolated dermal involvement or full-blown systemic disease. Skin lesions commonly found on the lower and upper extremities may also be on the buttocks or elsewhere. They are characterized by urticarial macular and papular reddish violaceous lesions and may be discrete or may coalesce into palpable purpuric lesions. On skin biopsy, there is a leukocytoclastic angiitis with evidence of IgA containing immune complexes along with IgG, C3, and properidine, but not C4 or C1q. Gastrointestinal manifestations

Course, Prognosis, and Treatment In most patients, HSP is a self-limited disease with a good long-term outcome. In general, there is a good correlation between the clinical renal presentation and the ultimate prognosis. Patients with focal mesangial involvement and only hematuria and mild proteinuria tend to have an excellent prognosis. A poor renal prognosis is predicted by an acute nephritic presentation, persistent nephrotic syndrome, older age, IgA deposits extending from the mesangium out along the peripheral capillary walls, and especially the presence of greater percentage of crescents on renal biopsy. There is no proven therapy for HSP. Although steroids have been associated with decreased abdominal and rheumatologic symptoms, they have not been proved to ameliorate the renal lesions in any controlled fashion. Patients with severe clinical features and especially those with more crescents on biopsy may benefit from more aggressive intervention with pulse methylprednisolone followed by oral corticosteroid therapy. Other regimens used in this setting have included varying combinations of corticosteroids, azathioprine, cyclophosphamide, chlorambucil, plasmapheresis, and intravenous immune gamma globulin.

¨ GREN SYNDROME SJO Sjo¨gren syndrome is characterized by a chronic inflammatory cell infiltration of the exocrine salivary and lacrimal glands and is associated with the “sicca complex” of xerostomia and xerophthalmia. Although this disease may present as an isolated exocrine gland disorder, patients may have a systemic inflammatory disease with renal involvement. Serologic abnormalities include hypergammaglobulinemia, circulating


are present in 25% to 90% of patients, and may include colicky 263 pain, nausea and vomiting, melena, hematochezia, and intussusception. Rheumatologic involvement is most common in the ankles and knees and less common in the elbows and wrists, and may consist of arthralgias or frank arthritis with CH 12 painful, tender effusions. Renal involvement ranges from 40% to 60% of patients and is characterized by a proliferative nephritis with prominent IgA deposition. The onset of the renal disease usually follows the onset of the systemic manifestations by days to weeks. Patients commonly have microscopic hematuria, active urinary sediment, and proteinuria. Up to one half of patients with clinical renal involvement develop the nephrotic syndrome, and some have a nephritic picture.

264 rheumatoid factor, cryoglobulins, a homogeneous or speckled-


pattern ANA, anti-Ro/SSA, and anti-La/SSB, but serum complement levels are generally normal unless the patient has associated SLE. The major clinical renal manifestations reflect IV tubulointerstitial involvement; distal RTA, impaired concentrating ability, hypercalciuria, and less frequently, proximal tubule defects. Most patients have a relatively bland urinalysis with only mild elevations of the serum creatinine level. In those patients with glomerular lesions, hematuria, proteinuria, and renal insufficiency are found. Some patients develop the full nephrotic syndrome, whereas others may develop renal vasculitis with prominent hypertension and renal insufficiency. Patients with immune complex glomerulonephritis and Sjo¨gren syndrome are generally treated in a similar fashion to those with SLE, and those with vasculitis generally receive cytotoxic therapy similar to that given for other necrotizing vasculitides.

SARCOIDOSIS The most common renal manifestations of sarcoidosis are interstitial nephritis (typically granulomatous), nephrolithiasis, and functional abnormalities of the tubule. Glomerular disease is infrequent and may be the coincidental expression of two unrelated disease processes in one individual rather than secondary to the sarcoidosis itself. A variety of glomerular lesions have been described in patients with sarcoidosis including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, MPGN, and proliferative and crescentic glomerulonephritis. Some patients have granulomatous renal interstitial nephritis in addition to the glomerular lesions, whereas others have only extrarenal histologic documentation of the sarcoidosis. The clinical presentation of glomerular disease in sarcoidosis is usually that of proteinuria, active urinary sediment at times, and most commonly the nephrotic syndrome. Patients have been treated with various forms of immunosuppression, including steroids, depending on their glomerular lesions.

AMYLOIDOSIS Amyloidosis comprises a diverse group of systemic and local diseases characterized by the deposition of fibrils in various organs. Amyloid fibrils bind Congo red (leading to characteristic apple-green birefringence under polarized light), have a characteristic ultrastructural appearance, and contain a 25-kD glycoprotein, serum amyloid P component. In primary

Primary and Secondary Amyloidosis In primary (AL) amyloidosis, fibrils are composed of the Nterminal amino acid residues of the variable region of an immunoglobulin light chain. The kidneys are the most common major organ to be involved by AL amyloid, and the absence of other organ involvement does not exclude amyloidosis as a cause of major renal disease. From 10% to 20% of patients over 60 years old with the nephrotic syndrome will have amyloidosis. Amyloidosis should be suspected in all patients with circulating serum monoclonal M proteins, and approximately 90% of primary amyloid patients will have a paraprotein spike in the serum or urine by immunofixation. The median age at presentation is approximately 60 years; fewer than 1% of patients are younger than 40 years. Men are affected twice as often as women. Presenting symptoms include weight loss, fatigue, lightheadedness, shortness of breath, peripheral edema, pain due to peripheral neuropathy, and purpura. Patients may have hepatosplenomegaly, macroglossia, or rarely enlarged lymph nodes. Secondary amyloidosis is due to the deposition of amyloid A (AA) protein in chronic inflammatory diseases. Secondary amyloid is observed in rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, bronchiectasis, and occasionally in poorly treated osteomyelitis. The diagnosis of amyloid is usually established by tissue biopsy of an affected organ. Liver and kidney biopsy are positive in as many as 90% of clinically affected cases. A diagnosis may be made with less invasive techniques including fat pad aspirate (60–90%), rectal biopsy (50–80%), bone marrow aspirate (30–50%), gingival biopsy (60%), or dermal biopsy (50%) in selected series. Serum amyloid P (SAP) whole-body scintigraphy, following injection of radiolabeled SAP, may allow the noninvasive diagnosis of amyloidosis. In AL amyloidosis, detection of an abnormal ratio of free kappa to lambda light chains in the serum is a new technique to detect plasma cell dyscrasias, and has a higher sensitivity than either serum or urinary electrophoretic techniques. This technique also allows assessment of response to therapy by following the level of abnormal free light chain in the serum. Patients with hereditary amyloidosis due to


(AL) amyloidosis, the deposited fibrils are derived from the 265 variable portion of immunoglobulin light chains produced by a clonal population of plasma cells. Secondary (AA) amyloid is due most frequently to the deposition of serum amyloid A protein in chronic inflammatory states. Forms of hereditary CH 12 amyloid involving the kidney include mutations in transthyretin, fibrinogen A chain, apolipoprotein A-I, lysozyme, apolipoprotein A-II, cyclostatin C, and gelosin.

266 deposition of abnormal transthyretin, apolipoproteins, lyso-


zyme, and other proteins may present in a fashion similar to AL amyloid. Clinical manifestations of renal disease depend on the locaIV tion and extent of amyloid deposition. Renal involvement predominates as the primary organ system involved in AL amyloidosis. Most patients have proteinuria, approximately 25% of patients have nephrotic syndrome at diagnosis, and others present with varying degrees of azotemia. Proteinuria is almost universal but the urinalysis is typically otherwise bland. In patients with proteinuria greater than 1 g/day, over 90% have a monoclonal protein in the urine. The amount of glomerular amyloid deposition does not correlate well with the degree of proteinuria. Despite the literature suggestion of enlarged kidneys in AL amyloid, most patients have normalsized kidneys by ultrasonography. Hypertension is found in 20% to 50% of patients, but many have orthostatic hypotension due to autonomic neuropathy. Occasionally, patients have predominantly tubule deposition of amyloid with tubule defects such as distal renal tubular acidosis (RTA) and nephrogenic diabetes insipidus.

Course, Prognosis, and Treatment The prognosis of patients with AL amyloidosis is poor, with some series having a median survival of less than 2 years. The baseline serum creatinine level at diagnosis and the degree of proteinuria are predictive of the progression to ESRD. The median time from diagnosis to onset of dialysis is 14 months and from dialysis to death is only 8 months. Factors associated with decreased patient survival include evidence of cardiac involvement, l versus k proteinuria, and an elevated serum creatinine level. The optimal treatment for AL amyloid is unclear. Most treatments focus on methods to decrease the production of monoclonal light chains akin to myeloma therapy using chemotherapeutic drugs such as melphalan and prednisone, high-dose dexamethasone, chlorambucil, and cyclophosphamide. Recent reports using high-dose melphalan followed by allogeneic bone marrow transplant or stem cell transplant have given promising results. Thus, for younger patients with predominantly renal involvement, stem cell transplantation is a reasonable alternative therapy for AL amyloid. Regardless of whether chemotherapy or marrow transplant is used, the treatment of amyloid patients with nephrotic syndrome involves supportive care measures. These may include judicious use of diuretics and salt restriction in those with nephrotic edema, treatment of orthostatic hypotension (autonomic neuopathy) with compression stockings, fludrocortisone, and midodrine, an oral a-adrenergic agonist.


The treatment of AA amyloid focuses on the treatment of the 267 underlying inflammatory disease process. Alkylating agents have been used to control AA amyloidosis secondary to rheumatologic diseases in a number of studies, with responses including decreased proteinuria and prolonged renal survival CH 12 noted. In familial Mediterranean fever, colchicine has long been used successfully to prevent the febrile attacks. However, in patients with nephrotic syndrome at presentation or an elevated serum creatinine level, colchicine does not appear to prevent progression to ESRD. A recent multicenter randomized controlled trial compared a glycosaminoglycans (GAG) mimetic, used to block fibrillogenesis, to placebo in 183 patients with AA amyloid. The GAG mimetic reduced the risk of doubling the serum creatinine by 54% and halved the risk of a 50% decrease in creatinine clearance. Several promising experimental therapies for managing amyloid include using antiamyloid antibodies, and the use of an inhibitor of the binding of amyloid P component to amyloid fibrils.

MONOCLONAL IMMUNOGLOBULIN DEPOSITION DISEASE Monoclonal immunoglobulin deposition disease, which includes light chain deposition disease (LCDD), light and heavy chain deposition disease (LCDD/HCDD), and heavy chain deposition disease (HCDD), is a systemic disease caused by the overproduction and extracellular deposition of monoclonal immunoglobulin proteins. In LCDD, the constant region of the immunoglobulin light chain is typically deposited. Patients with LCDD are generally older than 45 years of age, and many patients have, or subsequently develop, frank myeloma or lymphoplasmacytic B cell disease such as lymphoma or Waldenstro¨m macroglobulinemia. Patients with renal involvement usually have significant glomerular involvement and thus present with heavy proteinuria accompanied by hypertension and renal insufficiency. The prognosis for patients with LCDD is uncertain and appears to be better than that for AL amyloidosis. As in amyloidosis, death is often attributed to cardiac disease or infectious complications. Treatment with melphalan and prednisone has led to stabilization or improvement in renal function in some cases. However, therapy is not successful in patients with a plasma creatinine higher than 4 mg/dL (350 mmol/L). Patient survival is about 90% at 1 year and 70% at 5 years, with renal survival of 67% and 37% at 1 and 5 years, respectively. Marrow or stem cell transplantation may be the optimal treatment for many patients with LCDD in the future.

268

GLOMERULAR DISEASE IN MYELOMA


Renal impairment is a common complication of multiple myeloma, occurring in 50% of patients. Renal involvement IV includes myeloma cast nephropathy, light chain deposition disease, AL amyloid, plasma cell infiltration, and glomerulonephritis. Other factors, such as hypercalcemia, hyperuricemia, infection, hyperviscosity, and nephrotoxic drugs can precipitate or exacerbate acute and chronic renal failure. Glomerular and vascular lesions are usually restricted to those patients with associated AL amyloidosis or monoclonal LCDD or HCDD or both (see above). The glomeruli are usually spared and may appear normal by LM or have only mild GBM thickening or minor amounts of mesangial matrix deposition without mesangial hypercellularity. In rare cases, glomerular crystals with associated granulomatous reaction or exudates of proteinaceous material in the urinary space have been reported. Crescentic glomerulonephritis and MPGN have been reported rarely, particularly in patients with associated cryoglobulinemia.

Myeloma Kidney Myeloma cast nephropathy (myeloma kidney) is an important cause of acute kidney injury in myeloma. The underlying pathogenesis involves the precipitation of filtered light chains within the tubule lumen and the subsequent obstruction of urine flow. Light chains may also be directly toxic to the proximal tubule cells and can trigger the development of the Fanconi syndrome. Patients are equally susceptible to cast nephropathy whether the filtered light chain is of the k or l variety; an inherent ability to bind with Tamm-Horsfall protein is an important determinant of whether or not the light chain precipitates. Other factors favoring the development of cast nephropathy include a low urine flow rate as may occur during volume depletion, hypercalcemia, and diuretic or NSAID use. Clinical findings include features of myeloma, including a serum and urine paraprotein, and, occasionally, evidence of Fanconi syndrome (proximal RTA, glycosuria). Of note, a routine urine dipstick test may not detect the positively charged light chains, and hence quantitative determination of urine protein should be performed if cast nephropathy is suspected. The definitive diagnosis requires a renal biopsy. The pathologic findings include preservation of the normal glomerular architecture and tubular casts that stain positive for either k or l light chains on immunofluoresence. Management involves treatment of exacerbating factors including removal of offending agents (diuretics, NSAIDs, ACE inhibitors), volume expansion, treatment of hypercalcemia, and,

¨ M MACROGLOBULINEMIA WALDENSTRO Waldenstro¨m macroglobulinemia is a syndrome characterized by a circulating monoclonal IgM protein in association with a B-cell lymphoproliferative disorder. This slowly progressive disorder occurs in older patients who present with fatigue, weight loss, bleeding, visual disturbances, peripheral neuropathy, hepatosplenomegaly, lymphadenopathy, anemia, and often a hyperviscosity syndrome. Renal involvement is uncommon but may manifest as microscopic hematuria and proteinuria, which may be nephrotic. Patients may have enlarged kidneys. The pathology seen in Waldenstro¨m macroglobulinemia is varied. Some patients have invasion of the renal parenchyma by neoplastic lymphoplasmacytic cells. Acute kidney injury associated with intraglomerular occlusive thrombi of the IgM paraprotein has also been reported. By IF, these glomerular “thrombi” stain for IgM and a single light chain, consistent with monoclonal IgM deposits. By EM, the deposits contain nonamyloid fibrillar or amorphous electron-dense material. Other potential presentations include MPGN with an associated type I or II cryoglobulinemia, LCDD, intratubule casts deposition similar to myeloma cast nephropathy, and amyloidosis. Treatment of Waldenstro¨m macroglobulinemia consists of therapy directed against the lymphoproliferative disease with alkylating agents and, at times, plasmapheresis for hyperviscosity signs and symptoms. Newer therapies include fludarabine, cladribine, interferon alfa, rituximab, and marrow transplantation.

MIXED CRYOGLOBULINEMIA Cryoglobulinemia refers to a pathologic condition caused by the production of circulating immunoglobulins that precipitate on cooling and resolubilize on warming. It is associated with a variety of infections as well as collagen-vascular disease, and lymphoproliferative diseases. Cryoglobulins have


possibly, the induction of an alkaline diuresis, though this last 269 point remains controversial. Ultimately, clearance of the paraprotein is required and this may be achieved by chemotherapy aimed at the underlying plasma cell dyscrasia. Plasmapheresis had been suggested in the management of patients with a high CH 12 paraprotein burden and acute kidney injury in whom conservative measures have failed to improve renal function. However, a recent large randomized controlled trial failed to demonstrate any benefit of this approach.

270 been divided into three major groups based on the nature of the circulating immunoglobulin:


• Type I: The cryoglobulin is a single monoclonal immunoglobulin often found associated with Waldenstro¨m macroIV globulinemia or myeloma. • Type II: The cryoglobulin is a monoclonal immunoglobulin (IgM k in > 90%) directed against polyclonal IgG and has rheumatoid factor activity. • Type III: The cryoglobulin contains polyclonal IgG and IgM directed against polyclonal IgG. The majority of patients with types II and III mixed cryoglobulins have been shown to have hepatitis C virus (HCV) infection.

Clinical and Laboratory Findings The majority of patients with cryoglobulinemia are asymptomatic. Type I disease typically presents with symptoms related to peripheral hyperviscosity including livido reticularis, Raynaud phenomenon, or digital ischemia. Systemic manifestation of types II and III are more nonspecific and include weakness, malaise, Raynaud phenomenon, arthralgias and arthritis, hepatosplenomegaly, peripheral neuropathy, and purpuric skin lesions. Renal disease occurs at presentation in less than one quarter of patients but develops in as many as 50% over time. The majority of patients with renal disease due to cryoglobulin deposition within the kidney have a slow, indolent course characterized by proteinuria, hypertension, hematuria, and renal insufficiency. However, in up to one third of patients an acute nephritic picture develops. A rapidly progressive glomerulonephritis presentation is rare. About 20% of patients present with the nephrotic syndrome. Some studies of type II cryoglobulinemia have shown evidence of hepatitis B infection. However, recent studies have clearly documented HCV as a major cause of cryoglobulin production in most patients previously believed to have essential mixed cryoglobulinemia (types II and III). Antibodies to HCV antigens have been documented in the serum, and HCV RNA and anti-HCV antibodies are enriched in the circulating cryoglobulins. HCV antigens have also been localized by immunohistochemistry in the glomerular deposits. Low levels of total complement and especially C4 are common. The diagnosis rests on the demonstration of a circulating cryoglobulin.

Course and Treatment The treatment of cryoglobulinemia is based both on the severity of symptoms and the underlying etiology. Mild disease in


the absence of end-organ injury should be managed conserva- 271 tively (analgesics and cold avoidance). In type I disease with evidence of end-organ injury, therapy is directed against the underlying lymphoproliferative disease; in idiopathic cases, treatment includes steroids and cyclophosphamide. Most CH 12 cases of type II and III disease are associated with HCV infection and are managed with a combination of interferon alfa and ribavirin. In severe disease with fulminant renal involvement, therapy may be initiated with plasmapheresis to remove the circulating cryoglobulin, corticosteroids to control the inflammatory response, and oral cyclophosphamide to prevent new cryoglobulin generation. Although this regimen typically extinguishes the acute inflammatory injury, activation of HCV replication is a real concern and antiviral therapy should proceed in parallel with immunosuppressive therapy. Most patients suffer episodic exacerbations of their systemic and renal disease. Mean patient survival rate is 70% at 5 years after diagnosis, with death typically resulting from infection and cardiovascular disease. Renal survival rate is greater than 80% at 10 years.

HEREDITARY NEPHRITIS, INCLUDING ALPORT SYNDROME Alport syndrome is an inherited (usually X-linked) disorder associated with progressive renal failure, hearing loss, and ocular abnormalities. Renal failure develops as a result of structural abnormalities in the GBM consequent to abnormalities in the COL4A5 gene encoding the a5 subunit of collagen type IV. Alport syndrome accounts for 2.5% of children and 0.3% of adults with ESRD in the United States.

Clinical Features The disease usually manifests in children or young adults as microscopic hematuria, with episodic gross hematuria that may be exacerbated by respiratory infections or exercise. Proteinuria is usually mild at first and increases progressively with age. Hypertension is a late manifestation. Slowly progressive renal failure is common and ESRD usually occurs in males between the ages of 16 and 35. As this is usually an X-linked disorder, most females have only mild disease. More severe disease in females suggests an autosomal pattern of inheritance. High-frequency sensorineural deafness occurs in 30% to 50% of patients and is always accompanied by renal involvement. Ocular abnormalities occur in 15% to 30% of patients. Anterior lenticonus is virtually pathognomonic of Alport syndrome.

272 Course and Treatment


Recurrent hematuria and proteinuria may be present for many years followed by the insidious onset of renal failure. Virtually IV all affected males reach ESRD, but there is considerable interkindred variability in the rate of progression. The rate of progression within male members of an affected family is usually, but not always, relatively constant. There is no proven therapy for Alport syndrome. Because weakening of the GBM appears important, it has been proposed that reducing intraglomerular pressures with aggressive control of hypertension and using ACE inhibitors might slow the rate of progression in patients with hereditary nephritis. Renal transplantation may be performed in patients with hereditary nephritis. Allograft survival is comparable to other patients with ESRD. In approximately 2% to 4% of patients receiving a renal transplant, anti-GBM antibody disease may develop, particularly following a second transplant. These antibodies are directed against the Goodpasture antigen in the a3 chain, which presumably does not exist in the kidneys of patients with hereditary nephritis and is thus recognized as being a nonself antigen.

THIN GLOMERULAR BASEMENT MEMBRANE DISEASE Thin GBM disease, also known as benign familial hematuria, describes a condition that differs from Alport disease in its benign course and lack of progression. The true incidence of thin GBM disease is unknown; reports evaluating patients with isolated hematuria suggest that 20% to 25% of such patients have thin GBM disease.

Clinical Features Patients usually present in childhood with microhematuria. Hematuria is usually persistent but may be intermittent in some patients. Episodic gross hematuria may occur, particularly with upper respiratory infections. Patients do not typically have overt proteinuria, but when present, this may suggest progression of disease.

Pathogenesis In most kindreds with benign familial hematuria, the disorder appears to be transmitted in an autosomal dominant pattern. Thin GBM disease has been linked to the COL4A3 and COL4A4 genes suggesting that type IV collagen defects can cause both benign hematuria and Alport syndrome.

INHERITED MUTATIONS OF PODOCYTE PROTEINS

273

Two novel proteins have been associated with the steroid-resistant nephrotic syndrome in childhood: nephrin and podocin. CH 12

Congenital nephrotic syndrome of the Finnish type (CNF) was originally described in Finland, but has been reported in other countries. The gene responsible for this form of nephrotic syndrome has been called NPHS1, and the gene product is a podocyte protein named nephrin.

Clinical Features The disease manifests in utero with heavy proteinuria, and the affected infants are small for gestational age. Infants exhibit massive proteinuria, ascites, anasarca, and polycythemia associated with a failure to thrive and recurrent infectious complications. Associated abnormalities include pyloric stenosis and severe gastroesophageal reflux resulting in aspiration pneumonia. The GFR progressively declines, and most infants develop renal failure within the first few years of life.

Pathogenesis CNF is inherited in an autosomal recessive pattern. The gene affected in this disorder has been localized to chromosome 19 (19q13.1) and has been termed NPHS1; the gene product is known as nephrin. In the kidney, nephrin expression is restricted to the podocyte; nephrin localizes to the slit diaphragm but its precise function is unknown. Prenatal diagnosis is possible.

Treatment Treatment strategies to support infants include intravenous albumin substitution, optimizing nutrition, administration of thyroxin, and anticoagulation, until bilateral nephrectomy can be performed (at around 1 year of life). Patients are maintained on dialysis until renal transplantation (at around 2 years of age). Other authors have reported success in reducing proteinuria, thus avoiding nephrectomy, with ACE inhibition in combination with indomethacin.

Podocin: Autosomal Recessive Nephrotic Syndrome Podocin mutations have also been reported in familial cases of steroid-resistant nephrotic syndrome. The clinical course is


Nephrin: Congenital Nephrotic Syndrome of the Finnish Type

274 characterized by early-childhood onset of proteinuria, rapid


progression to ESRD, and focal segmental glomerulosclerosis on the kidney biopsy. The podocin gene (NPHS2) is located on chromosome 1q25-1q31. Podocin has been localized to IV the slit diaphragm and co-localizes with nephrin. Podocin and nephrin interact at the level of the slit diaphragm possibly to maintain podocyte ultrastructural integrity.

a-Actinin-4: Autosomal Dominant Nephrotic Syndrome Mutations in a-actinin-4 have been associated with an autosomal dominant form of FSGS. The phenotype in these families is characterized by subnephrotic proteinuria and progressive renal insufficiency. The penetrance is high, but a small number of persons in these families do not have clinical disease. NPHS2 mutations have also been identified in adult-onset focal and segmental glomerulosclerosis (FSGS).

FABRY DISEASE (ANGIOKERATOMA CORPORIS DIFFUSUM UNIVERSALE) Fabry disease is an X-linked inborn error of glycosphingolipid metabolism involving a lysosomal enzyme, a-galactosidase A. It is characterized by an accumulation of globotriaosylceramide and related neutral glycosphingolipids leading to multiorgan dysfunction.

Clinical Features The estimated incidence in males is 1 in 40,000 to 1 in 60,000. The initial clinical presentation begins in childhood with episodic pain in the extremities and acroparesthesias. Renal involvement presents with hematuria and proteinuria, which often progress to nephrotic levels with progressive renal failure by the fifth decade. The skin is commonly involved with reddish purple macules (angiokeratomas) typically found on the abdomen, buttocks, hips, genitalia, and upper thighs. The nervous system is involved, with peripheral and autonomic neuropathy. Premature arterial disease of coronary vessels leads to myocardial ischemia and arrhythmias at a young age. Corneal opacities are seen in virtually all homozygotes and most heterozygotes. Posterior capsular cataracts, edema of the retina and eyelids, and tortuous retinal and conjunctival vessels may also been seen in the eye. Up to one third of female carriers have been reported to have significant disease manifestations.

Pathogenesis

275

Diagnosis The diagnosis in affected males may be established by measuring levels of a-galactosidase A in plasma or peripheral blood leukocytes. Female carriers may have enzyme levels in the low-to-normal range; to diagnose female carriers, the specific mutation in the family must be demonstrated. Prenatal diagnosis can be made in amniotic fluid by measuring amniocyte enzyme levels.

Treatment Two randomized, controlled trials have shown that recombinant human a-galactosidase A replacement therapy is safe and can improve clinical parameters including neuropathic pain and creatinine clearance. Treatment has also been shown to decrease microvascular endothelial deposits of globotriaosylceramide in the kidney. Enzyme replacement therapy should be administered as early as possible in all males with Fabry disease (including those with ESRD) and female carriers with substantial disease manifestations.

SICKLE CELL NEPHROPATHY See Chapter 13, Microvascular Diseases of the Kidney.

LECITHIN-CHOLESTEROL ACYLTRANSFERASE DEFICIENCY This familial disorder is characterized by proteinuria, anemia, hyperlipidemia, and corneal opacity. Most patients are of Scandinavian origin; however, subsequent reports have been from other countries.

Clinical Features The triad of anemia, nephrotic syndrome, and corneal opacities suggests lecithin-cholesterol acyltransferase (LCAT) deficiency. Renal disease is a universal finding, with albuminuria noted


Deficiency of the a-galactosidase leads to accumulation of globotriaosylceramide, especially in the vascular endothelium, with subsequent ischemic organ dysfunction. Accumulation CH 12 in podocytes leads to proteinuria.

276 early in life. Proteinuria increases in severity during the fourth


and fifth decades, often with development of nephrotic syndrome and progressive renal failure. Most patients are mildly anemic with target cells and poikilocytes on the peripheral IV smear. There is evidence of low-grade hemolysis. Corneal opacities are noted during childhood, which appear as grayish spots over the cornea accompanied by a lipoid arcus.

Diagnosis Patients have little or no LCAT activity in their blood circulation because of mutations in the LCAT gene. In patients suspected of having LCAT deficiency, measurements of plasma enzyme should be performed. Other abnormalities of lipids frequently accompany LCAT deficiency. The plasma is turbid, total cholesterol varies, triglycerides are increased, HDL is reduced, and all fractions contain higher amounts of cholesterol.

Treatment A low-lipid diet or lipid-lowering drugs have not been shown to be of benefit. Plasma infusions may provide reversal of erythrocytic abnormalities, but long-term benefits have yet to be demonstrated. The lesions may recur in the allograft, but renal function is adequately preserved.

GLOMERULAR INVOLVEMENT WITH BACTERIAL INFECTIONS Infectious Endocarditis In the preantibiotic era, Streptococcus viridans was the most common causative organism in endocarditis-related glomerulonephritis. However, with the use of prophylactic antibiotics in patients with valvular heart disease and an increase in intravenous drug use, Staphylococcus aureus has replaced S. viridans as the primary pathogen. The incidence of glomerulonephritis with S. aureus endocarditis ranges from 22% to 78%, being higher in those series consisting predominantly of intravenous drug users.

Clinical Features Renal complications of infectious endocarditis include infarcts, abscesses, and glomerulonephritis (all of which may coexist). The spectrum of glomerulonephritis ranges from mild asymptomatic urinary abnormalities including hematuria, pyuria, and albuminuria to rapidly progressive renal failure with crescents. Although hypocomplementemia is frequent, it is

Pathogenesis Endocarditis-related glomerulonephritis is an immune complex–mediated disease. The demonstration of hypocomplementemia, antibody deposition in the glomeruli, and the detection of bacterial antigen in the deposits supports this hypothesis.

Treatment With the initiation of antibiotic therapy, the manifestations of glomerulonephritis begin to subside. Plasmapheresis and corticosteroids have been reported to promote renal recovery in some patients with renal failure. However, the risk of worsening infectious aspects of the disease while ameliorating immunologic manifestations should be kept in mind while using this approach.

Shunt Nephritis Ventriculovascular (ventriculoatrial, ventriculojugular) and ventriculoperitoneal shunts used for the treatment of hydrocephalus may become colonized with microorganisms, most commonly Staphylococcus albus (75%). Patients commonly present with fever, arthralgia, and malaise. Anemia, hepatosplenomegaly, and lymphadenopathy are found on examination. Renal manifestations include hematuria (microscopic or gross), proteinuria (nephrotic syndrome in 30% of patients), azotemia, and hypertension. Laboratory abnormalities include presence of rheumatoid factor, cryoglobulins, elevated ESR and C-reactive protein levels, hypocomplementemia, and presence of circulating immune complexes.

Treatment Antibiotic therapy and prompt removal of the infected catheter lead to remission of the glomerulonephritis.

Other Bacterial Infections and Fungal Infections Congenital, secondary, and latent forms of syphilis may be rarely complicated by glomerular involvement. Patients are typically nephrotic, and proteinuria usually responds to


not invariable. The majority of patients demonstrate activation 277 of the classic pathway and the degree of complement activation correlates with the severity of renal impairment. Circulating immune complexes have been found in the serum in up to 90% of patients. Mixed cryoglobulins and rheumatoid factor CH 12 may also be present.

278 penicillin therapy. Membranous nephropathy with varying


degrees of proliferation and with granular IgG and C3 deposits is the most common finding on biopsies. Renal involvement including azotemia, proteinuria, nephrotic syndrome, renal IV tubule defects, and hematuria is not uncommon in leprosy, especially with the lepra reaction. Rarely, presentation with rapidly progressive glomerulonephritis and ESRD can occur. Mesangial proliferation, diffuse proliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, MPGN, microscopic angiitis, and amyloidosis all may be seen in kidney biopsies. Membranous nephropathy, MPGN, crescentic glomerulonephritis, and amyloidosis have been associated with Mycobacterium tuberculosis. Mycoplasma has been reported to be associated with nephrotic syndrome and rapidly progressive glomerulonephritis. Antibiotics do not seem to alter the course of the disease. Acute glomerulonephritis with hypocomplementemia has been reported with pneumococcal infections. Proliferative glomerulonephritis with deposition of IgG and IgM, complements C1q, C3, and C4, and pneumococcal antigens have been observed in renal biopsies. In infections with Brucella, patients may present with hematuria and proteinuria (usually nephrotic) and varying degrees of renal functional impairment. There is usually improvement after antibiotic therapy, but histologic abnormalities, proteinuria, and hypertension may persist. Mesangial proliferation, focal and segmental proliferation, diffuse proliferation, and crescents may be found in renal biopsies. IF may show no deposits, IgG, or occasionally IgA deposition. Asymptomatic urinary abnormalities may be seen in as many as 80% of patients infected with Leptospira. Patients usually present with acute kidney injury due to tubulointerstitial nephritis. Rarely, mesangial or diffuse proliferative glomerulonephritis may be seen.

GLOMERULAR INVOLVEMENT WITH PARASITIC DISEASES Malaria Clinically overt glomerular disease is uncommon in falciparum malaria (Plasmodium falciparum). However, severe falciparum malaria may be manifest with hemoglobinuric acute kidney injury. In quartan malaria (Plasmodium malariae) with renal involvement, proteinuria is the cardinal manifestation and significant hematuria is unusual. Serum complement may be depressed in early stages of the disease. There is progression to end-stage renal failure within 3 to 5 years. Spontaneous remissions may occur but are rare. Antimalarial treatment fails to improve the renal outcome, and response to steroids is disappointing.

Schistosomiasis

279

Leishmaniasis Leishmaniasis, also known as kala-azar, is caused by Leishmania donovani. Renal involvement in kala-azar appears to be mild and reverts with antileishmanial treatment. Renal biopsies show mesangial proliferation or focal proliferation. IgG, IgM, and C3 may be observed in areas of proliferation. Amyloidosis may also complicate kala-azar.

Trypanosomiasis and Filariasis Trypanosoma brucei, T. gambiense, and T. rhodesiense cause African sleeping sickness and have rarely been associated with proteinuria. Filariasis is caused by organisms in the genera Onchocerca, Brugia, Loa, and Wuchereria. Hematuria and proteinuria (including nephrotic syndrome) have been described. Renal manifestations may appear with treatment of infection. Renal biopsy findings have included mesangial proliferative glomerulonephritis with C3 deposition, diffuse proliferative glomerulonephritis, and collapsing glomerulopathy.

GLOMERULAR INVOLVEMENT WITH VIRAL INFECTIONS HIV-Associated Nephropathy Clinical Features HIV-associated nephropathy (HIVAN) was first reported in 1984 and is characterized by a collapsing form of focal glomerulosclerosis. There is a strong predilection for HIVAN among black HIV-infected patients with a black-white ratio


Schistosomiasis is a visceral parasitic disease caused by the blood flukes of the genus Schistosoma. Schistosoma mansoni and S. japonicum cause cirrhosis of the liver and S. hematobium CH 12 causes cystitis. Glomerular involvement in S. mansoni includes mesangial proliferation, focal sclerosis, membranoproliferative lesions, crescentic changes, membranous nephropathy, amyloidosis, and eventually ESRD. Schistosomal antigens have been demonstrated in renal biopsies in such patients. Treatment with antiparasitic agents does not appear to influence progression of renal disease. S. hematobium is occasionally associated with the nephrotic syndrome, which may respond to treatment of the parasite.

280 of 12:1. Although intravenous drug use has been the most


common risk factor for HIVAN, the disease has been seen in all groups at risk for AIDS. HIVAN usually occurs in patients with a low CD4 count, but full-blown AIDS is certainly not a IV prerequisite for the disease. The prevalence of HIVAN in patients who test positive for HIV is reported to be 3.5%. The clinical features of HIVAN include proteinuria, typically in the nephrotic range (and often massive), and renal insufficiency. Some patients, however, present with subnephrotic-range proteinuria and urinary sediment findings of microhematuria and sterile pyuria. The renal ultrasound in HIVAN shows echogenic kidneys with preserved or enlarged size (an average size of more than 12 cm) in spite of the severe renal insufficiency.

Pathogenesis HIV appears to be able to infect glomerular endothelial cells and, to a lesser degree, mesangial cells in vitro. HIV-1 RNA is detectable in renal tubule epithelial cells and glomerular epithelial cells (visceral and parietal) by in situ hybridization in human subjects. Based on animal models, it appears likely that a viral gene product or indirect effects on host cytokine production mediate glomerular injury.

Course and Treatment The natural history of HIVAN during the early part of the AIDS epidemic was characterized by rapid progression to ESRD. However, early institution of zidovudine antiviral therapy in HIVAN is associated with an improvement in outcome. The role of combined antiviral therapies and the use of newer agents in the treatment of HIVAN have been investigated in small numbers of patients with apparent beneficial effect. Indeed, the incidence of HIVAN-related ESRD has decreased substantially with the introduction of highly active antiretroviral therapy. At present, the therapy of HIVAN should include use of multiple antiviral agents as in HIV-infected patients without nephropathy. Use of ACE inhibitors or angiotensin II receptor blockers is likely to be beneficial and should be considered in all patients.

GLOMERULAR MANIFESTATIONS OF LIVER DISEASE Hepatitis B Hepatitis B antigenemia is associated with membranous nephropathy, MPGN, and PAN. In countries where the virus is endemic (sub-Sahara Africa, Southeast Asia, and Eastern

Europe), hepatitis B–associated nephropathy occurs in these 281 children with a 4:1 male preponderance. In the industrialized world, where hepatitis B is acquired by parenteral routes or sexually, the nephropathy affects mainly adults and has a different clinical course from the endemic form. CH 12 Most patients present with proteinuria or the nephrotic syndrome and have normal renal function at time of presentation. There may be urinary erythrocytes, but the majority have a bland sediment. Liver disease may be absent (carrier state) or chronic, and clinically mild. Serum aminotransferases may be normal or modestly elevated. Liver biopsies in these patients often show chronic active hepatitis. Some patients ultimately develop cirrhosis in their biopsies. There is often spontaneous resolution of the carrier state with resolution of renal abnormalities.

Treatment In children with a mild endemic form of hepatitis B– associated nephropathy, no treatment other than supportive care is advocated and spontaneous recovery is common. In patients with progressive renal dysfunction, interferon alfa has been used with mixed results. Steroids do not significantly improve proteinuria and may potentially enhance viral replication. Nucleoside analogs including lamivudine (3TC), adefovir, and lobucavir have also demonstrated clinical utility in treating hepatitis B infection; their role in treating the nephropathy remains to be established. Preemptive lamivudine therapy in renal transplant recipients has shown improved survival compared to historical control subjects.

Hepatitis C Renal disease associated with HCV infection includes MPGN, with or without associated mixed cryoglobulinemia, and membranous glomerulopathy (see Chapter 11, Primary Glomerular Disease, and previous discussion in this chapter). The MPGN is most often type I, with fewer cases of type III. Rare cases of diffuse proliferative and exudative glomerulonephritis, polyarteritis, and fibrillary and immunotactoid glomerulopathy have also been described in association with HCV. Most patients have evidence of liver disease as reflected by elevated plasma transaminase levels. However, transaminase levels are normal in some cases, and a history of acute hepatitis is often absent.

Pathogenesis The pathogenesis of HCV-related nephropathies is immune complex–mediated. HCV-specific proteins have been isolated


Clinical Features

282 from glomerular lesions. The disappearance of viremia in

response to interferon (see later) is associated with a diminution of proteinuria; a relapse of viremia is accompanied by rising proteinuria.


IV

Treatment A number of reports demonstrate a beneficial response to interferon alfa therapy in patients with HCV-induced renal disease. Vasculitic symptoms, viral titers, proteinuria, and, in some studies, plasma creatinine level improve in 50% to 60% of patients receiving interferon alfa for periods up to a year. Cessation of interferon therapy, however, is associated with recurrence of viremia and cryoglobulinemia in a majority of patients in these studies. Interferon therapy may paradoxically exacerbate proteinuria and hematuria that appears to be unrelated to viral antigenic effects. Combination therapy with ribavirin and interferon may offer benefits over interferon alfa alone. However, it may not be well tolerated in the presence of significant renal dysfunction. Interferon alfa treatment of renal transplant patients with HCV has been associated with acute kidney injury and acute humoral rejection. Cyclophosphamide treatment has been used successfully in HCV glomerulonephritis, even if interferon alfa resistant. Cyclophosphamide treatment may be associated with a temporary, reversible increase in viral load.

Cirrhosis Cirrhotic glomerulonephritis is usually a clinically silent disease; however, the diagnosis can be suspected by finding proteinuria or abnormalities of the urine sediment. Glomerular morphologic abnormalities with IgA deposition have been noted in more than 50% of patients with cirrhosis at both necropsy and biopsy, although this has also been found in some autopsies of noncirrhotic kidneys. Clinically, there may be mild proteinuria or hematuria, or both. Rarely, HSP with rapidly progressive glomerulonephritis has been described in association with cirrhosis.

GLOMERULAR LESIONS ASSOCIATED WITH NEOPLASIA The occurrence of glomerular syndromes, both nephrotic and nephritic, may be associated with malignancy, but this is rare (85%) and include headache, altered mental status, paresis, aphasia, dysphasia, paresthesias, visual problems, seizures, and coma. Fever is almost universal. Renal involvement in TTP

285

286 (>80%) is usually mild. In HUS, hemolytic anemia and renal


involvement are uniformly present. AKI is detected in 50% to 90% of patients and neurologic symptoms occur less commonly than in TTP. In children, HUS is commonly associated with IV infection of shiga-toxin–producing Escherichia coli. Nonshiga-toxin–associated HUS accounts for 5% to 10% of all cases. It can be familial or sporadic and has a poor outcome. Neurologic symptoms and fever can occur in 30%. Pulmonary, cardiac, and gastrointestinal manifestations can also occur.

Laboratory Findings The hallmark laboratory finding, essential for the diagnosis of HUS/TTP, is a microangiopathic hemolytic anemia. The laboratory findings include the following: • Schistocytes on the peripheral smear (burr cells, helmet cells, and other fragments) • Anemia (hemoglobin levels < 6.5 mg/dL in 40%) • Reticulocytosis • Elevated lactate dehydrogenase (LDH)/low haptoglobin level • Negative Coombs test • Thrombocytopenia (cell count usually < 60,000/mm3) Moderate leukocytosis may accompany the hemolytic anemia, but white blood cell counts rarely exceed 20,000/mm3. In contrast to disseminated intravascular coagulation, the prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen level, and coagulation factors are normal.

Renal Involvement Evidence of renal involvement is present in the majority of patients with HUS/TTP. Microscopic hematuria and subnephrotic proteinuria are the most consistent findings. Male sex, hypertension, prolonged anuria, and hemoglobin levels greater than 10 g/L at onset are associated with a higher risk of renal sequelae in children. More than 90% of patients with HUS have significant renal failure at presentation, one third of whom are anuric. Dialysis is required in a large percentage of these patients. The mean duration of renal failure is 2 weeks. Severe AKI or anuria occurs in fewer than 10% of cases of classic TTP.

Etiology Hemolytic Uremic Syndrome Diarrhea-associated HUS (DþHUS) is associated with infection by shiga-toxin–producing E. coli serotype O157:H7 and has an

Microvascular Diseases of the Kidney

excellent prognosis. Transmission can occur through contami- 287 nated foodstuffs or through municipal water, airborne transmission, and person-to-person contact. Hemolytic uremic syndrome can also follow non-shiga-toxin–producing E. coli (STEC) O15:H7 infections, and such infections are almost cer- CH 13 tainly undetected. Diarrhea starts 2 to 12 days after ingestion of the vehicle; it is bloody in 90% of cases. Most patients, however, are afebrile. Abdominal pain is severe. Thrombocytopenia is the first abnormality in all patients and hemolysis usually precedes azotemia. Non–diarrhea-associated HUS (D-HUS) typically affects adults, but can occur at any age, in sporadic or familial forms. It is noninfective and is usually precipitated by drugs or pregnancy. Several studies have demonstrated genetic predisposition in atypical HUS, involving two regulatory proteins of the complement alternative pathway: factor H (FH) and membrane cofactor protein (MCP or CD46). In a small number of children with recurrent atypical HUS, anti-FH antibodies have been described, suggesting an autoimmune-mediated acquired FH deficiency.

Thrombotic Thrombocytopenic Purpura and ADAMTS13 ADAMTS13 is a protease that cleaves von Willebrand factor (vWF) inhibiting inappropriate vWF-platelet interaction. This is a critical step in preventing inappropriate hemostasis under the high shear stress conditions in the capillaries and arterioles. Severe deficiency of ADAMTS13 has been described in patients with TTP. In patients with sporadic TTP the deficiency appears to be autoimmune. IgG molecules isolated from patients with TTP suppress ADAMTS13 activity in normal plasma. Drug-induced HUS/TTP is well recognized. HUS/TTP has also been reported after chemotherapy with many chemotherapeutic agents (Table 13-1). Thrombotic microangiopathy, unrelated to chemotherapy, has been described in conjunction with vascular tumors, acute promyelocytic leukemia, and prostatic, gastric, and pancreatic carcinomas. Ticlopidine, an antiplatelet agent, was associated with the development of TTP with an estimated incidence of 1 case per 1600 to 9000 patients treated. A reversible calcineurin inhibitor–induced TMA has been observed in bone marrow and solid organ transplant recipients. Postpartum HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) is discussed in Chapter 24. Other drugs and disease processes less commonly associated with HUS/TTP are listed in Table 13-1. Many of the infectious agents and drugs implicated in the etiology of HUS/TTP are toxic to the vascular endothelium. The shiga-like toxins, which include the verocytotoxins produced by E. coli O157:H7, directly damage human vascular

288

Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura: Causes and Associations

IV

Infectious Agents


Table 13-1

Bacteria Escherichia coli O157:H7 (verotoxin-producing) Shigella dysenteriae type Salmonella typhi Streptococcus pneumoniae Campylobacter jejuni Yersinia pseudotuberculosis Pseudomonas species Bacteroides Mycobacterium tuberculosis Viruses Togavirus (rubella) Coxsackievirus Echoviruses Influenza virus Epstein-Barr virus Rotaviruses Cytomegalovirus Human immunodeficiency virus Drugs Immunosuppressants Cyclosporine and FK-506 OKT3 Chemotherapeutics Mitomycin C Cisplatin Daunorubicin Cytosine arabinoside Gemcitabine Other agents Oral contraceptives Ticlopidine Clopidogrel Pregnancy Prepartum or postpartum Other Causes/Associations Malignant neoplasm Transplantation Systemic lupus erythematosus Polyarteritis nodosa Primary glomerulopathies

Local Thrombosis and Fibrin Deposition Reduced fibrinolytic capacity of the vessel wall has been proposed in the pathophysiology of TTP. Under normal circumstances, secreted vWF multimers undergo proteolytic cleavage by ADAMTS13, preventing intravascular thrombosis. In the absence of ADAMTS13, uncleaved vWF multimers cause the formation of platelet thrombi in the arterioles and capillaries with microvascular injury. Retrospective studies have demonstrated that the majority of patients with acute sporadic TTP had severe deficiency of ADAMTS13 due to the presence of IgG antibodies that disappeared in most of the patients during remission.

Prognosis and Treatment If HUS/TTP is left untreated, the mortality rate approaches 90%. With the use of plasma exchange or plasma infusion therapy, 60% to 90% of the patients survive the acute episodes. In HUS the mortality rate is less than 10% among young patients with shiga-toxin–associated HUS, but it approaches 90% among the elderly. Several prognostic factors have been postulated to predict the outcome for patients with HUS. Younger children who present during the summer with the “typical” diarrheal prodrome have a better prognosis than older children with HUS that occurs in the colder months of the year and is not heralded by diarrhea.

Management of Shiga-Toxin–Associated Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura Strict attention to volume assessment and judicious fluid administration is essential to maintain renal perfusion while avoiding fluid overload. Antibiotics should not be administered to patients with possible shiga-toxin–producing E. coli


endothelial cells, enable leukocyte-dependent inflammation, 289 and promote loss of thromboresistance properties leading to microvascular thrombosis. Recent genetic studies have shown that mutations in factor H, membrane cofactor proteins, and factor I regulatory proteins of the alternative complement path- CH 13 way predispose to non-shiga-toxin–associated HUS. FH normally deposits at the surface of human glomerular endothelial cells, protecting them against complement attack. Mutations in FH can lead to qualitative or quantitative deficiencies. Membrane cofactor protein regulates glomerular C3 activation. In the presence of stimuli that activate the complement system, reduced levels of MCP may lead to microvascular damage.

290 infection because their use in this setting is associated with a


higher rate of HUS. Blood transfusion to correct the anemia should be given during dialysis. Platelet transfusion exacerbates thrombosis and is discouraged. Plasma exchange is the treatment of choice for both children IV and adults with HUS/TTP. Response rates vary between 60% and 80%. As compared to plasma infusion alone, plasmapheresis has the advantage of removing inhibitory autoantibodies against vWF protease and supplying larger amounts of the protease enzyme. Typically, plasma exchange is performed once a day and replaces one plasma volume (40 mL/kg). Plasma exchange should be performed daily until remission is achieved, remission being normalization of platelet count, or resolution of neurologic symptoms, or both. Hemoglobin level, percent schistocytosis, reticulocyte count, and renal indices do not appear to be determinants of initial response to therapy, because they may be abnormal for an undefined period after remission. Continuation of plasma exchange for several sessions after remission has been achieved has been advocated to prevent relapses. TTP relapses occur between 1 and 140 months (median, 20 months) after the initial episode in as many as 40% of the patients. Patients with non-shiga-toxin–associated HUS may respond to plasma treatment. Plasma exchange may be better than plasma infusion for removal of toxic substances and increasing platelet counts. Corticosteroids have been used in addition to plasma therapy for management of TTP. In view of recent data concerning autoantibody-induced ADAMTS13 deficiency, a pathophysiologic basis seems to explain therapeutic strategies: plasma exchange may remove antibodies, fresh frozen plasma (FFP) replaces lacking proteases, and corticosteroids suppress immunity. Of note, cancer- and chemotherapy-induced HUS/ TTP carries a poor prognosis despite treatment.

Management of Renal Failure in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura Severe renal insufficiency resulting from HUS/TTP often requires dialysis. Renal transplantation has also been performed. Kidney transplantation is safe and effective for DþHUS patients who have progressed to end-stage renal disease (ESRD), with recurrence rates of 0% to 10%. In D-HUS, 1-year graft survival rate is less than 30% with 50% recurrence in the grafted organ. For patients with factor H mutation, recurrence rate is between 30% and 100%; because FH is synthesized in the liver, concomitant liver and kidney transplantation should be performed to correct the disease.

SYSTEMIC SCLEROSIS

291

Clinical Features

• • • • •

Raynaud phenomenon (>90%) Telangiectasias on the skin of the face and upper torso Arthralgias or arthritis in most patients Myopathy of the shoulder and pelvic girdle (20%) Esophageal hypomotility or diminished tone of the lower esophageal sphincter (75%) • Diffuse pulmonary fibrosis (45%) • Pericarditis (20%) • Myocardial fibrosis leading to arrhythmia (40%)

Laboratory Findings About 70% of the patients with systemic sclerosis have a positive antinuclear antibody titer (ANA 1:16), typically in a speckled or nucleolar pattern. Antibodies to DNA topoisomerase I (anti-Scl-70) are more specific, but they are found in only 30% of patients with diffuse cutaneous involvement and in only 15% of those with the limited form. Anticentromere antibodies are present in half of the patients, most of whom have limited systemic sclerosis. Approximately 30% of the patients have positive tests for rheumatoid factor. Antibodies to double-stranded DNA are rarely noted.

Renal Involvement Kidney involvement in systemic sclerosis (80%) manifests as a slowly progressing chronic renal disease or as scleroderma renal crisis (SRC), which is characterized by malignant hypertension and acute azotemia. Clinical indicators of chronic renal involvement in systemic sclerosis include proteinuria, hypertension, and decreased glomerular filtration rate (GFR). Renal manifestations rarely antedate the other features of systemic sclerosis.


Systemic sclerosis is a rare disease affecting predominantly CH 13 women between the ages of 30 and 50 years. The overall annual incidence is unclear and estimates range from 2 to 20 cases per million. Involvement of the skin and subcutaneous tissue is the predominant feature of systemic sclerosis. In the diffuse cutaneous form of the disease, thickening of the skin is observed on the face, trunk, and distal and proximal extremities. This phase is followed by sclerosis, which leads to a taut, shiny appearance of the skin and tapering of the fingertips (sclerodactyly). Other extrarenal manifestations include the following:

292


Scleroderma renal crisis is defined by the sudden onset of accelerated or malignant arterial hypertension, followed by rapidly progressive oliguric renal failure. Ten percent of patients with scleroderma, in general, and 25% of those with IV diffuse scleroderma develop SRC typically within the first 4 years of the disease. Patients with the diffuse cutaneous form are at much higher risk for development of SRC than are those with limited cutaneous systemic sclerosis, and black patients are also at higher risk compared with white patients. The symptomatology is predominantly that of accelerated/ malignant hypertension. Oliguria and a rapidly rising serum creatinine concentration follow shortly thereafter. The urinalysis reveals proteinuria, microscopic hematuria, and granular casts. Plasma renin activity is markedly elevated during SRC. SRC progresses rapidly to severe renal failure that requires dialysis. Other clinical manifestations of SRC include microangiopathic hemolytic anemia with thrombocytopenia.

Pathogenesis The pathogenesis of systemic sclerosis is poorly understood. Postulated mechanisms include abnormal vasomotor control, enhanced collagen production, immune-mediated injury, and primary endothelial abnormalities. Although several antinuclear autoantibodies have been detected in patients with systemic sclerosis, it is unclear whether these immunologic changes constitute primary events in systemic sclerosis or are epiphenomena.

Management of Renal Complications Angiotensin-converting enzyme (ACE) inhibition has revolutionized the management of SRC. One-year patient survival rates have improved from less than 20% to over 70% with the advent of ACE inhibition. Close monitoring of renal function is required and an additional antihypertensive agent may be required to effect adequate hypertensive control. Blood pressure should be lowered gradually (10–20 mm Hg/day) to avoid renal hypoperfusion and acute tubular necrosis. Diuretics are best avoided because of their ability to stimulate renin release. Disappointing outcomes with the use of angiotensin receptor blockers (ARBs) have been noted. Both peritoneal dialysis and hemodialysis have been employed in the management of ESRD in systemic sclerosis. Occasionally, recovery of renal function is observed even after prolonged renal replacement therapy. Evidence exists suggesting that aggressive use

ATHEROEMBOLIC RENAL DISEASE Atheroembolic renal disease results from embolization of cholesterol crystals from atherosclerotic plaques present in large arteries, such as the aorta, to small arteries in the renal vasculature. Patients with cholesterol embolization syndrome often have a history of ischemic macrovascular disease, congestive heart failure, or renal insufficiency. Precipitating factors include vascular surgery, arteriography, angioplasty, anticoagulation, and thrombolytic therapy. An estimated 15% of patients with atheroembolism do not have any of the known risk factors.

Clinical Features The mode of onset of clinical manifestations varies greatly. It may be sudden, developing in a few days after a precipitating factor, or insidious, over weeks or months. Clinical manifestations include the following: • • • • •

Livedo reticularis, “purple” toes or toe gangrene (40–50%) Fever, myalgias, headaches, and weight loss (50%).

Treatment No effective therapy for atheroembolic renal disease has been reported. Anticoagulants should be avoided because of the risk of precipitating more atheroembolization. In fact, withdrawal of anticoagulation may be beneficial. Despite the high mortality rate and the absence of effective therapy, kidney function improves in a minority of patients even after prolonged periods of renal insufficiency. An aggressive therapeutic approach with patient-tailored supportive measures, including statin therapy, withdrawal of anticoagulants, postponement of aortic procedures, control of hypertension and heart failure, dialysis therapy, and adequate nutritional support, may be associated with favorable clinical outcomes.

RENAL INVOLVEMENT IN SICKLE CELL DISEASE Clinical Manifestations Sickle cell anemia, and occasionally the heterozygous forms of sickle cell disease, can lead to multiple renal abnormalities,

which include tubular, medullary, and glomerular dysfunc- 295 tion or a combination of these. Clinical manifestations include the following: Microscopic and gross hematuria (>50%) Renal papillary necrosis (15–36%) Proteinuria (26–40%) Nephrotic syndrome (3%) Polyuria Progressive renal failure (5%)

The onset of proteinuric progressive renal failure usually occurs after age 30. Progression to ESRD occurs within 2 years in 50% of these patients, and survival time is approximately 4 years, even with dialysis therapy. Acute or chronic deterioration in renal function may reflect concomitant infection, rhabdomyolysis, or, less commonly, renal vein thrombosis or intravascular hemolysis. Sickling in the medullary microcirculation causes chronic medullary ischemia, which manifests as an inability to maximally concentrate the urine and in an incomplete form of distal renal tubule acidosis. A highly aggressive form of renal cell carcinoma has been described in some patients with sickle cell disease.

Pathogenesis Hb-SS polymer formation is promoted by higher degrees of deoxygenation, increased intracellular hemoglobin concentration, and the absence of hemoglobin F. The pathogenesis of medullary renal lesions in sickle cell disease is attributed largely to microvascular occlusion. Erythrocytes passing through the vessels of the inner renal medulla and the renal papillae are vulnerable to sickling because of relative hypoxia and the high osmolality of the blood, which leads to cell shrinkage and increased hemoglobin concentration. The pathogenesis of sickle cell glomerulopathy is generally attributed to secondary hyperfiltration.

Treatment The management of patients with sickle cell disease is targeted at limiting sickle cell crises and end-organ damage. Factors that trigger sickling, such as infection and dehydration, should be treated aggressively. Exposure to hypoxia, cold, or medications that may induce sickle cell crisis should be avoided. Treatment options include transfusion therapy and, more recently, bone marrow transplantation. Hydroxyurea increases the hemoglobin F concentration, which results in over 40% reduction in the median annual rate of pain crises. However, it is not known

CH 13


• • • • • •

296 whether a reduction in the frequency of sickle cell crises trans-


lates to a lower incidence of renal disease. ACE inhibitors should be used in the presence of proteinuric renal insufficiency to retard disease progression. Patients with sickle cell disease IV who reach ESRD have a 60% survival rate at 2 years after the administration of renal replacement therapy. Dialysis is the most common form of renal replacement therapy employed. Kidney transplantation has been performed in small numbers of patients. One-year survival rates are broadly comparable with other causes of ESRD but there is a trend toward a lower allograft survival thereafter. Nevertheless, patient survival appears better with renal transplantation compared with maintenance hemodialysis.

Chapter 14

Tubulointerstitial Diseases Tubulointerstitial disease is common to all chronic progressive renal diseases, irrespective of the initial trigger or site of injury. Progressive inflammation or injury to the tubulointerstitial region typically destroys extensive amounts of kidney tissue and, as a result, usually produces irreversible chronic kidney disease (CKD). Interstitial inflammation can begin either from within the interstitial compartment or as a secondary event following glomerular or vascular injury and, if left unchecked, can evolve into irreversible tubulointerstitial fibrosis. Although some forms of injury to the tubulointerstitial compartment are the result of toxic insult or exposure to infection and drugs, much of the inflammatory process is immunologically mediated. Many studies have pointed to the degree of tubulointerstitial fibrosis as an accurate prognostic marker of severe interstitial disease in a variety of glomerular diseases.

ACUTE INTERSTITIAL NEPHRITIS Acute interstitial nephritis (AIN) presents clinically with an abrupt deterioration in renal function and is characterized histopathologically by inflammation and edema of the renal interstitium. AIN is an important cause of acute kidney injury due to drug hypersensitivity reactions. AIN has been reported to occur in approximately 5% to 15% of renal biopsies in patients with acute kidney injury.

Etiology The most frequent causes of AIN can be found in three general categories: drug-induced, infection-associated, and cases associated with autoimmune idiopathic lesions (Table 14-1).

Drugs Drugs are frequently recognized as etiologic factors in AIN because of the increased use of renal biopsy and the characteristic clinical presentation. Approximately a third of cases of drug-related AIN are due to antibiotics. Tubulointerstitial disease is more commonly seen with b-lactam antibiotics (including cephalosporins), but other antibiotics (sulfonamides,

297

298 Table 14-1

Acute Interstitial Nephritis: Causative Factors

Drugs


IV

Antibiotics

Cephalosporins, ciprofloxacin, ethambutol, isoniazid, macrolides, penicillins, rifampin, sulfonamides, tetracycline, vancomycin

NSAIDs

Almost all agents

Diuretics

Furosemide, thiazides, triamterene

Miscellaneous

Acyclovir, allopurinol, amlodipine, azathioprine, captopril, carbamazepine, clofibrate, cocaine, creatine, diltiazem, famotidine, indinavir, mesalazine, omeprazole, phenteramine, phenytoin, pranlukast, propylthiouracil, quinine, ranitidine

Infectious Agents Bacteria

Corynebacterium diphtheriae, Legionella, staphylococci, streptococci, Yersinia, Brucella, Escherichia coli, Campylobacter

Viruses

Cytomegalovirus, Epstein-Barr virus, hantaviruses, hepatitis C virus, herpes simplex virus, human immunodeficiency virus, mumps virus, polyomavirus

Other agents

Leptospira, Mycobacterium, Mycoplasma, Rickettsia, Treponema pallidum (syphilis), Toxoplasma, Chlamydia

Idiopathic Immune

Anti-tubule basement membrane disease, tubulointerstitial nephritis and uveitis (TINU) syndrome

rifampin, vancomycin, ciprofloxacin) have also been involved. b-Lactams cause interstitial nephritis because they behave like haptens, which may bind to serum or cellular proteins to be subsequently processed and presented by MHC molecules as hapten-modified peptides. Approximately 1% to 5% of patients exposed to NSAIDs develop diverse nephrotoxic syndromes warranting potential physician intervention. Whereas, on the surface, this relatively low prevalence is not alarming, the extensive use profile of these analgesic, anti-inflammatory, and antipyretic agents implies that an enormous number of patients are at risk for consequential kidney dysfunction. The combination of AIN with moderate or heavy proteinuria and nearly normal glomeruli showing extensive epithelial foot process spreading—minimal change glomerulopathy—is seen in fewer than

0.2 per 1000 subjects who take NSAIDs other than aspirin. The 299 onset of proteinuria combined with interstitial nephritis may manifest after several days or months of NSAID exposure (range, 2 weeks to 18 months) and is commonly observed with fenprofen therapy. CH 14

AIN is associated with primary renal infections such as acute bacterial pyelonephritis, renal tuberculosis, and fungal nephritis. Systemic infections can cause direct injury because of pathologic processes in the kidney or can be associated with indirect injury caused by medications used in the treatment of infections. For example, human immunodeficiency virus (HIV) can be responsible for AIN caused by opportunistic infections or by using drugs such as indinavir, sulfonamide antibiotics, and others. Sometimes, depressed cell-mediated immunity may protect the patients from developing AIN.

Idiopathic Acute Interstitial Nephritis Immunologic diseases such as Behc ¸et disease, Sjo¨gren syndrome, sarcoidosis, systemic lupus erythematosus, or the vasculitides may cause severe renal interstitial involvement. However, acute kidney injury due to idiopathic AIN is quite uncommon. Anti–tubular basement membrane (TBM) nephritis is occasionally manifested in association with membranous nephropathy. The clinical characteristics of this combination include a predominance of males, onset in early childhood, microscopic hematuria, and nephrotic-range proteinuria. Affected patients show tubular dysfunction, circulating anti-TBM antibodies, and progression to end-stage renal disease (ESRD). Circulating anti-TBM antibodies from these patients react exclusively with the proximal TBM, not with GBM. Idiopathic tubulointerstitial nephritis (TIN) associated with bilateral uveitis, termed TINU syndrome, describes a syndrome characterized by anterior uveitis, bone marrow granulomas, hypergammaglobulinemia, increased erythrocyte sedimentation rate, and acute kidney injury with renal histologic features of AIN due to numerous interstitial inflammatory cells, consisting mainly of eosinophils. TINU syndrome among adults occurs predominantly in females (3:1). The anterior uveitis may precede, concur with, or follow the nephropathy. These patients generally suffer from weight loss and anemia and have a raised erythrocyte sedimentation rate. Prolonged steroid therapy usually leads to improvement in both renal function and uveitis, although the latter may relapse.

Tubulointerstitial Diseases

Infections

300 Pathology


The hallmark of AIN is the infiltration of inflammatory cells within the renal interstitium, with associated edema, usually IV sparing the glomeruli and blood vessels. In acute allergic interstitial nephritis, the predominant pathology is interstitial, is cortical rather than medullary, and comprises edema and inflammatory infiltrate. The most numerous cells are lymphocytes. However, eosinophils are often present. The inflammatory reaction may be concentrated around, or even be seen to be invading, tubular epithelium (so-called tubulitis). Granulomas may occur in the interstitium, but vasculitis is uncommon. Immunofluorescence microscopy may show, with diminishing frequency, no complement or immunoglobulin; immune complexes sometimes with complement along the TBM; or linear IgG and complement on the TBM. In AIN with minimal change glomerulopathy induced by NSAIDs, the interstitial inflammatory exudate resembles that of acute allergic interstitial nephritis except that eosinophils are uncommon.

Clinical Features AIN should be considered in any patient with a rising serum creatinine but little or no evidence of glomerular or arterial disease, no prerenal factors, and no dilatation of the urinary collecting system on ultrasonography. The typical presentation of AIN is that of acute kidney injury, most commonly in an asymptomatic patient who has experienced an intervening illness, or who was commenced on a new medication. Occasionally, the nephritis is severe enough to require renal replacement therapy. The classic signs of drug-associated AIN include the following: • Fever (75%) • Skin rash (50%) • Eosinophilia (80%) The entire triad, however, is observed in fewer than one third of patients. IgE levels are occasionally increased. Other symptoms include lumbar pain due to distention of the renal capsule from diffuse swelling of the kidney. The onset of drug-induced nephritis ranges from days to weeks following initiation of therapy. The onset of renal failure can be precipitous (days), especially in those patients re-exposed to a nephropathic agent; conversely, it can be protracted, with a steadily declining glomerular filtration rate over months. A previous allergic history is only rarely obtained. Dipstick evaluation typically reveals mild to moderate proteinuria and hematuria in the majority of cases. Gross hematuria is uncommon. The sediment typically shows red and white blood


cells. The diagnostic value of urine eosinophils remains unclear. 301 The positive and negative predictive values for urinary eosinophiluria have been reported as 38% and 74%, respectively. The magnitude of proteinuria in acute tubulointerstitial disease is usually modest and nearly always less than CH 14 3 g/24 hours. Nephrotic-range proteinuria is not usually seen in acute interstitial nephritis unless there is a coexisting glomerular lesion after exposure to NSAIDs. The fractional excretion of Naþ is usually greater than 1. Affected patients are often oliguric, but nonoliguric renal failure also occurs. Oliguria may be related to interstitial inflammation severe enough to cause tubular obstruction and impede urine flow. The kidney in AIN is usually normal or slightly increased in size by ultrasonographic criteria. Many features of the patient’s history, presentation, urinalysis, and laboratory evaluation may suggest the diagnosis of AIN. Unfortunately, none of these findings are pathognomonic, and ultimately the diagnosis can be established with certainty only by renal biopsy. Renal biopsy is the “gold standard” for diagnosis of AIN; it is not, however, required in those patients for whom a probable precipitating drug can be easily withdrawn, or who improve readily after withdrawal of a potentially offending drug. Supportive management can proceed safely without renal biopsy. Patients who do not improve after withdrawal of likely precipitating medications, who have no contraindications to renal biopsy and do not refuse the procedure, and who are being considered for steroid therapy are good candidates for renal biopsy.

Course and Treatment Most patients with AIN, in whom offending medications are withdrawn early, can be expected to recover normal or nearnormal renal function within a few weeks. Patients who discontinue offending medications within 2 weeks of the onset of AIN (measured by increased serum creatinine) are more likely to recover nearly baseline renal function. However, as many as a quarter of patients are left with residual CKD and 10% to 15% with ESRD. Withdrawal of medications that are likely to cause AIN is the most significant step in early management of suspected or biopsy-proven AIN. If multiple potentially precipitating medications are being used by the patient, it is reasonable to substitute other medications for as many of these as possible and to withdraw the most likely etiologic agent among medications that cannot be substituted. The majority of patients with AIN improve spontaneously after the withdrawal of medications that resulted in renal failure. The role of steroids in

302 the treatment in AIN remains to be defined. Small case


reports and studies have demonstrated rapid diuresis, clinical improvement, and return of normal renal function within 72 hours after starting steroid treatment. The decision to use IV steroids should be guided by the clinical course following withdrawal of offending medications. Steroid therapy is indicated in the TINU syndrome. Both the ocular and the renal changes of these patients respond dramatically to a brief course of steroid therapy. The merits of immunosuppressive agents, specifically cyclophosphamide or cyclosporine, are questionable. They should be considered in those cases in which the biopsy reveals immune complex deposits and in those with evidence of circulating anti-TBM antibodies or complement consumption. Considerations should be also given to patients who fail to respond to a 2-week course of steroid therapy.

CHRONIC INTERSTITIAL NEPHRITIS Patients with chronic interstitial disease present either because of systemic symptoms of a primary disease or because of nonspecific symptoms of renal failure. Typical laboratory findings include modest proteinuria, microscopic hematuria and pyuria, glycosuria, and positive urine cultures in up to 30% of patients. Acidifying and concentrating defects are common. Some causes of chronic interstitial disease display characteristic patterns of tubular dysfunction (proximal or distal renal tubular acidosis) or marked early concentrating defects (primary medullary dysfunction). Anemia occurs relatively early in the course of certain forms of chronic interstitial disease, presumably because of early destruction of erythropoietin-producing interstitial cells. Table 14-2 lists the more common causes of chronic interstitial nephritis.

Analgesic Nephropathy Analgesic nephropathy (AN) is a specific form of renal disease characterized by renal papillary necrosis (RPN) and chronic interstitial nephritis caused by prolonged and excessive consumption of analgesic mixtures. It is caused by compound analgesic mixtures containing aspirin or antipyrine in combination with phenacetin, paracetamol, or salicylamide and caffeine or codeine in popular over-the-counter proprietary mixtures. AN has been one of the more common causes of chronic kidney disease (CKD), particularly in Australia and parts of

Table 14-2

Common Causes of Chronic Interstitial Nephritis Infection Bacterial pyelonephritis Hantavirus Leptospirosis Malacoplakia Xanthogranulomatous pyelonephritis Hematologic Disorders Sickle cell disease Light chain nephropathy Amyloidosis Secondary Secondary chronic tubulointerstitial nephritis encompasses disease in which the primary pathogenic process begins in vascular, glomerular, or tubular systems, and is followed by damage to the tubulointerstitial compartment

Europe. AN was responsible for 13% to 20% of cases of CKD in Australia, Belgium, and Switzerland.

Clinical Features The renal manifestations of AN include slowly progressive CKD, sterile pyuria, and mild proteinuria (10–15 yr

6 mo to 2 yr

>20 yr

>6 mo

Kidney imaging

Shrunken

Shrunken

Shrunken

Slightly shrunken

Irregular contours

Irregular contours

Smooth surface

Smooth

Papillary calcifications

No calcification

No calcification

No calcification

Histology Cellular infiltration

þþ

þ

þ

þþþ

Fibrosis

þþ

þþ

þþ

þþ

þþ

þþ

þþþ

þ

Capillarosclerosis

þ

þ/?

þ

/?

Apoptosis

?

?

þ

?

Urothelial malignancies

þ*

þ

þ

þ

Familial occurrence

þ

Etiology

Analgesics

Aristolochic acid

?Aristolochia clematis

5-Aminosalicylic acid

þAddictive substances

þDiuretics þVasoconstrictive substances

Atrophy

*As long as phenacetin was part of the analgesic mixture.

þ/?

305

306 only after several years of analgesic abuse, interstitial nephri-


tis associated with 5-ASA was already observed during the first year of treatment in 7 out of 17 reported cases, most of whom had started 5-ASA therapy with documented normal IV renal function. The cumulative dose of 5-ASA is not predictive for development of interstitial nephritis.

Diagnosis and Treatment Because this type of chronic TIN produces few, if any, symptoms and, if diagnosed at a late stage, progresses to irreversible chronic ESRD, serum creatinine levels should be measured in any patient with IBD treated with 5-ASA at the start of the treatment, every 3 months for the remainder of the first year, and annually thereafter. If serum creatinine increases in a patient with IBD treated with 5-ASA, a renal biopsy is the only way to determine a correct diagnosis.

Chinese Herbs—Aristolochic Nephropathy Aristolochic nephropathy was first described in Belgian women presenting with CKD following their exposure to a slimming regimen containing Chinese herbs. A plant nephrotoxin, aristolochic acid (AA), has been proposed as a possible etiologic agent. Histologic examinations of the kidneys and genitourinary tract revealed renal tubular atrophy, interstitial infiltration/fibrosis, and atypical and malignant uroepithelial cells.

Clinical Features Patients present with renal insufficiency and other features indicating a tubulointerstitial disease. The blood pressure is either normal or only mildly elevated, and the urine sediment reveals only a few red and white blood cells. The urine contains subnephrotic proteinuria and evidence of proximal tubular dysfunction. Stable renal function may be anticipated in most patients with an initial plasma creatinine concentration below 2 mg/dL. However, progressive renal failure resulting in dialysis or transplantation may ensue in patients with more severe disease.

Diagnosis and Treatment No specific criteria exist for the diagnosis of this type of renal disease. The diagnosis should be suggested in any patient with unexplained relatively fast progressive renal disease who is using/abusing herbal remedies. The presence of tubular proteinuria may be a clue to the diagnosis, particularly in the early stages. The histologic appearances are not specific. On CT scan, bilateral shrunken kidneys with irregular contours and no parenchymal calcification can be observed.

Lithium

307

Pathogenesis and Pathology Lithium is eliminated from the body almost entirely by the kidney. It accumulates in the kidney, particularly in the collecting tubule, entering these cells through sodium channels in the luminal membrane. Hence, its principal toxicity relates to distal tubular function, in which inhibition of adenylate cyclase and generation of cyclic adenosine monophosphate (cAMP) results in down-regulation of aquaporin-2, the collecting tubule water channel, and a decrease in antidiuretic hormone receptor density, leading to resistance to antidiuretic hormone. It has been difficult to determine the nature of lithiuminduced chronic renal damage; epidemiologic studies have given conflicting results regarding the risk of CKD with lithium use. Long-term lithium therapy does not influence glomerular function in the majority of patients. However, up to 20% of long-term lithium patients may exhibit slowly progressive CKD. It appears that the duration of lithium therapy and the cumulative dose of lithium are the major determinants of nephrotoxicity. The prevalence of lithium-related ESRD has been estimated as 2 of every 1000 dialysis patients (0.22% of all cases).

Diagnosis and Treatment Polyuria and polydipsia due to nephrogenic diabetes insipidus usually disappear rapidly if lithium is withdrawn. In most cases, the lithium is so clearly beneficial that the polyuria is accepted as a side effect and treatment continued. It is likely that the serum concentration of lithium is important and that renal damage is more likely to occur if the serum concentration is consistently high or if symptoms of lithium toxicity recur. The serum lithium concentration should, therefore, be monitored carefully (at least every 3 months) and maintained at the lowest level that will provide adequate control of the manic-depressive psychosis. Much more difficult is the situation in which a patient on long-term lithium therapy is found to have impaired renal function, for which there is no obvious alternative cause. As stated previously, renal failure may progress even if lithium therapy is withdrawn, and in some patients, the discontinuation of lithium can lead to a devastating deterioration in their psychiatric condition.


Lithium is used extensively in the treatment of bipolar psychosis. Different forms of renal effects/injury have been described: most frequently, nephrogenic diabetes insipidus, CH 14 but also renal tubular acidosis, chronic interstitial nephritis, nephrotic syndrome, and focal segmental glomerular sclerosis/ global glomerular sclerosis.

308 Lead


Lead toxicity affects many organs, resulting in encephalopathy, anemia, peripheral neuropathy, gout, and renal failure. IV Although low-level lead exposure in the general population is associated with mild but significant depression of renal function, its role in the development of ESRD is still a matter of debate. However, recent evidence suggests that low-level environmental lead exposure is associated with accelerated deterioration of renal function.

Etiology and Pathogenesis The pathogenesis of the renal disease seen in the context of lead exposure may be related to proximal tubule reabsorption of filtered lead, with subsequent accumulation in proximal tubule cells. Aminoaciduria, glycosuria, and phosphaturia, representing the Fanconi syndrome, are observed after lead exposure and are believed to be related to an effect of lead on mitochondrial respiration and phosphorylation. Because lead is also capable of reducing 1,25-dihydroxyvitamin D synthesis, prolonged hyperphosphaturia and hypophosphatemia caused by lead poisoning in children may result in bone demineralization and rickets. Chronic lead poisoning can affect glomerular function: after an initial period of hyperfiltration, the GFR is reduced and nephrosclerosis and CKD may ensue.

Clinical Features Renal failure becomes apparent years after the exposure and is associated with gout in most, if not all, cases. Hypertension is a very common feature of lead nephropathy. Although hyperuricemia is common in renal failure, gout is unusual and its presence should raise the possiblity of lead nephropathy.

Diagnosis and Treatment As the blood lead level only reflects recent lead exposure and is usually normal in patients with CKD due to their previously sustained low level of lead exposure, the diagnosis has to be based on measurement of the body lead burden as assessed by an EDTA mobilization test. The diagnosis of lead nephropathy should be considered in any patient with progressive renal failure, mild-to-moderate proteinuria, significant hypertension, history of gout, and an appropriate history of exposure. EDTA chelation therapy may slow the progression of renal insufficiency in patients with an elevated body lead burden.

Cadmium

309


Exposure to cadmium after inhalation or ingestion can give rise to nephrotoxicity in humans. High levels of cadmium exposure triggers tubular proteinuria, renal glucosuria, amino- CH 14 aciduria, hypercalciuria, phosphaturia, polyuria, and, in severe cases, progressive CKD. The extent to which chronic low-level environmental exposure to cadmium affects renal function is less clear. A number of studies have demonstrated an increased prevalence of kidney stones among individuals occupationally exposed to cadmium. Minimizing exposure to cadmium is the most important therapeutic measure. Occupational exposure should be kept as low as technically feasible. Other than general supportive therapy, no specific methods are available for treating acute cadmium poisoning. Although various chelating agents have been tried in animals, none has been shown to be efficient in humans.

Balkan Endemic Nephropathy Balkan endemic nephropathy (BEN) is a chronic, familial, noninflammatory tubulointerstitial disease of the kidneys associated with high frequency of urothelial atypia. BEN is most commonly seen in southeastern Europe among those living along the confluence of the Danube River. There is a very high prevalence in endemic areas, with ranges as high as 20% if the disorder is suspected and carefully screened for in an at-risk population. A striking observation is that nearly all affected patients are farmers.

Pathogenesis and Pathology Although the etiology of BEN is unknown, many environmental and genetic factors have been evaluated as possible underlying causes. Given that it is endemic to a specific geographic area, toxins and environmental exposures that are unique to the Balkans have been investigated. One intriguing possibility is that the mutagenic and nephrotoxic alkaloid found in the plant Aristolochia clematis may underlie both Chinese herbal nephropathy and BEN. Striking pathologic and clinical similarities exist between the progressive interstitial fibrosis observed in young women who have been on a slimming regimen including Chinese herbs (as well as other agents) and BEN.

Clinical Features BEN is a slowly progressive tubulointerstitial disease that may culminate in ESRD. Clinical manifestations first appear in patients 30 to 50 years of age. Initially characterized by tubular dysfunction, a progressive decrease in concentrating

310 ability and in the GFR follows over many years. Patients are


usually nonedematous and normotensive, hypertension developing only with end-stage disease. Intrarenal calcifications are not observed. BEN is also associated with the development IV of transitional cell carcinoma of the renal pelvis or ureter, with studies noting a wide range in incidence (2% to nearly 50%). These tumors are generally superficial and slow growing.

Diagnosis and Treatment The diagnosis of BEN is based upon the presence of some combination of the following findings: symmetrically shrunken kidneys with absence of intrarenal calcifications. As with many other chronic tubulointerstitial diseases of unclear origin, there is no specific prevention or treatment. Therapy is, therefore, largely supportive, with renal replacement therapy being initiated in patients with ESRD.

Chronic Urate Nephropathy The principal lesion of chronic urate nephropathy is the deposition of microtophi in the interstitium. This results in a secondary chronic inflammatory response, potentially leading to interstitial fibrosis and CKD. Evidence linking CKD to gout is weak, however, and the long-standing notion that chronic renal disease is common in patients with hyperuricemia has been questioned in the light of prolonged follow-up studies of renal function in people with this condition. Furthermore, the deterioration of renal function in those with hyperuricemia of a lower magnitude has been attributed to the higher-than-expected occurrence of hypertension, diabetes mellitus, abnormal lipid metabolism, and nephrosclerosis. Nonetheless, it seems reasonable to prescribe allopurinol (in a dose appropriate to the level of renal function) to those very rare patients with biopsy evidence of “gouty nephropathy,” and, possibly, to patients with CKD who have a grossly elevated serum urate.

Chronic Hypokalemia Persistent hypokalemia can induce a variety of changes in renal function, impairing tubular transport, and possibly inducing chronic tubulointerstitial disease and cyst formation. Hypokalemic nephropathy in humans produces characteristic vacuolar lesions in the epithelial cells of the proximal tubule and, occasionally, the distal tubule. More severe changes, including interstitial fibrosis, tubular atrophy, and cyst formation that is most prominent in the renal medulla, occur if prolonged

hypokalemia is maintained. Renal cyst formation as a conse- 311 quence of chronic hypokalemia has now been reported in a patient with Bartter syndrome resulting from a gene defect in CLC-KC. CH 14

Clinically important renal involvement in sarcoid is an occasional problem—hypercalciuria and hypercalcemia are most often responsible, although granulomatous interstitial disease, glomerular disease, obstructive uropathy, and, rarely, ESRD may also occur. Most affected patients have clear evidence of diffuse active sarcoidosis, although some patients present with only minimal extrarenal manifestations.

Clinical Features Hypercalciuria, hypercalcemia, nephrolithiasis, granulomatous interstitial nephritis, glomerular disease, and urinary tract disorders can all be observed in patients with sarcoidosis. Macrophages in a sarcoid granuloma contain a 1a-hydroxylase enzyme, capable of converting vitamin D to its active form. The resultant increase in the absorption of calcium from the gut leads to hypercalciuria and, in roughly 2.5% to 20% of cases, to hypercalcemia. Most patients remain asymptomatic, but nephrolithiasis, nephrocalcinosis, renal insufficiency, and polyuria are important complications. Nephrocalcinosis, observed in over half of those with renal insufficiency, is the most common cause of CKD in sarcoidosis. An interstitial nephritis with granuloma formation is common in sarcoidosis, but the development of clinical disease manifested by renal insufficiency is unusual. Renal biopsy reveals normal glomeruli, interstitial infiltration mostly with mononuclear cells, noncaseating granulomas in the interstitium, tubular atrophy, and, with more chronic disease, interstitial fibrosis. Glomerular involvement is rare in sarcoidosis. Occasionally, retroperitoneal lymph node involvement, retroperitoneal fibrosis, or renal stones may produce ureteral obstruction.

Diagnosis and Treatment Sarcoid nephropathy should be considered in any patient with unexplained renal failure and hypercalcemia, renal tubular defect, nephrocalcinosis, or increased immunoglobulins. The presence of granulomas on renal biopsy, although not specific to sarcoidosis, should strongly suggest this diagnosis in an appropriate setting. Granulomatous interstitial nephritis can be treated effectively with glucocorticoids, typically prednisolone 1 to 1.5 mg/kg initially, with dose tapering in response to the signs and symptoms of disease activity. The


Sarcoidosis

312 hypercalcemic/hypercalciuric


syndrome also responds quickly to corticosteroids: In general, the dose needed to treat this complication is significantly lower than that required to treat granulomatous interstitial nephritis and can be as low IV as 35 mg of prednisolone daily. Although uncommon in patients with sarcoidosis, ESRD requiring renal replacement therapy is most often due to hypercalcemic nephropathy rather than granulomatous nephritis. Graft loss due to disease recurrence has been reported exceptionally.

Chapter 15

Urinary Tract Infection, Pyelonephritis, and Reflux Nephropathy BACTERIOLOGY OF URINARY TRACT INFECTION General Considerations: The Urine Culture and Urinalysis There is an incomplete correlation between the clinical symptoms of urinary tract inflammation and the presence of true urinary tract infection (UTI), so objective evidence of the presence and the type of infection is of great importance. Urine cultures with at least 105 CFU/mL (often termed “significant bacteriuria”) have a high probability of true infection; those with lesser numbers of colony-forming units (CFUs) (“insignificant bacteriuria”) probably reflect contamination. However, women who present with symptoms of acute, uncomplicated UTI are thought to have true infection when at least 103 CFU/mL of a single species of uropathogen are found on quantitative culture. In patients with symptoms of acute pyelonephritis (fever, rigors, flank pain, with or without dysuria or frequency), the cutoff is at least 104 CFU/mL. Circumstances associated with lower densities of bacteria in the urine when the patient has true infection include acute urethral syndrome, infection with Staphylococcus saprophyticus and Candida species, prior administration of antimicrobial therapy, rapid diuresis, extreme acidification of the urine, obstruction of the urinary tract, and extraluminal infection. Polymicrobial UTI is uncommon and is observed in only a few clinical situations, including long-term urinary catheterization, inadequate emptying of the bladder, particularly when repeated instrumentation is necessary, and when there is a fistulous communication between the urinary tract and the gastrointestinal or female genital tract. Other than these clinical scenarios, the isolation of two or more bacterial species on urine culture usually signifies a contaminated specimen. Examination of the urine for leukocytes is another validation test that can be applied in the evaluation of patients with possible UTI. When a randomly collected urine sample is examined in a hemocytometer and at least 10 leukocytes

313

314 per cubic millimeter are found, there is a high probability of


clinical infection. Most symptomatic women with pyuria without significant bacteriuria have urinary infection with either bacterial uropathogens present in colony counts of less 5 IV than 10 CFU/mL (which will respond to appropriate antimicrobial therapy) or with some other condition. Possibilities include Chlamydia trachomatis infection, interstitial cystitis, genitourinary tuberculosis, and contiguous infection resting on the ureter or bladder and inducing “sympathetic inflammation” in the urine. In patients with indwelling urinary catheters the finding of pyuria does not necessarily indicate infection.

Etiologic Agents Bacterial Pathogens • Enterobacteriaceae (including Escherichia coli) and Enterococcus faecalis account for over 95% of UTIs. • Previous antimicrobial therapy, instrumentation, and urinary obstruction favor other organisms including Serratia marcescens and Pseudomonas aeruginosa. • Staphylococcus saprophyticus is an important cause of symptomatic UTI in young, sexually active women. • In contrast, the organisms that commonly colonize the distal urethra and skin of both men and women, and the vagina of women, rarely cause UTI (Staphylococcus epidermidis, corynebacteria, lactobacilli, Gardnerella vaginalis). • Hematogenous seeding ( 1%, and osmolality < 350 mOsm). Alternatively, in acute obstruction, urinary chemistry values may be consistent with prerenal azotemia (urinary Naþ < 20 mEq/L, FENa < 1%, and osmolality > 500 mOsm).

Radiologic Evaluation

339

Plain Film Imaging of the Abdomen If a renal calculus is suspected, a plain film of the abdomen (kidney, ureter, and bladder) can provide information on the size and overall contour of the kidneys and may detect a calculus along the course of the ureter or in the bladder, as 90% of calculi are radiopaque.

Ultrasonography When obstruction is suspected, ultrasonography is the preferred screening modality because it is safe, cost effective, and lacks ionizing radiation, making it ideal for pregnant patients. Moreover, because no contrast agent is involved, it is well suited to patients with an elevated or rising serum creatinine level. Utrasonography can determine the size and shape of the kidney, show dilation of the pelvis and calyces, and may demonstrate thinned cortex in the case of severe long-standing hydronephrosis. It has both high sensitivity and specificity for detecting hydronephrosis. However, it may fail to detect obstruction in the first 48 hours when hydronephrosis has not, as yet, developed. False-positive conclusions may be the result of a large extrarenal pelvis, parapelvic cysts, vesicoureteral reflux, or high urine flow rate.

Antenatal Ultrasonography Prenatal hydronephrosis is diagnosed with an incidence of 1 in 100 to 1 in 500 maternal-fetal ultrasonographic studies. Both obstructive and nonobstructive processes can cause dilation of the urinary tract (see earlier discussion). The long-term morbidity of mild hydronephrosis (pelviectasis without calyceal dilation) is low. Cases of severe hydronephrosis (pelvicalyceal dilation with parenchymal thinning) may require postnatal surgical intervention for declining renal function, infection, or symptoms. Overall, approximately 5% to 25% of patients with antenatal hydronephrosis will ultimately require surgical intervention. Therefore, long-term follow-up of these patients is required. Functional imaging is required for patients with persistent postnatal hydronephrosis. All infants with prenatally detected hydronephrosis, confirmed by postnatal studies, should be placed on antibiotic prophylaxis pending the outcome of further evaluation. An infection in

Urinary Tract Obstruction

A variety of radiologic techniques are used in the evaluation of obstructive uropathy. The risk of using radiocontrast material in the setting of renal insufficiency, as well as that of CH 16 exposure to radiation in pregnant women, must always be taken into consideration.

340 the setting of ureteral obstruction can cause significant mor-

bidity in the uroseptic infant, and renal damage is a potential comorbidity. Oral amoxicillin (10 mg/kg/day) is the most commonly used prophylactic antibiotic.


IV

Intravenous Urography Intravenous urography (IVU; also known as intravenous pyelography, or IVP) provides both functional and anatomic data, particularly of the ureter. Until recently, it was considered to be the gold standard for imaging in acute renal colic. However, the procedure has significant drawbacks including contrast nephrotoxicity and the fact that it is contraindicated in pregnancy. Furthermore, kidneys may not be visualized in cases of severe obstruction as the suppressed glomerular filtration rate (GFR) may not allow excretion of the contrast material. All these concerns have led to replacement of IVU with computed tomography (CT), ultrasound (US), and magnetic resonance imaging (MRI) in many cases.

Computed Tomography CT has the distinct advantage of being able to visualize a dilated collecting system, even without contrast enhancement, and can also be performed more quickly than IVU. Non–contrastenhanced CT is more effective than IVU in precisely identifying ureteral stones; it is as effective as IVU in determining the presence or absence of ureteral obstruction and can identify even radiolucent stones. CT is useful in identifying extrinsic causes of obstruction (e.g., retroperitoneal fibrosis, lymphadenopathy, hematoma). CT can also detect extraurinary pathology and can establish nonurogenital causes of pain. All of these advantages establish non– contrast-enhanced helical CT as the diagnostic study of choice for the evaluation of the patient with acute flank pain.

Isotopic Renography Isotopic renography, or renal scintigraphy, can diagnose upper urinary tract obstruction while avoiding the risk of radiocontrast agents. Although it provides a functional assessment of the obstructed kidney, anatomic definition is poor. Isotopic renography is typically used to estimate the fractional contribution of each kidney to overall renal function, and repeat studies can gauge the extent to which relief of the obstruction has restored renal function.

Magnetic Resonance Imaging MRI can be used to explore the urinary tract when obstruction is suspected. Because MRI does not use ionizing radiation, it is especially useful in children and pregnant woman. It was previously considered to be safe in patients

Retrograde and Antegrade Pyelography When standard radiographic methods fail to yield a diagnosis, or when obstruction must be promptly relieved (bilateral obstruction, obstruction of a solitary kidney, symptomatic infection in the obstructed system), more invasive investigation, with a combination of treatments, may be necessary. Retrograde pyelography is performed by cystoscopically guided cannulation of the ureteral orifice and contrast injection. The procedure can be combined with placement of a ureteral stent to relieve an obstruction, or with possible stone extraction. Antegrade pyelography is performed by percutaneous cannulation of the kidney, and injection of the contrast material into the kidney and ureter. This procedure should establish the proximal level of obstruction, and may also serve as a first step in relieving obstruction by means of percutaneous nephrostomy.

TREATMENT OF URINARY TRACT OBSTRUCTION AND RECOVERY OF RENAL FUNCTION Once the presence of obstruction is established, intervention is usually indicated to relieve it. The type of intervention depends on the location of the obstruction, its degree and etiology, as well as the presence or absence of concomitant diseases and complications and the general condition of the patient. The first step usually involves prompt relief of the obstruction, followed by the definitive treatment. Infravesical obstruction (e.g., benign prostatic hyperplasia or urethral stricture) can be relieved easily with placement of a urethral catheter. If the urethra is impassable, suprapubic cystostomy may be necessary. Alternatively, insertion of a nephrostomy tube or ureteral stent may be indicated when supravesical urinary obstruction is present. The urgency of the intervention depends on the degree of renal impairment, the presence or absence of infection, and the overall risk of the procedure. The presence of infection in an obstructed urinary tract, or urosepsis, is a urologic emergency, which requires prompt relief of the obstruction and antibiotic therapy.


with renal insufficiency and renal allografts, as it avoided the 341 risk of contrast nephropathy. However, recent recognition of the link between the use of certain gadolinium agents, most notably gadodiamide, and the development of nephrogenic systemic fibrosis in patients with severe renal insufficiency, CH 16 means that it must be used with caution in the presence of renal dysfunction, and avoided in those with an estimated GFR less than 30 mL/min/1.73m2 (see Chapter 3, Diagnostic Kidney Imaging and Interventional Nephrology, for a more detailed discussion). MRI provides no substantial diagnostic advantages in comparison to combined US and CT.

342 Acute kidney injury, associated with bilateral ureteral obstruc-


tion or with the obstruction of a single functioning kidney, also calls for emergent intervention. Calculi, the most common form of acute unilateral urinary IV obstruction, can usually be managed conservatively with analgesics to control pain, and intravenous fluids to increase urine flow. Ninety percent of stones smaller than 5 mm pass spontaneously, but as stones get larger, it becomes progressively less likely that they will. Surgery or instrumentation is indicated for persistent obstruction, uncontrollable pain, or urinary tract infection. Current treatment options include cystoscopic placement of ureteral stents, nephrostomy with urine drainage, extracorporeal shock wave lithotripsy (which may require ureteral stent placement if the patient is symptomatic), and ureteroscopy with stone fragmentation (usually with laser lithotripsy). Large renal stones can be fragmented through nephrostomy. These newer approaches have all but eliminated the need for open surgical procedures. Intramural or extrinsic ureteral obstruction may be relieved by placement of a ureteral stent through the cystoscope. If this cannot be accomplished, or is ineffective (especially in cases of extrinsic ureteral compression by the tumors), then nephrostomy tubes will need to be inserted to effect prompt relief of the obstruction. For infravesical obstruction due to benign prostatic hyperplasia, surgery can be safely delayed or completely avoided in patients with minimal symptoms, lack of infection, and an anatomically normal upper urinary tract. If needed, transurethral resection of the prostate, laser ablation, or other techniques can be used for definitive treatment. Internal urethrotomy with direct visualization may be effective in the treatment of urethral strictures, as dilation usually has only temporary effect. Suprapubic cystostomy may be necessary in patients with impassable urethral strictures, followed by open urethroplasty to restore urinary tract continuity, when possible. Patients with neurogenic bladder require a variety of approaches, including frequent voiding, often by external compression, medications to stimulate bladder activity or relax the urethral sphincter, and intermittent catheterization using meticulous technique to avoid infection. Long-term indwelling bladder catheters should be avoided because they increase the risk of infection and renal damage. If more conservative measures such as frequent voiding or intermittent catheterization are not effective, ileovesicostomy or other form of urinary diversion should be considered. In many forms of obstruction, initial stabilization of the patient’s condition is followed by a decision as to whether continued observation remains appropriate, or definitive surgery or nephrectomy is required. The actual course chosen depends on the likelihood that renal function will improve with the relief

Estimating Renal Damage and Potential for Recovery As noted earlier, when deciding whether to bypass or reconstruct drainage of an obstructed kidney rather than excise it, the potential for meaningful recovery of function in the affected kidney represents a critical issue. Isotopic renography with a variety of isotopes can be used to examine renal function, as outlined earlier. This approach is a far more reliable indicator of potential renal function when applied well after temporary drainage of the obstructed kidney (e.g., by nephrostomy tubes) has been achieved rather than performed while the obstruction is still present. Of course, anatomic studies will reveal the remaining size and volume of the kidney, and can provide some idea of the extent to which the tissue remains viable. All of these considerations contribute to the final clinical judgment as to whether attempts should be made to salvage the kidney.

Recovery of Renal Function after Prolonged Obstruction The potential for recovery of renal function depends primarily on the extent and duration of the obstruction, but other factors, such as the presence of other illnesses and the presence or absence of urinary tract infection, play an important role as well. Recovery of renal function in humans has been documented following release of obstruction of over 60 days’ duration. Because it is difficult to predict whether renal function will recover when temporary relief of obstruction has been achieved, it makes sense to measure function repeatedly with isotopic renography over time, before deciding on a definitive surgical course. Chronic bilateral obstruction, as seen in benign prostatic hyperplasia, can cause chronic kidney disease, especially when the obstruction is of prolonged duration and when it is accompanied by urinary tract infections. Progressive loss of renal function can be slowed or halted by relieving the obstruction and treating the infection. When obstruction has been relieved and there is poor return of renal function, interstitial fibrosis and inflammation may have supervened.


of obstruction. The decision to operate and the choice of surgical 343 procedure are influenced by several factors including the age and general condition of the patient, the appearance and function of the obstructed kidney and the contralateral one, the cause of the obstruction, and the presence of infection. The extent CH 16 of recovery of renal function depends on the extent and duration of the obstruction.

344

POSTOBSTRUCTIVE DIURESIS


Release of obstruction can lead to marked natriuresis and diuresis with the wasting of potassium, phosphate, and divalent IV cations. It is notable that clinically significant postobstructive diuresis usually occurs only in the setting of prior bilateral obstruction, or unilateral obstruction of a solitary functioning kidney. The mechanisms involved include a combination of intrinsic damage to tubular salt, solute, and water reabsorption, as well as the effects of volume expansion, solute (e.g., urea) accumulation, and attendant increases in natriuretic substances, such as atrial natriuretic peptide. Management of the patient with postobstructive diuresis focuses on avoiding severe volume depletion due to salt wasting, and other electrolyte imbalances, such as hypokalemia, hyponatremia, hypernatremia, and hypomagnesemia. Postobstructive diuresis is typically self-limited. It usually lasts for several days to a week, but may, in rare cases, persist for months. Volume or free water replacement is appropriate only when the salt and water losses result in volume depletion or a disturbance of osmolality. In many cases, excessive volume or fluid replacement prolongs the diuresis and natriuresis. Because the initial urine is isosthenuric, with an initial Naþ of approximately 80 mEq/L, an appropriate starting fluid for replacement may be 0.45% saline, given at a rate somewhat slower than that of the urine output. During this period, meticulous monitoring of vital signs, volume status, urine output, and serum and urine chemistry and osmolality is imperative. This data will determine the need for ongoing replacement of salt, free water, and other electrolytes. With massive diuresis, these measurements will need to be repeated frequently, up to four times daily, with frequent adjustment of replacement fluids as needed.

Chapter 17

Diabetic Nephropathy Persistent albuminuria (>300 mg/24 hours) is the hallmark of diabetic nephropathy, which can be diagnosed clinically if the following additional criteria are fulfilled: the presence of diabetic retinopathy and the absence of clinical or laboratory evidence of other kidney or renal tract disease. This clinical definition of diabetic nephropathy is valid in both type 1 and type 2 diabetes. During the last decade longitudinal studies have shown that microalbuminuria strongly predicts the development of diabetic nephropathy in both type 1 and type 2 diabetes. Microalbuminuria is defined as urinary albumin excretion greater than 30 mg/24 hours (20 µg/min) and less than or equal to 300 mg/24 hours (200 µg/min), irrespective of how the urine is collected. Diabetic nephropathy is the single most common cause of end-stage renal disease (ESRD) in Europe and the United States, accounting for 25% to 45% of patients enrolled in ESRD programs. Nephropathy is a major cause of illness and death in diabetes and is associated with strikingly high rates of cardiovascular disease (CVD), particularly in type 2 diabetic patients.

EPIDEMIOLOGY OF MICROALBUMINURIA AND DIABETIC NEPHROPATHY Prevalence and Incidence The overall prevalence of micro- and macroalbuminuria is around 30% to 35% in both type 1 and 2 diabetes. The highest prevalence is found in Native Americans with type 2 diabetes, followed by black Americans, Mexican Americans, Asian Indians, and white Europeans. Diabetic nephropathy rarely develops before 10 years’ duration of type 1 diabetes, whereas approximately 3% of newly diagnosed type 2 diabetic patients have overt nephropathy. The incidence peak (3% per year) is usually found between 10 and 20 years of diabetes, after which a progressive decline in incidence takes place. Thus, the risk of developing diabetic nephropathy for a normoalbuminuric patient with a diabetes duration of greater than 30 years is very low.

345

346 Microalbuminuria Predicts Nephropathy


Several longitudinal studies have shown that microalbuminuria strongly predicts the development of diabetic nephropathy in IV type 1 diabetic patients (risk ratio > 20). The predictive value is somewhat lower in microalbuminuric type 2 diabetic patients (risk ratio, 8.5). In addition to microalbuminuria, several other risk factors or markers for development of diabetic nephropathy have been documented, including poor glycemic control, hypertension, male sex, familial clustering, smoking, age under 20 years at disease onset, and ethnicity.

Prognosis in Microalbuminuria Microalbuminuria is a strong predictor of total and cardiovascular fatality and cardiovascular morbidity in diabetic patients. The mechanisms linking microalbuminuria and death from CVD are poorly understood. Microalbuminuria has been proposed as a marker of widespread endothelial dysfunction, which might predispose to enhanced penetrations in the arterial wall of atherogenic lipoprotein particles and as a marker of established cardiovascular disease. It is associated with an excess of well-known and potential cardiovascular risk factors: raised blood pressure, dyslipoproteinemia, increased platelet aggregability, endothelial dysfunction, insulin resistance, and hyperinsulinemia have all been demonstrated in microalbuminuric diabetic patients. Recent echocardiographic studies have revealed impaired diastolic function and cardiac hypertrophy in microalbuminuric insulin-dependent (IDDM) and non–insulin-dependent diabetes mellitis (NIDDM) patients. Left ventricular hypertrophy predisposes the individual to ischemic heart disease, ventricular arrhythmia, sudden death, and heart failure.

Prognosis in Diabetic Nephropathy Type 1 diabetic patients without proteinuria have a low and constant relative mortality rate, whereas patients with proteinuria have a significantly higher relative mortality rate (>10fold). However, the prognostic importance of proteinuria in type 2 diabetic patients is considerably less than in type 1 diabetes (2- to 5-fold). The cumulative death rate 10 years after the onset of abnormally elevated urinary albumin excretion in European type 2 diabetic patients is approximately 70%, compared to 45% in normoalbuminuric patients. Indeed, much of the excessive cardiovascular mortality rate associated with type 2 diabetes is concentrated in patients with proteinuria.

CLINICAL COURSE AND PATHOPHYSIOLOGY

347

Normoalbuminuria Approximately one third of type 1 diabetic patients have a glomerular filtration rate (GFR) above the upper normal range of age-matched healthy nondiabetic subjects. The degree of hyperfiltration is less in type 2 diabetic patients. The GFR elevation is particularly pronounced in newly diagnosed diabetic patients and during other intervals with poor metabolic control. Intensified insulin treatment and near-normal blood glucose

Systemic blood pressure

Hyperlipidemia

Proteinuria

Dietary protein intake

Glycemic control

Smoking

Glomerular hypertension ACE/ID polymorphism Oligonephropathy Figure 17-1. Putative promoters for progression of diabetic nephropathy. ACE/ID, angiotensin-converting enzyme insertion/ deletion. (From Parving H-H, Mauer M, Ritz E: Diabetic nephropathy. In Brenner BM: Brenner & Rector’s The Kidney, 8th ed. Philadelphia, WB Saunders, 2008.)

Diabetic Nephropathy

A preclinical phase consisting of a normo- and a microalbuminuria stage and a clinical phase characterized by albuminuria are well documented in both type 1 and type 2 diabetic CH 17 patients. Figure 17-1 depicts the putative promoters for progression of diabetic nephropathy.

348 control reduce GFR toward normal levels after a period of days


to weeks in both type 1 and type 2 diabetic patients. Longitudinal studies suggest that hyperfiltration is a risk factor for subsequent increase in urinary albumin excretion IV and development of diabetic nephropathy in type 1 diabetic patients, but this has not been conclusively established. The prognostic significance of hyperfiltration in type 2 diabetic patients is unclear.

Microalbuminuria Subclinical albumin excretion rate has been termed microalbuminuria and can be normalized by improved glycemic control. In addition to hyperglycemia, many other factors can induce microalbuminuria in diabetic patients such as hypertension, massive obesity, heavy exercise, various acute or chronic illnesses, and cardiac failure. Furthermore, the day-to-day variation in the urinary albumin excretion ratio (AER) is high, 30% to 50%, and consequently more than one urine sample is needed to determine whether an individual patient has persistent microalbuminuria. Urinary albumin excretion within the microalbuminuric range (30–300 mg/24 hours) in at least two out of three consecutive nonketotic sterile urine samples is the generally accepted definition of persistent microalbuminuria. Persistent microalbuminuria is exceptional in the first 5 years of diabetes. The annual rate of rise of urinary albumin excretion is about 20% in both type 1 and type 2 diabetic patients with persistent microalbuminuria. The prevalence of arterial hypertension (140/90 mm Hg) in adult type 1 diabetic patients is 42%, 52%, and 79% in subjects with normo-, micro-, and macroalbuminuria, respectively. The prevalence of hypertension in type 2 diabetes is 71%, 90%, and 93% in the normo-, micro-, and macroalbuminuria groups, respectively.

Clinical Features and Natural History Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 hours), a relentless decline in GFR, and raised arterial blood pressure. Although albuminuria is the first sign, peripheral edema is the first symptom of diabetic nephropathy. Fluid retention is frequently observed early in the course of this kidney disease, that is, at a stage with well-preserved renal function and only slight reduction in serum albumin. The natural history of diabetic nephropathy is a relentless, often linear, but highly variable rate of decline in GFR ranging


from 2 to 20 mL/min/year, with a mean of 12 mL/min/year. 349 Type 2 diabetic patients suffering from nephropathy display the same degree of loss in GFR. Systemic hypertension accelerates the progression of diabetic nephropathy and a close correlation between blood pressure and the rate of decline in GFR has CH 17 been documented in type 1 and type 2 diabetic patients. Impaired or abolished renal autoregulation of renal plasma flow (RPF), as demonstrated in type 1 and type 2 diabetic patients with nephropathy, contributes to increased glomerular pressures in diabetic nephropathy: glomerular hypertension. Proteinuria itself may contribute to renal damage. Indeed, type 1 diabetic patients with diabetic nephropathy and nephroticrange proteinuria (>3 g/24 hours) have the worst prognosis. For many years it was believed that once albuminuria had become persistent, then glycemic control was unimportant because a “point of no return” had been reached. This is a misconception and studies dealing with large numbers of type 1 diabetic patients have documented the important impact of glycemic control on progression of diabetic nephropathy. In contrast, most of the studies dealing with proteinuric type 2 diabetic patients have failed to demonstrate any significant impact of glycemic control on disease progression.

Extrarenal Complications Diabetic retinopathy is present in virtually all type 1 diabetic patients with nephropathy, whereas only 50% to 60% of proteinuric NIDDM patients suffer from retinopathy. Absence of retinopathy should prompt further investigation for nondiabetic glomerulopathies (see later discussion). Blindness due to severe proliferative retinopathy or maculopathy is approximately five times greater in type 1 and type 2 diabetic patients with nephropathy compared to normoalbuminuric patients. Macroangiopathies—for example, stroke, carotid artery stenosis, congestive heart failure, and peripheral vascular disease—are two to five times more common in nephropathic patients. Peripheral neuropathy is present in almost all patients with advanced nephropathy. Foot ulcers with sepsis leading to amputation occur frequently (>25%), probably due to a combination of neural and arterial disease. Autonomic neuropathy may be asymptomatic and simply manifest as abnormal cardiovascular reflexes, or it may result in debilitating symptoms. Over half of the patients with advanced nephropathy have symptoms of autonomic neuropathy: gustatory sweating, impotence, postural hypotension, and diarrhea. Diabetic cystopathy is also a frequent (>30%) problem in these patients (Table 17-1).

350

Major Microvascular and Macrovascular Complications in Patients with Diabetic Nephropathy

IV

Microvascular Complications


Table 17-1

Retinopathy Polyneuropathy including autonomic neuropathy (gastroparesis, diarrhea/obstipation, detrusor paresis, painless myocardial ischemia, erectile dysfunction; supine hypertension/orthostatic hypotension) Macrovascular Complications Coronary heart disease, left ventricular hypertrophy, congestive heart failure Cerebrovascular complications (stroke) Peripheral artery occlusive disease Mixed Complications Diabetic foot (neuropathic, vascular)

TREATMENT Glycemic Control Primary Prevention Intensive blood glucose control has a significant beneficial effect on the progression from normo- to microalbuminuria in type 1 diabetic patients. A worsening of diabetic retinopathy may be observed during the initial months of intensive therapy, but in the longer term, the rate of deterioration is slower than in conventionally treated type 1 diabetic patients. Side effects are a major concern with intensive therapy and the frequency of severe hypoglycemia is higher in intensively treated patients. In the Diabetes Control and Complications Trial (DCCT) intensive therapy reduced the occurrence of microalbuminuria by 39% and that of albuminuria by 54%. Despite these impressive results, 16% of subjects in the primary prevention cohort and 26% in the secondary prevention cohort developed microalbuminuria during the 9 years of intensive treatment. This clearly documents the need for additional treatment modalities to avoid or reduce the burden of diabetic nephropathy. Intensive metabolic control has been confirmed to have a beneficial effect on progression of normoalbuminuria to micro- and macroalbuminuria in type 2 diabetes by the U.K. Prospective Diabetes Study (UKPDS).

Secondary Prevention The impact of intensive versus conventional diabetic treatment on the progression or regression of microalbuminuria in type 1


diabetic patients has shown conflicting outcomes. These disap- 351 pointing results might partly be due to the relatively short length of the follow-up period, because the UKPDS study with 15 years of follow-up documented a progressive beneficial effect with time on the development of proteinuria and a two- CH 17 fold increase in plasma creatinine. Furthermore, pancreatic transplantation can reverse glomerulopathy in patients with type 1 diabetes, but reversal requires more than 5 years of normoglycemia. Recently, intensified multifactorial intervention (pharmacologic therapy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria) in patients with type 2 diabetes and microalbuminuria has been demonstrated to substantially slow progression to nephropathy, retinopathy, and autonomic neuropathy.

Blood Pressure Control Primary Prevention Recent laboratory observations are consistent with the concept that glomerular hypertension is a major factor in the pathogenesis of diabetic glomerulopathy, and indicate that lowering of systemic blood pressure without concomitant reduction of glomerular capillary pressure may be insufficient to prevent glomerular injury. Lowering of systemic blood pressure by angiotensin-converting enzyme (ACE) inhibitors or conventional antihypertensive treatment affords significant renoprotection in experimental models of diabetic nephropathy. Three randomized placebo-controlled trials in normotensive type 1 and type 2 diabetic patients with normal albumin excretion ratios (AERs) have suggested a beneficial effect of ACE inhibition on the development of microalbuminuria. In contrast, studies comparing the effect of ACE inhibitors versus a long-acting dihydropyridine calcium antagonist or b-blockade in hypertensive type 2 diabetic patients with normoalbuminuria have shown equivalent protection. The UKPDS study reported that, by 6 years, patients under tight blood pressure control had a 29% reduction in risk of developing microalbuminuria. Beneficial effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy, and incidence of stroke have recently been demonstrated.

Secondary Prevention ACE inhibitors significantly reduce the risk of progression to macroalbuminuria compared to placebo in type 1 patients with microalbuminuria (odds ratio, 0.38). In addition, regression to normoalbuminuria occurs more frequently, and urinary albumin excretion ratio is 50% lower in patients taking ACE

352 inhibitors. Furthermore, the beneficial effect of ACE inhibitors


in preventing progression from microalbuminuria to overt nephropathy is long-lasting and is associated with preservation of normal GFR. Antihypertensive treatment has a IV renoprotective effect in hypertensive patients with type 2 diabetes and microalbuminuria, particularly when achieved using angiotensin II receptor blockers (ARBs). Based on the trials with ARBs the American Diabetes Association now recommends: “In hypertensive type 2 diabetic patients with microalbuminuria or clinical albuminuria, ARBs are the initial agents of choice.”

Established Nephropathy Control of hypertension and blockade of the renin-angiotensin system are key therapeutic interventions in established diabetic nephropathy. Indeed, the prognosis of type 1 diabetic patients suffering from diabetic nephropathy has improved during the past decade, largely because of effective antihypertensive treatment with conventional drugs (b-blockers, diuretics) and ACE inhibitors. Early and aggressive antihypertensive treatment reduces albuminuria and the rate of decline in GFR in young men and women with type 1 diabetes and nephropathy. In addition, regression of kidney disease (DGFR 1 mL/min/year) or remission of proteinuria for at least 1 year (proteinuria 1 g/ 24 hours) has been documented in up to 20% of type 1 diabetic patients receiving aggressive antihypertensive therapy for diabetic nephropathy. The renoprotective effect of interruption of the renin-angiotensin blockade on the progression of diabetic nephropathy has been conclusively proved in both type 1 (ACE inhibition) and type 2 (ARB) diabetes mellitus. Moreover, these agents offer an additional significant mortality benefit in this patient population. Initiation of antihypertensive treatment usually induces an initial drop in GFR. This phenomenon occurs with conventional antihypertensive treatment with b-blockers, diuretics, and when ACE inhibitors or ARBs are used. This initial decline in GFR is due to a functional (hemodynamic) effect of antihypertensive treatment; however, this is accompanied thereafter by a slower decline in kidney function reflecting the beneficial effect on progression of nephropathy. This is an important clinical point. Many patients with diabetic nephropathy will experience a modest increment in serum creatinine following initiation of ACE inhibition or ARB therapy. These changes should be anticipated and should not trigger withdrawal of the agent. However, the development acute kidney injury should prompt consideration of the possibility of coexisting bilateral renal artery stenosis or effective or actual volume depletion (e.g., congestive heart failure or excessive diuresis).

Lipid Lowering

353

Dietary Protein Restriction Short-term studies in normoalbuminuric, microalbuminuric, and macroalbuminuric type 1 diabetic patients have shown that a low-protein diet (0.6–0.8 g/kg/day) reduces urinary albumin excretion and hyperfiltration, independent of changes in glucose control and blood pressure. Longer-term trials in type 1 patients with diabetic nephropathy suggest that protein restriction reduces the progression of kidney function, but the data are not definitive.

END-STAGE RENAL DISEASE IN DIABETIC PATIENTS Diabetic nephropathy is the leading cause of ESRD in most Western countries. Survival of the diabetic patient on hemodialysis is poorer whether diabetic or primary nondiabetic renal disease accounts for end-stage renal failure (Table 17-2). The diabetic patient with ESRD has several options for renal replacement therapy: 1. Transplantation (kidney only, simultaneous pancreas plus kidney, pancreas after kidney) 2. Hemodialysis (HD) 3. Continuous ambulatory peritoneal dialysis (CAPD)

Table 17-2

Frequent Therapeutic Challenges in the Diabetic Patient with Renal Failure

Hypertension (blood pressure amplitude, circadian rhythm) Hypervolemia Glycemic control (insulin half-life, accumulation of oral hypoglycemic agents) Malnutrition Bacterial infections (diabetic foot) Timely creation of vascular access


Hyperlipidemia may promote the progression of chronic renal disease including diabetic nephropathy. However, the renoprotective effect of 3-hydroxy-3-methylglutaryl–coenzyme A CH 17 (HMG-CoA) reductase inhibitors in patients with type 1 or type 2 diabetes with micro- or macroalbuminuria appears to be highly variable. These agents should be prescribed only if a coexisting indication is present.

354


There is consensus today that medical rehabilitation and survival are best after transplantation, particularly after transplantation of pancreas plus kidney. The results of CAPD and HD are inferior to transplantation but comparable between IV CAPD and HD.

Management of the Patient with Advanced Renal Failure The diabetic patient with advanced renal failure has usually a much higher burden of microvascular and macrovascular complications than the diabetic patient without nephropathy. The diabetic patient with advanced renal impairment, even if he or she is asymptomatic, must therefore be monitored at regular intervals for timely detection of these complications (ophthalmologic examination at half-yearly intervals, cardiac and angiologic status yearly, foot inspection at each visit). The most vexing clinical problems are related to coronary heart disease (CHD) and autonomic polyneuropathy.

Hypertension Blood pressure tends to be higher in diabetic compared to nondiabetic patients with renal failure. Because of their beneficial effect on cardiovascular complications and disease progression, ACE inhibitors or ARBs are obligatory in all patients unless there are contraindications (e.g., renal artery stenosis or resistant hyperkalemia). Patients with diabetic nephropathy are sodium avid and have a marked tendency to develop hypervolemia and edema. Therefore, dietary salt restriction and the use of loop diuretics are usually indicated. Thiazides are not sufficient as monotherapy once GFR is below 40 to 50 mL/min. When the creatinine concentration is elevated, multidrug therapy is usually necessary to normalize blood pressure with, on average, three to five antihypertensive agents. In these patients hypertension is also characterized by a wide pulse pressure (as a result of increased aortic stiffness) and by an attenuated nighttime decrease in blood pressure, which in itself is a potent risk predictor.

Glycemic Control The half-life of insulin is prolonged in advanced kidney disease causing a tendency to develop hypoglycemia. This risk is further compounded by anorexia and by accumulation of most sulfonylurea compounds. Glinides and glitazones do not accumulate, but long-term safety data in renal failure are not available.

Malnutrition

355

Acute and “Acute-on-Chronic” Kidney Disease Diabetic patients with nephropathy are particularly prone to develop “acute-on-chronic” kidney disease. The most common causes include emergency cardiologic interventions involving administration of radiocontrast material, septicemia, low cardiac output, and shock. The high susceptibility of the kidney to ischemic injury may be a contributory factor. Often the acute kidney injury (AKI) is irreversible and necessitates chronic HD. This mode of presentation as irreversible AKI has a particularly poor prognosis.

Vascular Access Timely creation of vascular access is of overriding importance. It should be considered when the GFR is approximately 20 to 25 mL/min. Although venous runoff problems are not unusual, inadequate arterial inflow is increasingly recognized as the major cause of fistula malfunction. If distal arteries are severely sclerotic, anastomosis at a more proximal level may be necessary. Arteriosclerosis of arm arteries not only jeopardizes fistula flow but also predisposes to the steal phenomenon with digital ischemia.

Initiation of Renal Replacement Therapy Many nephrologists would agree that renal replacement therapy should be started earlier than in nondiabetic patients and at a GFR of approximately 15 mL/min. An even earlier start may be justified when hypervolemia and blood pressure become uncontrollable, or when the patient is anorectic and cachectic.

Hemodialysis In recent years, survival of diabetic patients on HD has improved, with a 5-year survival rate in type 2 diabetic patients on HD of approximately 30%.


Patients with ESRD due to diabetic nephropathy are typically catabolic and are predisposed to develop malnutrition, particularly during periods of intercurrent illness and fasting. Therefore, protein-restricted diets are discouraged in advanced CH 17 renal insufficiency, particularly in anorectic patients. Anorectic obese patients with type 2 diabetes and advanced renal failure often undergo massive weight loss leading to normalization of fasting and even postloading glycemia. Wasting with low muscle mass is an important reason why physicians misjudge the severity of renal failure, because at any given level of GFR, serum creatinine concentrations are spuriously low.

356 Intradialytic and Interdialytic Blood Pressure


Diabetic hemodialysis patients are more hypertensive than nondiabetic patients, and the blood pressure is exquisitely volume-dependent. The problem is compounded by the fact IV that patients are predisposed to intradialytic hypotension, so that it is difficult to reach the target “dry weight” by ultrafiltration. The main causes of intradialytic hypotension are autonomous neuropathy and diastolic dysfunction so that cardiac output decreases abruptly when left ventricular filling pressure diminishes during ultrafiltration. Longer dialysis sessions, omission of antihypertensive agents immediately before dialysis sessions, and correction of anemia by erythropoietin therapy may lower the incidence of this complication.

Cardiovascular Problems Cardiovascular disease accounts for over half of all deaths in diabetic patients on HD. The prevalence of CHD is significantly higher in diabetic compared to nondiabetic patients entering ESRD programs. In addition, the diabetic patient is at higher risk when coronary complications supervene. The impact of ischemic heart disease is amplified by coexisting cardiac abnormalities such as congestive heart failure, left ventricular hypertrophy, and disturbed sympathetic innervation, as well as microvessel disease with diminished coronary reserve. Observational studies suggest that good glycemic control before or during dialysis reduces overall and cardiovascular mortality rates. It is sensible to reduce afterload (blood pressure control) and preload (hypervolemia). The value of lipid lowering by statins has not been proved but is currently being investigated in type 2 diabetic patients on dialysis. Diabetic patients with renal failure are characterized by premature and more pronounced anemia, so that timely and effective treatment with recombinant human erythropoietin (rhEPO) is advisable. Pharmacologic blockade of the reninangiotensin system using ACE inhibitors or ARBs is also advised based on an extrapolation of the results of the Heart Outcome Prevention Evaluation (HOPE) study. In the patient with symptomatic CHD, active intervention, for example, percutaneous transluminal coronary angioplasty (PTCA) or CABG (coronary artery bypass graft), has been shown to be superior to medical treatment alone. A recent retrospective analysis of dialysed diabetics suggested that CABG using internal mammary grafts (but not CABG using venous grafts) yielded superior outcome compared to PTCA with or without stenting.

Malnutrition Because of anorexia and prolonged habituation to dietary restriction, the dietary intake of diabetic patients on HD often falls short of adequate energy (30–35 kcal/kg/day) and protein

(1.3 g/kg/day) intake. This is particularly undesirable because 357 malnutrition is a potent predictor of death. All patients should be reviewed on a regular basis by a clinical nutrition service.

Peritoneal Dialysis

Transplantation Kidney Transplantation Although survival of the diabetic patient with a kidney graft is worse compared with a grafted nondiabetic patient, the gain in life expectancy of the diabetic patient with a graft, compared with the dialyzed diabetic patient on the waiting list, is proportionally much greater than in the nondiabetic patient, because survival of the diabetic patient is so much poorer on dialysis. The higher mortality rate of the diabetic with a kidney graft is mainly explained as the consequence of preexisting vascular disease, left ventricular hypertrophy, and post-transplant hypertension. Diabetic patients must be subjected to rigorous pretransplantation evaluation, which in most centers includes routine coronary angiography. Patients should also be examined by Doppler sonography of pelvic arteries and, if necessary, angiography, to avoid placement of a renal allograft into an iliac artery with compromised arterial flow at risk of ischemia of the extremity and amputation.

Kidney-Plus-Pancreas Transplantation Survival of patients with simultaneous pancreas-kidney transplantation (SPK) approaches that of patients transplanted for nondiabetic renal disease and is clearly superior to that for


In the United States, 7% of all patients with diabetes receiving renal replacement therapy are treated with peritoneal dialysis (PD), but these rates are much higher in Western Europe. There are very good a priori reasons to initially offer CAPD treatment to diabetic patients including difficulties in vascular access placement, improved survival during the first 2 years, survival in patients treated with PD compared to HD (excluding the very elderly), and avoidance of rapid fluctuations of fluid volumes and electrolyte concentrations. Some evidence suggests that patients who start on PD and then transfer to HD when residual renal function declines have better long-term survival than patients who started on HD. Although protein is lost across the peritoneal membrane, the main nutritional problem is gain of glucose and calories because high glucose concentrations in the dialysate are necessary for osmotic removal of excess body fluid. This leads to weight gain and obesity.

CH 17

358 diabetic recipients of living donor kidney-only grafts and par-


ticularly of cadaver kidney-only grafts. Reversibility of established microvascular complications after SPK is minor at best, with the important exception of autonomic polyneuIV ropathy, particularly improved cardiorespiratory reflexes, potentially contributing to increased survival, and some improvement in nerve conduction. Further benefits include improved gastric and bladder function, as well as superior quality of life, better metabolic control, and improved survival, so that today SPK should be the preferred treatment for the type 1 diabetic who meets the selection criteria. There is an increasing tendency for early or even preemptive SPK.

Pancreas-After-Kidney Transplantation An alternative strategy must be considered in the diabetic patient who has a live kidney donor: to first transplant the living donor kidney, and subsequently, once stable renal function is achieved (GFR > 50 mL/min), to transplant a cadaver donor pancreas. Recent data suggest a poorer outcome in such patients compared to conventional treatment.

Islet Cell Transplantation Islet cell transplantation is an area of emerging interest. Successful islet cell transplantation achieving insulin independence in seven consecutive patients using a steroid-free immunosuppression regimen consisting of sirolimus, tacrolimus, and taclizumab has been reported.

BLADDER DYSFUNCTION Bladder dysfunction as a sequela of autonomous diabetic polyneuropathy is frequent in diabetic patients, leading to straining, hesitancy, and the sensation of incomplete emptying of the bladder; disabling symptoms, however, are rare (with the exception of the frail elderly). Because of its association with autonomous polyneuropathy, it is not surprising that bladder dysfunction is frequently associated with postural hypotension, gastroparesis, constipation, and nocturnal diarrhea. Cystometry shows increased bladder volume at first desire to void and increased maximal bladder capacity associated with decreased detrusor contractility. Cystopathy with residual volume after voiding renders eradication of urinary tract infection (UTI) difficult.

URINARY TRACT INFECTION It is not absolutely certain whether the frequency of bacteriuria is higher in diabetic patients, but there is no doubt that symptomatic UTIs are more severe and more aggressive.


UTIs in diabetes also lead to complications, such as prostatic 359 abscess, emphysematous cystitis and pyelonephritis, intrarenal abscess formation, renal carbuncle, and penile necrosis (Fournier disease). Papillary necrosis should be suspected in diabetic patients with recurrent episodes of UTI, renal colic, CH 17 hematuria, or obstructive uropathy. Extrarenal bacterial metastases are common, particularly after UTI with methicillin-resistant staphylococci. In community-acquired UTI, the predominant microbe is E. coli, but Klebsiella is more frequently found in diabetic patients than in control subjects. The reasons for the potentially higher frequency and the definitely higher severity of UTI in diabetes are not known but may include more favorable conditions for bacterial growth (glucosuria), defective neutrophil function, increased adherence to uroepithelial cells, and impaired bladder evacuation (detrusor paresis). As to the management of UTI, no clear benefits of antibiotic treatment have been demonstrated for treatment of asymptomatic bacteriuria in diabetic patients. Community-acquired symptomatic lower UTI may be managed with trimethoprim, trimethoprim with sulfamethoxazole, or gyrase inhibitors. For nosocomially acquired UTI, sensitivity tests and sensitivity-directed antibiotic intervention are necessary. Invasive candiduria can be managed with amphotericin by irrigation or systemic administration of fungicidal substances.

OTHER RENAL DISORDERS IN DIABETIC PATIENTS It has been reported that renal disorders such as minimal change disease and membranous nephropathy occur with greater frequency in the type 1 diabetic patient population than among nondiabetics. In fact, fewer than 1% of type 1 patients with 10 or more years of diabetes and fewer than 4% of those with proteinuria and long diabetes duration will have conditions other than, or in addition to, diabetic nephropathy. However, proteinuric type 2 diabetic patients without retinopathy, or with unusual features, may have a high incidence of other renal diseases. Proteinuria in type 1 diabetic patients with less than 10 years of diabetes duration or type 2 diabetic patients without retinopathy should be thoroughly evaluated for other renal diseases, and renal biopsy for diagnosis and prognosis should be strongly considered.

Chapter 18

Nephrolithiasis CLINICAL PRESENTATION The lifetime risk of nephrolithiasis is 7% to 13%. The majority of crystals are composed of calcium (>80%) complexed with oxalate or phosphate. Other stones are composed of uric acid, magnesium ammonium phosphate (struvite), or cystine, either alone or in combination. The mean age at onset of symptomatic stone disease is 45 years for men and 41 years for women, and the overall male-female ratio is 1.7:1. In addition to age and gender, race, geography, and body mass index are factors in the prevalence of kidney stones, with sun exposure and obesity significant risk factors. The most characteristic symptoms of nephrolithiasis are pain, hematuria, nausea, and vomiting. Other presentations include urinary tract infection and acute kidney injury, if stones cause bilateral renal tract obstruction or unilateral obstruction in a single functioning kidney.

Pain The classic presentation of pain in patients with nephrolithiasis is severe ureteral colic. This pain is often of abrupt onset and intensifies over time into an excruciating, severe flank pain that resolves with stone passage or removal. The pain may migrate anteriorly along the abdomen and inferiorly to the groin, penis, or labia majora as the stone moves toward the ureterovesical junction. Gross hematuria, urinary urgency, frequency, nausea, and vomiting may be also present. Stones smaller than 2 mm have a 97% likelihood of spontaneous passage, at 3 mm an 86% chance of passage, at 4 to 6 mm a 50% chance, but if larger than 6 mm, it has only a 1% chance of spontaneous passage and will almost certainly require urologic intervention.

Hematuria Stone disease commonly causes hematuria, both microscopic and macroscopic. In general, macroscopic hematuria occurs most commonly with large calculi and during urinary infection and colic. Although typically associated with loin pain or

360

Loin Pain Hematuria Syndrome The combination of loin pain with hematuria syndrome (LPHS) in the absence of renal stones is a poorly understood condition that must always be considered in the differential diagnosis of patients presenting with the clinical manifestations of nephrolithiasis. This diagnosis is reached by exclusion when the patients, often young to middle-aged females, present with loin pain and persistent microscopic or intermittent macroscopic hematuria. Careful evaluation is required to exclude small stones, tumor, and urinary tract infection as a cause of the pain. Inconsistent angiographic abnormalities implying intrarenal vasospasm or occlusion have been reported, as have renal biopsy abnormalities typified by deposition of complement C3 in arteriolar walls. Denervation of the kidney by autotransplantation is rarely successful, and although nephrectomy has been attempted, often the pain recurs promptly in the contralateral kidney.

Asymptomatic Stone Disease Even obstructive uropathy caused by large staghorn calculi may be painless; thus, nephrolithiasis should always be considered in the differential diagnosis of unexplained renal failure.

Special Clinical Problems Pregnancy Complications of pregnancy are not increased above those of the general population in patients with nephrolithiasis except for a slightly higher rate of urinary tract infection. Furthermore, the rate of stone formation during pregnancy is no higher than that observed in nongravid stone formers.

Uric Acid and Calcium Stones A small fraction of patients who form calcium stones also form uric acid stones and, occasionally, stones composed of both calcium oxalate and uric acid. These patients display an unusually high recurrence rate; the average recurrence is

Nephrolithiasis

ureteric colic, nephrolithiasis may cause hematuria in the 361 absence of pain. The clinical differential diagnosis of hematuria is therefore wide and includes tumor, infection, and stones, as well as glomerular and interstitial renal parenchymal disease. Painless microscopic hematuria in children may occur with CH 18 hypercalciuria in the absence of demonstrable stones.

362 over 65 stones per 100 patient-years—nearly twice the average


rate for calcium stone formers in general. These patients may have a mixture of metabolic disorders involving both calcium and uric acid, which, if present, must be treated or stone IV recurrence will continue.

MANAGEMENT OF A FIRST URINARY STONE Investigations After a first episode of a stone, the 10-year recurrence rate is about 50% and the metabolic profile of single stone formers is not different from that of recurrent stone formers. Furthermore, there may be underlying conditions, such as primary hyperparathyroidism, the diagnosis of which should not be deferred. Therefore, all stone formers merit further evaluation. Patient age and family history are important for inherited causes or possibility of underlying structural abnormalities. States of volume contraction and oliguria, such as low fluid intake, excessive sweating, and diarrhea, should be noted. A careful nutritional history of estimated dietary contents of calcium, oxalate, sodium, acid (protein), potassium-rich citrus fruits, and purine can be conducted in a semiquantitative fashion by a physician before or without consultation with a dietician. Gastrointestinal diseases such as any chronic diarrhea states, ileal resection, jejunoileal bypass, or weight reduction surgery are all important in the history. Underlying conditions that lead to hypercalcemia and hypercalciuria include immobilization, metastatic diseases, multiple myeloma, and primary hyperparathyroidism; a history of bone pain, nontraumatic fractures, and systemic symptoms of hypercalcemia are important features. Distal renal tubular acidosis (RTA) can present solely with kidney stones, although in more severe cases in children, stunted growth may be noted. Recurrent urinary tract infection with urease-positive organisms can cause kidney stones. Gout, diabetes, obesity, and the metabolic syndrome are risk factors for kidney stone formation and, particularly, uric acid stones.

Radiologic Evaluation The plain abdominal film remains a very common radiologic examination; its overall diagnostic accuracy, however, is less than satisfactory. Certain characteristics of stones that help differentiate between stone types are listed in Table 18-1. Ultrasonography is less useful because it often yields suboptimal visualization in the kidney and is almost useless for ureteral

Table 18-1

Stone Appearance on Plain Radiographs Characteristics

Calcium Calcium oxalate-monohydrate Calcium oxalate-dehydrate Calcium phosphate (apatite; brushite)

Radiopaque Well circumscribed

Uric acid

Radiolucent Rarely staghorn Can be staghorn

Struvite (magnesium ammonium phosphate) Cystine

Mildly opaque “Ground-glass” look Can be staghorn

stones, although it is excellent in detecting obstruction caused by kidney stones. Although the intravenous pyelogram has served well as the standard procedure for decades, unenhanced CT scan is currently the diagnostic procedure of choice.

Laboratory Studies A simple urinalysis can offer important information. Urine crystals are of variable assistance in the diagnosis, because crystalluria can be encountered in the absence of kidney stones. However, the presence of distinctive hexagonal cystine stones is extremely valuable in prompting the diagnosis of cystinuria and cystine stones. Specific gravity and osmolality provide a clue to the habitual fluid intake of a given individual. A low urinary pH (7.4) usually indicates splitting of urea into ammonium and

Table 18-2

Basic Metabolic Evaluation of Nephrolithiasis

Analysis of stone composition Urinalysis (including sediment examination) Urine culture Serum chemistry Blood urea nitrogen/creatinine Total CO2 Uric acid Calcium (repeat if high normal) Intact parathyroid hormone if calcium high or high-normal

CH 18

Nephrolithiasis

Crystal

363

364

Complete Metabolic Evaluation of Nephrolithiasis*

24-Hour Urine Collections

Normal Values

IV

Total volume

>2 L


Table 18-3

Calcium

age 10) and insulin-dependent diabetes mellitus (particularly after renal transplantation). Hepatomegaly and splenomegaly with little clinical impact occur in more than 40% of patients after age 10. Cystinosis is usually diagnosed by measuring the cystine content of peripheral leukocytes or cultured fibroblasts. Cystinotic patients usually have values exceeding 2 nmol of half-cystine per milligram of protein (normal < 0.2 nmol of half-cystine per milligram of protein). Alternatively, the appearance of characteristic corneal crystals on slit-lamp examination is also diagnostic. In utero diagnosis can be made by cystine measurements in amniocytes or chorionic villi, or at birth using cystine measurements of the placenta.

Treatment Early diagnosis, and appropriate treatment with cysteamine, dialysis, and renal transplantation has improved the outcome of patients with nephropathic cystinosis, and most patients now reach adulthood. Symptomatic treatment involves rehydration, particularly during episodes of gastroenteritis. Replacement of bicarbonate losses with citrate or bicarbonate-containing salts is frequently indicated. Phosphate losses are replaced with phosphate salts and oral vitamin D therapy. Indomethacin has been used for decreasing the renal salt- and water-wasting syndrome. Recombinant human growth hormone can also be given to increase growth, and does not increase the rate of progression of renal failure. The cystinedepleting drug cysteamine slows the rate of progression of renal failure, increases growth in affected patients, and is now widely used for cystinosis. Kidney function stabilizes upon initiation of therapy and may allow patients treated at an early age to reach adulthood without developing end-stage renal failure. Topical cysteamine eyedrops can be used to treat

398 ocular complications of cystinosis, and results in dissolution of corneal crystals. Transplantation is now routinely performed in cystinotic patients.

Genetic Basis of Kidney Disease

V

Lowe Oculocerebrorenal Syndrome The oculocerebrorenal syndrome of Lowe (OCRL; OMIM 309000) is an X-linked recessive multisystem disorder characterized by congenital cataracts, mental retardation, and renal Fanconi syndrome. Mutations in the OCRL1 gene are responsible for OCRL. This gene encodes a 105-kDa Golgi protein involved in the inositol phosphate signaling pathway, believed to influence membrane traffic and actin dynamics. Renal dysfunction (Fanconi syndrome) is a major feature of the disorder and usually occurs within the first year of life. It is characterized by proteinuria, generalized aminoaciduria, wasting of carnitine, phosphaturia, and bicarbonaturia. Glucosuria is usually not present. Glomerular function falls with age, with renal failure developing between the second and fourth decades of life. Linear growth decreases after 1 year of age. Neurologic findings include infantile hypotonia, mental retardation (not universal), and areflexia. Cranial magnetic resonance imaging shows mild ventriculomegaly and cysts in the periventricular regions. Status epilepticus is also frequent. Prenatal development of cataracts is universal, and other ocular abnormalities include glaucoma, microphthalmos, and corneal keloid formation. In the absence of reliable biochemical tests or a confirmed family history, the diagnosis is made clinically based on the cardinal ocular, renal, and neurologic manifestations. Carrier detection can be performed by slit-lamp examination, mutation detection, or linkage analysis of markers if the specific mutation is unknown. Levels of the muscle enzymes creatine kinase, aspartate aminotransferase, and lactate dehydrogenase, as well as total serum protein, serum a2-globulin, and high-density lipoprotein cholesterol, are elevated. Treatment is supportive and includes repletion of bicarbonate, phosphate, sodium, and vitamin D.

Hereditary Fructose Intolerance Hereditary fructose intolerance caused by aldolase B deficiency (fructose-1,6-bisphosphate aldolase) is an autosomal recessive disorder characterized by vomiting shortly after fructose ingestion. The disease is associated with proximal tubule dysfunction (aminoaciduria, bicarbonaturia, and phosphaturia) and lactic acidosis. Hypoglycemia is unfortunately frequently absent. Liver dysfunction progressing to cirrhosis, renal

INHERITED DISORDERS OF RENAL AMINO ACID TRANSPORT Amino acids are freely filtered by the glomerulus; however, the proximal tubule reabsorbs up to 99.9% of the filtered load. Aminoaciduria occurs when a renal transport defect of the proximal tubule decreases the reabsorptive capacity for one or several amino acids, or when the threshold for reabsorbing an amino acid is exceeded by elevated plasma levels due to a metabolic defect (“overflow aminoaciduria”). Clinically, the most significant renal aminoaciduria is cystinuria (Table 20-2). Most of the other disorders are rarely symptomatic. Most amino acids are reabsorbed by more than one transporter and almost completely reclaimed. Amino acids can share transporters with

Table 20-2

Classification of the Aminoacidurias

Disease

Category

Amino Acid(s)

Cystinuria

Basic amino acids

Cystine, lysine, ornithine, arginine

Lysinuric protein intolerance

Lysine, arginine, ornithine

Isolated cystinuria

Cystine

Lysinuria Hartnup disease

Lysine Neutral amino acids

Alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine

Blue diaper syndrome

Tryptophan

Iminoglycinuria

Glycine, proline, hydroxyproline

Glycinuria

Glycine

Methioninuria

Methionine

Inherited Disorders of the Kidney

dysfunction, and growth retardation result from prolonged 399 exposure to noxious sugars. The incidence is 1 in 23,000. The pathophysiology of the renal Fanconi syndrome is not clear, but may be related to impaired acidification and recycling of endosomes similar to that seen in Dent disease. The treatment CH 20 of hereditary fructose intolerance involves withdrawal of sucrose, fructose, and sorbitol from the diet.

400 low affinity but high transport capacity, and have a specific


transporter for one amino acid that has a high affinity and low maximal transport capacity. The transport of amino acids is coupled to the sodium gradient established by the basolateral þ þ V Na /K -ATPase.

Cystinuria Cystinuria (OMIM 220200) is an autosomal recessive disorder associated with defective transport of cystine and the dibasic amino acids ornithine, lysine, and arginine, involving the epithelial cells of the renal tubule and gastrointestinal tract. The formation of cystine calculi in the urinary tract, leading to infection and renal failure, is the hallmark of the disorder. Cystine is the least soluble of the naturally occurring amino acids, particularly at low pH. The prevalence is approximately 1 in 7000 but varies depending on the geographic location.

Pathogenesis Cystinuria is caused by mutations in either of two genes implicated in dibasic amino acid luminal transport by the proximal tubule. Type A (or type 1, OMIM 220100) cystinuria is a completely recessive disease caused by mutations in SLC3A1on chromosome 2, which encodes the renal proximal tubule S3 segment and intestinal dibasic amino acid transporter. Jejunal uptake of cystine and dibasic amino acids is absent and there is no plasma response to an oral cystine load. The risk of nephrolithiasis is very high. Type B (or non-type 1, OMIM 600918) cystinuria is an incompletely recessive form in which both parents usually excrete intermediate amounts of cystine (100–600 mmol/g creatinine) but may also have normal excretory function. The disease is caused by mutations in the SLC7A9 gene located on chromosome 19q13, which encodes a protein BAT1. It belongs to a family of light subunits of amino acid transporters, expressed in the kidney, liver, small intestine, and placenta.

Clinical Presentation The only known manifestation of cystinuria is nephrolithiasis. Clinical expression of the disease typically starts during the first to third decades. Males tend to be more severely affected than females, although the incidence is equal in both sexes. Cystine stones are made of a yellow-brown substance (sulfurcontaining), are very hard, and appear radiopaque. Stones are frequently multiple, have a staghorn configuration, and tend to be smoother than calcium stones. Magnesium ammonium phosphate and calcium stones can also form as a result of infection.

Treatment Management involves maintaining a high urine flow rate and reducing sodium in the diet, which results in lower urinary cystine concentrations. Fluid intake should ideally reach 4 L/day because many patients excrete 1 g or more of cystine daily. Cystine solubility can also be increased by alkalinization of the urine with potassium citrate, but the solubility of cystine does not increase until the pH reaches 7.0 to 7.5; the requirements for alkali may reach 3 to 4 mmol/kg. Patients who are unable to comply with a regimen of high-fluid intake and urine alkalinization or who fail despite adequate treatment can be given D-penicillamine in doses of 30 mg/kg up to a maximum of 2 g/day. Through a disulfide exchange reaction D-penicillamine forms the disulfide cysteine-penicillamine, which is much more soluble than cystine. This drug has variable tolerability and frequent side effects (including rash, fever, membranous nephropathy, epidermolysis, and loss of taste) complicate therapy. Another drug that may be useful in cystinuria is mercaptopropionylglycine, whose mechanism of action is identical to that of D-penicillamine. This drug is as effective as D-penicillamine in reducing urine cystine excretion but this agent also has substantial side effects including skin rash, fever, nausea, proteinuria, and membranous nephropathy. The introduction of extracorporeal shock wave lithotripsy has not been of great benefit to cystinuric patients as cystine stones are difficult to pulverize. Consequently, percutaneous lithotripsy is more effective. Urinary alkalinization with direct irrigation of the urinary tract with D-penicillamine or N-acetylpenicillamine to form disulfide compounds has resulted in dissolution of stones, although dissolution may require several weeks of therapy with the attendant complications of catheterization. Transplantation is sometimes necessary for patients who develop end-stage renal disease from chronic obstruction or infection. A kidney from an unaffected donor will not form cystine stones.


Diagnosis can be made by demonstration of the presence of 401 characteristic hexagonal cystine crystals in the urine. Acidification of concentrated urine with acetic acid can precipitate crystals not visible on initial urine microscopy. Diagnosis is ultimately made by measurement of cystine excretion in the CH 20 urine, usually performed in specialized centers using chromatographic methods. The cyanide-nitroprusside test has been widely applied as a qualitative screening procedure and is particularly useful for the detection of homozygotes. False-positive fndings include homocystinuria and patients with acetonuria.

402 Hartnup Disease


Hartnup disease (OMIM 234500) is an autosomal recessive condition characterized by excessive urinary excretion of the V neutral amino acids alanine, asparagine, glutamine, histidine, isoleucine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, and valine. Its incidence has been estimated in newborn screening programs at 1 in 26,000. The disease is due to mutations in the neutral amino acid transporter B(0)AT1 (SLC6A19). The clinical features of this disorder, if any, are due to nicotinamide deficiency, which is partly derived from tryptophan. These features include a photosensitive erythematous skin rash (pellagra-like) that is clinically identical with that due to niacin deficiency, intermittent cerebellar ataxia, and rarely mental retardation. The diagnosis is easily made by performing a urinary aminogram and shows increased excretion of neutral amino acids, but not glycine, cystine, and dibasic, dicarboxylic, and imino amino acids. Thus, Hartnup disease can be easily differentiated from the generalized aminoaciduria of Fanconi syndrome. Treatment of symptomatic cases involves the administration of nicotinamide in doses of 50 to 300 mg/ day. The value of treating asymptomatic patients is unclear, but given the benign nature of treatment, it seems reasonable to undertake therapy in these cases.

INHERITED DISORDERS OF RENAL PHOSPHATE TRANSPORT Inherited disorders of renal phosphate transport are characterized by hypophosphatemia due to a reduction in renal tubule reabsorption of inorganic phosphate (Pi). These disorders are characterized by metabolic bone disease presenting as rickets in childhood and osteomalacia in adults. Normal phosphate intake in adults varies from 800 to 1600 mg/day and the average serum phosphate levels remain normal over a wide range of intake. Intestinal phosphate absorption is greatest in the jejunum and ileum and is regulated by vitamin D metabolites. In the normal state, moderate phosphate deprivation that leads to a marginal decrease in serum phosphate levels induces a reduction in urine excretion of phosphate and an increase in 1,25(OH)2D3 levels. Renal proximal tubular reabsorption of phosphate is mediated by a Na/Pi-co-transporter system, which is down-regulated by PTH and hyperphosphatemia and up-regulated by phosphate deprivation. The proximal tubule is insensitive to the action of PTH in states of phosphate deprivation.

X-Linked Hypophosphatemic Rickets

403

Pathogenesis


X-linked hypophosphatemic rickets (OMIM 307800) is an X-linked dominant disorder and is the most common inherited CH 20 hypophosphatemic disorder, accounting for 80% of cases of familial phosphate wasting. It is characterized by hypophosphatemia with phosphaturia, normal serum calcium and parathyroid hormone (PTH) levels, normal to low serum 1,25 (OH)2D3 levels, and elevated levels of serum alkaline phosphatase. The mutated gene, PHEX, encodes a cell surface–bound metalloprotease. The role of PHEX in phosphate metabolism has not been elucidated, although it has been suggested that it is involved in the inactivation of a phosphaturic hormone or activation of a Pi-conserving hormone. Down-regulation of the sodium-phosphate co-transporter in the proximal tubule is also thought to be important. PHEX is expressed in osteoblasts and in tumor tissue associated with the paraneoplastic syndrome of renal phosphate wasting.

Clinical Presentation The hallmark of X-linked hypophosphatemic rickets (XLH) is inappropriately normal 1,25(OH)2D3 levels in the presence of hypophosphatemia and rickets. There is no renal wasting of amino acids and glucose. The patients demonstrate growth retardation, femoral or tibial bowing presenting early in life, and evidence of rickets and osteomalacia. Serum phosphate levels are usually lower than 2.5 mg/dL (0.8 mmol/L). The earliest sign of the disease in children may be increased serum alkaline phosphatase levels. Males are usually more severely affected than females and there is variable penetrance.

Treatment

Early therapy with 1,25(OH)2D3 (1–3 mg/day) and phosphate (1–2 g/day in divided doses) has a beneficial effect on growth and bone disease. Nephrocalcinosis due to vitamin D and phosphate therapy can lead to deterioration of renal function.

Autosomal Dominant Hypophosphatemic Rickets Autosomal dominant hypophosphatemic rickets (ADHR; OMIM 193100) is characterized by low serum phosphorus concentration, phosphaturia, inappropriately low or normal 1,25(OH)2D levels, and bone mineralization defects that result in rickets, osteomalacia with bone pain, lower extremity deformities, and muscle weakness. ADHR is phenotypically similar to X-linked hypophosphatemic rickets, but is much less common, and is

404 characterized by variable age of onset and incomplete pene-


trance. The gene responsible for ADHR encodes a new member of the fibroblast growth factor (FGF) family, FGF-23. FGF-23 expression is not readily detectable in normal tissues, but is V abundantly expressed in tumors removed from patients with oncogenic hypophosphatemic osteomalacia, an acquired renal Pi-wasting disorder with features of XLH and ADHR.

Hereditary Hypophosphatemic Rickets with Hypercalciuria Hereditary hypophosphatemic rickets associated with hypercalciuria (OMIM 241530) is a very rare autosomal disease, with apparently recessive inheritance. The disease has been mapped to chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Affected subjects appear to have a chronic renal phosphate leak with an appropriate response to hypophosphatemia. Stimulation of 1a-hydroxylase by hypophosphatemia leads to increased 1,25(OH)2D3 production and increased intestinal absorption of calcium and phosphate leading to hypercalciuria. Other characteristic features include rickets, short stature, normal serum calcium levels, and suppression of PTH leading to a reduction in bone mineralization and growth. Patients respond to administration of daily oral phosphate (1–2.5 g/day).

Hereditary Selective Deficiency of 1a,25(OH)2D3 This rare form of autosomal recessive vitamin D–responsive rickets (OMIM 264700) is not a disease of tubule transport per se, but a deficiency in 1a-hydroxylation. It results from inactivating mutations in the P-450 enzyme 1a-hydroxylase on chromosome 12q14. Patients usually appear normal at birth but develop muscle weakness, tetany, convulsions, and rickets starting at 2 months of age. Serum calcium levels are low; PTH levels are high, with low to undetectable 1,25(OH)2D3. Serum levels of 25(OH)D3 are normal or slightly increased. 1,25(OH)2D3 therapy results in healing of rickets and restores the plasma calcium, phosphate, and PTH levels.

Hereditary Generalized Resistance to 1a,25(OH)2D3 This rare autosomal recessive disorder (OMIM 277400) has a similar phenotype to selective deficiency of 1a,25(OH)2D3. The salient clinical features include increased serum levels of 25(OH)D3 and 1a,25(OH)2D3 and resistance to exogenous

1a,25(OH)2D3 and 1a-(OH)D3. Approximately half of cases 405 described have alopecia. The disease is caused by mutations in the vitamin D receptor gene.

Under normal conditions, glucose is almost completely reabsorbed by the proximal tubule via a Naþ-coupled active transport located in the brush border membrane. Only very small amounts of glucose are present in the urine of most normal people. The appearance of glycosuria suggests hyperglycemia (overload glucosuria) and, rarely, abnormal handling of glucose by the kidney. Renal glucosuria may be part of a generalized defect of the proximal tubule (Fanconi syndrome) or present as an isolated defect.

Renal Glucosuria Familial renal glucosuria (FRG; OMIM 233100) is generally a benign clinical condition that denotes a renal tubular abnormality characterized by persistent isolated glucosuria in the absence of hyperglycemia. FRG is transmitted as a codominant trait with incomplete penetrance. Homozygotes may demonstrate glucosuria above 60 g/day, evidence of renal sodium wasting, mild volume depletion, and raised basal plasma renin and serum aldosterone levels. Selective aminoaciduria may occasionally be seen, unlike the generalized aminoaciduria seen in the Fanconi syndrome. Mutations in the sodium/glucose co-transporter SGLT2 coding gene, SLC5A2, are responsible for the disorder. Mutations in the GLUT2 glucose transporter are thought to be responsible in some Japanese kindreds. A currently accepted stringent definition of glucosuria proposes the following diagnostic criteria: 1. The oral glucose tolerance test, levels of plasma insulin and free fatty acids, and glycosylated hemoglobin levels should all be normal. 2. The amount of glucose in the urine (10–100 g/day) should be relatively stable except during pregnancy, when it may increase. 3. The degree of glucosuria should be largely independent of diet but may fluctuate according to the amount of carbohydrates ingested. All specimens of urine should contain glucose. 4. The carbohydrate excreted should be glucose. Other sugars (e.g., fructose, sucrose, galactose, lactose) are not found. 5. Subjects with renal glucosuria should be able to store and utilize carbohydrates normally.

CH 20


INHERITED DISORDERS OF RENAL GLUCOSE TRANSPORT

406

INHERITED HYPOKALEMIC HYPOTENSIVE DISORDERS


Familial hypokalemic, hypochloremic metabolic alkalosis is not V a single entity but rather a set of closely related disorders. The distinguishing features of these disorders are outlined in Table 20-3.

Bartter Syndrome Pathogenesis Bartter syndrome (OMIM 601678, 241200, 607364, and 602522) is a group of autosomal recessive disorders affecting the function of the thick ascending limb of the loop of Henle, giving a clinical picture of salt-wasting and hypokalemic metabolic alkalosis. Hyperplasia and hypertrophy of the juxtaglomerular apparatus is seen. It is caused by inactivating mutations in one of at least four genes encoding membrane proteins (Bartter syndrome I–IV) expressed in this nephron segment: 1. The Naþ/Kþ/2Cl co-transporter (SLC12A1 encoding NKCC2) 2. The apical inward-rectifying potassium channel (KCNJ1 encoding ROMK) 3. ClC-Kb, a basolateral chloride channel (CLCNK encoding ClC-Kb) 4. Barttin (BSND), a protein that acts as an essential activator b-subunit of ClC-Ka and ClC-Kb Gain-of-function mutations in the extracellular calcium ion–sensing receptor (CaSR) cause a variant of Bartter syndrome with hypocalcemia.

Clinical Presentation Most cases of Bartter syndrome present antenatally or in the neonatal period. Polyhydramnios and premature labor are commonly found. Polyuria and polydipsia are invariable. Postnatal findings include failure to thrive, growth retardation, volume depletion, hypotension, muscle weakness, seizures and tetany, paresthesias, and joint pain due to chondrocalcinosis. In contrast to patients with Gitelman syndrome, those with Bartter syndrome are virtually always hypercalciuric and normomagnesemic. Nephrocalcinosis occurs almost universally in patients with NKCC2 and ROMK mutations but in only 20% of those with ClC-Kb mutations. Patients with ROMK mutations may present with hyperkalemia at birth, which converts to hypokalemia within the first weeks of life, and may be misdiagnosed with pseudohypoaldosteronism type I. In contrast to other Bartter patients, they do not need potassium supplementation. The type III Bartter syndrome (ClC-Kb) phenotype is highly variable, and may present either as a typical antenatal

Table 20-3

Clinical Differences between Bartter and Gitelman Syndromes Bartter Syndrome Type 1 (NKCC2)

Type II (ROMK)

Type III (ClC-Kb)

Type IV (Barttin)

Gitelman Syndrome

Polyhydramnios

þ

þ

þ

þ

Failure to thrive

þ

þ

þ

þ

Growth retardation

þ

þ

þ

þ

Polyuria

þ

þ

þ

þ

Polydipsia

þ

þ

þ

þ

Muscle cramps/spasm

Chondrocalcinosis

Nephrocalcinosis

þ

þ

þ

Sensorineural deafness

þ

407

408 variant or as a “classic” Bartter variant characterized by onset in


early childhood and less severe or absent hypercalciuria and nephrocalcinosis. Barttin mutations are usually associated with an extremely severe phenotype of intrauterine onset that V includes profound renal salt and water wasting, renal failure, sensorineural deafness, and motor retardation. Sensorineural deafness is specific for Barttin mutations because it is an essential subunit of chloride channels in the inner ear.

Treatment The treatment of Bartter syndrome involves oral potassium supplementation combined with interventions to reduce distal potassium secretion including spironolactone and nonsteroidal anti-inflammatory drugs in addition to oral potassium supplementation. Adjunctive use of angiotensin-converting enzyme inhibitors has also been successful. Therapy should lead to catch-up growth for infants.

Gitelman Syndrome Pathogenesis Gitelman syndrome (OMIM 263800) is an autosomal recessive disorder usually diagnosed in adults. It results from inactivating mutations in the SLC12A3 gene encoding the thiazide sensitive Naþ/Cl co-transporter, or NCCT. This results in sodium and chloride wasting with secondary activation of the reninangiotensin-aldosterone system. The increased sodium load to the cortical collecting duct leads to increased sodium reabsorption by the epithelial sodium channel (ENaC), counterbalanced by increased potassium and hydrogen excretion, resulting in hypokalemia and a metabolic alkalosis. Hypocalciuria is due to enhanced passive Ca2þ transport in the proximal tubule, rather than active Ca2þ transport in the distal convoluted tubule. Hypomagnesemia remains unexplained. Down-regulation of the epithelial Mg2þ channel transient receptor potential channel subfamily M, member 6 (TRPM6) has been recently demonstrated.

Clinical Presentation Unlike Bartter syndrome (see Table 20-3), Gitelman syndrome does not present symptomatically in the neonatal period and is often discovered incidentally. Patients have a hypokalemic metabolic alkalosis, but in contrast with Bartter syndrome, they are hypocalciuric and hypomagnesemic and may not have signs of overt volume depletion. Polyuria and polydipsia are not features of Gitelman syndrome. Urinary prostaglandin E2 levels are normal. The major differential diagnosis of Gitelman syndrome is diuretic abuse and chronic bulemia.

A careful history, as well as measurement of urinary chloride 409 (low in surreptitious vomiting) and a urinary diuretic screen, should help differentiate these conditions.

Treatment

INHERITED HYPOKALEMIC HYPERTENSIVE DISORDERS Causes of hypertension and hypokalemia are rare and include excess secretion of aldosterone or other mineralocorticoids and abnormal sensitivity to mineralocorticoids. These disorders are characterized primarily by low or low-normal plasma renin, normal or low serum potassium, and salt-sensitive hypertension, suggesting enhanced mineralocorticoid activity. However, most patients with hypokalemia and hypertension have essential hypertension associated with the use of diuretics or secondary aldosteronism from renal artery stenosis, or primary hyperaldosteronism from adrenal gland hyperplasia or adenoma.

Congenital Adrenal Hyperplasia Inherited abnormalities in two of the key enzymes required for steroid biosynthesis can result in hypertension in association with congenital adrenal hyperplasia: 11b-hydroxylase deficiency and 17a-hydroxylase deficiency. In these autosomal recessive disorders, overproduction of cortisol precursors results in a loss of negative feedback inhibition of ACTH (adrenocorticotropic hormone) release. These precursors either have intrinsic mineralocorticoid activity or are metabolized to mineralocorticoid agonists. This activity induces volume- and salt-dependent forms of hypertension with suppressed renin and reduced potassium concentrations.

11b-Hydroxylase Deficiency Inactivating mutations in the gene encoding 11b-hydroxylase (OMIM 202010) are responsible for 5% of cases of congenital adrenal hyperplasia (90% of cases are caused by 21-hydroxylase

CH 20


The treatment of Gitelman syndrome includes potassium supplementation and spironolactone. Nonsteroidal anti-inflammatory drugs are usually not helpful, as prostaglandin levels are normal. Symptoms of volume depletion may require intravenous repletion of saline. Pregnancy may exacerbate symptoms with significantly increased requirements for fluid and electrolyte repletion, and has been associated with oligohydramnios and intrauterine growth restriction.

410 deficiency, which is not associated with hypertension). This dis-


ease is associated with excess production of deoxycortisone (DOC), 18-deoxycortisol, and androgens. DOC has significant intrinsic mineralocorticoid activity, and high levels trigger V hypokalemic hypertension. Because the androgen pathway is unaffected, prenatal masculinization occurs in females and postnatal virilization occurs in both sexes. The diagnosis of 11b-hydroxylase is made by the detection of increased levels of DOC and 18-deoxycortisol. Treatment consists of exogenous corticoids that inhibit ACTH secretion. Correction of mild salt wasting from reduced mineralocorticoid production may be necessary.

17a-Hydroxylase Deficiency 17a-hydroxylase deficiency (OMIM 202110) results in reduced conversion of pregnenolone to progesterone and androgens, with absent sex hormone production. The resulting hypogonadism and male pseudohermaphroditism is usually detected at adolescence because of failure to undergo puberty. Elevated glucocorticoid-suppressible levels of DOC and corticosterone, as well as their 18-hydroxylated products, are responsible for hypertension, hypokalemia, and renin-aldosterone suppression. In severe 17a-hydroxylase deficiency, both the 17a-hydroxylase and 17,20-lyase activities are reduced or absent, resulting in excess mineralocorticoid activity, hypertension, and a universal female phenotype due to absent sex steroid production in both the adrenal and gonad. Partial 17a-hydroxylase deficiency occurs and can present as sexual ambiguity in males, without hypertension. Corticosteroid replacement corrects ACTH levels and hypertension. Females usually require hormone replacement, as do genetic males reared as females. Genetic males reared as males require surgical correction of their external genitalia and androgen replacement therapy.

Liddle Syndrome Pathogenesis Liddle syndrome (OMIM 177200) is an autosomal dominant form of hypertension characterized by hypokalemia and low levels of plasma renin and aldosterone, resulting from mutations in the b- or g-subunits of the amiloride-sensitive epithelial sodium channel (ENaC) in the distal convoluted tubule and collecting duct. ENaC activity in the kidney is tightly controlled by several distinct hormonal systems, including aldosterone. In Liddle syndrome, mutations within the b- and g-subunits of ENaC lead to constitutive activation of the channel. SCNN1B b-subunit mutations or SCNN1G g-subunit mutations could lead to an increase in the number of channels in the membrane or an increased probability of the channels being open.

411

Clinical Presentation

Treatment Hypertension is not improved by mineralocorticoid receptor inhibitors (spironolactone), but can be corrected by a low-salt diet and ENaC antagonists (amiloride or triamterene).

Apparent Mineralocorticoid Excess Pathogenesis Apparent mineralocorticoid excess (AME; OMIM 207765) is a rare autosomal recessive disorder that results in hypokalemic hypertension, with low serum levels of renin and aldosterone. It is caused by a deficiency of the 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) enzyme, responsible for the conversion of cortisol to the inactive metabolite cortisone. In AME, cortisol acts as a potent mineralocorticoid and causes salt retention, hypertension, and hypokalemia with a suppression of the renin-angiotensin-aldosterone system (RAAS). Inhibition of 11b-HSD2 by licorice (glycyrrhetinic acid) or carbenoxolone can also result in the development of hypokalemic, hyporeninemic hypertension.

Table 20-4

Urinary Steroid Profiles in Mendelian Forms of Low-Renin Hypertension

Liddle Syndrome

GlucocortcoidRemediable Aldosteronism

Apparent Mineralocorticoid Excess

Aldosterone

Decreased

Increased

Decreased

TH-aldo

Decreased

Increased

Decreased

18-Hydroxy-TH-aldo

Decreased

Increased

Decreased

18-Hydroxycortisol-F

Not detected

Increased

Not detected

Tetrahydrocortisol (TH-F)

Normal

Normal

Increased

Tetrahydrocortisone (TH-E)

Normal

Normal

Decreased

TH-F/TH-E

Normal

Normal

Increased

TH-aldo, tetrahydroxyaldosterone. Data from Warnock DG: Liddle syndrome: An autosomal dominant form of human hypertension. Kidney Int 53:18–24, 1998.


Constitutive activation of the ENaC causes inappropriate renal Naþ reabsorption, blunted Naþ excretion, and low-renin hypertension. Affected individuals are at increased risk of cerebrovascular and cardiovascular accidents, but renal fail- CH 20 ure is notoriously rare. Liddle syndrome can be differentiated from other rare mendelian forms of low-renin hypertension with urinary or plasma hormonal profiles (Table 20-4).

412 Clinical Presentation


AME is associated with severe juvenile low-renin hypertension, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and nephrocalcinosis. The urinary cortisol metaV bolites demonstrate an abnormal ratio: tetrahydrocortisol is increased while tetrahydrocortisone is decreased. The milder form of AME (type 2), also due to mutations in the 11b-HSD2 gene, has similar clinical features but lacks the typical urinary steroid profile; that is, biochemical analysis reveals a moderately elevated cortisol-to-cortisone metabolite ratio. The heterozygote state is phenotypically normal but associated with subtle defects in cortisol metabolism.

Treatment The treatment of AME is sodium restriction and either triamterene or amiloride. Spironolactone is not effective. Additional antihypertensive agents can be used as needed, particularly in older patients.

Glucocorticoid-Remediable Hyperaldosteronism Pathogenesis Glucocorticoid-remediable hyperaldosteronism (GRA) or familial hyperaldosteronism type 1 (OMIM 103900) is an autosomal dominant form of hypertension caused by a chimeric gene duplication arising from unequal crossover between aldosterone synthase and 11b-hydroxylase, two highly similar genes with the same transcriptional orientation lying 45,000 base pairs apart on chromosome 8. Normally 11b-hydroxylase is expressed at high levels and is regulated by ACTH, whereas aldosterone synthase is expressed at low levels and is regulated by angiotensin II. The genetic defect in this disorder results in the aldosterone synthase gene coming under the control of regulatory promoter sequences of the 11b-hydroxylase. The chimeric gene product is expressed at high levels in both the zona glomerulosa and zona fasciculata, and is controlled by ACTH. This leads to increased production of 18-hydroxycortisol and aldosterone metabolites and subsequent hypokalemic, hyporeninemic hypertension.

Clinical Presentation The phenotypic spectrum of disease is broad, ranging from patients with mild hypertension and normal biochemistry to patients with early onset of severe hypertension, hypokalemia, and metabolic alkalosis. GRA is associated with high morbidity and mortality rates from early onset of hemorrhagic stroke and ruptured intracranial aneurysms (20%). The diagnosis is usually established by demonstrating high levels of 18-hydroxycortisol or 18-oxocortisol metabolites in the urine (which are normally

secreted in negligible amounts) or with the dexamethasone sup- 413 pression test. Inhibition of ACTH via glucocorticoid administration can suppress excessive aldosterone secretion. The diagnosis of GRA can be definitively established demonstrating the chimeric gene by molecular techniques. CH 20 Simple glucocorticoid replacement is the treatment for GRA. Salt restriction combined with either ENaC inhibition or spironolactone is also effective.

INHERITED HYPERKALEMIC HYPOTENSIVE DISORDERS Pseudohypoaldosteronism Type I Pathogenesis Pseudohypoaldosteronism type I (PHA-I) is a rare genetically heterogeneous disorder of which there are two subtypes—an autosomal recessive form (OMIM 264350 and 177735) with severe manifestations that persist into adulthood, and an autosomal dominant form (OMIM 177735) with milder manifestations that remit with age. The autosomal recessive form is caused by inactivating mutations in any of the three subunits (a, b, g) of ENaC, resulting in resistance to the effects of aldosterone; the autosomal dominant form is due to mutations in the mineralocorticoid receptor (MR) gene.

Clinical Presentation Autosomal recessive PHA-I presents in early life with renal salt wasting, hypotension, hyperkalemia, metabolic acidosis, and on occasion, failure to thrive. Biochemical features include hyponatremia, high plasma and urinary aldosterone levels despite hyperkalemia, and elevated plasma renin activity. The differential diagnosis includes aldosterone synthase deficiency, salt-wasting forms of CAH, and adrenal hypoplasia congenita. Bartter syndrome resulting from mutations in the ROMK gene may present in the neonatal period with a similar (transient) clinical picture. Autosomal dominant PHA-I presents with milder manifestations with remission of the syndrome with age. This is consistent with progressively reduced dependence on aldosterone.

Treatment Treatment consists of salt supplementation. Administration of aldosterone, fludrocortisone, and deoxycorticosterone is not helpful. Patients with the recessive form usually need lifelong treatment for salt wasting and hyperkalemia, whereas in the dominant form, treatment can usually be withdrawn in adulthood.


Treatment

414

INHERITED HYPERKALEMIC HYPERTENSIVE DISORDERS Pseudohypoaldosteronism Type II


V

Pathogenesis Pseudohypoaldosteronism type II (PHA-II; OMIM 145260), also known as Gordon’s syndrome, is a volume-dependent low-renin form of hypertension characterized by persistent hyperkalemia despite a normal GFR. Hypertension is attributable to increased renal salt reabsorption; hyperkalemia to reduced renal Kþ excretion. A metabolic acidosis is commonly seen, due to reduced Hþ excretion. The features of PHA-II are chloride-dependent, and are corrected when infusion of sodium sulfate or bicarbonate is substituted for sodium chloride. In addition, the clinical abnormalities are ameliorated by thiazide diuretics, which inhibit salt reabsorption in the distal nephron. The disease is genetically heterogeneous and three loci have now been mapped to chromosomes 17, 1, and 12. Two genes identified on chromosomes 12 and 17 encode members of the WNK family of serine-threonine kinases, WNK1 and WNK4, that localize to the distal nephron. Both overactivity of the thiazide-sensitive Na-Cl co-transporter (NCCT) and increased paracellular reabsorption of Cl (“chloride shunt”) have been suggested as possible causes. WNK4 negatively regulates surface expression of NCCT and mutations result in enhanced surface expression of the co-transporter. Recent data suggest that WNK1 plays a general role in the regulation of epithelial Cl flux and gain-of-function mutations may lead to enhanced co-transporter activity.

Clinical Presentation PHA-II is usually diagnosed in adults, but it may also be seen in the neonatal period. The severity of hyperkalemia varies greatly and is influenced by prior intake of diuretics and salt. In its most severe form, it is associated with muscle weakness (from hyperkalemia), short stature, and intellectual impairment. Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin activity are findings variably associated with the trait. The plasma renin response to upright posture or to a lowsodium diet is blunted. Aldosterone levels vary from low to high depending on the level of hyperkalemia. Urinary concentrating ability, acid excretion, and proximal tubular function are all normal.

Treatment Treatment with thiazide diuretics reverses all the biochemical abnormalities. Lower than average doses can be given if overcorrection is seen.

DIABETES INSIPIDUS

415

Pathogenesis


The major action of arginine vasopressin (AVP) is to facilitate CH 20 urinary concentration by allowing water to be transported passively down an osmotic gradient between the tubular fluid and the surrounding interstitium. AVP acts via the vasopressin V2 receptor located on the basolateral membrane of collecting duct cells, initiating a cascade of events that leads to the exocytic insertion of specific water channels, aquaporin2 (AQP-2), into the luminal membrane, thereby increasing the water permeability of this membrane. When AVP is not available, water channels are retrieved by an endocytic process, and the tubule becomes water impermeable. In nephrogenic diabetes insipidus (NDI), the kidney is unable to concentrate urine despite normal or elevated concentrations of AVP. In congenital NDI, the obvious clinical manifestations of the disease (polyuria and polydipsia) are present at birth and need to be immediately recognized to avoid severe episodes of dehydration. Most (>90%) congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 receptor. In fewer than 10% of families studied, congenital NDI has an autosomal recessive inheritance and mutations have been identified in the AQP-2 gene (AQP2) located in chromosome region 12q13, that is, the vasopressin-sensitive water channel. Other inherited disorders with mild, moderate, or severe inability to concentrate urine include Bartter syndrome, cystinosis, and autosomal dominant hypocalcemia.

Clinical Presentation Loss-of-Function Mutations of the AVPR2 X-linked NDI (OMIM 304800) is secondary to AVPR2 mutations that result in loss-of-function or dysregulation of the V2 receptor. Males who have an AVPR2 mutation have a phenotype characterized by early dehydration episodes, hypernatremia, and hyperthermia as early as the first week of life. Dehydration episodes can be life-threatening. The infants are irritable, cry almost constantly, and although eager to suck, will vomit milk soon after ingestion unless prefed with water. The history given by the mothers often includes persistent constipation, erratic unexplained fever, and failure to gain weight. Heterozygous females exhibit variable degrees of polyuria and polydipsia because of skewed X chromosome inactivation. Historically, mental retardation consequent to repeated episodes of dehydration was a prevalent feature.

416 Early recognition and treatment of X-linked NDI with an abun-


dant intake of water allows a normal life span with normal physical and mental development. A variant of this disorder is autosomal dominant NDI, which occurs secondary to mutaV tions in the prepro-arginine-vasopressin-neurophysin II gene. Patients with autosomal dominant NDI retain some limited capacity to secrete AVP during severe dehydration and the polyuric-polydipsic symptoms usually appear after the first year of life when the infant’s demand for water is more likely to be understood by adults.

Loss-of-Function Mutations of AQP2 Mutations in the AQP2 gene that encodes the aquaporin2 channel result in nephrogenic DI. The gene is located in chromosome region 12q13. Evidence suggests that both autosomal recessive and autosomal dominant NDI phenotypes could be secondary to novel mutations in the AQP2 gene. Mutations appear to impair trafficking of aquaporin-2 and decrease channel function.

Chapter 21

Cystic Diseases of the Kidney Renal cysts are a common abnormality that arise primarily from the renal tubule epithelium. They are composed of a layer of epithelium enclosing a cavity filled with urine-like liquid or semisolid material. They are extremely rare in infants, but their prevalence increases with age. A relatively large number of clinical conditions are associated with renal cysts (Table 21-1). Cystic kidneys of different etiologies may appear morphologically similar, whereas the same etiologic entity may cause a wide spectrum of renal abnormalities.

HEREDITARY POLYCYSTIC KIDNEY DISORDERS Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are the principal single-gene disorders that cause polycystic kidney disease.

Autosomal Dominant Polycystic Kidney Disease ADPKD occurs worldwide and in all races, with prevalence estimated to be between 1 in 400 and 1 in 1000 individuals. It is inherited as an autosomal dominant trait with complete penetrance. In approximately 5% of cases, no family history is found, suggesting a relatively high spontaneous mutation rate. ADPKD is genetically heterogeneous with one of two known mutations in genes on chromosomes 16 (PKD1 on chromosome 16p13.3; 85% of cases) and 4 (PKD2 on chromosome 4q21; 15% of cases) responsible for disease development. PKD1 and PKD2 encode proteins polycystin-1 and -2, respectively, which are located in the plasma membranes overlying primary cilia. It is uncertain whether a third gene accounts for a small number of unlinked families. Homozygous or compound heterozygous genotypes are lethal in utero. The exact mechanism whereby the genetic mutations trigger cystogenesis remains incompletely understood. ADPKD may not be clinically apparent until the third or fourth decade of life. There is significant intrafamilial

417

418

Table 21-1

Classification of Renal Cysts

Autosomal dominant polycystic kidney disease (ADPKD)


V

Autosomal recessive polycystic kidney disease (ARPKD) Autosomal or X-linked dominant disease in the differential diagnosis of ADPKD Orofaciodigital syndrome Tuberous sclerosis von Hippel-Lindau syndrome Familial renal hamartomas associated with hyperparathyroidism– jaw tumor syndrome Autosomal recessive disease in the differential diagnosis of ARPKD Meckel-Gruber syndrome Other multiple malformation syndromes Hereditary cystic disease with interstitial nephritis Nephronophthisis Joubert syndrome Bardet-Biedl syndrome Alstro¨m syndrome Medullary cystic kidney disease Cystic renal dysplasia Multicystic kidney dysplasia Hepatocyte nuclear factor-1b mutations Other cystic kidney disorders Simple cysts Localized or unilateral renal cystic disease Medullary sponge kidney Acquired cystic kidney disease Renal cystic neoplasms Cystic renal cell carcinoma Multilocular cystic nephroma Mixed epithelial and stromal tumor Cystic partially differentiated nephroblastoma Cysts of nontubular origin Cystic disease of the renal sinus Perirenal lymphangiomas Subcapsular and perirenal urinomas Pyelocalyceal cysts

variability in the severity of both renal and extrarenal manifestations, suggesting the role of environmental modifying factors in addition to genetic factors. It is difficult to predict in young patients whether or when renal failure will develop, although a number of risk factors have been identified with a more rapid and severe course. These include onset of hypertension before age 35, renal hemorrhage (with first episode of hematuria before age 30), hyperlipidemia, low levels of high-density lipoprotein, male gender, and the PKD1 disease genotype. Parental hypertension, particularly in the nonaffected parent,

Pathogenesis of Renal Failure Cystic kidneys usually retain their reniform shape, with size ranging from minimally or moderately enlarged in early disease to more than 20 times normal in advanced disease. Cysts begin as outpouchings from preexisting renal tubules, but most become detached from the parent tubule once they have exceeded a few millimeters in size. The cells in the vast majority of cysts are thought to be relatively immature or partially de-differentiated tubular epithelium. A minority of cysts continue to function, as evidenced by their ability to generate transepithelial electrical gradients and to secrete NaCl and fluid in vitro. Renal failure results from the progressive expansion and encroachment on adjacent parenchyma, rather than by loss of function in individual renal tubules. Vascular remodeling is also thought to play an important role. At end-stage disease, there is only scant evidence of normal-appearing parenchyma, found in isolated patches. There is abundant subcapsular fibrous tissue, and cysts may be encapsulated by fibrous bands. Tubulointerstital fibrosis and arteriolar sclerosis are cardinal features of the end-stage kidney. Hypertension is thought to develop secondary to disturbances in the microvasculature, leading to activation of the renin-angiotensin system, which in turn accelerates the tubulointerstitial fibrosis. Clinical measurements of glomerular filtration rate (GFR) in ADPKD are poor predictors of the future course of slowly progressive renal disease. Indeed, relatively young patients may have profoundly distorted renal anatomy and extreme renal enlargement, yet the GFR may be within normal limits. This finding reflects the fact that GFR is maintained within the normal range in patients with advanced cystic change through compensatory hyperfiltration in residual glomeruli. Only after the compensatory mechanisms fail is a fall in GFR seen, which may be relatively precipitous.

Cystic Diseases of the Kidney

increases the risk of hypertension and end-stage renal disease 419 (ESRD). A strong relationship with renal enlargement has been noted; the CRISP (Consortium of Imaging Studies to assess the Progression of Polycystic Kidney Disease) study showed that kidney and cyst volumes are the strongest predic- CH 21 tors of renal functional decline, with renal blood flow (or vascular resistance) an independent predictor, indicating the importance of vascular remodeling in disease progression. PKD1 and PKD2 disease are clinically similar, except that the progression to ESRD is slower in PKD2. Most individuals with PKD1 mutations experience renal failure by age 70 years, whereas more than 50% of adults with PKD2 mutations have adequate renal function at that age (mean age of onset of ESRD 54.3 years for PKD1; 74 years for PKD2).

420 Diagnosis


In those patients in whom a family history is not evident, diagnosis of ADPKD in its fully developed form is not difficult. Many patients will have noticed loin pain, hematuria, V or increased abdominal girth. In an individual with a positive family history of ADPKD, the diagnosis is based on radiologic testing. Counseling should be done prior to testing with full explanation of the implications of diagnosis, including genetic transmission, and potential discrimination in terms of employment and insurability. Ultrasonography, the preferred screening method, reveals multiple echo-free areas in both kidneys. Standard sonographic criteria for the diagnosis of ADPKD include at least two cysts in at least one kidney in patients younger than 30 years of age. Patients between the ages of 30 and 59 years should have at least two cysts in each kidney, and patients older than 60 years of age should have at least four cysts in each kidney. A negative radiologic evaluation in a patient over the age of 30 effectively excludes the diagnosis of ADPKD, but is less sensitive in younger individuals, particularly those with PKD2 mutations. If ultrasonography is equivocal, then contrast-enhanced CT and MRI provide better anatomic definition and can readily distinguish between solid and cystic renal masses, demonstrating the diffuse distribution of large and small cysts, a characteristic that is important in differentiating ADPKD from multiple simple cysts. CT and MRI will also reveal small cysts in the liver, a finding that helps to further differentiate ADPKD from acquired cystic disorders. Gene linkage analysis can be used to determine obligate ADPKD gene carriers, but this method has not gained widespread clinical use. The differential diagnosis of ADPKD includes ARPKD in children, tuberous sclerosis, multiple simple cysts, multicystic dysplastic kidney, von Hippel-Lindau syndrome, and acquired cystic kidney disease.

Renal Manifestations and Therapy

Cyst Development and Growth. Many manifestations are directly related to the development and enlargement of renal cysts. The CRISP study evaluated patients with a yearly MRI examination, and demonstrated exponential increases in total kidney volume and cyst volume, with a mean increase in kidney volume of 5.3% per year over 3 years. Baseline total kidney volume predicted the subsequent rate of increase of kidney volume and was associated with declining GFR in patients with baseline total kidney volume higher than 1500 mL. Renal Function Abnormalities. Urinalysis is usually unremarkable early in the disease course. Impairment of urinary concentrating ability is common, however, even at early stages, with up to 60% of affected children unable to


maximally concentrate the urine. Mild to moderate persistent 421 proteinuria may be found in significant numbers in middle to late stage disease, and is indicative of more progressive disease. Massive proteinuria is rare and, if found, should prompt a search for an additional renal disorder. Patients with pro- CH 21 teinuria may also excrete oval fat bodies. Plasma vasopressin levels are elevated. Recent studies have suggested that the urinary concentrating defect and elevated vasopressin may contribute to cystogenesis, and may also contribute to glomerular hyperfiltration, with consequent hypertension and progression of chronic kidney disease. Reduced renal blood flow is another early functional change. Hypertension. Hypertension develops in more than 50% of patients with ADPKD and is an important risk factor for progression of kidney disease. The development of hypertension is accompanied by a reduction in renal blood flow, increased filtration fraction, abnormal renal handling of sodium, and extensive renal vasculature remodeling. The association between renal size and prevalence of hypertension supports the hypothesis that stretching and compression of the vascular tree by cyst expansion causes ischemia and activation of the renin-angiotensin system. Other factors thought to contribute to the development of hypertension in ADPKD include increased sympathetic nerve activity, impaired nitric oxide– dependent endothelial vasorelaxation, and insulin resistance. The diagnosis of hypertension in ADPKD is often delayed, and 24-hour ambulatory blood pressure monitoring of children or young adults without documented hypertension may reveal elevated blood pressures, attenuated nocturnal blood pressure dipping, and exaggerated blood pressure response during exercise, which may be accompanied by left ventricular hypertrophy and diastolic dysfunction. Uncontrolled hypertension increases the risk of hematuria, proteinuria, and a faster decline in renal function, with increased morbidity and mortality rates from valvular heart disease and aneurysms. The presence of hypertension also increases the risk of fetal and maternal complications during pregnancy. Current recommendations for blood pressure targets derive from studies of renal diseases in general and a target level of less than 130/80 mm Hg is appropriate. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are effective in the treatment of hypertension in patients with ADPKD and should be the agents of first choice. Close monitoring of the serum creatinine is warranted after initiation and during episodes of cyst hemorrhage or infection. Calcium channel blockers, b-adrenergic blockers and a2-adrenergic agonists may be helpful in refractory cases. Pain and Hematuria. Pain is the most common symptom (60%) reported by adult patients with ADPKD. Acute pain

422 is associated with renal hemorrhage, passage of stones, and


urinary tract or cyst infections; tumors should also be considered. Some patients develop chronic flank pain without identifiable cause other than the cysts alone. Long-term V administration of nephrotoxic agents should be avoided, and narcotic analgesia should be reserved for acute episodes. A number of interventions may help to minimize the risk of analgesic dependence in chronic pain, including reassurance, a supportive attitude on the part of the physician, psychological input, lifestyle modification, avoidance of aggravating activities, tricyclic antidepressants, and pain clinic interventions, such as splanchnic nerve blockade with local anesthetic or steroids. Pain may also be associated with the enlargement of one or more cysts in a kidney, and some relief may be obtained by percutaneous aspiration of fluid combined with instillation of a sclerosing agent. Alternatively, surgical aspiration and unroofing of cysts has been performed for the treatment of extremely large kidneys filled with cysts. This radical therapy may produce relief that lasts for several years. Percutaneous laparoscopic methods have been developed for cyst unroofing or total nephrectomy with reasonably good outcomes. Laparoscopic renal denervation or thoracoscopic sympathosplanchnicectomy can be considered, particularly in patients without large cysts. Renal cell carcinoma (RCC) is a rare cause of pain in ADPKD. It does not occur with greater frequency in the ADPKD population, but may present at an earlier age, with frequent constitutional symptoms, and a higher proportion of sarcomatoid, bilateral, multicentric, and metastatic tumors. A solid mass on ultrasound, speckled calcifications on CT and contrast enhancement, or tumor thrombus and regional lymphadenopathy on CT or MRI should raise the suspicion of carcinoma. Vascular endothelial growth factor (VEGF) produced by the cystic epithelium may promote angiogenesis, hemorrhage into cysts, and gross hematuria, which is caused by the rupture of a cyst into the pelvis of the kidney. Symptomatic episodes likely underestimate the frequency of cyst hemorrhage. Episodes resolve within 2 to 7 days, and can usually be treated with bed rest and analgesics. Segmental arterial embolization or surgery may be required in refractory cases. Renal Infection. As in the general population, urinary tract infections (UTIs) in ADPKD predominantly affect women. Diffuse pyelonephritis is suggested by fever, bacteremia, leukocytosis, bacteriuria, pus casts in the urine, and exquisite tenderness on deep palpation of the kidneys. In contrast, isolated cyst infection may not be associated with either bacteriuria or bacteremia, and may be suspected if the infection fails to respond to conventional parenteral therapy. Radiologic


studies are not generally useful as the changes induced by 423 infection are similar to those of hemorrhage. Most infections are caused by Enterobacteriacae. Pyelonephritis should be treated as for patients without cystic disease. Cyst infections pose a particular problem and CH 21 treatment failure may be due to poor antibiotic penetrance by polar antibiotics, such as cephalosporins and aminoglycosides. Lipophilic agents (such as ciprofloxacin and newer derivatives, chloramphenicol, erythromycin, tetracyclines) consistently penetrate cysts. If fever persists after 1 to 2 weeks of appropriate antimicrobial therapy, complicating features such as obstruction, perinephric abscess, or calculus should be excluded, and percutaneous or surgical drainage of infected cysts may be undertaken. Nephrectomy is reserved for intractable infection after parenteral antibiotic therapy has been unsuccessful. Nephrolithiasis. Approximately 20% of ADPKD patients have kidney stones, usually composed of uric acid and calcium oxalate. Metabolic factors include decreased ammonia excretion, low urinary pH, and low urinary citrate concentration. Urinary stasis due to distorted renal anatomy may also play a role. The treatment of urolithiasis is similar to that for patients without ADPKD, and often includes potassium citrate. Extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrostolithotomy have been performed successfully without undue complications. See Chapter 18, Nephrolithiasis. End-Stage Renal Disease, Dialysis, and Transplantation. As previously discussed, the development of renal failure in ADPKD is highly variable. ADPKD patients on dialysis do as well or better than others with nondiabetic renal disorders. Patients may have higher hematocrit values and less profound anemia than individuals with other renal diseases, due to cystic secretion of erythropoietin. Despite renal size and increased risk for hernias, peritoneal dialysis is usually possible. Renal transplantation is used routinely to treat patients with end-stage ADPKD. Post-transplantation patient and kidney survival rates appear to be equal to, if not better than, those in other renal disorders. Indications for pre- or posttransplantation bilateral nephrectomy include severe pain, unrelenting infection, persistent bacteriuria, recurrent severe urinary tract hemorrhage, renal neoplasm, nephrolithiasis, and extreme kidney size with compression of intra-abdominal vessels and viscera leading to symptoms.

Extrarenal Manifestations

Vascular Manifestations. Vascular manifestations include intracerebral aneurysms (ICAs) and dolichoectasia, thoracic aortic and cervicocephalic artery dissections, and coronary

424 artery aneurysms, caused by alterations in the vasculature


directly related to mutations in PKD1 or PKD2. ICAs occur in approximately 6% of patients with a negative family history and approximately 16% of patients with a clear family hisV tory of cerebral aneurysm; angiographic screening (usually magnetic resonance angiography) is reserved for individuals with a family history of aneurysm and for those with symptoms consistent with intracerebral disease. Aneurysms are most often asymptomatic, although focal signs such as cranial nerve palsies or seizures can result from compression of local structures. The risk of rupture depends on many factors (see later). The mean age of rupture is lower than in the general population (39 years versus 51 years). Most patients have normal renal function and up to 30% will have normal blood pressure at the time of rupture. Conservative management is usually recommended for small (200 mEq/day), and in the immediate preoperative period, saline infusion may be required. b-Adrenergic Blockade. b-Blockers are usually not required and should not be given prophylactically for tachycardia or arrhythmias. In PHEO, b-blockade can increase vascular resistance owing to unopposed a-adrenergic–mediated vasoconstriction if concurrent a-blockade is inadequate. b-Blockade is indicated for patients with cardiac complications, such as atrial tachyarrhythmias and myocardial ischemia, that do not respond to a-blockade. It is essential that (1) effective a-blockade is established before treatment with a b-blocker is started, and (2) a b1-selective blocker (e.g., metoprolol, atenolol) is used at the lowest dose that is effective. Combined a- and b-blockers limit the ability to carefully titrate adrenergic blockade and, thus, should not be used routinely in patients with PHEO. Angiotensin-Converting Enzyme Inhibition. Compared with patients with primary hypertension, those with PHEO have higher PRA levels. Indications for ACE inhibitor treatment include (1) hypertension that is resistant to a-blockade, particularly when the PRA level is high, and (2) HF due to systolic dysfunction. Calcium Channel Blockade. Long-acting forms of verapamil and diltiazem can be effective for controlling atrial tachyarrhythmias that are refractory to a-blockade and subsequent b-blockade. Dihydropyridine calcium channel blockers with short durations of action have been associated with cardiovascular complications and have no role in the treatment of PHEO. Hypertensive Crisis. Prompt treatment with an a-blocker is required while the patient is monitored in an intensive care unit. Phentolamine infusion at an initial rate of infusion of 1 to 5 mg/min enables rapid, controlled reduction of BP. Affected patients are also likely to be markedly volume depleted and require aggressive volume repletion. Central venous monitoring is usually required to optimize fluid management. In the hemodynamically stable patient with a PHEO, preoperative adrenergic blockade for several weeks is indicated to optimize BP, volume status, and other metabolic or cardiac complications that may be present. By contrast, PHEO crisis is an indication for emergency resection of the tumor. In this case, hypovolemia should be corrected for 24 hours prior to operation, in addition to concurrent a-blockade, to minimize the risk of postoperative hypotension.

Bilateral Renovascular Hypertension

457

See Chapter 23, Renovascular Hypertension and Ischemic Nephropathy.

Primary Hyperaldosteronism Primary hyperaldosteronism (PAL) describes the clinical syndrome characterized by hypertension, hypokalemia, hypernatremia, alkalosis, and periodic paralysis caused by an aldosterone-secreting adenoma. There are distinct subsets of PAL. The majority of patients with PAL can have hypertension and metabolic abnormalities ameliorated by unilateral adrenalectomy due to an aldosterone-producing adenoma. A subset of patients with autonomous aldosterone production do not manifest adrenal adenomas. This variant has been referred to as primary adrenal hyperplasia (PAH).

Glucocorticoid-Remediable Aldosteronism Glucocorticoid-remediable aldosteronism (GRA), also termed familial hyperaldosteronism type 1 (FH-1), is an autosomal dominant disorder in which aldosterone biosynthesis is regulated by adrenocorticotropic hormone (ACTH), rather than by the RAAS. The exaggerated aldosterone responsiveness to ACTH in GRA can be corrected by glucocorticoid treatment. Clinical features include a strong family history of hypertension, early-onset hypertension, and an increased risk of intracerebral hemorrhage or aortic dissection. The most common routine laboratory finding is a low plasma renin activity (PRA) level; however, other biochemical evidence of aldosterone excess may be absent (e.g., hypokalemia). A key diagnostic feature is the overproduction of 18hydroxycortisol and 18-oxocortisol, which are formed when cortisol is accepted by aldosterone synthase as a substrate for methyloxidation. GRA is caused by a chimeric gene duplication resulting from the fusion of the ACTH-responsive promoter region of the 11-hydroxylase gene and coding sequences of the aldosterone synthase gene. It results in ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata that is stimulated by ACTH instead of angiotensin II. Treatment of this syndrome with low doses of exogenous glucocorticoid inhibits ACTH secretion, suppresses aldosterone production, thereby promoting natriuresis, normalizes PRA, and consequently reduces BP and corrects the metabolic abnormalities caused by mineralocorticoid excess.

CH 22

Hypertension

SODIUM-DEPENDENT FORMS OF HYPERTENSION

458

Hypertension and the Kidney

The preferred diagnostic test for GRA is direct genetic analysis to identify the chimeric CYP11B1/CYP11B2 gene. Other tests include 24-hour urine collection demonstrating overproduction of cortisol C-18 oxidation metabolites (i.e., 18-hydroxycortisol, VI 18-oxocortisol), and the dexamethasone suppression test.

Familial Hyperaldosteronism Type 2 In this familial form of primary aldosteronism, termed FH-2, aldosterone production is not suppressed by glucocorticoid treatment. The inheritance pattern of FH-2 has not been completely determined.

Apparent Mineralocorticoid Excess Apparent mineralocorticoid excess (AME) is characterized by hypertension, low PRA, low urinary aldosterone excretion rate, and increased urinary excretion of metabolites of cortisol rather than cortisone. Normally, the mineralocorticoid receptor in vitro binds cortisol and aldosterone with equal affinity, whereas cortisone binding is less avid. Although the serum concentration of cortisol is normally 1000-fold greater than aldosterone, cortisol is inactivated by conversion to cortisone (which has a relatively low affinity for the mineralocorticoid receptor) by 11b-hydroxysteroid dehydrogenase at mineralocorticoid responsive tissues. This allows aldosterone, rather than cortisol, to gain access to the mineralocorticoid receptor. Thus, it is 11b-hydroxysteroid dehydrogenase rather than the mineralocorticoid receptor, per se, that confers tissue specificity for aldosterone. Treatment options in AME include (1) blockade of either the mineralocorticoid receptor (e.g., spironolactone) or the renal apical Na channel (amiloride), or (2) suppression of endogenous cortisol production with dexamethasone, which has a low affinity for the mineralocorticoid receptor. Licorice ingestion can cause hypertension with features that are similar to AME. Glycerrhyzic acid, the active ingredient of licorice, inhibits 11b-hydroxysteroid dehydrogenase and thereby allows cortisol to gain access to the mineralocorticoid receptor.

Liddle System Liddle syndrome is an autosomal dominant condition characterized by low renin hypertension, hypokalemia, renal potassium wasting, and low levels of aldosterone. The genetic defects responsible for this syndrome are mutations in the C-terminus of the b/g-subunits of the renal epithelial Na channel (ENaC). These gain-of-function mutations lead to constitutive activation of ENaC, resulting in electrogenic Na reabsorption and kaliuresis. Amiloride, which blocks the apical Na channel, is effective treatment.

Epidemiology

459

Clinical Characteristics Symptoms include nocturia and urinary frequency, reflecting the urinary concentrating defect induced by the potassium deficit. In patients with more severe hypokalemia, other manifestations including muscular weakness, frontal headaches, polydipsia, paresthesias, visual disturbances, temporary paralysis, cramps, and tetany may occur. If the patient is normokalemic, these characteristic symptoms are usually mild or absent. Patients with an adenoma, however, usually have more extensive manifestations of mineralocorticoid excess than those with hyperplasia, including more severe hypertension. The physical examination is not usually distinguishable from primary hypertension, unless hypokalemia is severe. Serum potassium levels are significantly lower in adenoma patients (40%) compared with patients with hyperplasia ( 200 mEq/day) • ARR greater than 50, with a concurrent serum aldosterone greater than 15 ng/dL • Failure to increase PRA after Na restriction, furosemideinduced diuresis • Supine plasma 18-hydroxycorticosterone levels above 50 ng/dL or ratio of plasma 18-hydroxycorticosterone to cortisol greater than 3 after saline infusion Measurements of aldosterone should be performed only after potassium supplementation because aldosterone secretion is attenuated by the potassium deficit and, thus, may obfuscate the diagnosis. The presence of hypokalemia and renal potassium wasting (24-hour urine K > 40 mEq), together with the characteristics described previously, confirms the diagnosis of primary aldosteronism. The sensitivity and specificity of each of these diagnostic maneuvers can be adversely influenced by concurrent use of antihypertensive medications. Therefore, antihypertensive medications should be discontinued for at least 2 weeks before diagnostic evaluation and potassium supplements provided to hypokalemic patients. Spironolactone should be discontinued for at least 1 month before these biochemical assessments because it has a long duration of action. Figure 22-1 is a diagnostic algorithm that can be useful for directing treatment when biochemical screening tests are indicative of PAL.

Treatment Idiopathic Hyperaldosteronism (Bilateral Adrenal Hyperplasia) The cornerstone of medical therapy in PAL caused by idiopathic hyperaldosteronism is a mineralocorticoid receptor antagonist (i.e., spironolactone, eplerenone). Side effects of

Figure 22-1. Algorithm for diagnostic testing in patients with suspected primary aldosteronism. A/C ratio, aldosterone/ cortisol ratio; CT, computed tomography; DOC, deoxycorticosterone; GRA, glucocorticoid aldosteronism; 18OHB, plasma 18-hydroxycorticosterone; 18-OHF, 24-hour urine 18-hydroxycortisol; PRA, plasma renin activity. (From Vaughan E, Blumenfeld J: The adrenals. In Wein AJ, Kavoussi LR, Novick AC, et al (eds): Campbell-Walsh Urology, vol. 4. Philadelphia, WB Saunders, 2006, pp 1819–1867.)

463

Hypertension

PRA

CH 22

No

Plasma aldosterone ≥ 15 mg/dL

Primary aldosteronism unlikely

Yes Na loading K repletion

24 hr urine: • Na > 200 mEq • Aldosterone ≥ 15 mg Plasma aldosterone > 15

No

Check cortisol DOC

Yes Positive GRA screen

Medication

Negative Adrenal CT scan

Adrenal vein sampling

Lateralized ratio > 5 (A/C ratio of dominant/nondominant adrenal vein)

Contralateral ratio > 1 (A/C ratio of non-dominant adrenal vein/IVC)

Unsuccessful or no lateralization

Ancillary tests Postural stimulation Plasma 18-OHB 24 hr urine 18-OHF

Unilateral adrenalectomy Positive • Repeat adrenal vein sampling • Medication

Negative • Medication • No further diagnostic tests

Hypertension

≥0.65 mg/hr

20 mg/dL (7 mmol/L)

8

16

Potassium < 3.4 mEq/L

8

16

Urinary casts

9

20

32

46

Age at onset > 50 yr Family history of hypertension

Proteinuria

Syndromes Associated with Renovascular Hypertension 1. 2. 3. 4. 5. 6.

Early- or late-onset hypertension (50 yr) Acceleration of treated essential hypertension Deterioration of renal function in treated essential hypertension Acute kidney injury during treatment of hypertension “Flash” pulmonary edema Progressive renal failure

Renovascular Hypertension and Ischemic Nephropathy

Clinical Presentation of Renal Artery Stenosis

474 damage. Such cases are most often seen with acute renovascular


events, such as sudden occlusion of a renal artery or branch vessel. More commonly, RAS presents as a progressive worsening of preexisting hypertension, often with a modest rise in serum creVI atinine. Since the prevalence of both hypertension and atherosclerosis rises with age, this disorder must be considered, particularly in older patients with progression of blood pressure elevation. Some of the most striking examples of renovascular hypertension are in older individuals, in whom previously well-controlled hypertension has deteriorated with an accelerated rise in systolic blood pressure and target organ injury, such as stroke. Declining renal function during antihypertensive therapy is a common manifestation of progressive renal arterial disease. In critical renal arterial stenosis, blood flow and perfusion pressures to the kidney are dependent on an elevated systemic blood pressure. Any reduction in systemic arterial pressure, induced by any antihypertensive regimen, can precipitate acute falls in renal perfusion pressure and hence glomerular filtration rate (GFR). This phenomenon has become particularly common since the introduction of angiotensin-converting enzyme (ACE) inhibitors, and more recently with angiotensin receptor blockers (ARBs), which specifically interrupt A-II mediated efferent arteriolar vasoconstriction. A sudden rise in serum creatinine soon after starting these agents suggests bilateral RAS or stenosis to a solitary functioning kidney. Other syndromes heralding occult RAS include rapidly developing episodes of circulatory congestion (so-called flash pulmonary edema).This usually arises in patients with hypertension and with left ventricular systolic function that may be well preserved. Renovascular disease favors volume retention and resistance to diuretics in such cases. Further volume expansion (e.g., high-salt diet or diuretic withdrawal) triggers a rapid rise in arterial pressure, which in turn impairs cardiac function due to rapidly developing diastolic dysfunction leading to abrupt onset pulmonary edema. Such episodes tend to be rapid both in onset and in resolution. A similar sequence of events may produce symptoms of crescendo angina from otherwise stable coronary disease. When the role of RAS is identified, renal revascularization can prevent its recurrence. Another clinical presentation of RAS is advanced renal failure, occasionally at end stage, requiring renal replacement therapy. Some estimates indicate that between 12% and 14% of patients reaching end-stage renal disease (ESRD) with no other identifiable primary renal disease may have occult, bilateral RAS. Unfortunately, most patients with advanced renal dysfunction and RAS typically have multiple co-morbid diseases and commonly have irreversible renal injury on biopsy. Those with declining renal function have a poor survival rate regardless of intervention, the strongest predictor of which is a

Progressive Vascular Occlusion Atherosclerosis is a progressive disorder and the impetus to intervene in RAS depends, in many cases, on predicting the likelihood of progression in the individual patient. Importantly, clinical events such as detectable changes in renal function or accelerating hypertension bear only a limited relationship to vascular progression. Retrospective angiographic studies from the 1970s indicate that atherosclerotic lesions progress to more severe levels in 40% to 60% of patients followed from 2 to 5 years, with up to 16% of renal arteries developing total occlusion. More recent prospective studies suggest that current rates of progression are approximately 20% over 3 years, with less than 10% of patients developing complete occlusion. The improved management of cardiovascular risk factors including the widespread use of aspirin and statin drugs, diminishing tobacco use, and more intensive antihypertensive therapy may have resulted in a change in the natural history of this disorder; however, this hypothesis remains unproved.

DIAGNOSTIC TESTING FOR RENOVASCULAR HYPERTENSION AND ISCHEMIC NEPHROPATHY Goals of Evaluation The goals of the diagnostic evaluation in the patient with suspected renovascular disease are outlined in Table 23-3.


low baseline GFR. The likely benefit of revascularization 475 regarding salvage, or at least stabilization, of renal function is greatest when the GFR is relatively well preserved. Remarkably, RAS can be associated with proteinuria, occasionally to nephrotic levels. Such proteinuria can diminish or resolve CH 23 entirely following renal revascularization. Clinical manifestations and prognosis differ when renovascular disease affects one of two kidneys or affects the entire functioning renal mass. Although blood pressure levels may be similar, response to renal revascularization leads to a greater fall in bilateral disease. Most patients with episodic pulmonary edema have bilateral disease or a solitary kidney. Long-term mortality rate during follow-up is higher when bilateral disease is present, regardless of whether renal revascularization is undertaken, reflecting an overall higher atherosclerotic disease burden. The causes of death in patients with atherosclerotic RAS are mainly related to cardiovascular disease, including stroke and congestive heart failure.

476

Goals of Diagnostic Evaluation and Therapeutic Intervention in Renovascular Hypertension and Ischemic Nephropathy

VI

Goals of Diagnostic Evaluation


Table 23-3

Establish presence of renal artery stenosis: location and type of lesion Establish whether unilateral or bilateral stenosis (or stenosis to a solitary kidney) is present Establish presence and function of stenotic and nonstenotic kidneys Establish hemodynamic severity of renal arterial disease Plan vascular intervention: degree and location of atherosclerotic disease Goals of Therapy I. Improved blood pressure control Prevent morbidity and mortality of high blood pressure Improve blood pressure control and reduce medication requirement II. Preservation of renal function Reduce risk of renal-adverse perfusion from use of antihypertensive agents Reduce episodes of circulatory congestion (“flash” pulmonary edema) Reduce risk of progressive vascular occlusion causing loss of renal function Salvage renal function (i.e., recover glomerular filtration rate)

Diagnostic tests in renovascular disease fall into three general categories: 1. Functional studies to evaluate the role of stenotic lesions particularly related to activation of the renin-angiotensin system 2. Imaging studies to identify the presence and degree of vascular stenosis 3. Studies to predict the likelihood of benefit from renal revascularization

Physiologic and Functional Studies of the Renin-Angiotensin System Peripheral plasma renin activity (PRA) and its response to administration of an ACE inhibitor such as captopril have been proposed as a marker of renovascular disease. While these studies are promising when studied in patients with known renovascular

Studies of Individual Renal Function Separate renal functional measurements can be obtained with radionuclide techniques. These methods use a variety of radioisotopes (e.g., technetium Tc 99m mertiatide or technetium Tc 99m pentetate) to estimate fractional blood flow to each kidney and estimate single kidney GFR. Prior administration of captopril magnifies differences between the kidneys, primarily by delaying excretion of the filtered isotope, due to removal of the efferent arteriolar effects of ACE inhibition. Some authors rely upon such measurements to follow progressive renal artery disease and its effect on unilateral kidney function to determine the need for revascularization. Serial measurement of individual renal function by radionuclide studies may allow more precise identification of progressive ischemic injury to the affected kidney in unilateral renal artery disease than can be determined from the overall GFR.

Noninvasive Imaging and Assessment of the Renal Vasculature Current practice favors limiting invasive arteriography to the occasion of endovascular intervention, for example, the placement of stents and/or angioplasty. Although renal arteriography remains the “gold standard” for evaluation of the renal


hypertension, they have lower performance as diagnostic tests 477 when applied to wider populations, and their sensitivity and specifity are too low for them to be used as major determinants in clinical decision making. In contrast, measurement of renal vein renin levels has been widely applied in planning surgical revas- CH 23 cularization. These measurements are obtained by sampling renal vein and inferior vena cava blood individually. The level of the vena cava is taken as comparable to the arterial levels in each kidney and allows estimation of the contribution of each kidney to total circulating levels of plasma renin activity. Lateralization is defined usually as a ratio exceeding 1.5 between the renin activity of the stenotic kidney and the nonstenotic kidney. In general, the greater the degree of lateralization, the more probable that clinical blood pressure benefit will accrue from revascularization on that side. In recent years, the shift away from revascularization for control of blood pressure toward revascularization for preservation of renal function has led to a decline in the use of renal vein assays. However, in patients in whom it is important to establish the degree of pressor effect of a specific kidney before considering nephrectomy, measurement of renal vein renins remains a useful diagnostic test.

478 vasculature, its invasive nature and potential hazards (con-


trast nephropathy, atheroembolism) make it most suitable for those in whom intervention is planned, often during the same procedure. As a result, most clinicians favor preliminary VI noninvasive studies beforehand.

Captopril Renography Imaging the kidneys using the radiopharmaceuticals technetium Tc 99m pentetate and technetium 99m mertiatide provides useful information regarding the size and glomerular filtration rates of both kidneys. The change in glomerular filtration characteristics after ACE inhibition allows inferences regarding the dependence of glomerular filtration upon A-II. Captopril renography has a reasonably high specificity, and thus can be used in populations at low pretest probability, with an expectation that a normal study will exclude significant renovascular hypertension in more than 95% of cases. Important considerations in the use of captopril renography include a lower sensitivity and specificity in the presence of renal insufficiency (usually defined as creatinine > 2 mg/ dL, 175 mmol/L) and the need to withdraw diuretics and ACE inhibitors for 4 to 14 days before the study. It should be emphasized that renography provides functional information but no direct anatomic information, that is, the location of renal arterial disease, the number of renal arteries, or associated aortic or ostial disease.

Doppler Ultrasound of the Renal Arteries Duplex interrogation of the renal arteries provides measurements of localized velocities of blood flow with a sensitivity and specificity as high as 90% in experienced hands. This affords an inexpensive means of measuring vascular occlusive disease to establish the diagnosis of RAS, following its progression, and monitoring for restenosis following endovascular intervention. Its main drawbacks relate to the difficulties of obtaining adequate studies in obese patients and interoperator variability. Recent studies emphasize the potential for Doppler ultrasound to characterize the small vessel flow characteristics within the kidney. The resistive index provides an estimate of the relative flow velocities in diastole and systole. A resistive index above 80 is suggested as a means of identifying irreversible parenchymal disease that will not respond to renal vascularization. In contrast, a resistive index of less than 80 is proposed to reliably predict a favorable blood pressure response and GFR response to revascularization.

Magnetic Resonance Angiography Gadolinium-enhanced magnetic resonance angiography (MRA) of the abdominal and renal vasculature is becoming a

Computed Tomography Angiography CT angiography using “helical” or multiple head scanners and intravenous contrast agent can provide excellent images of both kidneys and the vascular tree. Resolution and reconstruction techniques render this modality capable of identifying smaller vessels, vascular lesions, and parenchymal characteristics, including stones. When used for detection of RAS, CT angiography correlates well with conventional arteriography, and sensitivity may reach 98% and specificity 94%. Although this technique offers a noninvasive examination of the main renal vessels, it has the drawback of requiring a considerable amount of contrast material. As a result, it is less suited for evaluation of renovascular hypertension or ischemic nephropathy in patients with impaired renal function.

MANAGEMENT OF RENAL ARTERY STENOSIS AND ISCHEMIC NEPHROPATHY In most cases, the management of the patient with renovascular disease represents a balance between the pharmacologic management of hypertension and cardiovascular risk factors and the decision whether or not to proceed with renal revascularization. What should not be taken for granted is the premise that renal revascularization is likely to prolong life, prevent ESRD, or control hypertension. Indeed, both endovascular and surgical intervention in the aorta and renal vasculature carry substantial risks, including irreversible loss of renal function. It should be emphasized that consideration of renal artery disease takes place


mainstay of evaluating renovascular disease in many institu- 479 tions. Comparative studies indicate that sensitivity ranges from 83% to 100% and specificity from 92% to 97%. Advantages include the avoidance of radiation and the ability to estimate parenchymal volume and relative function from the nephrogram. CH 23 Drawbacks include the expense, a tendency to overestimate the severity of atherosclerotic lesions, and an inability to perform follow-up studies of metallic stents due to signal degradation. The utility of MRA is now limited as a consequence of the recognition of the association between the development of the debilitating condition nephrogenic systemic fibrosis (NSF) in patients with advanced renal dysfunction and the prior administration of gadolinium. NSF only develops in patients with estimated GFR levels less than 30 mL/min/1.73 m2. For that reason, the Food and Drug Administration (FDA) has issued a cautionary warning against its use in patients with advanced chronic kidney disease (see Chapter 3, Diagnostic Kidney Imaging and Interventional Nephrology, for a more detailed discussion).

480 in the broad context of managing other cardiovascular


risk factors, including withdrawal of tobacco use, reduction of cholesterol levels, and treatment of diabetes and obesity. The goals of therapy in renovascular disease can be divided VI into three categories: 1. Prevention of morbidity and fatality associated with hypertension 2. Preservation of kidney function 3. Facilitation of volume management in congestive cardiac failure Newer antihypertensive agents and the expanding use of agents that block the renin-angiotensin system for indications other than hypertension have fundamentally changed the presentation and clinical management of renovascular disease. “Uncontrollable” hypertension is now rarely the main reason for considering renal revascularization. Rather, the hazards of underperfusion of kidney tissue, leading to irreversible renal failure, have led many to consider revascularization for “preservation” of renal function. Importantly, it must be emphasized that long-term clinical outcomes in patients with atherosclerotic renovascular disease are commonly determined by other disease entities (termed competing risk), and this has important implications for decisions concerning invasive therapy. The burden of atherosclerotic disease associated with RAS is often widespread and the causes of death include a broad array of cardiovascular events. An algorithm for managing these patients is illustrated in Figure 23-2.

Management of Unilateral Renal Artery Stenosis Since the introduction of agents that block the renin-angiotensin system, most patients (86–92%) with unilateral renal artery disease can achieve blood pressure levels of less than 140/90 mm Hg

Figure 23-2. Algorithm summarizing general management scheme for patients with renovascular hypertension or ischemic nephropathy, or both. Optimizing antihypertensive and medical therapy of comorbid disease, particularly hyperlipidemia, is paramount to reducing cardiovascular morbidity and mortality in atherosclerotic disease. Decisions regarding timing of renal revascularization procedures depend both upon the clinical manifestations and whether blood pressures and kidney function remain stable. ACE, angiotensin-converting enzyme; GFR, glomerular filtration rate; PTRA, percutaneous renal artery angioplasty; RAS, renal artery stenosis.

481

Hypertension ± reduced GFR

Initiate therapy: antihypertensive medications Lifestyle, risk factor, and dyslipidemia management

CH 23

Low

High

Stable renal function Excellent blood pressure

Low

Optimize antihypertensive and medical therapy

Non-invasive imaging: RAS present ? Comorbid disease risk ? Indications for revascularization • Circulatory congestion • Deteriorating kidney function ACE inhibitor Advanced renal failure • Bilateral high-grade RAS • Solitary functioning kidney • Uncontrolled hypertension Moderate

Repeat assessment: 3–6 months ? Significant disease progression

High: Rx failure

Renal intervention PTRA/stent Surgical revascularization Stable Progression Nephrectomy (nonsalvageable pressor kidney) Stable renal function Excellent blood pressure No Repeat assessment: 6–12 weeks ? Excellent blood pressure control ? Stable renal function

Yes

No

May need repeat procedure

? Recheck for vessel patency ? Restenosis ? Technical failure ? De novo/contralateral lesions ? Atheroemboli

Optimize antihypertensive and medical therapy


Suspicion of renovascular disease ? Age, associated vascular disease ? Diminishing GFR/proteinuria ? Clinical features/abrupt onset (see text)

482 with medical regimens based upon these agents. Indeed, the


widespread use of ACE inhibitors and ARBs ensures that subcritical levels of renovascular disease are treated without being identified. The experience of ACE inhibition in trials of congestive VI cardiac failure is reassuring with regard to the use of ACE inhibition in patients with diffuse vascular disease, including renovascular disease. Thousands of patients with marginal arterial pressures and clinical heart failure have been treated with blockade of the renin-angiotensin system over many years. Many of these patients have undetected renal artery lesions and although minor changes in serum creatinine are observed in approximately 10% of patients, a rise sufficient to lead to withdrawal of these agents under trial monitoring conditions occurs in only 1% to 2%. More importantly, patients with congestive heart failure and moderate chronic kidney disease (creatinine 1.4–2.3 mg/dL, 120–200 mmol/L), many of whom will have RAS, have a major survival benefit from ACE inhibition. It follows, therefore, that many patients with unilateral RAS can be managed without restoration of blood flow for a long period, often indefinitely. The judgment on endovascular intervention in the individual patient revolves about the clinical response to conservative management and the anticipated outcome of revascularization. In trials addressing the relative value of endovascular repair, specifically angioplasty, as compared to medical therapy in atherosclerotic RAS, endovascular intervention has demonstrated little or no advantage over antihypertensive drug therapy in patients whose blood pressure was controlled adequately by pharmacologic intervention, although patients managed conservatively usually required a higher number of antihypertensive medications. The benefits of angioplasty, even in the short term, are moderate compared to effective antihypertensive therapy. However, patients failing to respond to medical therapy often improve after revascularization and many clinicians support a role for endovascular intervention in the management of patients with refractory hypertension and RAS. However, convincing randomized control data are awaited in this regard.

Progressive Renal Artery Stenosis in Medically Treated Patients As noted above, the potential for progressive vascular occlusion is central to the management of patients with renovascular disease. It may be argued that failure to revascularize the kidneys exposes the patient to the hazard of undetected, progressive occlusion, potentially leading to total occlusion and irreversible loss of renal function. However, prospective studies indicate that rates of progression of renovascular disease are moderate

Surgical Treatment of Renovascular Hypertension and Ischemic Nephropathy With the advent of endovascular techniques, surgical intervention is less commonly performed in the current era. Several of the options developed for renal artery reconstruction are listed including endarterectomy, aortorenal bypass, splenorenal bypass, and hepatorenal bypass grafting. The majority of these methods now focus on reconstruction of the vascular supply for preservation of nephron mass. Benefits of surgical intervention include excellent long-term patency (>90%) both for renal artery procedures alone and in combination with aortic reconstruction. This leads some clinicians to favor this approach for younger patients with longer life expectancy. Risk factors for poor outcome include advanced age, elevated creatinine (>3 mg/dL, 265 mmol/L), and associated aortic or other vascular disease.

Endovascular Renal Procedures The ability to restore renal perfusion in high-risk patients with endovascular methods represents a major advance in the management of renovascular hypertension and ischemic nephropathy. The past two decades have been characterized by a major shift from surgical reconstruction toward preferential application of endovascular procedures, particularly in the elderly and patients with high levels of co-morbidity. The introduction of endovascular stents has accelerated the trend away from surgical intervention, in part because of the improved patency rates achieved with ostial atherosclerotic lesions compared to angioplasty alone. However, it is often difficult to ascertain the risk-benefit ratio of these procedures from the published literature.

Angioplasty for Fibromuscular Disease Most lesions of medical fibroplasia are located at a distance away from the renal artery ostium. Many of these have multiple webs within the vessel, which can be successfully traversed and opened by balloon angioplasty so that stents


and occur at widely varying rates. Often, such patients can be 483 managed well without revascularization for many years. The clinical issue in a specific patient frequently hinges on whether the risks of revascularization are truly less than the risks of progression. It is clear that for many patients with progressive dis- CH 23 ease, optimal long-term stability of kidney function and blood pressure control can be achieved by successful surgical or endovascular restoration of the renal blood supply.

484 are rarely required. Clinical benefit regarding blood pressure


control has been reported in observational outcome studies in 65% to 75% of patients. Cure of hypertension, defined as sustained blood pressure levels less than 140/90 mm Hg with VI no antihypertensive medications, may be obtained between 35% and 50% of the time. Predictors of cure include lower systolic blood pressures, younger age, and shorter duration of hypertension. In general, such patients have relatively less aortic disease and are at less risk for the major complications of angioplasty than patients with atherosclerotic renal disease. Because the risk for major procedural complications is low, most clinicians advocate early intervention for patients with FMD, with the hope of reduced antihypertensive medication requirements after successful angioplasty.

Angioplasty and Stent Placement for Atherosclerotic Renal Artery Stenosis Few advances in renovascular disease have been associated with the level of controversy as that associated with the use of endovascular stent placement for atherosclerotic renovascular disease. Ostial lesions commonly fail to respond to angioplasty alone, in part because of extensive recoil of the plaque which typically extends into the main portion of the aorta. Endovascular stents represent a major technical advance in this area. Intermediate (6–12 months) vessel patency is significantly better following stent placement compared to angioplasty alone (29% versus 75%), and restenosis rates are below 15% as compared to almost 50% with angioplasty. The demographic features of patients undergoing renal revascularization have changed during the last decades. The mean age of patients undergoing either surgery or angioplasty (with or without stents) has climbed from 55 years to more than 75 years, as many patients are now offered endovascular procedures who otherwise would not be considered candidates for major surgical procedures, such as aortic or renal reconstruction. The outcomes of patients undergoing placement of renal artery stenting are considered in terms of (1) blood pressure control and (2) preservation or salvage of renal function in ischemic nephropathy. While “cures” are rare, typical falls in standardized blood pressure measurement are in the range of 5 to 10 mm Hg systolic, which may result in the need for fewer medications. Other reported benefits include improvement in anginal and congestive cardiac failure symptoms, presumably due to amelioration of diastolic dysfunction and improvements in natriuretic capacity. The ambiguity in outcome of many clinical trials may reflect the problem of patient selection, which likely understates the benefit of revascularization. Most trials have excluded accelerated hypertension, advancing


renal dysfunction, or recent congestive cardiac failure, settings 485 in which successful revascularization can offer major benefit. Importantly, the crossover rate from medical therapy ranged from 26% to 44% in the prospective trials, indicating that medical therapy alone simply does not succeed in a subset of patients CH 23 with renovascular hypertension. In general, changes in renal function for atherosclerotic RAS following endovascular intervention, as reflected by serum creatinine levels, have been small. Careful evaluation of the literature indicates that three distinctly different clinical outcomes are routinely observed. In some instances (approximately 27%), revascularization results in a distinct improvement in kidney function. There can be no doubt that such patients benefit from the procedure and can avoid the major morbidity (and probably mortality) associated with advanced renal failure. The bulk of patients, however, have no measurable change in renal function (approximately 52%). Whether such patients benefit much depends upon the true clinical likelihood of progressive renal injury if the stenotic lesion were managed without revascularization, as discussed earlier. Those without the risk of progression likely gain little. The most significant concern, however, is the group of patients whose renal function deteriorates further after a revascularization procedure. In most reports, this ranges from 19% to 23%. In some instances, this represents atheroembolic disease, or a variety of complications, including vessel dissection with thrombosis. Hence, nearly 20% of patients face a relatively rapid progression of renal insufficiency and the potential for requiring renal replacement therapy, including dialysis or renal transplantation. Possible mechanisms of deterioration include atheroembolic injury, which may be nearly universal after any vascular intervention, and acceleration of oxidative stress producing interstitial fibrosis. Few studies have compared endovascular intervention (percutaneous renal artery angioplasty [PTRA] without stents) and surgical repair. A single study of nonostial, unilateral atherosclerotic disease, in which patients were randomly assigned to surgery or PTRA, indicates that although surgical success rates were higher and PTRA was needed on a repeat basis in several cases, the 2-year patency rates were 90% for PTRA and 97% for surgery.

Predictors of Likely Benefit Regarding Renal Revascularization Identification of patients most likely to obtain improved blood pressure or renal function after renal revascularization remains a difficult task. As noted, functional tests of renin release, such as measurement of renal vein renin levels, have

486 not performed universally well as predictors of outcome.


These studies are most useful when positive (e.g., the likelihood of benefit improves with more evident lateralization), but they have relatively poor negative predictive value, that VI is, when such studies are negative, outcomes of vessel repair may still be beneficial. As a clinical matter, recent progression of hypertension remains among the most consistent predictors of improved blood pressure after intervention. Predicting favorable renal functional outcomes is also difficult. As with hypertension, a recent deterioration of kidney function portends more likely improvement with reconstruction. Several series indicate that surgical or endovascular procedures are least likely to benefit those with advanced renal insufficiency, usually characterized by serum creatinine levels above 3 mg/dL (265 mmol/L). Small kidneys, as identified by length less than 8 cm, are less likely to recover function, particularly when little function can be identified on radionuclide renography. Reports of renal resistance index measured by Doppler ultrasound indicate that identification of lower resistance was a favorable marker for both improvement in GFR and blood pressure, whereas an elevated resistance index was an independent marker for poor outcomes; however, none of these criteria are absolute.

SUMMARY Renovascular disease is common, particularly in older people with atherosclerotic disease elsewhere. It can produce a wide array of clinical effects, ranging from asymptomatic “incidental” disease to accelerated hypertension and progressive renal failure. With improved imaging and older patients, significant renal artery disease is detected more often than ever before. Management of cardiovascular risk and hypertension is the primary objective of medical management. It is incumbent upon clinicians to evaluate both the role of renal artery disease in the individual patient and the potential risk-benefit ratio for timing renal revascularization. For most patients, the realistic goals of renal revascularization are to reduce medication requirements and to stabilize renal function over time. Patients with bilateral disease or stenosis to a solitary functioning kidney may achieve a lower risk of circulatory congestion (flash pulmonary edema or its equivalent) and a lower risk for advancing renal failure.

Chapter 24

The Kidney and Hypertension in Pregnancy PHYSIOLOGIC CHANGES OF PREGNANCY Hemodynamic and Vascular Changes of Normal Pregnancy Normal pregnancy is characterized by profound vascular and hemodynamic changes that reach far beyond the uterus and placenta (Table 24-1). By 6 weeks’ gestation, systemic vascular resistance (SVR) decreases and arterial compliance increases. Mean arterial blood pressure (MAP) falls by an average of 10 mm Hg below baseline by the second trimester. Sympathetic activity is increased, manifested by a 15% to 20% increase in heart rate. A significant increase in the cardiac output occurs early in the first trimester, peaking at 50% above prepregnancy levels in the middle of the third trimester. The renin-aldosterone-angiotensin system (RAAS) is activated, leading to salt and water retention. Increased renal interstitial compliance may also contribute to volume retention via attenuation of the renal pressure natriuretic response. Total body water increases by 6 to 8 L, causing both plasma volume and interstitial volume expansion. There is cumulative retention of approximately 950 mmol of sodium distributed between maternal extracellular compartments and the fetus. The plasma volume increases disproportionately to the red blood cell mass, leading to mild physiologic anemia.

Renal Adaptation to Pregnancy The kidney increases 1 to 1.5 cm in length, and kidney volume increases by 30% in pregnancy. There is physiologic dilatation of the collecting system with hydronephrosis, seen in up to 80% of women, usually more prominent on the right than the left side. These changes are likely due to mechanical ureteric compression between the gravid uterus and linea terminalis, although hormonal changes and prostaglandins may also affect ureteral structure and peristalsis. The glomerular filtration rate (GFR) increases by 40% to 65%, resulting from an up to 80% rise in renal blood flow

487

488

Table 24-1

Physiologic Changes in Pregnancy

Physiologic Variable


VI

Change in Pregnancy

Hemodynamic Plasma volume

" 30–50% above baseline

Blood pressure

# 10 mm Hg below prepregnancy level; nadir in second trimester; gradual " toward prepregnancy levels by term

Cardiac output

" 30–50%

Heart rate

" 15–20 beats/min

Renal blood flow

" 80% above baseline

GFR

150–200 mL/min (" 40–50% above baseline)

Biochemical/Hematologic Hemoglobin

# by an average of 2 g/L due to plasma volume expansion disproportionate to increase in RBC mass

Creatinine

# to 0.4–0.5 mg/dL

Uric acid

# to nadir of 2–3 mg/dL by 22–24 weeks, then rises to prepregnant levels toward term

pH

" slightly to 7.44

PCO2

# by 10 mm Hg to an average of 27–32 mm Hg

Calcium

" calcitriol stimulates " intestinal calcium reabsorption and " urinary calcium excretion

Sodium

# 4–5 mEq/L below nonpregnancy levels

Osmolality

Falls to a new osmotic set-point of 270 mOsm/kg

GFR, glomerular filtration rate.

by the early second trimester. This is maintained until the middle of the third trimester, when renal blood flow begins to decline toward prepregnancy levels. The increase in GFR results in a physiologic decrease in creatinine, blood urea nitrogen (BUN), and uric acid levels. Normal creatinine clearance in pregnancy rises to 150 to 200 mL/min, and average serum creatinine falls from 0.8 mg/dL to 0.5–0.6 mg/dL, and BUN from an average of 13 mg/dL to 8 to 10 mg/dL. Although not a feature of normal pregnancy, proteinuria is exacerbated in women with preexisting proteinuric renal disease in the second and third trimesters to a greater extent than would be expected with the increase in GFR alone.

The Kidney and Hypertension in Pregnancy

Serum uric acid declines in early pregnancy due to the rise in 489 GFR, reaching a nadir value of 2 to 3 mg/dL by 22 to 24 weeks. Thereafter, the uric acid level begins to rise, reaching nonpregnant levels by term. The late gestational rise in uric acid levels is attributed to increased renal tubular absorption of urate. CH 24 Pregnancy is characterized by several changes in renal tubular function. Due to the large increase in GFR, glomerular tubular balance requires a concomitant increase in tubular solute reabsorption in order to avoid excessive renal losses. Sodium balance is maintained; pregnant women have normal excretion of an exogenous solute load and appropriately conserve sodium when intake is restricted. The ability to excrete a water load is normally maintained, albeit at a lower osmotic set-point. The osmotic threshold for antidiuretic hormone (ADH) release and thirst is decreased, resulting in mild hyponatremia, with serum sodium typically falling by 4 to 5 mEq/L below prepregnancy levels. In contrast, a small number of pregnant women develop transient diabetes insipidus due to placental vasopressinase activity in the latter stages of pregnancy. This can be treated with the synthetic ADH analog, desmopressin (DDAVP), which is not metabolized by vasopressinase. Mild glucosuria and aminoaciduria can occur in normal pregnancy in the absence of hyperglycemia or renal disease, thought to be due to an increase in the filtered load of glucose and amino acids, coupled with less efficient tubular reabsorption.

Respiratory Alkalosis of Pregnancy Minute ventilation begins to rise by the end of the first trimester, and continues to rise until term. This is mediated by progesterone, which directly stimulates the respiratory drive, and increases the sensitivity of the respiratory center to CO2. This results in a mild respiratory alkalosis—PCO2 decreases to approximately 27 to 32 mm Hg—and a compensatory increase in renal excretion of bicarbonate. This large increase in minute ventilation allows maintenance of high-normal PO2 despite the 20% to 33% increase in oxygen consumption during pregnancy. The reduction in total buffering capacity predisposes pregnant women to more severe acidosis with the development of either ketoacidosis or lactic acidosis.

Mechanism of Vasodilation in Pregnancy The mechanisms mediating the widespread pregnancy-induced decrease in vascular tone are not fully understood. The fall in SVR is only partially attributable to the low-resistance

490 circulation in the pregnant uterus, as blood pressure and SVR


are noted to fall before this system is well developed. Reduced vascular responsiveness to vasopressors such as angiotensin II, norepinephrine, and vasopressin is well documented. PregVI nancy differs fundamentally from other conditions of peripheral vasodilation, which are characterized by increased, rather than decreased, renal vascular resistance, suggesting that there is a specific renal vasodilating effect that overrides vasoconstricting factors. Recent studies suggest that the hormone relaxin may be central to this process. Relaxin facilitates increased endothelin and nitric oxide production in the renal circulation, leading to generalized renal vasodilation, decreased renal afferent and efferent arteriolar resistance, and a subsequent increase in renal blood flow and GFR. The low-resistance, high-flow circulation of the fetoplacental unit also contributes to the low SVR characteristic of the second and third trimesters. The high-resistance uterine arteries are transformed during placental development into large-caliber capacitance vessels. This process, termed pseudovasculogenesis, appears to be driven by invasion of the maternal spiral arteries by fetal-derived cytotrophoblasts, which transform from an epithelial to an endothelial phenotype as they replace the endothelium of the maternal spiral arteries. The mechanisms governing this process are still being elucidated.

HYPERTENSIVE DISORDERS OF PREGNANCY The American College of Obstetrics and Gynecology clinical criteria for the diagnosis of hypertensive disorders of pregnancy are summarized in Table 24-2. These guidelines help to distinguish preeclampsia, chronic hypertension in pregnancy, gestational hypertension, and chronic hypertension with superimposed preeclampsia. The diagnosis of preeclampsia in women with chronic hypertension or proteinuric renal disease on clinical criteria alone remains challenging.

Preeclampsia and the HELLP Syndrome Preeclampsia is a systemic syndrome that is specific to pregnancy, typically characterized by new-onset hypertension and proteinuria after 20 weeks’ gestation. It affects 3% to 5% of pregnancies worldwide, although the incidence of preeclampsia varies among populations. Most cases occur in previously healthy nulliparous women, in whom the incidence is reported to be as high as 7.5%. Interestingly, multiparous women who are pregnant with a new partner appear to have an elevated preeclampsia risk similar to nulliparous women.

Table 24-2

Hypertensive Disorders of Pregnancy: Definitions and Classification Definition

Preeclampsia

Hypertension: BP 140 mm Hg systolic or 90 mm Hg diastolic occurring after 20 wk of gestation in a previously normotensive woman and Proteinuria: Excretion of 300 mg protein in a 24-hr specimen

Severe preeclampsia

Preeclampsia with one or more of the following: Systolic BP 160 mm Hg or diastolic BP 110 mm Hg on two occasions at least 6 hr apart while on bed rest Proteinuria (protein excretion > 5 g in a 24-hr specimen) or dipstick proteinuria (3þ on two random urine samples at least 4 hr apart) Oliguria (80%), even with attempts to postpone delivery, and maternal complications are common. For this reason, termination of pregnancy may be recommended in women with severe second trimester preeclampsia. The presence of nonreassuring fetal testing, thrombocytopenia, deteriorating liver/renal function, and symptoms such as unremitting headache, visual changes, nausea, vomiting, or epigastric pain are generally considered indications for expedient delivery. Suspicion of abruptio placentae, is, as ever, an indication for emergent delivery. In preeclampsia presenting between 24 and 34 weeks’ gestation without evidence of severe disease, postponing delivery may improve neonatal outcomes, although this must be balanced against the possibility of increased maternal morbidity as a result of delaying delivery. Studies suggest that expectant management may be safe with careful and intensive fetal and maternal monitoring, even in cases of severe disease. There are no randomized, controlled trials to evaluate optimal mode of delivery in severe preeclampsia, although retrospective evidence suggests that fetal and maternal outcomes are similar in women undergoing induction of labor compared to those undergoing cesarean section. Blood Pressure Management. Management of hypertension in the preeclamptic population is substantially different from

Table 24-3

Use and Safety of Antihypertensive Medications in Pregnancy

Drug

Advantages

Disadvantages

Methyldopa

Extensive safety data No apparent adverse fetal effects

Short duration of action (bid or tid dosing); occasional somnolence Rare side effects: elevated liver enzymes, hemolytic anemia

Labetalol

Appears safe; preferred to other b-blockers owing to theoretical benefit of a-blockade on uteroplacental flow Widespread use

Short duration of action (tid dosing)

Long-acting nifedipine

Appears safe Available in slowrelease formulation, allowing once-daily dosing

First-Line Agents Oral

Intravenous Labetolol

Good safety data

Nicardipine

Extensive safety data on use as a tocolytic during labor Effective Continued


that in the nonpregnant population. Aggressive treatment of 497 hypertension in pregnancy can compromise placental blood flow and fetal growth. Treatment of mild-moderate hypertension in pregnancy has not been shown to improve outcomes and has been associated with increased risk of small-for-gesta- CH 24 tional-age infants. Acutely, aggressive lowering of blood pressure can lead to fetal distress or demise, especially if the fetus is already compromised. Because of this, antihypertensive therapy for preeclampsia is usually withheld unless the blood pressure rises above 150 to 160 mm Hg systolic or 100 to 110 mm Hg diastolic, above which the risk of cerebral hemorrhage becomes significant. The use of specific antihypertensive agents for management of hypertension in pregnancy is reviewed in Table 24-3 and discussed in the following sections.

498 Table 24-3

Use and Safety of Antihypertensive Medications in Pregnancy—Cont’d Advantages

Disadvantages

Second-Line Agents


Drug

VI

Hydralazine (PO or IV)

Extensive clinical experience

" Risk of maternal hypotension and placental abruption when used acutely

Metoprolol

Potential for once-daily dosing with longacting formulation

Safety data less extensive than for labetolol

Verapamil, diltiazem

No evidence of adverse fetal effects

Limited data

Generally Avoided Diuretics

No clear evidence of adverse fetal effects

Theoretically may impair pregnancyassociated plasma volume expansion

Atenolol

May impair fetal growth

Nitroprusside

Risk of fetal cyanide poisoning if used for more than 4 hr

Contraindicated ACE inhibitors

Multiple fetal anomalies (including renal dysgenesis, pulmonary hypoplasia), oligohydramnios, fetal oliguric AKI, IUGR

Angiotensin receptor blockers

As for ACE inhibitors

ACE, angiotensin-converting enzyme; AKI, acute kidney injury; IUGR, intrauterine growth restriction.

Magnesium and Seizure Prophylaxis. Magnesium has been widely used for decades for the prevention and management of eclampsia, and has been proved superior to other agents including diazepam and phenytoin in reduction in risk of seizures in women with preeclampsia/eclampsia. It is usually given as a bolus, followed by a continuous infusion. In the therapeutic range (5–9 mg/dL), magnesium sulfate slows neuromuscular conduction and depresses central nervous system irritability. Women receiving continuous infusions should be


carefully monitored for signs of toxicity, including loss of 499 deep tendon reflexes, flushing, somnolence, muscle weakness, and decreased respiratory rate. Close monitoring is imperative in women with impaired renal function who have impaired urinary magnesium excretion. CH 24 Management of the HELLP Syndrome. The clinical course of HELLP syndrome usually involves inexorable and often sudden and unpredictable deterioration. Given the high incidence of maternal complications, some authors advocate immediate delivery in all cases of confirmed HELLP. Among women in the 24- to 34-week gestational window whose clinical status appears relatively stable with reassuring fetal monitoring, expectant management may be a viable alternative. The use of intravenous steroids has long been suggested as an adjunct to usual management, although a recent randomized controlled trial showed no benefit with the use of high-dose dexamethasone. Post-hoc analysis, however, suggested shorter average platelet count recovery and shorter hospitalization with steroid use in the subgroup with severe disease (platelet count < 50,000); further studies are required to evaluate the benefit in this population. Novel Therapies. Recent advances in our understanding of the pathophysiology of preeclampsia have revealed new potential therapeutic targets. Interference with the production or signaling of sFlt1 may ameliorate the endothelial dysfunction of preeclampsia. Phase 1 trials using recombinant vascular endothelial growth factor (VEGF) in the management of severe preeclampsia are planned.

Chronic Hypertension and Gestational Hypertension The diagnosis of chronic hypertension is usually based on a documented history of hypertension prior to pregnancy, or a blood pressure above 140/90 mm Hg prior to 20 weeks’ gestation. It is present in 3% to 5% of pregnancies, and is more common with advanced maternal age, obesity, and black race. Pregnant women with chronic hypertension have an increased risk of preeclampsia (21–25%), IUGR (10–15%), placental abruption (1–3%), and perinatal death (4.5%). Most adverse outcomes occur in women with severe hypertension (diastolic blood pressure > 110 mm Hg); women with mild, uncomplicated chronic hypertension usually have obstetric outcomes comparable to those in the general population. Both duration and severity of hypertension correlate with perinatal morbidity and preeclampsia risk. The presence of baseline proteinuria increases the risk of preterm delivery and IUGR but not preeclampsia per se. Gestational hypertension, in contrast, is usually first noted after 20 weeks’ gestation, and by definition, resolves after

500 delivery. However, the physiologic dip in blood pressure in


the second trimester that nadirs at about 20 weeks’ gestation occurs in women with chronic hypertension, and may mask presence of underlying chronic hypertension early in pregVI nancy, resulting in a false label of gestational hypertension when blood pressure rises once again in the third trimester. Gestational hypertension progresses to overt preeclampsia in 10% to 25% of cases. When gestational hypertension is severe, it carries similar risks for adverse outcomes as preeclampsia, even in the absence of proteinuria, and should be monitored equally carefully. Preeclampsia can occasionally present prior to 20 weeks’ gestation, and should always be suspected in women presenting with new hypertension and proteinuria close to midgestation. The diagnosis of superimposed preeclampsia on chronic hypertension can be difficult. In the absence of underlying renal disease, the new onset of proteinuria (>300 mg/day) is the most reliable sign of superimposed preeclampsia. When proteinuria is present at baseline, the diagnosis requires a significant exacerbation of hypertension (>30 mm Hg) over baseline levels, with other symptoms and signs of preeclampsia, and laboratory derangements including hemoconcentration, elevated liver enzymes, and elevated uric acid. Baseline investigations in the pregnant patient with hypertension should include routine urinalysis and culture; measurement of serum creatinine, blood urea nitrogen, glucose, and electrolytes; and spot protein/creatinine ratio.

Secondary Hypertension in Pregnancy Prepregnancy evaluation of women with chronic hypertension should include consideration and evaluation for secondary causes of hypertension, including renal artery stenosis, primary hyperaldosteronism, and pheochromocytoma, all of which may present during pregnancy, albeit rarely. Pheochromocytoma in particular can be devastating when first presenting during pregnancy, and may be unmasked during labor or delivery, when fatal hypertensive crisis can be triggered by vaginal delivery, uterine contractions, and anesthesia. Maternal and neonatal outcomes are much better when the diagnosis is made antepartum. A rare cause of early-onset hypertension is due to a mineralocorticoid receptor mutation, resulting in inappropriate activation by progesterone; affected women develop marked exacerbation of hypertension during pregnancy, but without proteinuria or other features of preeclampsia.

Management Blood pressure control should be optimized prior to conception where possible, and women should be appropriately counseled regarding potential adverse outcomes. When


hypertension is severe (diastolic blood pressure > 100 mm 501 Hg), antihypertensive therapy is clearly indicated for the prevention of stroke and cardiovascular complications. However, as discussed previously, there is little evidence that treatment of mild-moderate hypertension is of clear benefit to either CH 24 mother or fetus, and although it reduces the risk of developing severe hypertension, it has no beneficial effect on the development of preeclampsia, neonatal death, small-for-gestationalage babies, or other adverse outomes. Aggressive treatment of mild-moderate hypertension in pregnancy may impede fetal growth, attributed to decreased uteroplacental perfusion. Current guidelines suggest that treatment should be initiated in women with newly diagnosed chronic hypertension in pregnancy only if there is evidence of end-organ damage, including proteinuria, or if blood pressure exceeds 150–160/100– 110 mm Hg. Choice of Agents. Recommendations for the use of antihypertensive agents in pregnancy are summarized in the next section. Antihypertensive Drugs in Breastfeeding. In general, agents that are considered safe in pregnancy remain so in breastfeeding. Methyldopa, if effective and well tolerated, should be considered first-line. b-Blockers with high protein binding, such as labetolol and propranolol, are preferred to atenolol and metoprolol, which concentrate in breast milk. Diuretics may decrease milk production and should be avoided. ACE inhibitors are poorly excreted in breast milk are generally considered safe in lactating women. Hence, in women with proteinuric renal disease, reinitiation of ACE inhibition should be considered immediately after delivery. Specific data on the pharmacokinetics should be used to guide breastfeeding intervals to avoid peak excretion times.

Acute Fatty Liver of Pregnancy Acute fatty liver of pregnancy (AFLP) is a rare but potentially fatal complication of pregnancy, affecting about in 1 in 10,000 pregnancies, with a 10% case fatality rate. More than 90% of cases occur in the third trimester. The clinical picture is dominated by liver failure, with elevated serum aminotransferase levels and hyperbilirubinemia. Symptoms may be nonspecific. Severe cases have elevated ammonia levels and hypoglycemia. Preeclampsia may be present in up to 50% of cases. Hemolysis and thrombocytopenia are not prominent features, and their presence should prompt consideration of a diagnosis of HELLP syndrome or a thrombotic microangiopathy. Acute kidney injury associated with AFLP is seen mainly near term, but can occur any time after midgestation; the cause of kidney injury

502 is unclear, but may be due to hemodynamic changes. A defect in


mitochondrial fatty acid oxidation due to mutations in the longchain 3-hydroxyacyl coenzyme A (CoA) dehydrogenase (LCHAD) has recently been hypothesized as a risk factor for VI the development of AFLP. Management includes supportive care, comprising aggressive management of coagulopathy and prompt delivery of the fetus. The syndrome typically remits post partum with no residual hepatic or renal impairment, although it may recur in subsequent pregnancies.

Acute Kidney Injury in Pregnancy In general, the diagnostic approach to AKI is the same as in the nonpregnant patient, although with careful consideration to pregnancy-specific conditions. This requires a careful physical examination to observe for signs of volume depletion and evaluation of the urinary sediment for evidence of acute tubule necrosis (ATN) or a glomerular/tubulointerstitial process. If urinary tract obstruction is suspected, ultrasonography can be performed to rule out hydronephrosis, although given the physiologic hydronephrosis of pregnancy, this diagnosis can be difficult to make with certainty.

Acute Tubule Necrosis and Bilateral Cortical Necrosis ATN occurs as a complication of many conditions, most commonly sepsis or volume depletion complicating hyperemesis gravidarum or uterine hemorrhage. Bilateral cortical necrosis is a severe and often irreversible form of ATN that is most often associated with septic abortion and placental abruption. Women with septic abortion usually present with vaginal bleeding, lower abdominal pain, and fever hours to days after the attempted abortion. Untreated, progression to shock is rapid; patients may manifest a peculiar bronze color due to hemolytic jaundice with cutaneous vasodilation, cyanosis, and pallor. Renal failure complicates up to 73% of cases, and is often characterized by gross hematuria, flank pain, and oligoanuria. Other complications include acute respiratory distress syndrome, severe anemia, leukocytosis, severe thrombocytopenia, and disseminated intravascular coagulopathy. An abdominal x-ray may demonstrate air in the uterus or abdomen due to gas-forming organisms or perforation. Sepsis associated with septic abortion is usually polymicrobial: Clostridium welchii, Clostridium perfringens, Streptococcus pyogenes, and gram-negative organisms such as Escherichia coli and Pseudomonas aeruginosa are all known pathogens. Fatal toxic shock syndrome with Clostridium sordellii has been reported following medical termination of pregnancy using mifepristone and intravaginal misoprostol.

Acute Kidney Injury and Thrombotic Microangiopathy The similarity in the clinical, pathologic, and laboratory features seen in several of the pregnancy syndromes (preeclampsia/HELLP, TTP/HUS, AFLP, systemic lupus erythematosus (SLE) with the antiphospholipid antibody syndrome, and disseminated intravascular coagulation) means that establishment of a definitive diagnosis may be extremely challenging. The confluence of clinical clues can often establish a likely diagnosis, however (Table 24-4).

Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are two pathophysiologically distinct diseases characterized by thrombotic microangiopathy with thrombocytopenia, hemolysis, and AKI. Pregnancy appears to be associated with an increased risk of both TTP (usually presenting prior to 24 weeks) and HUS (typically occurring near term or post partum), and can also precipitate relapse in women with a history of TTP. Deficiency in the von Willebrand cleaving factor protease (ADAMTS-13) has been linked to the pathogenesis of TTP in nonpregnant states; ADAMTS-13 levels fall in the second and third trimesters, potentially contributing to the increased incidence of TTP in the latter half of pregnancy. Clinical distinction between HUS/TTP and preeclampsia/HELLP may be difficult but has a significant impact on management (see Table 24-4). Case series suggest plasmapheresis to be safe and effective for the treatment of HUS/TTP in pregnancy and post partum. Delivery does not appear to alter the course of the disease and thus is generally not recommended unless the fetus is compromised.


Cortical necrosis can involve the entire renal cortex, often 503 leading to irreversible renal failure, but more commonly, involvement is patchy or incomplete. In such cases, a protracted period of oligoanuria is followed by a variable return in renal function. The diagnosis can usually be established CH 24 by CT scan, which characteristically demonstrates hypodense areas in the renal cortex. The treatment if ATN in pregnancy is supportive with prompt restoration of fluid volume deficits, and in later pregnancy, expedient delivery. No specific therapy is effective in acute cortical necrosis, with the exception of dialysis when needed; both hemodialysis and peritoneal dialysis have been used during pregnancy, although peritoneal dialysis carries a risk of impedance of uteroplacental blood flow.

504 Table 24-4


VI

Comparison of Clinical and Laboratory Characteristics of Preeclampsia/HELLP, TTP/HUS, and AFLP

Clinical Feature

HUS/TTP

Preeclampsia/ HELLP

AFLP

Hemolytic anemia

þþþ

þþ

Thrombocytopenia

þþþ

þþ

Coagulopathy

CNS symptoms

þþ

Liver disease

þþþ

þþþ

AKI

þþ

þ

þþ

Hypertension

þþ

Proteinuria

þþ

Elevated AST

þþ

þþ

Elevated bilirubin

þþ

þ

þþ

Anemia

þþ

þ

Ammonia

Normal

Normal

High

Effect of delivery on disease

None

Recovery

Recovery

Management

Plasma exchange

Supportive care, delivery

Supportive care, delivery

AFLP, acute fatty liver of pregnancy; AKI, acute kidney injury; AST, aspartate transaminase; CNS, central nervous system; HELLP, hemolysis, elevated liver enzymes, low platelets; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.

Obstructive Uropathy and Nephrolithiasis AKI due to bilateral ureteral obstruction is a rare complication of pregnancy. The radiologic diagnosis of obstruction can be challenging due to the physiologic hydronephrosis of pregnancy; if clinical suspicion is high (marked hydronephrosis, elevated creatinine, abdominal pain), a percutaneous nephrostomy may be needed as a diagnostic and therapeutic trial. If present, obstruction may be managed by ureteral stenting. Massive hematuria from the right ureter has been reported in the postpartum period, subsiding spontaneously following decompression of the partially obstructed right collecting system. Despite the increased intestinal absorption and urinary excretion of calcium during pregnancy, there is no evidence that the risk of nephrolithiasis is increased, possibly due to concomitant increase in urine flow and dilatation of the urinary tract. Ultrasonography is the investigation of choice to visualize obstruction and stones. The management of urinary calculi is conservative, with adequate hydration and antibiotics. Nephrolithiasis complicated by urinary infection should

be treated with antibiotics for 3 to 5 weeks, followed by sup- 505 pressive treatment after delivery. Most stones pass spontaneously, although placement of a ureteral stent may be necessary. Although the prevalence of asymptomatic bacteruria is the same (2–10%) in pregnant as in nonpregnant women, it requires more aggressive management due to the greater propensity to develop pyelonephritis; untreated, it can progress to overt cystitis or acute pyelonephritis in up to 40% of cases. Asymptomatic bacteriuria has also been associated with increased risk of premature birth and low birth weight; treatment reduces these complications and improves perinatal morbidity and mortality rates. Acute pyelonephritis usually presents between 20 and 28 weeks of gestation with fevers, loin pain, and dysuria and may progress to shock. The usual clinical features of urinary tract infection can be unreliable in pregnancy, as symptoms of dysuria and urinary frequency are quite common in the latter half of pregnancy due to bladder pressure from the gravid uterus. Low-grade pyuria is often present due to contamination by vaginal secretions. Quantitative urine culture is preferred to dipstick for screening; greater than 105 bacteria/mL of a single specimen indicates significant bacteriuria. Screening for asymptomatic bacteriuria is recommended during the first prenatal visit and is repeated only in high-risk women, such as those with a history of recurrent urinary tract infections or urinary tract anomalies, including vesicoureteral reflux. If asymptomatic bacteriuria is found, prompt treatment is warranted (usually with a cephalosporin or ampicillin) for at least 3 to 7 days. Treatment with a single dose of fosfomycin has been successfully used. Trimethoprim sulfate and tetracyclines are contraindicated due to their association with birth defects. A follow-up culture 2 weeks after treatment is necessary to ensure eradication of infection. Suppressive therapy with nitrofurantoin or cephalexin is indicated for bacteruria that persists after two courses of therapy; prolonged suppressive therapy has been shown to reduce the incidence of pyelonephritis. Pyelonephritis should be treated aggressively with hospitalization, intravenous antibiotics, and hydration.

PREGNANCY IN WOMEN WITH RENAL DISEASE Women who enter pregnancy with CKD are at increased risk for adverse maternal and fetal outcomes, including rapid decline of renal function and perinatal fatality. The frequency of live births now exceeds 90% in this population, but with

CH 24


Urinary Tract Infections

506 significant elevation in the risk of preterm delivery, IUGR, peri-


natal death, and preeclampsia. The physiologic increase in GFR and renal blood flow seen in normal pregnancy is attenuated in CKD; preexisting hypertension and proteinuria commonly VI worsen. Overall maternal and fetal prognosis correlates with the degree of hypertension, proteinuria, and CKD present prior to conception. Women with underlying kidney disease but with only mild impairment, normal blood pressure, and no proteinuria have good fetal and maternal outcomes, with little or no risk of progression to ESRD or preterm delivery. Women who become pregnant with a serum creatinine greater than 1.4 to 1.5 mg/dL are more likely to experience a decline in renal function compared to nonpregnant women with comparable renal function. Initiating pregnancy with a serum creatinine greater than 2 mg/dL carries a high risk (>30%) for accelerated decline in renal function both during and after pregnancy. Among women with serum creatinine greater than 2.5 mg/dL, over 70% experience preterm delivery, and over 40% preeclampsia; a significant proportion of pregnancies in this population will not result in a live birth. Termination of pregnancy does not reliably reverse the decline in renal function. Goals of antihypertensive treatment are discussed earlier in this chapter.

Diabetic Nephropathy and Pregnancy Women with pregestational diabetes, with or without nephropathy, have a higher risk of adverse fetal and maternal outcomes compared to nondiabetics. The risk of preeclampsia is more than double that seen in the general population, and is further compounded by the presence of microalbuminuria. Poor glycemic control before and during pregnancy has also been linked to preeclampsia and serious adverse fetal outcomes. Pregnancy itself does not appear to adversely affect the progression of kidney disease if renal function is normal or near normal at the start of pregnancy; however, in women with impaired function at onset, there is typically a progressive decline in renal function after pregnancy. Aggressive blood pressure control before and after pregnancy may attenuate the postpartum decline in function. The diabetic milieu during pregnancy is speculated to lead to impaired nephrogenesis and reduced nephron mass in the offspring of affected mothers, with subsequent increased risk of renal disease and hypertension in later life.

Lupus Nephritis and Pregnancy Women with SLE are at increased risk of preterm birth, IUGR, spontaneous abortions, and preeclampsia, with further


increase in risk seen in the presence of associated renal dis- 507 ease. It is clear that active disease, compromised renal function, hypertension, or proteinuria at conception is associated with increased risk of adverse fetal and maternal outcomes. Specific subsets of women with SLE are at particularly high CH 24 risk: those with antiphospholipid antibodies have an increased risk of thrombosis, fetal loss, and preeclampsia, and those with proliferative lupus nephritis (WHO class III or IV) have an increased risk of preeclampsia and lower birth weights than those with mesangial (class II) or membranous (class V) lupus nephritis. Women with SLE should postpone pregnancy until lupus activity is quiescent and immunosuppressive agents have been minimized. Prophylactic treatment with steroids does not appear to prevent lupus flare during pregnancy; immunosuppressants have been used to manage flares during pregnancy in the hope of extending pregnancy duration. Distinguishing a flare of lupus nephritis from superimposed preeclampsia may be challenging, but is particularly critical in women presenting prior to 37 weeks’ gestation; those with disease flare may be treated as such and pregnancy allowed to continue, whereas preeclampsia may warrant immediate delivery. Unfortunately, low complement levels and the presence of hematuria are neither sensitive nor specific for a lupus nephritis flare. An active urine sediment is common in lupus nephritis, whereas the sediment in preeclampsia is typically bland. Frequent clinical assessments are required, and a renal biopsy may be necessary to determine the diagnosis. Clinical experience suggests that renal biopsy is safe if undertaken prior to 30 weeks’ gestation, after which biopsy becomes technically difficult due to the gravid uterus.

Pregnancy and Chronic Dialysis ESRD is characterized by severe hypothalamic-pituitarygonadal dysfunction that is reversed by transplantation but not by dialysis. Women on dialysis have menstrual disturbances, anovulation, and infertility; men may experience testicular atrophy, hypospermatogenesis, infertility, and impotence. Conception on dialysis is unusual but not impossible; adequate contraception is therefore important. The incidence of pregnancy in women of childbearing age undergoing chronic hemodialysis is less than 1%. When pregnancy does occur, significant changes in management are required. Current guidelines recommend increasing the weekly dialysis dose to 20 hours or more per week, as this has been associated with improved neonatal outcomes and longer gestations; this is often most realistically achieved by daily nocturnal dialysis.

508 Management of volume status is challenging because the dry


weight needs to be sequentially increased throughout pregnancy, and hypovolemia needs to be vigilantly avoided. Medications must be adjusted appropriately; erythropoietin in VI particular must be adjusted to approximate the physiologic anemia of pregnancy, as high hematocrit has been associated with adverse fetal outcomes. Exacerbation of hypertension is common; the incidence of preeclampsia is difficult to ascertain due to the inapplicability of standard diagnostic criteria. Close monitoring of fetal well-being in collaboration with an obstetrician is essential after 24 weeks’ gestation, as early fetal distress is common. Data on pregnancy outcomes in peritoneal dialysis are even more limited, but appear to be similar to hemodialysis.

Pregnancy in the Renal Transplant Recipient Kidney transplantation restores normal hormonal function and fertility within 6 months in approximately 90% of women of child-bearing age. Although the majority of pregnancies following kidney transplant lead to excellent outcomes for both mother and fetus, such pregnancies are not without risk, and require close monitoring by both obstetrician and nephrologist. Approximately 22% of pregnancies among renal transplant recipients end in the first trimester, 13% due to miscarriage, and the remainder due to elective termination. For pregnancies that continue, more than 90% result in a successful outcome. There is, however, a substantial risk of low birth weight (25–50%) and preterm delivery (30–50%). Ectopic pregnancy appears to be slightly increased, especially in pregnancies that occur soon after transplant, but the rate remains less than 1%. The rate of structural birth defects is not increased above the general population. Vaginal delivery is safe, and cesarean section should be performed only for obstetric indications. Pregnancy in the first 6 to 12 months following transplant is undesirable for several reasons. The risk of acute rejection is relatively high, immunosuppressants are at higher doses, and risk of infection is greatest. Although an interval of 2 years following successful transplant was traditionally advised, the American Society of Transplantation currently suggests that for women on stable, low doses of immunosuppressive medications, with normal renal function, and no rejection episodes, pregnancy could be considered as early as 1 year after transplant (Table 24-5). Pregnancy itself does not appear to adversely affect graft function, provided baseline graft function is normal and significant hypertension is not present. When pregnancy occurs

Table 24-5

Immunosuppressive Medications in Pregnancy Safety Comments

Prednisolone

Safe chronically at low-moderate doses (5–10 mg/day) Used acutely at high doses for acute rejection

Cyclosporine

Extensive clinical data suggest safe at low-moderate clinical doses Animal data suggest adverse fetal effects at high doses Changes in absorption and metabolism require close monitoring of levels and frequent dose adjustment

Tacrolimus

Similar to cyclosporine, although safety data are more limited

Sirolimus

Contraindicated in pregnancy: teratogenic in animal studies

Mycophenolate mofetil

Contraindicated in pregnancy: teratogenic in animal and human studies

Azathioprine

Considered safe at doses < 2 mg/kg/day

OKT-3

Case reports of successful use for induction in unsuspected pregnancy and for acute rejection; limited data

Antithymocyte globulin, dacilizumab, basiliximab

No data

1 to 2 years after transplant, the rejection rate is similar to that seen in nonpregnant control subjects (3–4%). Where baseline serum creatinine exceeds 1.5 to 1.7 mg/dL pregnancy carries a risk of progressive renal dysfunction, as well as increased risk of small-for-gestational-age infant and of preeclampsia. Owing to ongoing immunosuppression, transplant recipients are at increased risk of infections that have implications for the fetus, including cytomegalovirus (CMV), herpes simplex virus (HSV), and toxoplasmosis. The rate of urinary tract infections is increased (13–40%), but these infections are usually treatable and uncomplicated. Hypertension is the most common complication of pregnancy (30–75%); preeclampsia complicates 25% to 30% of pregnancies. The American Society of Transplantation recommends that hypertension in pregnant renal transplant recipients should be treated more aggressively, with target blood pressure close to normal,

CH 24


Medication

509

510 differing from the higher blood pressure goals in hypertensive


women in pregnancy in the absence of a transplant. Appropriate antihypertensive drugs are discussed earlier in this chapter. Calcineurin inhibitors and steroids, with or without azathioVI prine, form the basis of immunosuppressants during pregnancy. Steroids at low-moderate doses (5–10 mg/day) are safe; stress-dose steroids are required at time of, and for 24 to 48 hours after, delivery. Azathioprine is generally considered safe at dosages less than 2 mg/kg/day; higher doses are associated with congenital anomalies, immunosuppression, and IUGR. Experience with tacrolimus is more limited than that with cyclosporine, but is growing. Clinical data have not shown increased risk of congenital malformations, with the possible exception of low birth weight. Because of decreased gastrointestinal absorption, increased volume of distribution, and increased GFR, calcineurin levels can fluctuate significantly, mandating close monitoring with appropriate adjustment. Sirolimus and mycophenolate mofetil are contraindicated in pregnancy.

Management of Acute Rejection in Pregnancy The incidence of acute rejection in pregnancy is similar to that for the nonpregnant population, although diagnosis may be difficult. Biopsy of the renal graft should be performed to confirm the diagnosis prior to treatment. Although high-dose steroids have been associated with fetal malformations and maternal infections, they remain a mainstay of treatment of acute rejection. Little data are available on the safety of agents such as OKT-3, ATG, dacilizumab, or basiliximab in pregnancy.

Chapter 25

Antihypertensive Drugs INDIVIDUAL AGENTS Angiotensin-Converting Enzyme Inhibitors Class Mechanisms of Action The angiotensin-converting enzyme (ACE) inhibitors inhibit the activity of ACE, which converts angiotensin I (A-I) to the potent hormone angiotensin II (A-II). Because A-II plays a crucial role in maintaining and regulating blood pressure (BP) by promoting vasoconstriction and renal sodium and water retention, ACE inhibitors are powerful tools for targeting multiple pathways that contribute to hypertension, as shown in Table 25-1.

Class Members There are currently more than 15 ACE inhibitors in clinical use. Each drug has a unique structure but they all have remarkably similar clinical effects. The pharmacodynamic properties of the ACE inhibitors are outlined in Table 25-2.

Class Renal Effects ACE inhibitors have vast hemodynamic and nonhemodynamic effects that afford the kidney protection. The mechanisms by which this is achieved are outlined in Table 25-3. The antikaliuretic effect is typically transient but can be exacerbated by concomitant administration of potassiumsparing diuretics, supplements, and NSAIDs and should be monitored rigorously. The effectiveness of ACE inhibitors on angiotensin peptide levels depends on the responsiveness of renin secretion. When renin shows little increase in response to ACE inhibiton, the levels of A-II and its metabolites decrease markedly, with little change in A-I levels. Large increases in renin levels in response to ACE inhibition increase the levels of A-I and its metabolites, which can produce higher levels of A-II by uninhibited ACE and other pathways, thereby blunting the effect of ACE inhibition. This phenomenon is referred to as ACE escape, and may contribute to reduced ACE inhibitor efficacy when used chronically. The reduction of proteinuria is a key therapeutic goal in chronic kidney disease (CKD) management. All ACE inhibitors decrease urinary protein excretion in both normotensive and hypertensive patients with CKD of various origins.

511

512 Table 25-1

Antihypertensive Mechanism of Angiotensin-Converting Enzyme Inhibitors

# Vasodilatory bradykinins


# Peripheral vascular resistance

VI

Enhance vasodilatory prostaglandin synthesis Improve nitric oxide–mediated endothelial function Reverse vascular hypertrophy # Aldosterone secretion Induce natriuresis Augment renal blood flow Blunt sympathetic nervous system activity and pressor responses Inhibit norepinephrine and arginine vasopressin release Inhibit baroreceptor reflexes # Endothelin-1 levels Inhibit thirst Inhibit oxidation of cholesterol Inhibit collagen deposition in target organs

Table 25-2

Pharmacodynamic Properties of AngiotensinConverting Enzyme Inhibitors

Generic Name

Dose Range (mg)

Captopril Benazepril

Max Dose (mg)

Dosing Interval

Peak Response (hr)

12.5–50

150

bid/tid

1–2

10–20

40

qd

2–6

Duration Response (hr) 6–12 24

Enalapril

10–40

40

qd/bid

4–8

12–24

Quinapril

20–80

30

qd

2

24

Ramipril

qd/bid

3–6

24

qd

2–12

24

qd/bid

2–7

24

2.5–20

40

Trandolapril

2–4

8

Fosinopril

5–40

40

Perindopril

4–8

8

qd

3–7

24

20–40

40

qd

6–8

24

Lisinopril

Several mechanisms account for the reduction in proteinuria, including a decrease in glomerular capillary hydrostatic pressure, a decrease in mesangial uptake and clearance of macromolecules, and improved glomerular basement membrane permselectivity. Individual response rates vary widely and

Table 25-3

Potential Renoprotective Effects of Angiotensin-Converting Enzyme Inhibitors Associated Effects

Restore pressurenatriuresis relationship to normal

Results in natriuresis and lower arterial blood pressure; exaggerated response if restricted sodium intake

Inhibit tubule sodium resorption Decrease arterial pressure Decrease aldosterone production

Correlates with decreased potassium excretion

Decrease proteinuria

Variable individual response rates; antiproteinuric effects abolished by high salt intake

Improve altered lipid profiles Decrease renal blood flow Decrease filtration fraction Decrease renal vascular resistance Reduce scarring and fibrosis Attenuate oxidative stress and free radicals

are strongly influenced by drug dose and changes in dietary sodium. There is a clear dose-response relationship between increasing doses and reduction of proteinuria, independent of changes in BP, renal plasma flow, and glomerular filtration rate (GFR). Notably, the effect of ACE inhibitors on reduction of proteinuria is abolished with high salt intake. The ACE inhibitors have superior antiproteinuric efficacy compared with other classes of antihypertensive agents, with the exception of angiotensin receptor blockers (ARBs). The antiproteinuric effect is additive with the ARBs and does not depend on changes in creatinine clearance, GFR, or BP. Many patients with impaired renal function exhibit a reversible fall in GFR with ACE inhibitor therapy that is not detrimental. This fall in GFR occurs because of the hemodynamic changes, but the long-term reduction in perfusion pressure is renoprotective. Indeed, type 1 diabetic patients with the greatest initial decline in GFR have the slowest rate of loss of renal function over time. It should be emphasized that ACE inhibitors should not be withdrawn immediately if a modest increase in serum creatinine is noted; a 20% to

CH 25

Antihypertensive Drugs

Renoprotective Effects

513

514 30% decline in GFR can be expected and close monitoring is


warranted. The improvement in clinical outcome is not restricted to hypertensive patients. In normotensive diabetics, studies demonstrate that ACE inhibitors can normalize GFR, VI markedly reduce the progression of renal disease, and normalize microalbuminuria. In patients with an activated renin-angiotensin-aldosterone system (RAAS), ACE inhibitors cause a decrease in GFR and may be a cause of acute kidney injury. Patients with severe bilateral renal artery stenosis, unilateral stenosis of a solitary kidney, severe hypertensive nephrosclerosis, volume depletion, congestive heart failure, cirrhosis, or a transplanted kidney are at high risk for renal deterioration with ACE inhibitors. In these states of reduced renal perfusion related to low effective arterial circulating volume or flow reduced by an obstructed artery, the maintenance of renal blood flow and GFR is highly reliant on A-II-mediated increased efferent arteriolar vasoconstriction, and interruption of this causes a critical reduction in perfusion pressure, leading to dramatic reductions in GFR and urinary flow, worsening of renal ischemia, and in selected cases, anuria.

Class Efficacy and Safety ACE inhibitors are recommended for initial monotherapy in patients with mild, moderate, and severe hypertension regardless of age, race, or gender, and are safe to use in patients with mild, moderate, and severe renal insufficiency. Black hypertensive patients have been found to respond less well to lower doses than whites, but higher doses are as effective. ACE inhibitors elicit an adequate response in 40% to 60% of patients and response rates are enhanced by salt restriction or the addition of low-dose hydrochlorothiazide (HCTZ). Addition of the diuretic has been shown to be more effective than increasing the dose of ACE inhibitors. ACE inhibitors are indicated as first-line therapy in hypertensive patients with heart failure and systolic dysfunction, those with type 1 diabetes mellitus and proteinuria, patients after myocardial infarction with reduced systolic function, and patients with left ventricular dysfunction. ACE inhibitors reduce ventricular hypertrophy independent of reduction in BP. Indeed, all hypertensive diabetic patients, even those with no evidence of nephropathy, should be given ACE inhibitors for cardiovascular risk reduction. Primary and secondary prevention trials have shown a reduction in myocardial ischemia and infarction, stroke, and cardiovascular death with the use of ACE inhibitors. ACE inhibitors may cause fetal or neonatal injury or death when used during the second and third trimesters of pregnancy; first trimester use has also been associated with major


congenital malformations. If a patient becomes pregnant during 515 treatment, the ACE inhibitor should be discontinued and alternative treatment commenced; termination of pregnancy should be left to the discretion of the patient and treatment team. Hyperkalemia rarely requires discontinuation of therapy and CH 25 is more likely to develop in patients with renal insufficiency or diabetes or those taking potassium-sparing drugs. The most common side effect of ACE inhibitors is a dry, hacking, nonproductive, and often intolerable cough that is reported in up to 20% of patients, thought to be secondary to hypersensitivity to bradykinins, which are normally degraded by ACE. This is managed by switching to an ARB (see later discussion). Angioedema is a rare but potentially life-threatening complication of ACE inhibitor therapy, thought to be due to tissue accumulation of bradykinins and inhibition of C1 esterase activity. It occurs in less than 0.2% of patients within hours of the first dose of ACE inhibitor or occasionally after prolonged use. First-dose hypotension occurs more commonly in volumedepleted states, patients with high-renin hypertension, and those with systolic heart failure. In elderly patients, ACE inhibitor therapy more frequently causes nocturnal hypotension. In high-risk patients, therapy should be initiated with lower doses and preferably after discontinuation of diuretics. Other complications include a metallic taste sensation, leucopenia, and anemia. Fatal agranulocytosis has been reported. ACE inhibitors have been demonstrated to interfere with the response to erythropoietin, an effect that has been utilized therapeutically for post-transplant erythrocytosis.

Angiotensin II Type I Receptor Antagonists Class Mechanisms of Action The angiotensin receptor blockers (ARBs) allow more specific and complete blockade of the RAAS than ACE inhibitors by selectively antagonizing A-II directly at the angiotensin type 1 (AT1) receptor. Because A-II plays a crucial, multifactorial role in maintaining and regulating BP, blockade of the AT1 receptor with ARBs is a powerful tool for targeting multiple pathways that contribute to hypertension. The hypotensive effects of ARBs are mediated through the same mechanisms as ACE inhibitors, as listed in Table 25-1. The pharmacodynamic properties of the ARBs are outlined in Table 25-4.

Class Renal Effects A-II receptors are widely distributed within the kidney. The hemodynamic responses are achieved by mechanisms similar to those of ACE inhibitors, as described previously. Hypertensive patients treated with ARBs, with normal or slightly

516 Table 25-4


VI

Pharmacodynamic Properties of the Common Angiotensin II Receptor Blockers

Generic Name

Dose Range (mg)

Max Dose (mg)

Dosing Interval

Peak Response (hr)

Duration Response (hr)

Eprosartan

200–400

400

qd/bid

4

24

Irbesartan

150–300

300

qd

4–6

24

Losartan

50–100

100

qd/bid

6

12–24

Valsartan

80–160

300

qd

4–6

24

Candesartan

8–32

32

qd

6–8

24

Telmisartan

40–80

80

qd

3–6

24

Olmesartan

20–40

40

qd

1.4–2.8

24

impaired renal function, exhibit renal responses similar to, or slightly greater than, those treated with ACE inhibitors. In healthy and hypertensive patients, ARBs produce dosedependent increases in circulating A-II levels and plasma renin activity. Decreases in plasma levels of aldosterone have been reported but are variable. Angiotensin receptor blockade significantly decreases urinary protein excretion in a manner broadly similar to that observed with ACE inhibition. Antiproteinuric effects have been described in diabetic and nondiabetic patients and with renal transplant recipients. The maximal antiproteinuric effect occurs at 3 to 4 weeks. The antiproteinuric effects of ACE inhibitors and ARBs appear to be additive. In a number of trials, ACE inhibitor or ARB therapy reduced proteinuria by up to 40%; combination therapy resulted in a 70% reduction in proteinuria with no further changes in BP. Long-term renoprotection with these agents substantially retards the progression of renal disease and reduces overall mortality rate in patients with type 2 diabetes mellitus independent of changes in BP. Thus, the ARBs should be the foundation of therapy in patients with type 2 diabetes and nephropathy. It is recommended that patients receiving ACE inhibitor therapy with persistent hypertension or proteinuria should be considered for combined treatment with angiotensin receptor antagonist therapy. A property unique to the losartan molecule is induction of uricosuria. This effect is not associated with an increased risk of nephrolithiasis, nor is it observed with ACE inhibitors or other ARBs, and it is not related to inhibition of the RAAS. The decrease in serum uric acid may be beneficial, as it has been suggested that hyperuricemia is a risk factor for renal disease progression and coronary artery disease.

ARBs have multiple, nonhemodynamic effects that may 517 contribute to renal protection, including antiproliferative effects on the vasculature and mesangium, inhibition of atherogenesis, improved endothelial function, and reduction of oxidative stress. CH 25 All ARBs have been demonstrated to lower BP effectively and safely in patients with mild, moderate, and severe hypertension regardless of age, gender, or race. They are indicated as first-line monotherapy or add-on therapy for hypertension and are comparable in efficacy to ACE inhibitor therapy. They are safe and effective in patients with chronic kidney disease, diabetes, heart failure, renal transplants, coronary artery disease (CAD), and left ventricular hypertrophy (LVH), and have been shown to protect against hypertensive end-organ damage, such as LVH, stroke, endstage renal disease (ESRD), and possibly diabetes. Although they may not be the most efficacious agents in terms of BP reduction in black hypertensive patients, they are equally or more efficacious in offering target organ protection and arresting disease progression than agents that do not inhibit the RAAS. The long onset of action of 4 to 6 weeks avoids the firstdose hypotension and rebound hypertension commonly seen with other drugs. The addition of thiazide diuretics potentiates the therapeutic effect and increases response rates to 70% to 80%, and is more effective than increasing the dose of ARB. ARBs may cause fetal or neonatal death when used during the second and third trimesters of pregnancy. As with ACE inhibitors an abrupt decline in GFR may be observed in the setting of renal hypoperfusion; this typically responds to withdrawal of the drug or optimization of renal perfusion. In clinical trials, hyperkalemia occurs in less than 1.5% of patients and is comparable to that observed with ACE inhibitor therapy. It is more likely to develop in patients with renal insufficiency, those with diabetes, or those taking potassiumsparing drugs. ARBs tend to lower brain natriuretic peptide levels, which may explain their benefit in heart failure. They have no effect on serum lipids in hypertensive patients but may improve the abnormal lipoprotein profile of patients with proteinuric renal disease. Clinically relevant side effects are not observed more frequently than in placebo-treated patients. Because ARBs do not interfere with kinin metabolism, cough is rare and the incidence of cough in patients with a history of ACE inhibitor–induced cough is no greater than in those receiving placebo. Similarly, the incidence of angioedema and facial swelling is no greater than with placebo.


Class Efficacy and Safety

518 b-Adrenergic Antagonists

Mechanisms of Action


b-Adrenergic blocking drugs act via attenuation of sympathetic VI stimulation through competitive antagonism of catecholamines at the b-adrenergic receptor. In addition to b-blockade properties, certain drugs have antihypertensive effects mediated through several different mechanisms including a1-adrenergic blocking activity, b2-adrenergic agonist activity, and perhaps effects on nitric oxide–dependent vasodilator action. Partial agonist activity is a property of certain b-adrenergic blockers that results in less slowing of the resting heart rate; the overall clinical significance of this remains unclear. b-Adrenergic receptor blockers may be nonspecific and block both b1- and b2-adrenergic receptors, or they may be relatively specific for b1-adrenergic receptors. b1-Receptors are found predominantly in heart, adipose, and brain tissue, whereas b2-receptors predominate in the lung, liver, smooth muscle, and skeletal muscle. Many tissues, however, have both b1- and b2-receptors, including the heart, and it is important to realize that the concept of a cardioselective drug is only relative. b-Blockers differ significantly in terms of absorption, lipid solubility, and CNS penetrance and clearance; bioavailability varies greatly.

Class Members

The b-adrenergic antagonists are classified and reviewed on the basis of the following subclasses: nonselective b-adrenergic antagonism, nonselective b-adrenergic antagonism with partial agonist activity, and b1-selective adrenergic antagonism. Their pharmacodynamic properties are outlined in Table 25-5.

Renal Effects

Both a- and b-adrenergic receptors in the kidney mediate vasoconstriction, vasodilatation, and renin secretion. In general, the acute administration of a b-adrenergic blocker usually results in reduction of GFR. The degree of reduction in GFR is typically modest and not of clinical significance in most cases. b-Adrenergic antagonist therapy is usually associated with suppression of plasma renin activity.

Efficacy and Safety

b-Adrenergic antagonists are effective therapy for the management of mild to moderate hypertension; however, their use as a first-line agent has become controversial. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) has strongly recommended a thiazide diuretic as appropriate initial therapy for most patients with hypertension.

Table 25-5 Generic Name

Pharmacodynamic Properties of b-Adrenergic Antagonists b1-Selectivity

Partial Agonist Activity

Usual Daily Dose (mg)

Max Dose (mg)

Interval

Duration of Response (hr)

Nadolol

0

0

40–80

320

qd

Propranolol

0

0

80–320

640

bid

—

Timolol

0

0

20–40

60

bid

—

Pindolol

0

þ

10–40

Labetolol*

0

þ (weak)

200–800

Atenolol

þ

0

50–100

200

qd

Metoprolol

þ

0

100–200

450

qd/bid

Bisoprolol

þ

0

5–20

Nebivolol*

þ

0

5

Acebutalol

þ

þ

400–800

1200 50

Carveldilol

0

0

3.125–25

Celiprolol

þ

0

200–600

*Denotes vasodilatory properties.

60

qd/bid

1200–1400

40

bid

qd —

—

—

24 8–12 24 3–6 24

qd

24

qd

24

bid

24

qd

—

519

520 The use of b-adrenergic antagonists is suggested largely as sec-


ondary therapy for patients with specific co-morbidities for which b-adrenergic antagonists have been shown to be of specific value, such as heart failure, postmyocardial infarction, VI and angina. Meta-analyses have suggested that compared to therapy with other agents, the reduction in major cardiovascular events associated with b-adrenergic antagonist therapy is not seen in older patients, and that b-adrenergic antagonists should not be considered first-line therapy for older patients without specific indications for their use. b-Adrenergic antagonists are useful therapy for patients in all ethnic groups, although evidence suggests that the antihypertensive response may be less in older black patients, and that b-adrenergic blockers may be less efficacious in black than in white patients when compared with therapy with calcium channel blockers and thiazides. b-Adrenergic blockers have been used to treat women with hypertension in the third trimester of pregnancy, although they are generally avoided in early pregnancy. The main side effects associated with b-adrenergic blockade include central nervous system symptoms of lethargy, sedation, sleep disturbance, depression, and visual hallucinations; sexual dysfunction in males; constipation, diarrhea, nausea, or indigestion; hyperkalemia; and impaired glucose tolerance. b-Blockade can also blunt the effects of epinephrine secretion resulting from hypoglycemia, which may result in hypoglycemia unawareness. Patients with severe bronchospastic airway disease should not receive b-adrenergic blockers. In patients with mild to moderate disease, b1-selective agents may be used cautiously. Symptoms of peripheral vascular disease may be exacerbated by b-blocker therapy. Abrupt withdrawal of b-adrenergic blockers may be associated with overshoot hypertension and worsening angina in patients with coronary artery disease; myocardial infarction has been reported. These withdrawal symptoms may be due to increased sympathetic activity, reflecting possible adrenergic receptor up-regulation during chronic sympathetic blockade. Gradual tapering of b-blockers decreases the risk of withdrawal. Chronic use of b-adrenergic antagonists has been associated with an increase in triglyceride levels and decrease in high-density lipoprotein (HDL) cholesterol, although those with increased b1-selectivity or with partial agonist activity appear to have less effect.

Calcium Antagonists Mechanisms of Action Calcium antagonists (CAs) have emerged as an important therapeutic class of medications for a variety of cardiovascular disorders. Initially introduced in the 1970s as antianginal


agents, they are now widely advocated as first-line therapy for 521 hypertension. CAs do not directly antagonize the effects of calcium, but they inhibit the entry of calcium or its mobilization from intracellular stores. Each class of CA is quantitatively and qualitatively unique, possessing differential CH 25 sensitivity and selectivity for binding pharmacologic receptors as well as the slow calcium channel in various vascular tissues. This differential selectivity of action has important clinical implications for the use of these drugs and explains why the CAs vary considerably in their effects on regional circulatory beds, sinus and atrioventricular (AV) nodal function, and myocardial contractility. It further explains the diversity of indications for clinical use, ancillary effects, and side effects. CAs uniformly lower peripheral vascular resistance in patients regardless of race, salt sensitivity, age, or co-morbid conditions. CAs decrease vascular responsiveness to A-II, and the synthesis and secretion of aldosterone. Interestingly, the maximal vasodilatory response to the CAs is inversely related to the patient’s plasma renin activity. Thus, it is possible that these agents are of specific benefit in patients with low-renin hypertension, such as black hypertensive patients. CAs may also induce a mild diuresis.

Class Members CAs are a very heterogeneous group of compounds and differ with respect to pharmacologic profile, pharmacokinetic profile, clinical indications, and side effect profile (Table 25-6).

Table 25-6

Generic Name Diltiazem Diltiazem SR

Pharmacodynamic Properties of Calcium Antagonists Usual Daily Dose (mg)

Max Dose (mg)

Dose Interval

Duration Response (hr)

60–120

480

tid/qid

120–240

480

bid

12

8

Amlodipine

5–10

10

qd

24

Felodipine

5–10

20

qd

24

Isradipine

2.5–10

20

bid

12

Nicardipine

20–40

120

tid

8

Nifedipine

10–30

120

tid/qid

4–6

Nifedipine ER

30–90

120

qd

Verapamil

80–120

480

tid/qid

Verapamil SR

90–240

480

bid

24 8 12–24

522 The two primary subtypes are the dihydropyridines (nifedi-


pine, felodipine, amlodipine, nicardipine, isradipine, nisoldipine) and nondihydropyridines. The nondihydropyridines are further divided into two classes: benzothiazepines (diltiazem) VI and diphenylalkylamines (verapamil). Although all CAs vasodilate coronary and peripheral arteries, the dihydropyridines are the most potent. Their potent vasodilatory action prompts a rapid compensatory increase in sympathetic nervous activity, mediated by baroreceptor reflexes creating a neutral or positive inotropic stimulus. Longer acting dihydropyridines, however, do not appear to activate the sympathetic nervous system. In contrast, the nondihydropyridines are moderately potent arterial vasodilators but directly decrease AV nodal conduction and have negative inotropic and chronotropic effects, not abrogated by the reflex increase in sympathetic tone. Because of their negative inotropic action, they are contraindicated in patients with systolic heart failure. Shortacting agents are no longer recommended for the treatment of hypertension as the powerful stimulation of the sympathetic nervous system by the vasodilation may predispose patients to angina, myocardial infarction, and stroke.

Class Renal Effects There are multiple mechanisms whereby CAs alter or protect renal function, notably as natriuretics, vasodilators, and antiproteinuric agents. The natriuretic effect, apparently mediated by direct inhibition of renal tubule sodium and water absorption, appears to persist in the long term. The renal hemodynamic effects of CAs are variable. Experimentally, CAs improve GFR in the presence of the vasoconstrictors norepinephrine and A-II by preferentially attenuating afferent arteriolar resistance. Acute administration of CA results in little change or augmentation of the GFR and renal plasma flow, no change in the filtration fraction, and reduction of renal vascular resistance. The long-term effects of CAs on renal function are variable; some patients exhibit no change in GFR, but others exhibit an exaggerated increase in GFR and renal plasma flow. Variable antiproteinuric effects are also seen with respect to class of drug—some dihydropyridines increase protein excretion by up to 40%. In contrast, felodipine, diltiazem, and verapamil do not appear to have this effect and may lower protein excretion, possibly by also decreasing efferent arteriolar tone and glomerular pressure. The clinical implications remain to be determined. Studies have shown that in black hypertensive patients with mild to moderate renal insufficiency and proteinuria above 1 g/day, renoprotection with an ACE inhibitor far exceeds any effect of the dihydropyridine calcium channel blocker amlodipine, with which renal function may deteriorate. Hypertensive patients with

Class Efficacy and Safety Approximately 70% to 80% of stage I and II hypertensive patients respond to monotherapy. In contrast to other vasodilators, the CAs attenuate the reflex increase of neurohormonal activity that accompanies reduction in BP, and in the long term they inhibit or do not change sympathetic activity. The CAs are effective in young, middle-aged, and elderly patients with all ranges of hypertension. CAs are equally efficacious in patients with a high or low plasma renin activity, regardless of sex, dietary salt intake, or race, although their effect is diminished in smokers. They are effective and safe in patients with hypertension and coronary artery disease and ESRD. The long-acting agents produce sustained systolic and diastolic BP reductions of 16 to 28 mm Hg and 14 to 17 mm Hg, respectively, with no appreciable development of tolerance. Among the different classes, the dihydropyridines appear to be the most powerful at reducing BP but may also be associated with greater activation of baroreceptor reflexes. Verapamil and to a lesser extent diltiazem exert greater effects on the heart and less vasoselectivity. They typically reduce heart rate, slow AV conduction, and depress contractility. CAs are

Table 25-7

Class Dihydropyridines

Renal Effects of Calcium Antagonists

Na+ Excretion ↑

GFR

Renal Blood Flow

↑ to $

↑ to $

Renal Vascular Resistance Proteinuria #

↑

Diltiazem

↑

↑ to $

↑ to $

#

/#

Verapamil

↑

↑ to $

↑ to $

#

↑

GFR, glomerular filtration rate.


diabetic nephropathy also fare considerably worse with amlo- 523 dipine therapy than with an ARB both in terms of renoprotection and overall mortality. However, co-administration of amlodipine with an ARB does not abrogate the protective effect on kidney function. It is postulated that selective dila- CH 25 tion of the afferent arteriole favors an increase in glomerular capillary pressure that perpetuates renal disease progression. CAs represent an important treatment option for renal transplant recipients. Administration of CAs may help preserve long-term renal function by protecting against cyclosporine nephrotoxicity and, possibly, by contributing to immunomodulation (Table 25-7).

524 contraindicated in patients with severely depressed left ven-


tricular function (except perhaps amlodipine or felodipine), hypotension, sick sinus syndrome (unless a pacemaker is in place), second- or third-degree heart block, and atrial arrhythVI mias associated with an accessory pathway. They should not be used as first-line antihypertensive agents in patients with heart failure, patients after myocardial infarction, those with unstable angina, or blacks with proteinuria greater than 300 mg/day. Conversely, CAs are indicated, and may be preferred, in patients with metabolic disorders such as diabetes, peripheral vascular disease, and stable ischemic heart disease. They may also be ideal agents for elderly hypertensive patients because they tend to lower the risk of stroke more than other classes. The CAs are generally well tolerated and are not associated with electrolyte derangements, significant perturbations of glycemic balance, lipemic control, or sexual dysfunction. Orthostatic changes do not occur because venoconstriction remains intact. The most common side effect of the dihydropyridines is peripheral edema. It is a result of uncompensated precapillary vasodilation and is not responsive to diuretics but may improve with the addition of an ACE inhibitor, which preferentially vasodilates postcapillary beds. Other side effects related to vasodilation include headache, nausea, dizziness, and flushing. The nondihydropyridines verapamil and isradipine more commonly cause constipation and nausea. Another common side effect of the dihydropyridines is gingival hyperplasia, exacerbated in patients taking concomitant cyclosporine. Properties beyond their antihypertensive actions make the CAs particularly useful in certain clinical situations. CAs not only lower arterial pressure but increase coronary blood flow. With the exception of the short-acting dihydropyridines, most CAs reduce heart rate, improve myocardial oxygen demand, improve ventricular filling, and conserve contractility, making them ideal for patients with angina or diastolic dysfunction. Verapamil may also be used for secondary cardioprotection to reduce reinfarction rates in patients intolerant of b-blockers unless they have concomitant heart failure. In general, the antihypertensive effects of CAs are enhanced more in combination with b-blockers or ACE inhibitors than with diuretics. Concomitant therapy with b-blockers and nondihydropyridine CAs, however, is potentially dangerous as they may have additive effects on suppressing heart rate, AV node conduction, and cardiac contractility, especially in patients with ESRD. Drug interactions are not uncommon. Concurrent use of a CA and amiodarone exacerbates sick sinus syndrome and AV block. Diltiazem, verapamil, and nicardipine have been shown


to increase cyclosporine, tacrolimus, and sirolimus levels by 525 25% to 100% by inhibiting the cytochrome P4503A4 isoenzyme, which metabolizes the calcineurin inhibitors. Concomitant administration of nifedipine, diltiazem, nicardipine, and verapamil with the digitalis glycosides results in up to a 50% CH 25 increase in serum digoxin concentrations. CAs may be associated with an increased risk of gastrointestinal hemorrhage, particularly in elderly persons. There is clear evidence that CAs reduce cardiovascular mortality and morbidity rates, particularly for stroke; however, short-acting agents such as nifedipine have been associated with a small increased risk for myocardial infarction in meta-analyses when compared with other agents. Currently, there is no evidence to prove the existence of either additional beneficial or detrimental effects of CAs on coronary disease events, including fatal or nonfatal myocardial infarctions and other deaths from coronary heart disease. Because of a potential risk, however, as well as simplicity and improved compliance, longer-acting agents should be considered over short-acting CAs for the treatment of hypertension.

Central Adrenergic Agonists Mechanisms of Action Central adrenergic agonists act by crossing the blood-brain barrier and have a direct effect on a2-adrenergic receptors located in the midbrain and brainstem, or the more recently described I1 imidazole receptors. In addition to decreasing total sympathetic outflow, binding to these receptors results in increases in vagal activity. Clonidine is a stimulant of both a2- and I1 receptors, while a-methlydopa acts on the former. The classical a2-receptor agonists such as clonidine and a-methyldopa trigger vasodilatation in resistance vessels and hence a reduction in peripheral vascular resistance and BP. Despite the vasodilatory action, reflex tachycardia generally does not occur due to peripheral sympathetic inhibition. The selective I1 receptor agonists moxonidine and rilmenidine are predominantly arterial vasodilators, resulting in a reduction in peripheral vascular resistance. Moxonidine is also associated with reduction in plasma renin activity. The central a2-adrenergic agonists may also stimulate peripheral a2-adrenergic agonists, which mediate vasoconstriction, resulting in a paradoxic increase in BP.

Class Renal Effects

Central a2-agonists and imidazole I1 agonists have little, if any, clinically important effect on renal plasma flow, GFR, or the RAAS. These agents may result in decreased renal

526 vascular resistance mediated by a decrease in preglomerular

capillary resistance related to decreased levels of circulating catecholamines.


VI Antihypertensive Efficacy and Safety These agents have been shown to be effective monotherapy for hypertension in all age and racial groups. Additive effects are associated with the addition of a diuretic. Moxonidine and rilmenidine have been associated with decreased plasma glucose levels and may improve insulin sensitivity, and may also decrease total cholesterol, low-density lipoprotein (LDL), and triglycerides, suggesting a role in the management of the metabolic syndrome. These agents may also be of benefit in patients with congestive heart failure; treatment with moxonidine and rilmenidine has been shown to reverse LVH and improve arterial compliance, with an associated decrease in plasma atrial natriuretic levels. Stimulation of a2-adrenergic receptors in the central nervous system induces several side effects of these drugs, including sedation and drowsiness. The most common side effect related to a2-adrenergic activation is dry mouth due to a centrally mediated inhibition of cholinergic transmission. Clonidine in high doses may precipitate a paradoxic hypertensive response related to stimulation of postsynaptic vascular a2-adrenergic receptors. Methyldopa has been associated with a positive direct Coombs test with or without hemolytic anemia. The a2-adrenergic agonists are associated with sexual dysfunction and may produce gynecomastia in men and galactorrhea in both men and women. Abrupt cessation of a2-adrenergic blockers may result in rebound hypertension, tachycardia, tremor, anxiety, headache, nausea, and vomiting within 18 to 36 hours.

Direct-Acting Vasodilators Mechanisms of Action The direct-acting vasodilators reduce systolic and diastolic BP by decreasing peripheral vascular resistance. Decreases in arterial pressure are associated with a fall in peripheral resistance and a reflex increase in cardiac output. Sodium and water retention is promoted secondary to the stimulation of renin release.

Class Members Hydralazine is a direct-acting arteriole vasodilator. Initial oral doses in hypertension should be 10 mg four times daily increasing to 50 mg four times daily over several weeks. Patients may require doses of up to 300 mg/day. Dosing can be changed to twice daily for maintenance. The drug may also be used as an intravenous bolus injection or as a continuous


infusion. Oral absorption is 50% to 90% of the dose and the 527 drug is up 90% protein bound. Patients with mild to moderate renal insufficiency should have the dosing interval increased to every 8 hours. In severe renal failure, the dose interval should increase to every 8 to 24 hours. CH 25 Minoxidil is a direct vasodilator. It is more potent than hydralazine and induces a more marked activation of adrenergic drive. For severe hypertension the initial recommended dose is 5 mg as a single daily dose, increasing to 10 to 20 mg or 40 mg in single or divided doses. Minoxidil is usually used in conjunction with salt restriction and diuretics to prevent sodium retention. Concomitant therapy with a b-adrenergic blocking agent is often required to prevent increases in heart rate. The elimination half-life varies with the acetylation rate in the liver, and both slow and fast acetylators have been described. Renal excretion is 90%. Dosage adjustments may be required in patients with renal failure, although the mean daily doses required to control BP have been reported to be similar in patients with normal renal function.

Class Renal Effects Hydralazine and minoxidil both increase the secretion of renin and therefore cause elevations of A-II and aldosterone. Retention of salt and water may be due to direct drug effects on the proximal convoluted tubule. GFR and renal plasma flow are unaffected.

Efficacy and Safety Minoxidil is commonly reserved for severe or intractable hypertension. When added to a diuretic and a b-blocker, minoxidil is generally well tolerated. Hypertrichosis is common. Pericarditis and pericardial infusions have been observed. An increase in left ventricular mass has been reported, possibly due to adrenergic hyperactivity. Chronic treatment with hydralazine has been associated with the development of systemic lupus erythematosus (6–10% of patients receiving high doses of hydralazine for >6 months). Generally, the syndrome occurs early in therapy, but it can occur after many years of treatment. A positive antinuclear antibody titer is used to confirm a clinical diagnosis of lupus. It occurs primarily in slow acetylators. The syndrome is reversible when hydralazine is discontinued but may require months for complete clearing of symptoms. Hydralazine has frequently been used to treat pregnancy-associated hypertension.

Endothelin Receptor Antagonists The development of endothelin receptor antagonists heralds promise for the future management of hypertension, as

528 endothelin is one of the most potent vasoconstrictors known, and is also thought to be involved in vascular remodeling and end-organ damage.


VI Mechanisms of Action and Class Members Endothelin receptor antagonists were originally studied in the management of pulmonary hypertension and heart failure, with encouraging results. The two primary receptor sites ETA and ETB can be either selectively or simultaneously blocked. It has been hypothesized that selective ETA receptor antagonists might offer greater benefits in systolic heart failure patients. Bosentan, a mixed ETA/ETB receptor antagonist, and Darusentan, a selective ETA receptor antagonist, have both been studied in the treatment of hypertension, and have shown dose-dependent reductions in BP. Common side effects include peripheral edema, flushing, headache, and liver enzyme derangement.

Class Renal Effects The effects of endothelin receptor antagonists on the kidney have not been extensively investigated. When compared to the ACE inhibitor enalapril, although comparable in terms of BP reduction, bosentan was less effective in preventing the development of proteinuria.

Class Efficacy and Safety Despite the BP reduction evident with these drugs, clinical progress in defining the therapeutic index with endothelin receptor antagonists is as yet unknown.

Moderately Selective Peripheral a1-Adrenergic Antagonists Mechanisms of Action The nonselective agents phentolamine and phenoxybenzamine have an occasional role in hypertension management. Phentolamine is utilized parenterally, and the longer acting agent phenoxybenzamine has been used orally for the management of hypertension associated with pheochromocytoma.

Class Members

Phenoxybenzamine irreversibly binds to the a-receptors, lowering peripheral resistance and increasing cardiac output. The usual oral dose of phenoxybenzamine for pheochromocytoma is 10 mg twice daily, gradually increasing every other day to doses ranging between 20 and 40 mg two or three times a day. A b-blocker may be administered if tachycardia becomes excessive during therapy; however, the pressor

Renal Effects Phenoxybenzamine has no clear effect on the renin-angiotensin-aldosterone axis. Salt and water retention does not occur. GFR and effective renal plasma flow would be expected to increase, and renal vascular resistance to decrease in proportion to the degree of blockade of a-adrenergic receptors.

Efficacy and Safety

Tachycardia may result from a-adrenergic blockade, which unmasks b-adrenergic effects with epinephrine-secreting tumors. This may be controlled with concurrent use of a b-adrenergic antagonist. a-Adrenergic blockade must be initiated prior to b-adrenergic blockade to avoid paradoxic hypertension. Side effects of phenoxybenzamine are sedation, weakness, nasal congestion, hypertension, and tachycardia.

Peripheral a1-Adrenergic Antagonists Mechanisms of Action Drugs of this class (doxazosin, prazosin) are selective for the postsynaptic a1-adrenergic receptor. Because of the selective a1 action the reflex tachycardia associated with blockade of the presynaptic a2-receptor is decreased substantially.

Renal Effects GFR and renal blood flow are maintained during long-term treatment with these agents. Renal vascular resistance may be reduced. No dosage adjustment is necessary in patients with renal disease.

Efficacy and Safety Patients receiving doxazosin as their initial antihypertensive drug have been found to have poorer BP control compared to those receiving a chlorthalidone-based treatment. In clinical studies, patients receiving doxazosin had no difference in


effects of a pheochromocytoma must be controlled by a-blockade 529 before b-blockers are initiated. With oral use, symptoms of pheochromocytoma decrease after several days. Administration of phenoxybenzamine to patients with renal impairment should be done cautiously. Specific dosage recommendations CH 25 are not available. Phentolamine is an a-adrenergic blocking agent that produces peripheral vasodilatation in cardiac stimulation with a resulting fall in BP in most patients. The drug is used parenterally. The usual dose is 5 mg repeated as needed. The onset of activity with intravenous dosing is immediate. The drug is metabolized in the liver, with 10% excreted in the urine as unchanged drug.

530 fatal coronary heart disease or nonfatal myocardial infarction


but did have higher rates of stroke and congestive heart failure compared to diuretic-based regimens. There are potentially beneficial effects of a1-blockers on lipid metabolism. These VI drugs have been consistently shown to result in a modest reduction in total and LDL cholesterol and a small increase in HDL cholesterol. Prazosin has been shown to increase insulin sensitivity. The most important side effect of a1-adrenergic receptor blockers is the first-dose orthostatic hypotension effect resulting in lightheadedness, palpitations, and occasional syncope. This effect can be exacerbated in patients with underlying autonomic insufficiency and may be minimized by initiating therapy with a small dose taken at bedtime. a1-Adrenergic antagonists are also used for symptomatic treatment of prostatic hypertrophy.

Renin Inhibitors The development of renin inhibitors has been limited by difficulty with oral bioavailability, and as a result development on several drugs was canceled.

Class Mechanism of Action and Class Member Aliskiren is a potent and specific inhibitor of human renin in vitro, and is the first in a new class of orally effective renin inhibitors. Aliskiren is potent in reducing BP and has an effective half-life of 40 hours. It is not actively metabolized by the liver and is primarily excreted in the urine.

Class Renal Effects Renin inhibitors offer substantial promise for renoprotection in that they not only provide BP reduction, but also attenuation of the activity of the renin-angiotensin system, without a reactive increase in renin or other angiotensin peptides. Animal studies have suggested that aliskiren provides comparable renoprotection as an ACE inhibitor or an ARB. Preliminary data in humans indicate that aliskiren reduces proteinuria in conjunction with BP. There appears to be greater improvement in renal blood flow with the renin inhibitor when compared to ACE inhibitors, suggesting that it may be more effective in blocking A-II formation. Longer-term studies are required, however.

Class Efficacy and Safety Clinical trials of aliskiren have shown a dose-dependent efficacy in reducing both systolic and diastolic BP, and BP reduction comparable to ARB therapy, although with suppression of

plasma renin activity and angiotensin I and II levels. The tol- 531 erability of aliskiren is comparable to that of placebo, with a relatively low incidence of adverse events with all doses tested in the 150 to 600 mg range, with the exception of some diarrhea at the 600 mg dose. CH 25

Class Mechanism and Class Member Eplerenone is a selective aldosterone receptor antagonist that may have antihypertensive effects distinct from its diuretic properties. Although it is a much less potent mineralocorticoid receptor blocker than spironolactone, it is much more specific and has little agonist activity for estrogen and progesterone receptors. Therefore, it is associated with a lower incidence of gynecomastia, breast pain, and impotence in men and diminished libido and menstrual irregularities in women.

Class Renal Effects Selective aldosterone receptor antagonism may be renoprotective independent of its effects on BP. Both experimental and clinical studies have demonstrated that A-II may be the primary mediator of the RAAS associated with progression of renal disease. Despite having no observable effects on glomerular hemodynamics, selective aldosterone receptor antagonism therapy may provide an incremental opportunity to protect the kidney in addition to ACE inhibitor or A-II receptor blocker therapy by inhibiting the effects of aldosterone that persist despite therapy with these drugs.

Class Efficacy and Safety Eplerenone lowers BP when administered at 25, 50, or 200 mg twice daily in a dose-dependent fashion. Clinical trials also demonstrated that eplerenone has antihypertensive activity that is additive with that of either an ACE inhibitor or A-II receptor blocker. In diabetic hypertensive patients with microalbuminuria, adding eplerenone to ACE inhibitor therapy reduces proteinuria more than using the ACE inhibitor alone, independent of effects on BP. The advantage of eplerenone over spironolactone in clinical practice is probably related to fewer endocrine side effects because of more selective aldosterone receptor antagonism.

Tyrosine Hydroxylase Inhibitor Mechanisms of Action and Class Member Metyrosine, the only drug in this class, blocks the rate-limiting step in the biosynthetic pathway of catecholamines via


Selective Aldosterone Receptor Antagonists

532 inhibition of tyrosine hydroxylase, the enzyme responsible for


conversion of tyrosine to dihydroxyphenylalanine. In patients with pheochromocytomas, metyrosine reduces catecholamine synthesis by up to 80%. This results in decreased total periphVI eral resistance and increased heart rate and cardiac output. The recommended initial dose of metyrosine is 250 mg four times daily, increasing by 250 to 500 mg daily, to a maximum of 4 g/day. Metyrosine is primarily eliminated unchanged in the urine; dose reduction is appropriate in patients with renal failure.

Efficacy and Safety Metyrosine is used in the perioperative management of pheochromocytoma. Hypertension and reflex tachycardia may result from vasodilatation, and may be minimized by volume expansion. Side effects include sedation, changes in sleep patterns, and extrapyramidal signs. Metyrosine crystals have been noted in the urine in patients receiving high doses; patients should maintain a generous fluid intake.

SELECTION OF ANTIHYPERTENSIVE DRUG THERAPY Blood pressure is only one of many surrogate markers of risk contributing to cardiovascular disease; the optimal goal BP for different patients may be somewhat different, depending on coexistent cardiovascular risk factors. Therefore, the treatment of high BP and the estimation of goal BP necessitate careful individualization for each patient.

Choosing Appropriate Agents The choice of initial therapy in hypertension depends on a variety of factors including patient age, gender, race, obesity, and coexistent cardiovascular or renal disease. The major considerations for initial therapy in older patients should take into account the major pathophysiologic problem, which is an increase in peripheral vascular resistance. Systolic hypertension, a wide pulse pressure, diastolic dysfunction, reduction in cardiovascular baroreceptor reflex function, and a propensity for orthostasis are characteristic. Ideal therapeutic strategies for these patients include low dose of HCTZ, 12.5 to 25 mg/day. Thiazide diuretics function primarily as vasodilators and are particularly effective in controlling systolic BP. Thiazide diuretics also facilitate vasodilation with other therapeutic classes, particularly those that block the RAAS, and they can be utilized together as fixed-dose combinations.


Calcium channel blockers are also useful vasodilators in older 533 patients. They are much better tolerated in the lower half of their dosing range, and are quite effective even in the presence of a high-salt diet. a-Blockers may be useful in older men with benign prostatic hypertrophy. ACE inhibitors are also effective CH 25 vasodilators in older patients. b-Blockers may impair baroreceptor responses in older patients and worsen orthostasis and should be used with caution. Treatment of isolated systolic hypertension in older patients frequently requires multiple drugs. Regardless of the agents that are utilized, a slow careful titration approach is recommended, preferably not more frequently than every 3 months. Differences in gender may be important with regard to the selection of antihypertensive therapy. Women should avoid the use of ACE inhibitors and ARBs in pregnancy because of their possible teratogenic effects. Optimal therapy in a pregnant woman includes a-methyldopa, hydralazine, or b-blockers as they have a proven safety record with minimal risk of teratogenic effects. The treatment of pregnancyrelated hypertension is discussed further in Chapter 24, The Kidney in Hypertension and Pregnancy. In women with osteoporosis, thiazide diuretics are ideal agents because they antagonize calciuria and facilitate bone mineralization. Women experience more cough with ACE inhibitors and more pedal edema with calcium channel blockers compared with men. Race may play a role in the choice of antihypertensive agents. Blacks typically present with hypertension at an earlier age, have more substantial elevations in BP, and experience earlier development of target organ damage than similar demographically matched white counterparts. In addition, significant racial differences in the response to antihypertensive medications exist, possibly due to higher salt sensitivity in black patients. In general, thiazide diuretics and calcium channel blockers have more robust antihypertensive properties in lower doses in blacks than other commonly used therapeutic classes. Higher doses of ACE inhibitors or ARBs are frequently required in order to achieve the same level of BP reduction as seen in other racial groups. It is not uncommon for multiple drugs to be required to reach the target BP. Consequently, fixed-dose combinations may prove to be most useful in this population group as part of the strategy to simplify the approach. Hispanic and Asian populations do not appear to have different hypertensive responses to commonly used drugs compared with whites. Obese hypertensive patients frequently have other medical problems that complicate their hypertensive management. b-Blockers may be helpful in diminishing sympathoadrenal drive. Vasodilators, such as HCTZ and ACE inhibitors, ARBs,

534 and calcium channel blockers, are useful for reducing periph-


eral vascular resistance. Combinations of these drugs may also be helpful. Because of the tendency toward expanded plasma volume, thiazide diuretics can be helpful as they provide an VI opportunity to cause both vasodilation and mild volume reduction. Frequently, these patients require multiple drugs to achieve BP goals, and simplification strategies are important. Given the increased frequency of cardiovascular risk clustering phenomena in these patients, drug therapies that are metabolically neutral are ideal. In patients with coronary artery disease, it is important to remember that the majority of coronary artery perfusion occurs during diastole. Hence, pharmacotherapy should be targeted toward slowing heart rate in order to enhance perfusion during diastole. b-Blockers and heart rate–lowering calcium channel blockers, such as nondihydropyridines, are ideal in this respect. Agents that block the RAAS are the most effective in reducing LVH. In patients with heart failure, it is important to use an echocardiogram to distinguish between diastolic and systolic dysfunction. The treatment of diastolic dysfunction should include therapies that facilitate ventricular relaxation and reduce heart rate (b-blockers and calcium channel blockers). With systolic dysfunction, drugs that block the RAAS are more suitable to provide both preload and afterload reduction. b-Blockers are also helpful in addition to ACE inhibitors. In patients with kidney disease, optimal control of hypertension is an integral component of management to prevent progression of renal disease. RAAS blockers such as ACE inhibitors and ARBs provide greater renoprotection compared with other commonly used antihypertensives. The benefit of these drugs, in part, resides in their effects to facilitate efferent glomerular arteriolar dilation by antagonizing the effects of A-II as they lower BP. Sufficient diuretics should be employed to control blood volume; when the serum creatinine reaches 2 mg/dL volume reduction is more amenable to loop diuretics than thiazide diuretics.

Refractory Hypertension Refractory hypertension is a term used to characterize hypertension that fails to respond to what the clinician considers an adequate antihypertensive regimen. True refractory hypertension is unusual, and a methodologic approach should be taken to help achieve BP control in these patients. A variety of factors interfere with the ability to normalize BP, the most important of which is noncompliance. This problem derives from many factors including inadequate education, poor


clinician-patient relationship, lack of understanding about 535 side effects, and the complexity of multidrug regimens. Pseudohypertension is commonly observed in older hypertensive patients who have hardened atherosclerotic arteries, which are not easily compressible. This interferes with aus- CH 25 cultatory measurements of BP and greater apparent pressure is required to compress the sclerotic vessel than the intra-arterial BP requires. Another common cause of pseudohypertension is improper measurement. This occurs when the BP is taken with an inappropriately small cuff in people with large arm circumference. Because of the substantial proportion of hypertensive patients who are obese, it is critical to have the appropriate cuff size for determining auscultatory pressure. Some clinicians may view white coat hypertension as a cause of refractory hypertension. This is an area of contentious debate in that elevated office readings, despite lower home readings, still provide important predictive value for the development of cardiovascular events. Some clinical studies indicate that patients with so-called white coat hypertension also have LVH and may not have an appropriate nocturnal dip in BP. Volume overload is an important and common cause of refractory hypertension. It may be related to excessive salt intake or inability of the kidney to excrete an appropriate salt and water load because of either endocrine abnormalities or intrinsic renal disease. Salt sensitivity is particularly common in patients of African-American descent. A careful clinical examination coupled with judicious use of either thiazide or loop diuretics is critical in achieving ideal blood volume in order to restore the antihypertensive efficacy of most classes of drugs. It is also appropriate to consider educating the patient about avoiding foods that are rich in salt content, such as processed foods. Drug-related causes of refractory hypertension are common and need to be carefully assessed in each patient. Perhaps the most common drugs that cause refractory hypertension are over-the-counter preparations of sympathomimetics such as nasal decongestants, appetite suppressants, and NSAIDs. Unfortunately, patients may not always recognize overthe-counter preparations as a medication. Therefore, careful questioning specifically focusing on these types of medications should be routine during the evaluation for refractory hypertension. In addition, oral contraceptives, ethanol, cigarettes, and cocaine can be complicating factors that interfere with the ability of medications to lower BP. Obesity is an oft-overlooked cause of refractory hypertension and is commonly associated with obstructive sleep apnea. Nighttime ventilation techniques enhance the control of BP. Secondary causes of hypertension might also be considered as a cause of refractory hypertension. CKD and renal vascular

536 disease are not uncommon and are easily investigated. Addi-


tional endocrine abnormalities include hyperaldosteronism, pheochromocytoma, or hypo- or hyperthyroidism and hyperparathyroidism; rarely, aortic coarctation can be a cause of VI refractory hypertension. Often patients with subtle hyperaldosteronism will respond to the addition of a selective aldosterone receptor blocker. Strategies to control BP in patients with refractory hypertension should first deal with issues related to compliance, simplifying the medical regimen, and ensuring that side effects are not playing a role. Subsequently, one can evaluate the medications and try to choose those that work well with one another to facilitate a nearly additive antihypertensive response. Most drugs reduce systolic BP by approximately 8 to 10 mm Hg. Consequently, it is not unusual for patients who are 40 or 50 mm Hg from goal systolic BP to require four or five medications or possibly even more. One should also be careful to be sure that volume excess is controlled and that there are no drug-drug interactions or clinical situations that would promote diuretic resistance such as excessive salt intake.

DRUG TREATMENT OF HYPERTENSIVE URGENCIES AND EMERGENCIES The terms hypertensive urgency and hypertensive emergency are used loosely in clinical practice with a great deal of overlap. The distinction between the two is important because the management approach is substantially different. A hypertensive emergency is a clinical syndrome in which severe hypertension results in ongoing target organ damage manifested by encephalopathy, retinal hemorrhage, papilledema, acute myocardial infarction, stroke, or acute renal dysfunction. Any delay in control of BP may lead to irreversible sequelae, including death. Hypertensive emergencies are unusual but require immediate hospitalization in an intensive care unit, with careful and judicious use of intravenous vasodilators to lower systolic and diastolic BP cautiously to approximately 140/90 mm Hg (Table 25-8). In contrast, hypertensive urgencies are clinical situations in which a patient has a marked elevation in BP (>200/130 mm Hg) but no evidence of ongoing target organ damage. These patients can be managed cautiously on an outpatient basis (Table 25-9).

Parenteral Drugs, Direct-Acting Vasodilators Diazoxide is a pure arterial dilator that is used primarily in the treatment of acute hypertensive emergencies. The “minibolus”

Table 25-8

Parenteral Drugs Used in the Treatment of Hypertensive Emergencies

Class

Drug

Dose (max)

Onset of Action

Peak Effect

Duration of Action

Direct-acting vasodilators

Diazoxide

7.5–30 mg/min infusion or 1 mg/kg bolus q 5–15 min (300 mg max) 0.5–1 mg/min infusion or 10–50 mg IM 5–100 mg/min 0.25–10 mg/kg/min infusion

1–5 min

30 min

4–12 hr

1–5 min

10–80 min

3–6 hr

1–2 min Immediate

2–5 min 1–2 min

3–5 min 2–5 min

Hydralazine Nitroglycerine Nitroprusside b1-Adrenergic antagonist

Esmolol

250–500 mg/min 1 (loading), then 50–100 mg/kg/min 4 (maintenance); to max maintenance dose 300 mg/kg/ min

1–2 min

5 min

10–30 min

a1- and b1-Adrenergic antagonist

Labetolol

2 mg/min infusion or 0.25 mg/kg

5 min

10 min

3–6 hr

Ganglionic blockers

Trimethaphan

0.5–10 mg/min infusion bolus over 2 min (max 300 mg)

Immediate

1–2 min

5–10 min

ACE inhibitor

Enalaprilat

0.625–5 mg bolus over 5 min every 6 hr

5–15 min

1–4 h

6 hr Continued

537

538 Table 25-8

Parenteral Drugs Used in the Treatment of Hypertensive Emergencies—Cont’d

Class

Drug

Dose (max)

Onset of Action

Peak Effect

Duration of Action

Peripheral a-adrenergic antagonist

Phentolamine

0.5–1 mg/min infusion or 2.5–5 mg bolus

Immediate

3–5 min

10–15 min

Calcium antagonist

Nicardipine

5–15 mg/hr

5–10 min

45 min

50 hr

Dopamine D1-like receptor antagonist

Fenoldopam

0.01–1.6 mg/min constant infusion

5–15 min

30 min

5–10 min

Central a2-agonist

Methyldopa

250–500 mg bolus every 6 hr (max 2 g)

2–3 hr

3–5 hr

6–12 hr

ACE, angiotensin-converting enzyme.

Table 25-9

Rapidly Acting Oral Drugs Used in the Treatment of Hypertensive Urgencies Peak Effect (hr)

Duration of Action (hr)

Onset of Action

Labetolol

100–400 mg every 12 hr (max 2400 mg)

1–2 hr

2–4

8–12

Clonidine

0.2 mg initially, then 0.1 mg/hr (max 0.8 mg)

30–60 min

2–4

6–8

Diltiazem

30–120 mg every 8 hr (max 480 mg)

40%), or both. Several forms of intravenous iron are available: iron dextran, iron sucrose, and ferric gluconate. Iron dextran has been used for several decades and although clearly effective, its use is associated with risk of anaphylactoid reaction in approximately 0.6% of patients treated. These reactions are believed to be related to the drug’s dextran component and may be due to direct release of vasoactive mediators by mast cells. Iron sucrose and ferric gluconate are non-dextran forms of intravenous iron that appear to be safer than iron dextran with lower risk of anaphylactoid reactions, and a similar rate of serious adverse events when compared to placebo. Two strategies for administering intravenous iron to hemodialysis patients are in common use. The first entails surveillance for the presence of iron deficiency every 3 months and, if detected, treatment with a short, repletive course of intravenous iron. Typically, 1000 mg of either iron sucrose or ferric gluconate can be given in divided doses over a period of 2 to 3 weeks. Patients will generally demonstrate a significant improvement in responsiveness to rHuEPO thereafter. Many, however, will remain iron deficient, so assessment of iron stores should be repeated after completing such a course of treatment. A second strategy is to anticipate iron deficiency

Potential Adverse Effects of Iron Therapy Several complications may occur with inattentive intravenous iron use. Iron overload may occur if iron is administered indiscriminately, and without due regard for monitoring the parameters indicative of iron status. The role of iron exposure in the setting of infection is unclear, although several studies have demonstrated increased risk of infection and bacteremia with increased administration of intravenous iron. At present, it seems prudent to avoid the use of intravenous iron during periods of acute infection. Intravenous iron administration has also been shown to increase oxidative stress, thought to be due to the release of free iron into the circulation, although the quantitative importance of such induced oxidative stress is less clear. However, given our increasing knowledge of the importance of oxidative stress in such pathologic processes as atherosclerosis, and effects of oxidative tissue injury, including renal injury, this clearly may have significant implications on future use of intravenous iron and rHuEPO.

Potential Adverse Effects of rHuEPO Treatment Following the introduction of rHuEPO, general concern was expressed regarding the development of a variety of serious potential complications of therapy, including worsening hypertension (occasionally in an accelerated form), seizures, impaired solute clearance (particularly potassium), and an increased frequency of thrombotic events at, but not confined to, vascular access sites. Despite this, few have materialized over the course of time as major clinical issues in the routine use of rHuEPO.

Hematologic Aspects of Kidney Disease and Erythropoietin Therapy

by administering small weekly doses to maintain stable iron 593 stores. Weekly doses of 12.5 to 100 mg of intravenous iron may improve responsiveness to rHuEPO. The potential advantage of such an approach lies in linking iron replacement temporally with ongoing iron losses. Assessment of iron stores CH 28 should be performed quarterly, however, to ensure the adequacy of this approach. Although patients with CKD or those treated with peritoneal dialysis develop iron deficiency less frequently than hemodialysis patients, iron still plays a central role in the maintenance of responsiveness to rHuEPO, and deficiency states refractory to oral iron replacement develop frequently during the course of treatment, requiring administration of intravenous iron. Because of the inconvenience of needing to obtain sequential intravenous access in these patients, a larger infusion of iron is often used; for example, 5 infusions of 200 mg of diluted iron sucrose or ferric gluconate may be infused over a 2-hour period. Such an approach appears to be effective and well tolerated.

594 Hypertension

The Consequences of Renal Failure

Changes in blood pressure regulation, either de novo hypertension or increasing antihypertensive requirements, are frequent accompaniments to treatment, occurring in an estimated 23% VII in the largest meta-analysis undertaken. The etiology is likely multifactorial and includes increased erythrocyte mass with increased peripheral resistance (without a comparable decrease in cardiac output), diminished effect of nitric oxide (diminished synthesis or resistance), release of endothelin or vasoconstrictor prostanoids, and a trophic effect of rHuEPO on endothelial cell growth. Worsening blood pressure control should be managed with a reduction in extracellular fluid volume (assuming that hemoglobin does not greatly exceed the target range), initiation or alteration in antihypertensive medications, or more rarely, a decrease in rHuEPO dose.

Seizures The risk of precipitating seizures in patients receiving rHuEPO, apart from that associated with hypertensive encephalopathy, has not appeared to be increased once appropriate attention is paid to dosing and titration guidelines. A previous history of seizures should not preclude treatment with rHuEPO.

Loss of Dialytic Efficiency Initial concerns that increases in red blood cell mass, changes in blood rheology, and the use of high-efficiency/flux dialyzers with short dialysis times might result in worsening azotemia and hyperkalemia have not materialized as clinically significant issues. Although decrements in solute clearance have been reported with successful treatment, they are small (10–15%), and when the delivered dialysis dose is closely monitored, shortfalls in the delivered dialysis dose, as measured by the Kt/V equation, can be investigated and rectified prospectively.

Thrombosis In patients treated with rHuEPO, increases in factor VIII, von Willebrand factor antigen, fibrinogen, and whole-blood platelet aggregation are observed. Despite this, multiple studies of rHuEPO-treated patients, with mean hematocrit values of 34%, have revealed an average clotting incidence of only 7.5%. At present, there does not appear to be any added risk of thrombosis in rHuEPO-treated patients with either grafts or fistulas. Data from the U.S. Normalization of Hematocrit trial demonstrated a higher rate of both fistula and graft thrombosis in patients randomized to the higher hemoglobin group (Hgb 13g/dL), although no correlation between the hemoglobin concentration attained, rHuEPO dose, and access thrombosis was observed.

Pure Red Blood Cell Aplasia

595

Inadequate Response to rHuEPO Hyporesponsiveness to rHuEPO has been defined as failure to achieve target hematocrit in the presence of adequate iron stores at a dose of 450 IU/kg/week intravenously, or 300 IU/kg/week subcutaneously, over a period of 4 to 6 months, or failure to maintain it subsequently at that dose. This definition now merits revisiting, given current patterns of utilization. A significant proportion (20%) of patients in the United States receive an rHuEPO equivalent of 30000 IU/week, or 428 U/kg/week in a patient of 70 kg, suggesting a requirement for broader guidelines for evaluation of hyporesponsiveness to rHuEPO; it is now considered appropriate to investigate if (1) hemoglobin is inappropriately low for dose of rHuEPO administered, (2) if an increase in rHuEPO is required to maintain stable hemoglobin, (3) if a decrease in Hgb occurs at a constant dose of rHuEPO, (4) if a dose of more than 500 U/kg/week fails to increase Hgb to more than 11 g/dL. The establishment of an upper monthly dose limit for hormone reimbursement by Medicare has obvious implications for those patients manifesting profound rHuEPO resistance. Several conditions (Table 28-1) have been associated with an inadequate response to rHuEPO, of which some are discussed next.

*Casadevall N, Nataf J, Viron B, et al: Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 346:469–475, 2002.


Although reported only three times from the availability of rHuEPO until 1998, from 1998 to 2001 Casadevall and colleagues* noted 21 patients in whom pure red blood cell aplasia (PRCA) developed in the setting of rHuEPO treatment. These CH 28 patients possessed rHuEPO-neutralizing antibodies, which suppressed erythroid colony mutation from normal bone marrow cells. Immunosuppressive treatment or discontinuation or rHuEPO treatment resulted in the disappearance of antibody in the large majority of reported cases. To date, nearly 250 cases have been reported worldwide, almost exclusively in CKD patients receiving subcutaneous Eprex, a form of epoetin alfa only available outside the United States. This phenomenon has now been well characterized, and the likely cause elucidated. It was found that leachates from uncoated rubber syringe stoppers may have caused the immunogenicity resulting in PRCA. A switch to fluororesin coated stoppers coincided with a rapid decline in new causes of PRCA. Recovery has been reported following immunosuppressive therapy, including cyclosporine and renal transplantation.

596 Table 28-1


VII

Causes of Inadequate Response to Recombinant Human Erythropoietin Therapy

Iron deficiency Chronic blood loss (dialysis circuit/gastrointestinal tract) Iron malabsorption Infection/inflammation Malnutrition: folate or vitamin B12 deficiency Aluminum toxicity Severe secondary hyperparathyroidism Hemoglobinopathies (e.g., a- and b-thalassemia, sickle cell anemia) Malignancies Hemolysis Pure red blood cell aplasia ACE inhibitor use ACE, angiotensin-converting enzyme.

Iron Deficiency A suboptimal response to rHuEPO most commonly results from failure of delivery of an adequate amount of iron to the erythron, either consequent to iron (blood) loss, iron consumption by the growing erythron in an appropriate response to rHuEPO therapy, or inadequate gastrointestinal absorption. In CKD or peritoneal dialysis patients, issues of blood loss are far less common because of the absence of extracorporeal circulation and repetitive systemic anticoagulation. Most treated patients become iron deficient and therefore require more rHuEPO to maintain the same rate of RBC production, and if the iron balance is not restored by administration of oral or parenteral iron, an initial good response may falter.

Aluminum Overload Aluminum toxicity has been seen with decreasing frequency due to major improvements in water purification, declining use of aluminum-based phosphate binders, and the availability of non–aluminum-based agents. Mechanisms for the disorder have been variably ascribed to interference with enzymatic insertion of iron and competition between aluminum and iron for binding to transferrin before substrate delivery to erythropoietic elements. Basal serum aluminum concentrations greater than 50 ng/mL and aluminum levels greater than 175 ng/mL following a desferoxamine challenge test (a single dose of 500–1000 mg intravenously) suggest aluminum overload, although bone biopsy is the best method of diagnosis. Increasing rHuEPO dosing has generally proved effective in overcoming disruption in erythropoiesis, as has exclusion of aluminum, or when necessary, desferoxamine treatment of bone or central nervous system disease.

Infectious and Inflammatory Chronic Disease and Malignancy

597

Secondary Hyperparathyroidism A correlation exists between rHuEPO requirements and the degree of marrow fibrosis, osteoclastic and eroded surfaces seen on bone biopsy specimens, and PTH levels. This has been borne out in the Dialysis Outcomes and Practice Patterns Study (DOPPS), which demonstrated a relationship between attainment of a hemoglobin concentration of greater than 11 g/dL and local practices relating to the treatment of highturnover bone disease. A possible role for vitamin D has been suggested in improving erythropoiesis, independent of its effect on either serum calcium or PTH levels. Overall, effective management of high-turnover bone disease, either by surgical or biochemical intervention, may have a beneficial effect on the efficacy of rHuEPO treatment.

Carnitine Deficiency L-Carnitine is an essential cofactor for transmitochondrial transport for fatty acids for oxidation and is depleted by hemodialysis. A role for carnitine in maintaining erythrocyte membrane integrity and improving deformability, thereby increasing red blood cell survival, has been postulated. Studies have shown modest efficacy in raising hemoglobin levels or reducing rHuEPO requirements. Variable benefit has been shown for dyslipidemia or improvement in any specific abnormal lipid fraction.

Angiotensin-Converting Enzyme Inhibitors A relationship between the use of angiotensin-converting enzyme (ACE) inhibitors and declining hemoglobin levels has long been evident. Plasma levels of N-acetyl-seryl-aspartyllysyl-proline (AcSDKP), a physiologic inhibitor of erythropoiesis


In states of active inflammation (infectious processes, surgical insults, and malignancies), iron metabolism is directly altered, and access to iron from the reticuloendothelial system by CH 28 hematopoietic cells is blocked due to increased iron uptake by activated macrophages. Erythropoiesis is negatively regulated by several macrophage-derived cytokines, including tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1) and IL-6, and interferon-g (IFN-g), which are thought to impair the growth of erythroid progenitor cells, diminish local response to erythropoietin, and increase IFN production, culminating in rHuEPO resistance. These mediators may represent a link between inflammation, poor response to rHuEPO, and the larger syndrome of malnutrition, wasting, and increased mortality rate seen in dialysis patients. Studies have demonstrated associations between hypoalbuminemia, elevations in C-reactive protein, and an elevated rHuEPO dose, suggesting a convergent pathogenic process potentially associated with poor outcomes.

598 that is degraded in vivo by ACE, are elevated in patients with


CKD and ESRD. Treatment with ACE inhibitors therefore results in further increases in AcSDKP in both populations, although to a greater extent in dialysis patients, and the weekly rHuEPO VII dose has been shown to correlate with AcSDKP levels. This relationship has been used to therapeutic effect in the treatment of post-transplant erythrocytosis (see Table 28-1).

DISORDERS OF HEMOSTASIS IN CHRONIC KIDNEY DISEASE Uremic Bleeding Excessive bleeding has long been recognized as an important complication of the uremic state, the pathogenesis of which is multifactorial. Platelet abnormalities are considered the primary cause of the bleeding diathesis, and although the number of circulating platelets is generally normal, their function is often impaired (thrombasthenia). The most consistent abnormality is impaired platelet interaction with the vascular subendothelium, hindering platelet adhesion and aggregation. Endothelial production of nitric oxide, a powerful platelet inhibitor, is increased in uremia. The platelet itself is also intrinsically altered; activation of glycoprotein IIb-IIIa to facilitate its adhesion to vonWillebrand factor (vWF) is impaired. Anemia is a significant contributor and hemostatic improvement can be achieved with rHuEPO therapy. Given the increased propensity toward bleeding in the advanced CKD and ESRD populations, the additional use of anticoagulants or antiplatelet agents must be carefully considered, weighing the risk versus benefit ratio.

Therapeutic Strategies The treatment of uremic patients experiencing bleeding episodes requires the usual approach to a bleeding patient, including hemodynamic stabilization, identification of the bleeding source and etiology, and replacement of blood products as required. Particular to uremic bleeding is the need to correct platelet dysfunction and other contributing factors to the bleeding diathesis. The intensity of interventions to correct uremic platelet dysfunction is dictated by the severity of bleeding. Initiation of dialysis will lead to improvement in thrombasthenia and bleeding risk, with over two thirds of dialyzed patients demonstrating reduction in bleeding time. It is noteworthy, however, that hemodialysis may induce a transient deterioration in platelet dysfunction, thought to be multifactorial. A transient decrease of platelet membrane expression of


glycoprotein 1b has been shown to occur after dialysis, with 599 other potential factors thought to include the removal of younger platelets with greater function and impaired platelet function due to a secondary effect of activated leukocytes. Clearly, in the setting of acute bleeding, anticoagulation must be mini- CH 28 mized, or ideally avoided. The use of regional anticoagulation of the dialysis circuit with citrate may be a viable alterative. Treatment of anemia with rHuEPO may be the most effective treatment of uremic platelet dysfunction, most likely due to vessel flow phenomena. It is thought, however, that erythropoietin therapy itself may directly affect platelet function, potentially due to an increase in young circulating forms of platelets with improved functionality, improved platelet intracellular calcium mobilization, and repaired platelet signal transduction. Desmopressin (DDAVP), a synthetic form of antidiuretic hormone, is often used to treat uremic bleeding, and in some cases may be administered prophylactically in those considered high risk. Its primary mechanism of action is thought to be enhanced release of larger vWF multimers by endothelial cells; other factors may include improved platelet aggregation in contact with collagen. Intravenous infusion of 0.3 mg/kg intravenously (added to 50 mL of saline over 30 minutes) is most commonly used; intranasal administration of this drug at a dose of 3 mg/kg is also effective and is well tolerated. The response to DDAVP is heterogeneous and, when it occurs, lasts approximately 4 to 8 hours. Repeated administrations of DDAVP may result in diminished response with development of tachyphylaxis. Other therapeutic options include infusion of cryoprecipitate, a plasma product rich in vWF and fibrinogen. There is little published evidence to support its use, and response is highly variable. Cryoprecipitate use should be reserved for life-threatening bleeding due to attendant risk of infectious complications. Estrogens have been shown to improve platelet function in both males and females, with favorable effects on bleeding time seen following both oral (25 mg/day of conjugated estrogen) and intravenous (0.6 mg/kg/day for 5 days) administration, although the effect of intravenous estrogen is seen to begin earlier and last longer. The mechanism of action of estrogen has not been fully elucidated, but is thought to relate to inhibition of vascular nitric oxide production.

EFFECT OF RENAL FAILURE ON GRANULOCYTES AND MONOCYTES Renal failure is associated with an increased susceptibility to infections. In cell-mediated defense against infectious agents, granulocytes and monocytes move by chemotaxis to the site of injury. Cells then phagocytose microorganisms through

600 complex processes that include cell adhesion and the forma-


tion of oxygen free radicals (particularly H2O2) from O2. Many studies have found that leukocyte chemotaxis is impaired in uremia, possibly due to a circulating inhibitor of chemotaxis, VII decreased intracellular cyclic guanosine monophosphate– cyclic adenosine monophosphate ratio, or a plasma factor blocking granulocyte membrane receptors. Interestingly, the chemotactic activity of granulocytes is diminished further, rather than corrected, by hemodialysis (HD). Studies of granulocyte phagocytosis and respiratory burst in uremia are conflicting. HD has a profound effect on granulocyte kinetics. During the first 2 hours of HD, all patients develop peripheral neutropenia mediated by complement activation on the dialysis membrane and sequestration of granulocytes in the lung. In the hours following HD, the release of neutrophils from the bone marrow and sites of sequestration produces rebound neutrophilia. Thus, pulmonary dysfunction occurring within the first hours of HD may be the result of endothelial injury caused by massive granulocyte adherence to pulmonary vessels. During HD with nonbiocompatible membranes (e.g., cuprophane), there is a rapid increase in the surface expression of phagocyte adhesion receptors, leading to cell aggregation and sequestration in the pulmonary vasculature. These effects are observed to a lesser degree with newer biocompatible membranes. Monocytes are also markedly activated by contact with dialysis membranes, as documented by transient increases in plasma levels of IL-1 and TNF during HD. The functional consequences of monocyte activation during HD may include the possibility that cytokine release might trigger hypotension or augment susceptibility to infections and atherosclerosis. It has been known for many years that uremic patients suffer from an acquired form of immunodeficiency characterized by abnormal T-cell proliferation in response to antigenic challenges. This defect could well be the consequence of monocyte dysfunction, as T-cell activation is monocyte-dependent. The monocytes in uremic nonresponders to hepatitis B vaccination are unable to deliver to T lymphocytes the necessary signal required for triggering IL-2 synthesis. However, further studies are needed to clarify the true clinical impact of these changes on the immunodeficiency of uremic patients.

Chapter 29

Neurologic Complications of Kidney Disease End-stage renal disease (ESRD) is associated with at least five well-described disorders of the nervous system: • • • • •

Uremic encephalopathy Dialysis dysequilibrium syndrome (DDS) Dialysis dementia Stroke Sexual dysfunction

In addition to these five manifestations of neurologic dysfunction, which are specifically related to renal insufficiency, dialysis, or both, a number of other neurologic disorders occur with increased frequency in patients who have ESRD and are being treated with chronic hemodialysis. Subdural hematoma, acute stroke, certain electrolyte disorders (hyponatremia, hypernatremia, hyperkalemia, phosphate depletion, hypercalcemia), vitamin deficiencies, Wernicke encephalopathy, drug intoxication, hypertensive encephalopathy, and acute trace element intoxication must be considered in patients with chronic kidney disease (CKD) or ESRD who manifest an altered mental state. Patients with renal failure are also at risk for development of the same varieties of organic brain disease and metabolic encephalopathy that can affect the general population. Therefore, when a patient with ESRD presents with altered mental status, a thorough and complete evaluation is necessary.

UREMIC ENCEPHALOPATHY The term uremic encephalopathy is used to describe the early appearance and dialysis-responsiveness of the nonspecific neurologic symptoms of uremia. It is an acute or subacute organic brain syndrome that regularly occurs in patients with acute kidney injury (AKI) or CKD when the glomerular filtration rate (GFR) declines to less than 10% of normal. The causes of uremic encephalopathy are doubtless multiple and complex. As with other organic brain syndromes, these patients display variable disorders of consciousness, psychomotor behavior, thinking, memory, speech, perception, and emotion. The symptoms of uremic encephalopathy are shown in Table 29-1. Key early clinical features include daytime

601

602 Table 29-1

Signs and Symptoms of Uremic Encephalopathy

Early Uremia


VII

Anorexia Malaise Insomnia Diminished attention span Decreased libido Moderate Uremia Emesis Decreased activity Easy fatigability Decreased cognition Impotence Advanced Uremia Severe weakness and fatigue Pruritus Disorientation Confusion Asterixis Stupor, seizures, coma

drowsiness and insomnia with a tendency toward sleepinversion; impaired concentration; itching; and “restless legs.” Uremic symptoms are generally more severe and progress more rapidly in patients with AKI than in those with CKD. In more slowly progressive CKD, the number and severity of symptoms also typically vary cyclically, with intervals of acceptable well-being in an otherwise inexorable downhill course toward increasing disability. The symptoms are readily ameliorated by dialysis procedures and suppressed by maintenance dialysis regimens and are usually relieved entirely after successful renal transplantation. Therefore, the early recognition of the encephalopathy of renal failure is important, as it is decisively treatable by renal replacement therapy. In addition, since the widespread introduction of recombinant human erythropoietin (EPO) as a therapeutic agent in patients with ESRD treated with hemodialysis, it is now clear that brain function and quality of life are significantly ameliorated by correction of anemia with EPO, although the impaired cerebral oxygen utilization seen in ESRD is only partially improved. Parathyroid hormone (PTH) is known to have CNS effects in humans, even in the absence of impaired renal function, with neuropsychiatric symptoms reported to be among

Diagnosis of Uremic Encephalopathy The diagnosis of uremic encephalopathy in most patients is suspected if there is a constellation of clinical signs and symptoms indicative of renal disease or injury. However, as the presenting symptoms of uremia are similar to those of many other encephalopathic states (e.g., drug intoxication, hepatic encephalopathy), there is a risk of misdiagnosis and mistreatment, especially as patients with renal failure are subject to other intercurrent illnesses that may also induce encephalopathic effects. Moreover, if a drug with potential CNS toxicity is excreted or significantly metabolized by the kidney, the ensuing encephalopathic symptoms may be attributable to the fact that the drug has reached CNS toxic levels at doses inappropriate for a suppressed GFR. Despite the possibilities that such multiple causes of encephalopathy might occur simultaneously, uremic encephalopathy may be successfully differentiated in most instances by means of standard clinical and laboratory methods and, if necessary, a trial of dialysis.

Uremic Encephalopathy in Patients with Hepatic Insufficiency In patients with advanced liver disease with associated renal insufficiency, it is often difficult to differentiate whether the cause of encephalopathy is hepatic or renal. Under normal conditions, ammonia is formed by the metabolization of protein and amino acids, and enters the portal circulation, where it participates in the urea cycle to form urea. Over 90% of urea generated in the liver is excreted in the urine, with the remainder excreted into the gastrointestinal tract, where it is metabolized by colonic bacteria and mucosal enzymes to form ammonia. However, in patients with renal failure, consequent to the increase in blood urea, the amount of urea entering the colon rises, leading to enhanced ammonia production, which in the setting of hepatic dysfunction triggers an increase in plasma ammonia levels. Plasma ammonia levels have been shown to correlate well with the severity of hepatic encephalopathy. Therefore, patients with liver damage and ESRD are at particular risk for development of encephalopathy, because both conditions act synergistically to increase blood ammonia and hence the risk of encephalopathy.

Neurologic Complications of Kidney Disease

the most common manifestations of primary hyperparathyroid- 603 ism. In recent years, there has been considerable discussion on the potential role of PTH as a uremic toxin. In uremic patients, both electroencephalographic (EEG) changes and psychological abnormalities have been shown to improve following parathy- CH 29 roidectomy or medical suppression of PTH.

604


Further complicating the assessment, it should also be noted that plasma urea and serum creatinine are poor markers of renal function in patients with severe liver disease. Many patients who have liver disease with normal or near-normal plasma urea VII and creatinine values may, in fact, have severe renal impairment.

Restless Leg Syndrome Restless leg syndrome (RLS) is found in up to 50% of patients on maintenance renal replacement therapy. It is characterized by an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs, which worsen during rest/inactivity, particularly at night. The etiology is unclear and does not appear to be related to inadequate clearance on dialysis. Treatment with anti-parkinsonian therapies such as ropirinole, carbidopa, or levodopa, and more recently pramipexole, has met with some success.

CHRONIC KIDNEY DISEASE Cognitive functions impaired in uremia include sustained and selective attention capacity, speed of decision making, shortterm memory, and mental manipulation of symbols.

Electroencephalogram in Patients with Chronic Kidney Disease EEG findings in patients with CKD are usually less severe than those observed in patients with AKI. Several investigations have shown a good correlation between the slow delta wave activity and the decline of renal function as estimated by serum creatinine. After the initiation of dialysis, there may be an initial period of clinical stabilization during which time the EEG deteriorates (up to 6 months), but it subsequently approaches normal patterns. Significant improvement is seen in the EEG abnormalities following renal transplantation. The EEG abnormalities are likely to be multifactorial; however, as discussed previously, there is evidence to suggest that PTH may exert a direct effect on the brain, by increasing the brain content of calcium Ca2þ.

Psychological Testing in Patients with Chronic Kidney Disease Several different types of psychological tests have been applied to subjects with CKD and ESRD. These tests have been designed to measure the effects of dialysis, renal transplantation, or

ACUTE KIDNEY INJURY The clinical neurologic manifestations of AKI include abnormalities of mental status that can progress rapidly into disorientation and confusion. Fixed attitudes, torpor, and other signs of toxic psychosis are common, and if untreated, uremic coma often supervenes. Other clinical findings include cranial nerve signs such as nystagmus, transient mild facial asymmetries, visual field defects, and papilledema of the optic fundi. About half of the patients have dysarthria, and many have diffuse weakness and fasciculations. Marked asymmetrical variation of deep tendon reflexes is noted in most patients. Progression of hyperreflexia, with sustained clonus at the patella or ankle, is common and is an absolute indication for renal replacement therapy. The electroencephalogram is usually grossly abnormal with marked enhancement of slow wave (delta wave) activity. In patients with AKI, the EEG result is abnormal within 48 hours of onset, and is generally not affected by dialysis within the first 3 weeks.

NEUROLOGIC COMPLICATIONS OF END-STAGE RENAL DISEASE Dialysis Dysequilibrium Syndrome In patients with ESRD, several CNS disorders may occur as a consequence of dialytic therapy. Dialysis dysequilibrium syndrome (DDS) is a clinical syndrome that typically occurs in very uremic patients undergoing an initial hemodialysis treatment. The classic symptoms include headache, nausea, emesis, blurring of vision, muscular twitching, disorientation, hypertension, tremors, and seizures. However, milder symptoms, such as muscle cramps, anorexia, restlessness, and dizziness may occur. Although DDS has been reported in all age groups, it is more common among younger patients, particularly the


parathyroidectomy. In general, the performance outcomes are 605 poorer in CKD patients than those of normal subjects and there appears to be a consensus, based on psychological testing, that CKD results in organic-like losses of intellectual function, particularly information-processing capacities. Psychological testing CH 29 scores typically improve with treatment by dialysis or renal transplantation. Supporting a role for hyperparathyroidism in the development of uremic encephalopathy, patients who underwent parathyroidectomy for other medical reasons have shown significant improvements in several areas of psychological testing including general cognitive function, nonverbal problem solving, and visual-motor or visual-spatial skills.

606 pediatric age group. Those at highest risk are older patients,


with longer duration of CKD, and very high levels of blood urea nitrogen (BUN). The syndrome is most often associated with rapid hemodialysis of patients, with almost all cases reported VII occurring during the initial four hemodialysis sessions, but it has occasionally been reported after maintenance hemodialysis in patients with ESRD. The symptoms are usually self-limited, but recovery may take several days. Sporadic reports of death associated with DDS do exist, although it is unclear whether these were directly related to DDS or other dialysis-associated neurologic complications, such as acute stroke, subarachnoid hemorrhage, subdural hematoma, or hyponatremia. DDS can be prevented by the gradual institution of dialysis, requiring careful prescription of the dialysis treatment to ensure that reduction in BUN levels after the first dialysis treatments are not excessive. A general rule of thumb is that a urea reduction ratio (URR) of 20% is nearly universally tolerated, and the first hemodialysis session should aim to achieve this target, with an increase in the subsequent two sessions to achieve 30% and 40%, respectively, increasing thereafter. The precise prescription of dialysis to achieve this outcome includes such variables as membrane size, blood flow rate, and duration of treatment. Isolated ultrafiltration can continue for a longer period if volume removal is the critical management issue. Other less widely used options include the intravenous infusion of mannitol or glycerol. Administration of 50 mL of 50% mannitol at the initiation, and after 2 hours of the initial three hemodialysis treatments has generally been successful in preventing symptoms of DDS. The use of lower clearance targets in initial hemodialysis treatments has led to a sharp decline in reports of seizures, coma, and death and most presentations are generally mild, consisting of nausea, weakness, headache, fatigue, and muscle cramps. It is important to recognize that the diagnosis of DDS should be one of exclusion and a differential diagnosis of patients presenting with these symptoms is shown in Table 29-2.

Dialysis Dementia Dialysis dementia (also called dialysis encephalopathy) is a progressive, frequently fatal neurologic disease that has been reported almost exclusively in patients being treated with chronic hemodialysis. Recent reports suggest that some forms of dialysis dementia may be a part of a multisystem disease, which may include encephalopathy, osteomalacic bone disease, proximal myopathy, and anemia. The syndrome is not alleviated by increased frequency of dialysis or by renal transplantation. The etiology has not been elucidated and although an increase in brain aluminum content has been strongly implicated in some cases of dialysis dementia, it is not the sole

Table 29-2

Differential Diagnosis of Dialysis Disequilibrium Syndrome

607

Subdural hematoma

CH 29

Uremia Dialysis dementia Cardiac arrhythmia Dialysate composition error Hypoglycemia Hypercalcemia Hyponatremia

etiologic factor. Additional possible causes of dialysis dementia include other trace element contaminants, normal-pressure hydrocephalus, slow virus infection of the CNS, and regional alterations in cerebral blood flow. There are at least three subgroups, and in two of them the etiology of dialysis encephalopathy must be regarded as unknown (Table 29-3). At this time, there is no known satisfactory treatment for patients with dialysis dementia. Most patients reported in the literature have not survived, usually dying within 18 months from the time of diagnosis.

Clinical Manifestations of Dialysis Dementia The initial reports of dialysis dementia in the 1970s described patients who had usually been on dialysis for over 2 years, all of whom had the endemic form. Early clinical manifestations

Table 29-3

Characteristics of Subgroups of Dialysis Dementia

Sporadic Endemic No clear relation to aluminum (Al3þ) intake Worldwide distribution No known therapy Endemic Often related to Al3þ concentration in dialysis water Geographic clusters Treatment of dialysis water Likely associated trace metal accumulation Childhood No clear relation to Al3þ intake May be secondary to effects of uremia on immature brain


Acute cerebrovascular accident

608 consist of a mixed dysarthria-apraxia of speech with slurring,


stuttering, and hesitancy. Personality changes include psychoses, progressing to dementia, myoclonus, and seizures. Symptoms initially are intermittent and are often worse during VII dialysis, but eventually become constant. In most cases, the disease progresses to death within 12 to 18 months. Despite the fairly distinct clinical course, brain histologic appearance has generally been normal or nonspecific. Early in the disease, the EEG shows multifocal bursts of high-amplitude delta activity with spikes and sharp waves, intermixed with runs of more normal-appearing background activity. These EEG abnormalities may precede overt clinical symptoms by 6 months. The EEG has been said to be pathognomonic, but a similar pattern may also be seen in other metabolic encephalopathies. The diagnosis depends on the presence of the typical clinical picture and is confirmed by the characteristic EEG. Magnetoencephaly (MEG) has only recently been used in the evaluation of uremic patients, but not of patients with dialysis dementia.

Aluminum and Dialysis Dementia Aluminum intoxication was first implicated in the development of this disorder in the mid-1970s. The aluminum content of brain gray matter in patients with dialysis dementia is 11 times that of normal individuals and three times that of unaffected patients on chronic hemodialysis. Brain aluminum content is also elevated in patients with Alzheimer’s disease, with accumulation in protein moieties of neurofibrillary tangles and in amyloid cores of senile plaques, features also observed in most cases of dialysis dementia, although with reported variances in distribution. Aluminum-containing oral phosphate binders were originally suspected as the source of aluminum; the association of dialysis dementia epidemics with significant aluminum contamination of the water supply identified dialysate as another potential source. The increased total body burden of aluminum is not restricted to neural tissue, and high levels are also found in bone and other soft tissues. Most aluminum in blood is bound to transferrin, with little existing in free form. The brain contains few transferrin receptors, with negligible aluminum uptake into the brain as a result. Any free aluminum, usually existing as aluminum citrate, can readily enter the central nervous system. Therefore, it may be that patients who develop dialysis dementia have less transferrin binding capacity, less transferrin, or a greater density of transferrin receptors in the brain. Recent studies have suggested an association with dihydropteridine reductase, an enzyme involved in the synthesis of neurotransmitters, including acetylcholine and tyrosine. Erythrocyte levels of the enzyme activity were found to be less than predicted and correlated with plasma aluminum levels.

Prevention and Treatment of Dialysis Dementia Measures to limit aluminum exposure are the cornerstone of the prevention and treatment of dialysis dementia. The use of aluminum-based phosphate binders should be restricted to short courses in patients with refractory hyperphosphatemia and avoided completely in those suspected of having early clinical changes consistent with dialysis dementia. Lowering the dialysate aluminum to less than 20 mg/L by deionization appears to prevent onset of the disease in patients and is now the standard of care. Deionization may be beneficial by removing other trace elements which may cause CNS toxicity, including cadmium, mercury, and manganese. Among patients with overt disease, eliminating the source of aluminum has resulted in improvement in some but not all patients. The use of desferrioxamine to chelate aluminum or other trace elements is experimental; although there have been several reports of improvement following treatment with desferrioxamine, these results have not been confirmed and its current role is limited to the treatment of acute intoxication. Renal transplantation has generally not been helpful in patients with established dialysis dementia. Diazepam and clonazepam are useful in controlling associated seizure activity, but later become ineffective and do not alter the final outcome. Treatment of sporadic cases, in which the cause is not clear, is more difficult. Every effort should be made to identify a treatable cause (Table 29-4).

Chronic Dialysis-Dependent Encephalopathy It is currently not unusual for patients to survive on hemodialysis for 25 years. However, among patients who have been undergoing hemodialysis for longer than 10 years, there is often mental deterioration, with markedly decreased intellectual capability, even without medical evidence of stroke. The collective syndrome of chronic dialysis-dependent encephalopathy is a combination of probable organic mental disorders plus psychiatric disorders commonly associated with hemodialysis, although the exact etiology is likely multifactorial. The clinical manifestations of this are outlined in Table 29-5. There are several well-studied pathophysiologic mechanisms that likely


Following treatment with desferrioxamine, erythrocyte enzyme 609 activity levels doubled, suggesting that increased levels of aluminum in the brain would lead to decreased dihydropteridine reductase availability in the brain. The plasma aluminum level is poorly correlated with the degree of tissue aluminum deposi- CH 29 tion and the diagnosis of aluminum toxicity is usually suggested by a rise in plasma aluminum concentration (>200 ng/mL) following intravenous infusion of desferioxamine (40 mg/kg).

610


VII

Table 29-4

Differential Diagnosis of Dialysis Dementia

Metabolic encephalopathies Hypercalcemia Hypophosphatemia Hypoglycemia Hyperosmolality Hyponatremia Symptomatic uremia Drug/trace metal intoxications Hyperparathyroidism Structural brain lesions Subdural hematoma Normal pressure hydrocephalus Stroke Other disorders Hypertensive encephalopathy Dialysis disequilibrium

contribute to the potential dysfunction of brain tissue in patients with chronic dialysis-dependent encephalopathy including oxidative stress, inflammation, hyperhomocysteinemia, and neuronal apoptosis. Muscular weakness is an important component of the syndrome, the possible causes of which include anemia, hypothyroidism and antihypertensive therapy, a constellation of features similar to that labeled uremic myopathy. Uremic myopathy is a frequent cause of weakness, exercise limitation, and rapid onset fatigue in dialysis patients. In ESRD patients, there is impairment of oxidative metabolism in skeletal muscle, and evidence exists that correction of acidosis by dialysis increases protein breakdown in muscle. Vitamin D deficiency

Table 29-5

Clinical Manifestations of Chronic Dialysis-Dependent Encephalopthy

Decreased intellectual capability Impaired cognition Chronic depression Decreased capacity for physical activity Myopathy Deterioration of vision Suicidal behavior Sexual dysfunction Pruritus Psychosis

is an important and frequently overlooked cause of myopathy, 611 with an increased tendency toward falling. Pruritus is another component of this syndrome, which has proved difficult to treat. Recently, the k-opioid receptor agonist nalfurafine has shown promise. CH 29

The recent use of advanced neuroimaging techniques has led to increased understanding of the changes in the uremic brain in humans. Acute and subacute movement disorders have been observed in patients with ESRD. These have been associated with bilateral basal ganglia and internal capsule lesions. Cerebral atrophy has been observed in chronic hemodialysis patients and tends to worsen as dialysis therapy continues. Cerebral atrophy was previously thought to be associated with dialysis dementia, but this is apparently not the case. ESRD has also been reported to lead to deterioration of vision. Some cases are associated with uremic pseudotumor cerebri, and in these selected cases, surgical optic nerve fenestration may improve visual loss. There is probably neuronal loss not detectable by techniques currently in common use. In patients with CKD, prevalence of cerebral white matter lesions is increased, often with extensive vascular calcification, which is associated with small, maybe silent, cerebral infarcts. In uremic patients, there is some evidence of necrosis of the granular layer of the cerebral cortex. Small intracerebral hemorrhages and necrotic foci are seen in about 10% of uremic patients, and focal glial proliferation is seen in about 2%. The few available studies also suggest a disproportionately high incidence of cerebral atrophy.

OTHER CENTRAL NERVOUS SYSTEM COMPLICATIONS OF DIALYSIS Subdural Hematoma Subdural hematoma is an infrequent cause of death in patients maintained on chronic hemodialysis. This condition presents with headache, drowsiness, nausea, and vomiting and may proceed to loss of consciousness with clinical signs of increased intracranial pressure. On physical examination, there is often evidence of localized neurologic disease; there may be signs of meningeal irritation, and somnolence and focal seizures may be observed. The diagnosis of subdural hematoma can usually be made by CT or MRI and should be entertained as a possible cause of altered mental status particularly in dialysis patients


RADIOLOGIC AND PATHOLOGIC FINDINGS IN THE UREMIC BRAIN

612 taking anticoagulants. Rapid diagnosis and operative intervention is required if a fatal outcome is to be averted.


VII Technical Dialysis Errors Improper proportioning of dialysate, due to human or mechanical error, is an important cause of neurologic abnormality in dialysis patients. The usual effect of such mistakes is the production of hyponatremia or hypernatremia. Either of these abnormalities of body fluid osmolality can lead to seizures and coma, although different mechanisms are involved. In acute hypernatremia, there is excessive thirst, lethargy, irritability, seizures, and coma, with spasticity and muscle rigidity. In acute hyponatremia, there is weakness, fatigue, and dulled sensorium, which may also progress to seizures and coma, respiratory arrest, and death. Such symptoms developing soon after initiation of hemodialysis should alert the physician to the possibility of an error. A check of the dialysate osmolality or sodium concentration is the most rapid means of detecting this problem. Overly aggressive ultrafiltration in dialysis patients, particularly in those with diastolic dysfunction and large vessel arteriolosclerosis, may trigger overt hypotension. This can manifest as seizures that, although actually caused by cerebrovascular insufficiency, may be mistaken for DDS, particularly in diabetic subjects.

Stroke Key to the high incidence of stroke in patients with ESRD is the coincidence of many of the known risk factors for stroke in this population including hypertension, cigarette use, diabetes mellitus, and hyperlipidemia. Recent evidence has also shown that a chronic inflammatory state greatly increases the risk of stroke. There is a high incidence of chronic infection in dialysis patients, leading to increased circulating levels of atherogenic factors, such as cytokines. The process of hemodialysis itself may contribute to the chronic inflammatory milieu. As with the general population, most preventive interventions in CKD patients focus on cardiovascular risk factor minimization. More specific interventions include screening patients for the presence of carotid stenosis, or for the presence of large atherosclerotic plaques (>4 mm thick), which are important predictors for the possibility of stroke in the future. Atrial fibrillation, another major risk factor for both initial and recurrent stroke, should be ruled out. Transient ischemic attacks are often associated with numbness, weakness, or partial blindness, and the presence of such a

Therapy for Stroke in CKD/ESRD It is now clear that, in many cases, acute stroke can be successfully treated if timely therapy is initiated. An initial CT scan usually reveals acute stroke and serves to differentiate occlusive from hemorrhagic stroke. If acute ischemic stroke is diagnosed within an appropriate time window (within 3 hours after onset of symptoms), current treatment may include the administration of thrombolytic (intravenous or intra-arterial) therapy, although its use is controversial. Associated therapy includes antithrombotic and antiplatelet drugs, defibrinogenating agents, and neuroprotective drugs. Importantly, some cases of apparent acute stroke in dialysis patients are caused by subdural hematoma, which must always be considered in the differential diagnosis of stroke in dialysis patients, and some may be due to dissection of the carotid or vertebral arterial systems. Angiography may be required to further evaluate, with a preference usually for noninvasive imaging. The use of intravenous contrast agent for CT angiography must be balanced against the use of gadolinium-chelate contrast agents for magnetic resonance angiography, with the attendant risks of nephrogenic systemic fibrosis.

SEXUAL DYSFUNCTION IN UREMIA Pathogenesis of Uremic Sexual Dysfunction Disturbances in sexual function including erectile dysfunction, decreased libido, and decreased frequency of intercourse are a common complication of CKD. Sexual dysfunction is observed in over 80% of male patients receiving maintenance hemodialysis. A number of abnormalities associated with renal failure appear to be important in the genesis of impotence including autonomic nervous system dysfunction, impairment in arterial and venous systems of the penis, hypertension, drug-related side effects, and other associated endocrine abnormalities. Sexual dysfunction is also common in women who are treated with dialysis, characterized by significantly poorer quality of sexual intercourse, decreased libido, less lubrication, and decreased ability to achieve orgasm.


symptom complex should trigger a workup that includes 613 evaluation of the carotid arteries (ultrasound, CT, or MRI). Migraine is a common clinical disorder, often characterized by an aura, headache, and autonomic dysfunction. In patients with ESRD, headache is common, and the possible association CH 29 with impending stroke may not be appreciated. Other possible preventive measures include dietary antioxidants, low-dose aspirin, and dietary modification.

614 Therapy for Sexual Dysfunction in Uremia


The management of sexual dysfunction in the patient with renal disease must address the underlying cause and exacerVII bating factors. Many drugs used to treat hypertension can lead to impotence, including calcium channel blockers and b-blockers, and this should be considered in any evaluation. It is also important to exclude undiagnosed depression, as the incidence of mood disturbance is considerably higher in patients with advancing renal disease than in the general population. If these etiologic factors have been addressed and the problem persists, treatment options include the use of sildenafil (Viagra), which is highly effective in men with ESRD. If this proves unsuccessful, other treatment options include penile prostheses, direct intrapenile injection of alprostadil, and vacuum constrictive devices.

UREMIC NEUROPATHY Clinical Manifestations Peripheral neuropathy is probably present in about 65% of patients with ESRD at the time of institution of dialysis. Many patients with CKD who are neurologically asymptomatic may exhibit abnormalities on physical examination including evidence of autonomic neuropathy, such as postural hypotension. Moreover, in patients who have renal insufficiency, abnormal nerve conduction may be present in the absence of symptoms or abnormal findings on physical examination, although the routine application of this examination is limited due to patient discomfort. Clinical evidence of neuropathy is usually absent until the advanced stages of renal insufficiency. Uremic neuropathy is usually a distal, symmetrical, mixed polyneuropathy. In general, motor and sensory modalities are both affected, and lower extremities are more severely involved than are the upper extremities. Clinically, uremic polyneuropathy cannot be distinguished from the neuropathies associated with certain other metabolic disorders, such as diabetes mellitus, chronic alcoholism, and various deficiency states. The occurrence of neuropathy bears no relation to the type of underlying disease process (i.e., glomerulonephritis or pyelonephritis). However, certain diseases that can lead to renal failure may simultaneously affect peripheral nerve function in a manner separate from the manifestations of uremia. Such diseases include amyloidosis, multiple myeloma, systemic lupus erythematosus, polyarteritis nodosa, diabetes mellitus, and hepatic failure.

Peripheral Nerves

615

Metabolic Neuropathy Uremic neuropathy is one of a group of central-peripheral axonopathies, also known as dying-back polyneuropathies, which include neuropathies associated with diabetes, multiple myeloma, and certain hereditary polyneuropathies. There is also an associated degeneration of the spinal cord, particularly involving posterior columns, as well as other portions of the CNS (Table 29-6). In addition to uremic neuropathy, uremic myopathy is a frequent cause of weakness, exercise limitation, and rapid-onset tiredness in dialysis patients. Later, muscle wasting occurs, particularly in the limb muscles.

Table 29-6

Clinical Characteristics of Distal Axonopathies

Insidious onset Onset in legs (large and long axons affected early; sciatic nerve especially vulnerable) Stocking-glove sensory loss Early loss of Achilles reflex Moderate slowing of motor nerve conduction Normal cerebrospinal fluid protein content (pathologic changes usually distal with nerve root sparing) Slow recovery (axonal regeneration 1 mm/day) Residual disability


The restless leg syndrome is a common early manifestation of CKD. Clinically, patients experience sensations in lower extremities such as crawling, prickling, and pruritus. The sensa- CH 29 tions are worse distally than proximally and are generally more prominent in the evening. Another symptom experienced by patients with early uremic neuropathy is the burning foot syndrome, which is present in fewer than 10% of patients with chronic renal failure. Rather than “burning,” the actual symptoms consist of swelling sensations, constriction, and tenderness of the distal lower extremities. The physical signs of peripheral nerve dysfunction often begin with loss of deep tendon reflexes, particularly knee and ankle jerks. Impaired vibratory sensation is also an early sign of uremic neuropathy. Loss of sensation in the lower leg is common and often takes the form of “stocking glove” anesthesia of the lower leg. The sensory loss includes pain, light touch, vibration, and pressure.

Chapter 30

Mineral Bone Disease in Chronic Kidney Disease PATHOGENESIS OF MINERAL BONE DISEASE IN CHRONIC KIDNEY DISEASE In the absence of chronic kidney disease (CKD), normal serum levels of phosphorus and calcium are maintained through the interaction of two hormones: parathyroid hormone (PTH) and 1,25(OH)2D (calcitriol), the main metabolite that activates the vitamin D receptor (VDR). There is also increasing evidence to support the existence of a hormone, or hormones, that directly control the renal excretion of phosphorus termed phosphatonins, although their precise role has yet to be elucidated. These hormones act on three primary target organs: bone, kidney, and intestine. Because the kidney has a critical role in calcium and phosphorus homeostasis, derangements are initially seen at glomerular filtration rates (GFRs) of less than 60 mL/min and are nearly uniform at a GFR below 30 mL/min. The progression of CKD is eventually associated with the inability to maintain normal mineral homeostasis, ultimately resulting in (1) altered serum levels of calcium, phosphorus, PTH, and vitamin D; (2) disturbances in bone remodeling with fracture development; (3) impaired linear growth in children; and (4) extraskeletal calcification in soft tissues and arteries. Traditionally, this group of disorders was termed renal osteodystrophy. However, given the diverse and multisystem manifestations of mineral and bone abnormalities, the Kidney Disease Improving Global Outcomes (KDIGO) organization recently classified a new systemic disorder, termed CKDmineral bone disorder (CKD-MBD). In contrast, the term renal osteodystrophy should be reserved to define an alteration of bone morphology in patients with CKD, quantifiable by histomorphometry of bone obtained by biopsy (Table 30-1).

PHOSPHORUS Inorganic phosphorus is critical for numerous physiologic functions including skeletal development, mineral metabolism, cell membrane phospholipid content and function, cell signaling, platelet aggregation, and energy transfer through

616

Table 30-1

Kidney Disease Improving Global Outcomes (KDIGO) Classification of Chronic Kidney Disease (CKD)–Mineral Bone Disorder (MBD) and Renal Osteodystrophy

CKD-MBD is a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: 1. Abnormalities of calcium, phosphorus, parathyroid hormone, or vitamin D metabolism 2. Abnormalities in bone turnover, mineralization, volume, linear growth, or strength 3. Vascular or other soft tissue calcification Definition of Renal Osteodystrophy Renal osteodystrophy is an alteration of bone morphology in patients with CKD It is one measure of the skeletal component of CKD-MBD quantifiable by histomorphometry of bone biopsy specimen

mitochondrial metabolism. Normal homeostasis maintains serum phosphorus concentrations between 2.5 and 4.5 mg/dL (0.81–1.45 mmol/L). Levels are highest in infants and decrease throughout growth, reaching adult levels in the late teens. Approximately 85% of total adult body stores are contained in bone in the form of hydroxyapatite. Of the remainder, approximately 14% is intracellular, and 1% extracellular. Of the extracellular portion, 70% is organic (phosphate) and contained within phospholipids, and 30% is inorganic, of which 85% is either circulating freely or complexed with sodium, magnesium, or calcium. Serum measurements therefore reflect only a small fraction of total body stores. Under normal circumstances, approximately two thirds of ingested phosphate is excreted in urine, and one third in stool. Foods high in phosphate are generally high in protein; it is therefore challenging to balance dietary phosphate restriction while ensuring adequate protein intake in the dialysis population. Most well-nourished dialysis patients are therefore in positive phosphate balance, and dietary restriction alone is insufficient, requiring in addition the optimization of dialysis and the use of phosphate binders.

Phosphorus Homeostasis Between 60% and 70% of dietary phosphate is absorbed by the gastrointestinal tract, a process dependant both on passive transport and active transport stimulated by calcitriol and, to a much lesser extent, PTH. Most inorganic phosphate is freely

CH 30

Mineral Bone Disease in Chronic Kidney Disease

Definition of CKD-MBD

617

618 filtered by the glomerulus. Approximately 70% to 80% of


the filtered load is reabsorbed in the proximal tubule, the remainder in the distal tubule. Phosphate excretion is increased by increased plasma phosphate concentration, PTH, volume VII expansion, metabolic acidosis, glucocorticoids, and calcitonin. The majority of this regulation occurs in the proximal tubule through the sodium-phosphate co-transporter Npt2b. The exquisite sensitivity of renal phosphate excretion to changes in the serum phosphate levels led to the concept of phosphatonins, hormones thought to regulate phosphate excretion. Several phosphatonins have now been identified, including fibroblast growth factor 23 (FGF23). FGF23 is predominantly produced from bone cells during active remodeling, and exerts a host of effects, including regulation of the sodium-phosphate co-transporter independent of PTH, and inhibition of the 1ahydroxylase enzyme in the renal tubules, thereby decreasing the production of 1,25(OH)2D. In the setting of hyperphosphatemia, both PTH and FGF23 levels increase with phosphaturic effects.

Phosphorus Abnormalities in Chronic Kidney Disease As mentioned previously, disturbances in phosphate homeostasis are evident at GFR rates of less than 60 mL/min, and frank hyperphosphatemia is seen in most patients with a GFR below 30 mL/min. The maintenance of normal serum levels in CKD stage 3 is thought to be at the expense of progressive increase in PTH excretion. The regulation of PTH by phosphate is multifactorial and includes regulation of intracellular calcium, cell proliferation and growth, and reduction in the expression of the calcium-sensing receptor (CaR), thereby decreasing the ability of the parathyroid gland to respond to changes in ionized calcium. The inhibition of 1a-hydroxylase by hyperphosphatemia, decreasing the production of 1,25(OH)2D, also increases the secretion of PTH. Recent studies have demonstrated increased levels of FGF23 in CKD, with progressive elevation as GFR declines. The elevation in FGF23 is thought to further contribute to the development and exacerbation of secondary hyperparathyroidism. Interestingly, FGF23 has been shown in vitro to inhibit osteoblastic mineralization.

CALCIUM Serum calcium levels are normally tightly controlled within a narrow range, usually 8.5 to 10.5 mg/dL (2.1–2.6 mmol/L), although these levels are a poor reflection of overall total body

Calcium Homeostasis Calcium absorption across the intestinal membrane occurs via both a vitamin D–dependent, saturable pathway and a vitamin D–independent, nonsaturable pathway. The duodenum is the major source of calcium absorption, although the remainder of the small intestine and the colon also contribute. In the kidney, approximately 60% to 70% of calcium is reabsorbed passively in the proximal tubule, driven by a transepithelial electrochemical gradient generated by sodium and water reabsorption. A further 10% is absorbed in the thick ascending limb by paracellular transport. The regulation of reabsorption is via transcellular pathways that occur in the distal convoluted tubule, the connecting tubule, and the initial portion of the cortical collecting duct.

Calcium-Sensing Receptor The calcium-sensing receptor (CaR) is expressed in organs controlling calcium homeostasis, such as the parathyroid gland, thyroid C cells, intestine, and kidney. It is also expressed in a number of other tissues, although its expression in bone remains controversial. The primary ligand for the CaR is Ca2þ, but it also senses other divalent and polyvalent cations, including Mg2þ. Recent studies indicate that the CaR can also act as sensors for pH and L-amino acids. Activation of the CaR leads to mobilization of intracellular calcium and decrease in PTH secretion; the converse is also true. CaR expression is regulated by 1,25(OH)2D in parathyroid, thyroid, and kidney cells; studies have failed to find evidence supporting its regulation by calcium. Uremic animal models have shown down-regulation of CaR expression by a high-phosphate diet, occurring after the onset of parathyroid hyperplasia. Within the kidney, the CaR is expressed in mesangial cells and throughout the tubules. Interestingly, in rat studies, the CaR is present within the same endosomes that contain the vasopressin-regulated


calcium. Ionized calcium is the physiologically active compo- 619 nent, and generally makes up approximately 40% of total serum calcium levels. The nonionized component is bound to albumin or anions such as citrate, bicarbonate, and phosphate. Serum levels of ionized calcium are maintained within the nor- CH 30 mal range by alterations in the secretion of PTH, which acts to increase bone resorption, increase renal calcium reabsorption, and increase the conversion of 25(OH)D to 1,25(OH)2D, thereby increasing gastrointestinal calcium absorption.

620 water channel aquaporin-2, and responds to increases in intra-


luminal calcium concentration by reducing antidiuretic hormone–stimulated water absorption. This may be the mechanism by which the urine can remain dilute in the face of VII hypercalcemia/hypercalciuria, and may explain the polyuria seen in hypercalcemic patients.

VITAMIN D Vitamin D3 is metabolized in the skin from 7-dehydrocholesterol, a reaction facilitated by ultraviolet light and increased temperature. There are also dietary sources of vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 and D3 bind with vitamin D–binding protein (DBP), and are transported to the liver, where they undergo hydroxylation to yield 25(OH)D, called calcidiol. This compound is then further hydroxylated in the kidney by the action of 1a-hydroxylase to 1,25(OH)2D (calcitriol), which exerts the predominant effects of vitamin D in the body. The primary role of the DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of bioavailability, activation, and end-organ responsiveness. As discussed earlier in this chapter, calcitriol facilitates the uptake of calcium in intestinal and renal epithelium via voltage-dependent calcium channels and thereafter enhances its transport. Calcitriol also directly suppresses PTH synthesis and is important for normal bone turnover. The 1a-hydroxylase enzyme in the kidney is the site of regulation of 1,25(OH)2D synthesis by numerous factors, including low calcium, low phosphorus, estrogen, prolactin, growth hormone, 1,25(OH)2D itself, and FGF23. Vitamin D is also important in cell differentiation and proliferation. Additional studies have shown that vitamin D and many of its analogs inhibit the secretion of inflammatory cytokines and proliferation from lymphocytes, dendritic cells, and macrophages. Particular to CKD are direct effects of calcitriol on the cardiovascular system, leading to decreased vascular tone, decreased renin-angiotensin activation, decreased cardiac contractility, and decreased myocardial fibrosis, resulting in improved blood pressure and reduction in left ventricular mass. Serum calcitriol levels vary substantially at any given level of renal function although they typically decline as CKD advances. This biochemical disturbance adversely affects intestinal calcium absorption and contributes substantially to modest reductions in serum calcium concentration and to the hypocalciuria seen in patients with mild to moderate CKD, thereby directly stimulating PTH secretion.

Nutritional Vitamin D Deficiency

621


In the general population, 25(OH)D (calcidiol) levels are accepted as the standard measure of nutritional intake, as they correlate best with end-organ effects and with total body stores, CH 30 whereas calcitriol levels may be in a normal range despite severe vitamin D deficiency. Although there is no absolute level of calcidiol that defines deficiency, a level less than 10 ng/mL (25 nmol/L) is typically used, as it is associated with rickets in children and osteomalacia in adults. More recently, the term calcidiol insufficiency has been used to describe less severely deficient states. Although controversial, the typical range of insufficient calcidiol levels is 10 to 30 ng/mL (25–75 nmol/L). Calcidiol insufficiency has been found to be associated with increased intact PTH (iPTH) levels and osteoporosis. Studies have also indicated that calcidiol deficiency and insufficiency are common in CKD, with less than 30% of CKD stage 3 patients having sufficient levels. Proteinuria, which results in ongoing losses of DBP, along with vitamin D, increases the likelihood of vitamin D deficiency in CKD patients. There is concern that low calcidiol levels in CKD may contribute to secondary hyperparathyroidism. The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines suggest measuring calcidiol levels in patients with stage 3 or 4 CKD and an elevated PTH, although studies to date have been small and heterogeneous and have shown variable results following calcidiol supplementation. The vitamin D sterols developed for treatment of secondary hyperparathyroidism (SHPT), including paricalcitol and alfacalcidol, are not metabolized to 25-hydroxyvitamin D, and their use therapeutically does not raise serum 25-hydroxyvitamin D levels.

PARATHYROID HORMONE The primary function of PTH is to maintain calcium homeostasis by (1) increasing bone mineral dissolution, releasing calcium and phosphorus; (2) increasing renal reabsorption of calcium and excretion of phosphorus; (3) increasing the activity of 1a-hydroxylase; and (4) enhancing gastrointestinal absorption of both calcium and phosphorus via synthesis of 1,25(OH)2D. SHPT is common in the CKD population, develops early in the clinical course, and progresses as renal function declines. It is characterized by persistent elevation of PTH, leading to metabolic bone disease and disturbances in calcium and phosphate metabolism. PTH secretion occurs in response to hypocalcemia, hyperphosphatemia, and 1,25(OH)2D deficiency. It is, however, the extracellular concentration of ionized calcium that is the

622 most important determinant of minute-to-minute secretion of


PTH from stored secretory granules, a response modulated via the CaR. It appears that although calcium is more important in stimulating PTH release, calcitriol is more important in its inhiVII bition. Other factors causing increased PTH secretion include FGF23, down-regulation of the VDR, acidosis, and resistance to PTH at the skeletal level. PTH binds to the PTH1 receptor, which is found in many tissues including osteoblasts and vascular smooth muscle cells, and is widely expressed in the kidney. Although PTH-related protein (PTHrp) also binds to the PTH1 receptor, its effects are autocrine, whereas the effects of PTH are systemic. Plasma PTH levels generally serve not only as a noninvasive test for the initial diagnosis of renal bone disease, but also as a useful index for monitoring evolution of the disorder, and as a surrogate marker of bone turnover in CKD, with high levels associated usually with high-turnover bone disease, and low-turnover/adynamic bone disease with normal or reduced plasma PTH levels. Interpretation of early immunoassays for PTH was complicated by the fact that PTH circulates not only in the form of the intact 84-amino-acid peptide but also as multiple fragments of the hormone, particularly from the middle and COOH-terminal regions of the PTH molecule. More recently, two-site immunoradiometric assays that only detect intact PTH have been developed and are now widely commercially available. Some recent studies have suggested that PTH fragments may also have biologic actions.

BONE The majority of total body stores of calcium and phosphorus are located in bone. Trabecular (cancellous) bone is located predominantly in the epiphyses of long bones, is 15% to 25% calcified, and serves a metabolic function with a relatively short turnover rate of calcium, in contrast to cortical (compact) bone in the shafts of long bones, which is 80% to 90% calcified, and has a calcium turnover rate of months. The control of bone remodeling is highly complex but appears to occur in distinct phases: (1) osteoblast activation, (2) osteoclast recruitment resorption, (3) preosteoblast migration and differentiation, (4) osteoblast deposition of matrix, (5) mineralization, and (6) quiescent stage. Osteoclasts, the bone-resorbing cells, are derived from hematopoietic precursor cells, and act via the release of degradative enzymes. PTH, cytokines, and 1,25(OH)2D are all important in the control of osteoclast precursors. Bone strength reflects the integration of two main features: bone density and bone quality. These “quality” factors include

Bone Biopsy and Histomorphometry in Patients with Chronic Kidney Disease Bone biopsy is the gold standard for the assessment of bone turnover and remodeling, although is now used primarily for research purposes. Historically, renal osteodystrophy has been defined as a spectrum of disorders, ranging from low-turnover (adynamic) to high-turnover (osteitis fibrosa) disease, with a poorly defined entity termed mixed renal osteodystrophy, which represented various degrees of bone turnover with mineralization defects. The histologic features of high-turnover bone disease (predominant hyperparathyroidism or osteitis fibrosa) are characterized by increased rate of bone formation and resorption, extensive osteoclastic and osteoblastic activity, and a progressive increase in endosteal peritrabecular fibrosis. There is also abnormal alignment of collagen strands in the bone matrix that renders the bone more physically vulnerable to stress. Low-turnover or adynamic bone disease is histologically characterized by absence of osteoblastic and osteoclastic activity, osteoid formation, and endosteal fibrosis. Low-turnover disease was initially described as a result of aluminum toxicity, but remains common in its absence. Osteomalacia, characterized by an excess of unmineralized bone, a markedly decreased mineralization rate, and absence of cell activity, was frequently associated with aluminum toxicity. Risk factors for adynamic bone disease include age, diabetes, oversuppression of PTH with vitamin D and calcium-containing phosphate binders, peritoneal dialysis, and possibly calcium overload. Although


abnormal bone turnover or remodeling, and other indices of 623 bone architecture including mineralization and collagen crosslinking. Impaired bone quality in CKD/ESRD is clinically manifested by increased prevalence of hip fracture across all age groups in the dialysis population compared to the general popu- CH 30 lation, with dialysis patients in their 40s shown to have a relative risk of hip fracture 80-fold that of age- and sex-matched control subjects. CKD has also been shown to be an independent risk factor for hip fracture. Most studies have observed a high prevalence of osteopenia and osteoporosis as measured by dual x-ray absorptiometry (DEXA) in ESRD patients. There are limitations to the use of DEXA in the ESRD population, however, as DEXA can detect only the overall density of bone, rather than bone quality. Differences in pattern of mineral content and potential artefact from vascular calcification in ESRD patients are also considerations. Quantitative CT scanning may offer an alternative to DEXA, as it can differentiate cortical and trabecular bone, and local patterns of mineral content.

624 Table 30-2


VII

Bone Turnover, Mineralization, and Volume Classification System for Renal Osteodystrophy

Turnover

Mineralization

Volume

Low

Normal

Low

Normal

Abnormal

Normal

High

High

most patients with low-turnover bone disease are asymptomatic, they are at increased risk of fracture compared to impaired remodeling, and are at risk of vascular calcification due to an inability of bone to buffer an acute calcium load. The progression in our understanding of bone biology, however, has necessitated a new classification system. The KDIGO classification uses three key histologic components—bone turnover, mineralization, and volume (TMV system), where any combination of each component is possible in a given bone specimen. This new classification is consistent with the current classification, but provides more information on clinically relevant parameters (Table 30-2). As discussed earlier, serum PTH is currently used as a surrogate biomarker to predict bone turnover. However, studies evaluating the ability of PTH to predict both low- and highturnover disease have been disappointing. In general, the risk of high-turnover bone disease increases with the concentration of intact PTH, but its predictive ability is poor until iPTH levels reach 450 to 500 pg/mL. Conversely, levels below 100 pg/mL are reasonably reliable for the prediction of lowturnover bone disease, but not infallible. Despite initial hopes, other bone markers such as osteocalcin and bone-specific alkaline phosphatase have failed to offer additional benefit in the prediction of underlying bone histologic disease.

VASCULAR CALCIFICATION Classically, atherosclerotic disease has been characterized by fibrofatty plaque formation, associated with intimal calcification, where calcification was thought to be a late feature of the disease. More recent advances have demonstrated circumferential atherosclerosis, where calcification is an early feature. The medial layer may also be affected, leading to medial calcification of elastic arteries. This medial calcinosis, or Monckeberg calcification, is seen in patients with diabetes and kidney disease, and is associated with younger age, longer duration of hemodialysis, and serum calcium phosphate

Inhibitors of Vascular Calcification Vascular calcification, although very prevalent in the dialysis population, is not uniform, and the persistent absence of calcification in a subgroup of patients supports the presence of naturally occurring inhibitors of calcification. Animal models have shown that selective deletion of many genes, including matrix gla protein (MGP) and osteoprotegerin, leads to vascular calcification. Studies to date assessing circulating levels of MGP have shown disparate results, however. Another potential circulating inhibitor of extraskeletal calcification is fetuin-A, an abundant glycoprotein produced mainly in the liver. Fetuin-A inhibits the de novo formation and precipitation of the apatite precursor mineral basic calcium phosphate, but does not dissolve it once the basic calcium phosphate is formed, thereby allowing it to prevent undesirable calcification in the circulation without causing bone demineralization. Studies have shown that low fetuin-A levels are associated with increased cardiovascular mortality rate in dialysis patients, although it is unclear whether there is a relative deficiency of fetuin-A in setting of elevated calcium and phosphate, or if genetic polymorphisms are responsible for altered function. Pyrophosphate is another naturally occurring inhibitor of mineralization; circulating levels have been found to be decreased in dialysis patients and to be partially cleared by dialysis. The precise role


abnormalities. Medial calcification implies arteriosclerosis 625 with noncompliance of the large conduit vessels. It has been clearly shown to be associated with increased all-cause and cardiovascular calcification in CKD and in diabetic patients in the absence of CKD. CH 30 Although initially believed to be a bystander process, recent evidence suggests that vascular calcification is a tightly regulated process that resembles mineralization in bone. Vascular smooth muscle cells and vascular pericytes are capable of producing bone-like proteins in cell culture, and can form mineralized nodules in vitro in the presence of a phosphorus donor. Evidence for similar osteogenesis in vascular calcification in the dialysis population was found in small skin arterioles from dialysis patients with calcific uremic arteriolopathy (calciphylaxis) that expressed osteopontin and bone protein sialoprotein, whereas noncalcified vessels did not. Using an in vitro calcification model of vascular smooth muscle cells, several nontraditional cardiovascular risk factors can accelerate vascular calcification, including PTH, PTHrp, calcitriol, advanced glycation end products, alterations of lipoproteins, and homocysteine. Excess calcium can also induce mineralization in vitro, with effects additive to those of increased phosphorus.

626

Table 30-3

Clinical Features of Mineral Bone Disease

Bone pain—usually insidious and nonspecific; symptoms of pseudogout due to calcification of articular cartilage


VII

Myopathy—associated with SHPT, phosphate depletion, and vitamin D deficiency Spontaneous tendon rupture Pruritus—may reflect high levels of PTH, hypercalcemia, and a high calcium-phosphorus product Metastatic and extraskeletal calcifications Calciphylaxis (calcific uremic arteriolopathy) Ocular calcification—usually asymptomatic; dry or gritty eyes, conjunctival erythema Cardiovascular (discussed in detail in Chapter 27) PTH, parathyroid hormone; SHPT, secondary hyperparathyroidism.

of these and other inhibitors remains to be determined, but there are clearly multiple mechanisms involved in the regulation of extraskeletal calcification.

CLINICAL FEATURES OF MINERAL BONE DISEASE Bone disease in CKD patients is usually asymptomatic, with clinical features appearing only late in the course of disease, at which time significant biochemical and histologic changes are present (Table 30-3).

CALCIPHYLAXIS Calciphylaxis is a small vessel vasculopathy largely confined to patients with end-stage kidney disease and is also known as calcific uremic arteriolopathy. Ischemia of the skin and subcutaneous tissues is the most common clinical presentation, leading to necrosing skin ulcers, subcutaneous nodules of infarction, and areas of poor wound healing. The most common sites of involvement are subcutaneous tissue with increased adipose content, including the breast, abdominal wall, and thigh. The overall prognosis is poor, with death due to sepsis extremely common. The exact etiology of this disorder is unclear. Risk factors include obesity, white ethnic race, and diabetes mellitus. Much attention has also focused on the roles of hypercalcemia, hyperphosphatemia, SHPT, and high calcium phosphate product (Ca P). Sustained hyperphosphatemia in particular may be a risk factor for calciphylaxis. Although associated with severe SHPT, many cases occur in

RADIOLOGIC FEATURES OF MINERAL BONE DISEASE Considerable amounts of bone mineral can be lost prior to overt radiologic change, and radiologic changes correlate poorly with underlying histologic appearance. There is therefore no benefit to the routine use of skeletal imaging for screening for renal bone disease. The classical radiologic changes are briefly described in Table 30-4.

MANAGEMENT OF BONE DISEASE, MINERAL METABOLISM, AND PARATHYROID GLAND FUNCTION The clinical management of SHPT, renal bone disease, and disturbances in calcium and phosphorus metabolism associated with CKD is challenging, and requires continuous effort. The benefits and risks associated with each therapeutic intervention should be considered carefully.

Phosphate-Binding Agents As discussed previously, we are increasingly aware of the need for optimal control of hyperphosphatemia, as its role in SHPT, vascular mineralization, and cardiovascular morbidity


the absence of hyperparathyroidism at the time of diagnosis. 627 Protein calorie malnutrition, use of warfarin, vitamin K deficiency, and protein C and S deficiency have also been postulated as potential risk factors. Calciphylaxis is generally diagnosed clinically by the presence of subcutaneous and cuta- CH 30 neous nodules, necrotic lesions, and eschar with hyperesthesia of the skin. Tissue biopsy demonstrates calcification of small arterioles and venules. Biopsy is not always recommended because there is a high likelihood of poor healing at the biopsy site. Treatment outcomes for patients with calciphylaxis are poor, and only anecdotal case reports of successful treatment exist. Suggested strategies include lowering of the (Ca P) to less than 55 mg/dL, optimization of calcium/phosphate derangements, discontinuation of calcium-containing phosphate binders, vitamin D sterols, and the use of lower calcium dialysate concentrations. Isolated case reports have documented successful treatments with hyperbaric oxygen, bisphosphonates, subtotal parathyroidectomy, sodium thiosulfate, and more recently, the calcimimetic cinacalcet. Careful attention to analgesia, avoidance of trauma, and wound care are essential.

628


VII

Table 30-4

Radiographic Features of Mineral Bone Disease

Bone Disease Type

Specific Feature(s)

High-turnover

Subperiosteal bone resorption Cystic lesions or brown tumors (osteoclastomas) Osteosclerosis (“rugger-jersey” appearance on lateral view of spine) “Pepper-pot” skull

Osteomalacia

Pseudofractures or Looser zones (pathognomonic) Stress fractures Deformities of long bones (e.g., bowing) May also see features of high-turnover bone disease

Osteopenia

Decreased bone mineral density (nonspecific finding)

Metastatic calcification

Calcified large blood vessels; also calcifications in joints, skeletal muscle

Dialysis-related amyloidosis

Cystic bone lesions (not pathognomonic) Cysts of synovial joints, subchondral cysts

Destructive spondyloarthropathy

Usually affects cervical spine; reduction of disk space with destruction or sclerosis of adjacent end-plates (need to distinguish from infective osteomyelitis)

has been further defined. Dietary limitation of phosphorus, intrinsically linked as it is to protein restriction, is usually insufficient, and may lead to insufficient consumption of protein. Current recommendations, as listed in K/DOQI guidelines (Table 30-5), are to maintain normal serum levels for patients with CKD stage 3 and 4, and to maintain levels between 3.5 and 5.5 mg/dL in CKD stage 5 or dialysis patients. Phosphate-binding agents are widely used to diminish intestinal phosphate absorption by forming poorly soluble complexes with phosphate in the intestinal lumen. In the past, aluminum-containing compounds such as aluminum hydroxide or aluminum carbonate were widely used, and although they were potent phosphate-binding agents, their long-term use led to aluminum retention and toxicity, and they are now infrequently used.

Calcium-Containing Phosphate Binders Calcium carbonate and calcium acetate are two widely used phosphate-binding agents, and although both have similar efficacy, calcium acetate contains less elemental calcium (325 mg

Table 30-5

Recommended Serum Values for Selected Biochemical Parameters According to Stage of Chronic Kidney Disease (CKD)*

CKD Stage

GFR Range (mL/min/1.73 m2)

Phosphorus (mg/dL)

Calcium (corr) (mg/dL)

Ca P

Intact PTH (pg/mL)

3

30–59

2.7–4.6

8.4–10.2

—

35–70

4

15–29

2.7–4.6

8.4–10.2

—

70–110

5/ESRD

7 days before onset of encephalopathy Serum bilirubin > 17.5 mg/dL INR > 3.5

INR, international normalized ratio.

The King’s College criteria (Table 36-7) are utilized to aid decision as to when a patient should be listed for transplantation. Contraindications include uncontrolled intracranial hypertension, sepsis, adult respiratory distress syndrome, and dependence on pressors.

RENAL REPLACEMENT THERAPY IN THE INTENSIVE CARE UNIT For a complete discussion of dialytic modalities in AKI see Chapter 10, Acute Kidney Injury.

Chapter 37

Plasmapheresis The term plasmapheresis (PE) or therapeutic plasma exchange (TPE) involves the therapeutic removal of macromolecules from the plasma of patients with a variety of underlying medical conditions. The plasmapheresis process involves the replacement of plasma with albumin or other solutions (crystalloid or colloid) to maintain a normovolemic state.

TECHNICAL CONSIDERATIONS For most conditions, the aim of the procedure is the removal of pathologic autoantibodies or toxins, and the initial treatment goal is to exchange 1 to 1.5 times the plasma volume per plasmapheresis procedure. A formula to estimate plasma volume in an adult is as follows: Estimated plasma volume ðin litersÞ ¼ 0:07 weight ðin kgÞ ð100 hematocritÞ For removal of components predominantly restricted to the plasma space, the use of higher exchange volumes will require significantly longer procedure times without additional clinical benefit. The ultimate clinical success of the procedure depends on the abundance of abnormal protein and its rate of production, and unless additional therapies are employed (usually immunosuppressive or cytotoxic) to eliminate or reduce the source of the abnormal protein(s), it is unlikely to be of clinical benefit.

Plasma Separation Techniques There are two major modalities to separate the plasma from blood during a PE procedure: (1) centrifugation and (2) membrane filtration. The mechanism and equipment for these procedures vary significantly, and are usually employed by blood bank or hemodialysis facilities, respectively. The choice of method depends on the specific disease, as well as the resources of the health care facility concerned. If concurrent hemodialysis treatment is required, the membrane filtration method can be performed in combination with conventional hemodialysis.

777

778

Invasive Therapy of Renal Failure

The centrifugation method uses centrifugal force to separate whole blood into plasma and cellular fractions according to their density, and can be either an intermittent or continuous process. In intermittent centrifugation, sequential volumes of IX whole blood are removed and centrifuged, the cellular fraction is returned to the patient, and the process is repeated until the desired volume of plasma is removed. The advantages of intermittent centrifugation include relative simplicity of operation, machine portability, and the convenience of single-needle peripheral venipuncture. Disadvantages include time required (typically more than 4 hours per procedure) and the relatively large extracorporeal volume removed each time. In continuous centrifugation, blood is pumped continuously, plasma is removed at a specified rate, and cells plus replacement fluid are returned to the patient in a continuous manner. This method is faster, and more suitable for hemodynamically unstable patients, but it is more costly and requires two venipunctures or insertion of a dual-lumen central venous catheter. The membrane filtration technique is based on a synthetic membrane filter composed of many hollow fiber tubes, made of a membrane, with relatively large pore sizes, arranged in parallel, similar to a hemodialysis filter. The pores are sufficiently large to allow passage of plasma (proteins and plasma water), while retaining cells within the hollow fiber lumen before returning the cells to the patient through a typical hemodialysis circuit. This technique can be done with conventional or continuous hemodialysis equipment, with a blood flow rate of 100 (20) mL/min, and an optimal transmembrane pressure less than 70 mm Hg. Plasma is removed at a rate of 30 to 50 mL/min and the infusion rate of replacement fluid is adjusted to maintain intravascular volume. Potential disadvantages include activation of complement and leukocytes by the artificial membrane, and the need for a central large-bore catheter to obtain adequate blood flow rates.

Venous Access Successful implementation of the plasmapheresis procedure requires reliable venous access. Several factors need to be considered when deciding on venous access, particularly the potential requirement for long-term plasmapheresis and the method of plasmapheresis being utilized. A peripheral vein allows a maximum flow of between 50 and 90 mL/min, and intermittent centrifugation requires only a single venous access, whereas the continuous method will need two. If long-term (more than 1–2 weeks) plasmapheresis is required, or the membrane filtration method is used, a central venous

catheter will be required. Central venous catheters have the 779 risk of numerous complications including catheter thrombosis, infection, and central vein thrombosis. CH 37

The plasmapheresis procedure requires anticoagulation to prevent clotting of the extracorporeal circuit. For centrifugation procedures, the acid-citrate-dextrose (ACD) solution (1=9 volume of solute per volume of solution), given as a continuous intravenous infusion, is the most commonly used agent. Heparin, if not contraindicated, can be used alone or in combination with citrate when risk of catheter clotting is increased. For membrane filtration procedures, the use of standard unfractionated heparin is preferred, although approximately twice the amount needed for hemodialysis is required, as a significant amount of infused heparin is removed along with plasma. Systemic anticoagulation may be potentiated, however, due to the additional effect of dilution of clotting factors by nonplasma replacement solutions. The initial intravenous loading dose of heparin (40 U/kg) is usually followed by a continuous infusion (20 U/kg/hour), adjusted to maintain adequate circuit anticoagulation. If patients are receiving standard oral anticoagulation, regional citrate or heparin should be added to prevent circuit clotting. In critically ill patients with coagulation abnormalities, regional citrate is recommended. The use of citrate mandates careful monitoring of calcium levels. Hirudin and lepirudin (thrombin inhibitors) are effective for patients with contraindications to heparin use.

Replacement Fluid The choice of replacement fluids include 5% albumin, freshfrozen plasma (FFP) or other plasma derivatives such as cryosupernatant, and crystalloids (0.9% saline, Ringer’s lactate). Albumin is the most commonly used solution and is generally combined with saline on a 50:50 (volume %) basis. It lacks calcium, potassium, coagulation factors, and immunoglobulins. FFP contains complement and coagulation factors, and is the replacement fluid of choice in patients with thrombotic thrombocytopenic purpura (TTP), which is discussed in more detail later. Plasma may also be preferable in patients at increased risk of bleeding (e.g., liver disease, pulmonary-renal syndromes with potential for pulmonary hemorrhage) or in whom intensive therapy is required, as frequent albumin replacement will result in post-plasmapheresis coagulopathy

Plasmapheresis

Anticoagulation

780 and a net loss of immunoglobulins. Disadvantages of FFP use

include the risk of viral disease transmission and citrate overload.


IX

Complications Adverse events in plasmapheresis are common, the vast majority of which do not require termination of the procedure; death is rare. The common complications are summarized in Table 37-1.

Hypotension Plasmapheresis can lead to a reduction in blood pressure, usually due to decreased plasma volume. Intermittent centrifugal techniques use a greater volume of extracorporeal blood, with higher incidence of hypotension. Hypotension can also occur in response to complement-mediated reactions to the filter, or sensitivity to ethylene oxide used as a sterilant. Anaphylactoid reactions have been reported with FFP use, although cardiopulmonary collapse is rare.

Citrate-induced Complications: Hypocalcemia and Metabolic Alkalosis Citrate, either as an anticoagulant or as a component of FFP, can bind to free calcium to form soluble calcium citrate, thereby lowering the free, but not total, serum calcium

Table 37-1

Complications of Plasmapheresis

Component

Related Complication

Vascular access

Hematomas Pneumothorax Catheter infections/thrombosis

Replacement fluids

Anaphylactoid reactions to fresh-frozen plasma Coagulopathies Transmission of viral infections Hypocalcemia Hypokalemia

Miscellaneous

Hypotension Dyspnea (pulmonary edema; rarely, anaphylaxis causing noncardiogenic edema) Thrombocytopenia Removal of erythropoietin and drugs bound to plasma proteins Angiotension-converting enzyme inhibitors

Hypokalemia Replacement regimens using saline and albumin solutions can result in a 25% reduction in the plasma potassium concentration in the post-pheresis period. This can be minimized by the addition of potassium 4 mEq/L to the replacement solution.

Coagulation Abnormalities Albumin replacement produces a predictable decrease in clotting factors that may predispose to bleeding. A single plasma volume exchange increases the prothrombin time by 30% and the partial thromboplastin time by 100%. These changes return to normal within several hours, but with repeated treatments they may persist. Therefore, 3 to 4 units of FFP should be included with the replacement fluid each week or sooner in patients at risk for bleeding.

Infection Repeated plasmapheresis with albumin replacement will deplete a patient’s reserve of immunoglobulins for several weeks, and this, combined with complement removal, could result in an immunodeficient state. However, a study evaluating infection rates did not find increased likelihood of infection in patients treated with plasmapheresis. Should infection occur, a single infusion of intravenous immunoglobulin (100–400 mg/kg) will restore the plasma immunoglobulin rates to normal. Although estimates for the risk of viral transmission by the use of FFP are low, large volumes from multiple donors increase the risk in patients undergoing long-term treatment. Use of large-volume plasma from a single donor and use of the hepatitis B vaccine may reduce the risk of viral transmission.

PLASMAPHERESIS IN RENAL DISEASE Plasmapheresis should be considered when the pathogenic factor(s) are high-molecular-weight substances or the patient is deficient in a plasma component, whereas hemodialysis or

Plasmapheresis

concentration. Monitoring of serum calcium levels is man- 781 dated, therefore, and symptoms can be anticipated and reduced by either intravenous or oral administration of calcium. In the presence of renal failure, citrate administration can cause metabolic alkalosis, due to the generation of bicarbonate from the CH 37 metabolism of excess citrate.

782 Table 37-2

Pathologic Factors Removed by Plasmapheresis

Immune complexes


Autoantibodies

IX

Myeloma protein Cryoglobulin Complement products ADAMTS-13 Lipoproteins Protein-bound toxins Cells—platelets or white blood cells (modified procedure ¼ cytapheresis) ADAMTS-13, a disintegrin-like metalloprotease with thrombospondin type 1 repeats.

hemofiltration is more efficient for the removal of small molecules and toxins with a large volume of distribution. Table 37-2 lists the pathologic factors that may be removed with plasmapheresis.

Anti–Glomerular Basement Membrane Disease Anti–glomerular basement membrane (anti-GBM) antibody disease is a disorder in which circulating antibodies are directed against an antigen in the glomerular basement membrane, resulting in a rapidly progressive (usually catastrophic) glomerulonephritis. When accompanied by pulmonary hemorrhage, the disease is known as Goodpasture syndrome. Circulating anti-GBM antibodies are detected in excess of 90% of patients, and antibody titer correlates to disease activity. The pathophysiology of anti-GBM antibody disease is discussed further in Chapter 11, Primary Glomerular Disease. Historically, untreated patients do not recover renal function and have a substantial mortality rate, mainly from pulmonary hemorrhage. Plasmapheresis is used to rapidly remove the pathogenic autoantibodies, while further immunosuppression (usually cyclophosphamide and steroids) is administered to reduce additional antibody synthesis and reduce inflammation. All patients with anti-GBM antibody disease and severe renal failure who do not require immediate dialysis should be immunosuppressed and immediately receive intensive plasmapheresis—current evidence suggests daily plasmapheresis for at least 14 days. As pulmonary hemorrhage is associated with high mortality rate, plasmapheresis should be initiated in all Goodpasture patients with pulmonary hemorrhage regardless of the severity of renal failure.

Rapidly Progressive Glomerulonephritis

783

Plasmapheresis

Rapidly progressive glomerulonephritis (RPGN) is characterized by a rapid deterioration in renal function, occurring over a period of a few days to a few weeks. Histologically, CH 37 there is severe inflammation and necrosis of the glomeruli and, often, glomerular crescent formation. There are three major subgroups: (1) anti-GBM antibody disease, (2) immune complex–mediated processes, including systemic lupus erythematosus, postinfectious processes, and mixed cryoglobulinemia, (3) pauci-immune diseases that are most often associated with antineutrophil cytoplasmic antibodies (ANCA), including Wegener granulomatosis and microscopic polyangitis. These conditions are discussed in more detail in Chapter 11, Primary Glomerular Disease. There is limited data to support the use of plasmapheresis in immune complex– mediated processes. The rationale for using plasmapheresis in pauci-immune ANCA-associated disease was initially based on the similarity of the renal pathology to anti-GBM antibody disease. However, several studies performed in the 1990s failed to demonstrate significant additional benefit in the absence of dialysis dependence. Recently published results from the European Vasculitis Study Group (EUVAS), which evaluated ANCA-associated glomerulonephritis with severe renal involvement (creatinine > 5.7 mg/dL or >500 mmol/L), showed a lower incidence of dialysis dependence at 12 months in patients treated with plasmapheresis in addition to induction and maintenance of immunosuppression. For patients presenting with severe ANCA-associated glomerulonephritis and advanced renal involvement, there is therefore strong support for the use of plasmapheresis, although less evidence for those presenting without acute kidney injury. Plasmapheresis should be initiated in any patient who co-presents with anti-GBM antibody disease, and in any patient with acute pulmonary alveolar hemorrhage.

Lupus Nephritis Lupus nephritis is a common and potentially serious complication of systemic lupus erythematosus and is discussed in detail in Chapter 12, Secondary Glomerular Disease. Class IV lupus nephritis is associated with poor renal outcomes unless treated with immunosuppressive protocols utilizing cytotoxic therapy, although there is little data to support the use of plasmapheresis. A large randomized controlled trial evaluated the use of plasmapheresis, in addition to a standard therapy regimen of cyclophosphamide and prednisolone, in patients with lupus nephritis including histologic

784 subtypes III, IV, and V. Despite a significantly more rapid


reduction in serum concentrations of antibodies to doublestranded DNA in the plasmapheresis-treated group, no additional clinical benefit was seen. It is thought that selected IX patients with aggressive lupus nephritis may benefit, and it has been used with some reported success in patients relapsing on conventional therapy, but currently available data are insufficient to recommend its use.

Cryoglobulinemia Cryoglobulinemia refers to the presence of serum proteins that precipitate at temperatures below 37 C, and re-dissolve on warming. The pathophysiology of cryoglobulinemia is discussed in more detail in Chapter 12, Secondary Glomerular Disease. Hepatitis C virus (HCV)–related cryoglobulinemia and glomerulonephritis is related to the glomerular deposition of immune complexes. There are no randomized controlled studies of plasmapheresis for the treatment of cryoglobulinemia. However, the goal of removing pathogenic cryoglobulins is rational, and there are many case reports and uncontrolled studies that suggest that severe, active disease (as manifested by progressive renal failure, coalescing purpura, or advanced neuropathy) may benefit from the addition of plasmapheresis. Given the unique characteristics of cryoglobulins, modification of the plasmapheresis technique has been made to enhance their removal. Cryofiltration cools the plasma in an extracorporeal circuit allowing for more efficient removal of the pathogenic proteins, although this is best performed by a continuous process, requiring a machine designed for the purpose. Alternatively, a two-step procedure can be performed, in which the patient’s own plasma can be reinfused after cold incubation to precipitate out the abnormal proteins.

Renal Failure Associated with Multiple Myeloma Renal disease is a common problem in multiple myeloma and can be caused by a variety of factors, including precipitation of myeloma light chains within tubules, and direct toxicity to tubule epithelium. Other factors frequently implicated include hypercalcemia, hyperuricemia, amyloidosis, hyperviscosity, infections, and chemotherapeutic agents. Theoretically, the removal of nephrotoxic Bence Jones proteins with plasmapheresis could prevent or resolve the development of renal failure, but despite some early optimism, subsequent trials have failed to demonstrate clinical benefit following treatment with plasmapheresis.

Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

785

Plasmapheresis

These thrombotic microangiopathic disorders, although distinct in pathophysiology, share patterns of endothelial injury, CH 37 which are manifested by systemic or intrarenal aggregation of platelets, thrombocytopenia, mechanical injury to erythrocytes, and end-organ injury. Although historically considered to be the same disease, major advances have been made in recent years in our understanding of the distinct pathophysiology underlying each disease, and are discussed in more detail in Chapter 13, Microvascular Diseases of the Kidney. Genetic studies of congenital thrombotic thrombocytopenic purpura (TTP) led to the identification of defects in a metalloproteinase called von Willebrand factor–cleaving protease, now known as ADAMTS-13 (a disintegrin-like metalloprotease with thrombospondin type 1 repeats). Deficiencies in ADAMTS-13, now recognized to be due either to an inherited or autoantibody-mediated defect, lead to the accumulation of unusually large von Willebrand factor multimers in the circulation, which subsequently initiate endothelial injury. Historically, this disease was nearly uniformly fatal; however, the use of plasmapheresis has dramatically improved the prognosis, with response rates in adults of 60% to 80%. The use and success of plasmapheresis are supported by our knowledge of the underlying defect—in the case of inherited ADAMTS-13 deficiency, replacement of plasma with normal ADAMTS-13 activity, and in the case of an inhibitory autoantibody to ADAMTS-13, its removal by plasmapheresis. It appears, however, that there is a wide range of normal ADAMTS-13 activity, and deficiency alone may not be sufficient to cause disease in the absence of additional causes of endothelial injury. Hemolytic uremic syndrome (HUS) is classically associated with a prodromal diarrheal illness, with endothelial injury caused by verocytotoxin/shiga toxin–producing bacteria. Diarrhea-associated HUS is more common in children, and typically has a high recovery rate, requiring only supportive therapy, although therapy may include need for hemodialysis because the incidence of renal failure is high. It is now clear, however, that a significant proportion of cases of HUS are not associated with a diarrheal illness, suggesting other mediators of endothelial injury. Familial forms of HUS are described and have more aggressive clinical courses, with high relapse rates. Inherited complement disorders, including disorders of complement factor H (FH), factor I (FI), and membrane co-factor protein (MCP) (CD46), have been shown to be associated with HUS. Approximately 20% of cases of familial HUS are due to FH mutations. Inhibitory autoantibodies to FH have also been described. The

786 role of plasmapheresis in the treatment of HUS is less clear than


that for TTP, although the diseases are often clinically difficult to distinguish, particularly in the absence of a diarrheal prodrome, so that plasmapheresis may be commenced empirically. It is IX often used for severe or persistent disease, particularly in adults. The duration of plasmapheresis required is unknown, but it is performed daily until the platelet count has risen to normal, evidence for hemolysis has resolved, and resolution of neurologic symptoms has been achieved, although formal guidelines differ in terms of the absolute platelet count required prior to discontinuation of plasmapheresis. Improvements in the platelet count may not be seen for several days, and improvements in renal function often take longer. Upon achievement of a normal platelet count, plasmapheresis should be tapered gradually by increasing the interval between treatments. A significant proportion of patients may show evidence of ongoing active disease on discontinuation of therapy, mandating careful monitoring. For recurrent disease, additional immunosuppressive therapy is often required.

Recurrent Focal Segmental Glomerulosclerosis Recurrent focal segmental glomerulosclerosis (FSGS) is a common glomerular disease resulting in end-stage renal disease, and is the most common disease to recur in a renal allograft (20%). The immediate reappearance of proteinuria after transplantation suggests that a nondialyzable circulating factor may be present, altering glomerular permeability. The circulating factor is found in normal plasma and has not been definitively identified, but is thought to be a nonimmunoglobulin. Variable levels of this constituent in normal plasma may explain the discrepancy among studies evaluating the circulating factor. Removal of such a factor by plasmapheresis may account for the remission of the disease in some patients. Studies have shown benefit in the use of plasmapheresis, and early relapse rates improved with the extension of plasmapheresis to nine sessions. In recurrent FSGS after renal transplantation, beneficial results have been reported in children treated with plasmapheresis and cyclophosphamide, although the study numbers are very small. The evidence in adults is less clear, in the absence of controlled trials, although the use of plasmapheresis has been associated with better allograft outcomes.

Renal Transplantation In addition to its role in the treatment of recurrent FSGS after transplant, plasmapheresis has been utilized in several other clinical settings involving transplantation, including ABO

blood group incompatibility, positive T-cell cross-match, and 787 acute humoral rejection.

ABO-Incompatible Kidney Transplantation Plasmapheresis

ABO-incompatible kidney transplantation is an increasingly CH 37 attractive option for transplant candidates whose only living donor is blood group incompatible. The ABO blood group consists of four common categories, A, B, AB, and O, with types A and O the most frequently occurring in the U.S. population. The proteins comprising these antigens are on red blood cells, lymphocytes, and platelets, in addition to epithelial and endothelial cells. Historically, ABO incompatibility was an exclusion criterion for transplantation, as blood group antibodies arise against those antigens not native to the host, and mismatched renal transplantation in this situation can lead to acute humoral rejection. However, excellent reported outcomes with ABO-incompatible transplants from Japan kindled renewed interest in ABO-incompatible renal transplantation with a variety of desensitization procedures. Current desensitization protocols utilize intravenous immune globulin (IVIG), with and without plasmapheresis, to remove IgG and IgM antibodies against the ABO group of the potential recipient. These treatments are performed in addition to a variety of immunosuppression regimens including tacrolimus, mycophenolate, and steroids.

Positive T-Cell Cross-Match The most recent available data in the United States indicates that about 20% of patients awaiting kidney transplantation have reactive antibodies. Primary sensitization results from exposure to foreign HLA antigens via transfusion, transplantation, or pregnancy. Patients who have antibodies reactive with donor lymphocytes are at increased risk for hyperacute or acute antibody-mediated rejection and graft loss. There are currently two HLA antibody reduction protocols for which efficacy has been demonstrated: high-dose IVIG and plasmapheresis combined with IVIG. Plasmapheresis is used to remove anti-HLA antibodies and is followed by infusion of low doses of IgG during hemodialysis, which is postulated to have additional beneficial immunomodulating effects. Simultaneous to commencement of plasmapheresis, treatment with tacrolimus steroids (plus antimicrobial prophylaxis) is administered. Plasmapheresis is continued thrice weekly until the T-cell CDC cross-match is negative; in the setting of living donor transplantation, the transplant then takes place within 24 hours. Plasmapheresis and low-dose IgG are usually repeated several times during the first two posttransplant weeks to remove any rebounding antibody. The use of plasmapheresis-based desensitization protocols for patients awaiting deceased donor transplantation is more difficult, as

788 the availability of donor organs is unpredictable, and plasmapheresis is both difficult and expensive to continue indefinitely. Anti-HLA antibody titers will rebound upon discontinuation of plasmapheresis.


IX

Acute Humoral Rejection Acute humoral rejection is characterized by the presence of severe allograft dysfunction associated with the presence of circulating donor-specific antibodies. Poor outcomes are seen with acute humoral rejection and treatment with pulse steroids and antilymphocyte therapy is often ineffective. Removal of the donor specific antibodies with plasmapheresis has been successful when combined with tacrolimus and mycophenolate mofetil. It is now proposed that the combination of plasmapheresis and IVIG may lead to short-term recovery from acute antibody-mediated rejection in more than 80% of cases.

CONCLUSION The use of plasmapheresis to manage a variety of kidney diseases has grown significantly in recent years. In some cases, the rationale and benefit are supported by clinical studies, but in others the evidence is not robust. Additional studies are required to determine the potential benefits for plasmapheresis in these conditions.

Chapter 38

Extracorporeal Treatment of Poisoning Poisoning may result from an unintentional toxic exposure, an intentional misuse of a substance with or without selfdestructive intent, therapeutic error, or malicious activity. The treating physician must have a working knowledge of clinical pharmacokinetics and the relationship between a toxin’s characteristics and the ability to enhance its elimination with extracorporeal therapy.

GENERAL MANAGEMENT OF POISONING AND DRUG OVERDOSE The general approach to the intoxicated patient includes prompt resuscitation and stabilization, including airway and circulatory management, clinical and laboratory evaluation, and gastrointestinal decontamination. In certain cases, toxin elimination can be enhanced using various decontamination techniques, urinary alkalinization, and extracorporeal therapy. As patients may present in an obtunded state, a collateral history will be frequently required, including questions regarding habits, hobbies, prescription medications, behavioral changes, and antecedent events. Close clinical monitoring is mandated given the potential for sudden and rapid deterioration in clinical status. The distinguishing laboratory features of toxin exposure, including metabolic acidosis, and evaluation of the anion gap and osmolal gap, are discussed in detail later in this chapter. The anion gap and osmolal gap are two key features that assist in the determination of type of toxin ingested. A high anion gap metabolic acidosis is characteristic of salicylate, methanol, and ethylene glycol toxicity, or lactic acidosis secondary to hypotension/ hypoxia. A low anion gap is observed with lithium, nitrate, iodine, and bromide poisoning. Ketosis may be present with acetone, isopropanol (i.e., isopropyl alcohol), and salicylate ingestion. The osmolal gap is the difference between the measured serum osmolality and the calculated osmolality. The calculated osmolality is determined by the following formula: Osmcalculated ðmOsm=kgÞ ¼ 2½Naþ þ glucose ðmg=dLÞ=18 þ blood urea nitrogen ðmg=dLÞ=2:8

789

790


The osmolal gap indicates the presence of an unmeasured solute and is considered elevated if the value is more than 10 to 12 mOsm/kg H2O. An elevated osmolal gap is most commonly seen with ethanol, ethylene glycol, isopropanol, and IX methanol toxicity.

PRINCIPLES AND TECHNIQUES FOR ENHANCED RENAL ELIMINATION OF TOXINS Forced Diuresis and Manipulation of Urinary pH The physiologic mechanisms involved in the elimination of drugs by the kidney include (1) glomerular filtration of the drug (depends on degree of protein binding of the drug, as only unbound drug is readily filtered by the glomerulus), (2) active proximal tubule secretion of the drug into the urine (mediated by organic anion transporters), and (3) passive reabsorption of the drug in the distal tubule (occurs more frequently with the elimination of lipid-soluble, nonionized drugs). Historically, forced diuresis through volume expansion with isotonic fluids (0.9% NaCl or Ringer’s lactate), with or without comcomitant diuretics, has been used to enhance renal elimination of toxins. Early studies suggested that despite maximal proximal tubular secretion of a solute, urine volumes of 200 to 300 mL/hour inhibited solute tubular reabsorption due to an unfavorable concentration gradient. However, when passive tubular reabsorption of a solute was pH sensitive, increased urine volume through forced diuresis was not found to significantly enhance drug elimination when combined with urinary alkalinization. When considered with the common complications of forced diuresis, including volume overload, pulmonary and cerebral edema, electrolyte disorders, and metabolic alkalosis, the lack of clinical evidence supporting this approach means that it is now no longer recommended in the management of acute poisonings. Manipulation of urinary pH has also been used to enhance renal elimination of a toxin, based on the concept of ion trapping. As cell membranes are generally more permeable to lipid-soluble, nonpolar, nonionized forms, the goal of manipulating urinary pH is to favor the formation of the ionized form, which is lipid insoluble, thereby inhibiting passive reabsorption of the drug. The ionized form becomes trapped in the tubular lumen and is excreted in the urine. The clinical efficacy of urine alkalinization is dependent on the relative contribution of renal clearance to the total body clearance of active drug. Criteria that determine whether a drug is

Extracorporeal Treatment of Poisoning

amenable to urinary alkalinization are as follows: (1) it is 791 eliminated unchanged by the kidney, (2) it is distributed primarily in the extracellular fluid compartment, (3) it possesses low protein binding, and (4) it is weakly acidic with a dissociation constant (pKa) of 3 to 7.5. Urinary alkalinization can be CH 38 achieved with administration of sodium bicarbonate (1–2 mEq/kg every 3 to 4 hours) using an initial 1 ampule bolus of sodium bicarbonate, followed by intravenous 5% dextrose in water (D5W) with 2 to 3 ampules of sodium bicarbonate (50 mEq NaHCO3 per ampule) added to each liter. The rate of infusion should initially be based on the volume status of the patient. After volume expansion, the rate of fluid replacement should match the urine output, with a goal of 2 to 3 mL/kg/hour. In patients with altered sensorium, a urinary catheter may be placed for accurate monitoring of urinary output. Serum electrolytes and urinary pH must be closely monitored every 2 to 3 hours during alkaline diuresis, with a target urine pH between 7.5 and 8.5. Urinary alkalinization effectively increases elimination of drugs such as phenobarbital, barbital, and salicylates. Complications of urinary alkalinization include hypokalemia, fluid overload, pulmonary edema, cerebral edema, hypernatremia (if free water restricted), and alkalemia. Alkalemia is of special concern in patients with renal dysfunction who are unable to excrete the bicarbonate load. Relative contraindications are congestive heart failure, renal failure, pulmonary edema, and cerebral edema. The degree of hypokalemia may be profound, due to a combination of increased urinary potassium excretion and an intracellular potassium shift. It is essential that hypokalemia is corrected, as failure to do so will result in inhibition of alkaline urine excretion, due to preferential potassium reabsorption in the distal tubule in exchange for hydrogen ion secretion. Previously, urinary acidification was used to enhance the elimination of amphetamines, fenfluramine, phencyclidine, and quinine. However, acid diuresis has fallen out of favor because of its serious side effects including rhabdomyolysis, acute kidney injury, exacerbation of metabolic acidosis, and the lack of evidence supporting its use.

PRINCIPLES GOVERNING DRUG REMOVAL BY EXTRACORPOREAL TECHNIQUES The clearance of a drug or toxin by extracorporeal therapy is determined by the pharmacokinetic and pharmacodynamic properties of the drug and by factors related to the extracorporeal technique itself. The factors that favor extracorporeal removal are outlined in Table 38-1.

792 Table 38-1

Factors That Enhance Drug Removal by Extracorporeal Therapy

Low molecular weight ( 3 mg/dL but dialysis independent at 1 week); and (3) those with delayed graft function (DGF) in whom there is initial failure of allograft. The causes, management, and outcomes of SGF are similar to those for DGF (see next section).

Delayed Graft Function Delayed graft function is a clinical diagnosis based on the apparent failure of the renal allograft to function in the first week after transplant. Risk factors include male sex, black race, high panel reactive antibodies (PRA), prolonged cold ischemia time, and nontraumatic death in the donor. The causes of DGF fall into three categories: • Ischemic/nephrotoxic acute tubular necrosis (ATN) • Hyperacute or accelerated acute rejection • Major surgical complication (vascular thombosis, ureteric obstruction or leak) The diagnosis of the underlying cause of DGF is based on clinical, radiologic, and sometimes histologic findings. Ischemic ATN is the most common cause of DGF in cadaveric kidney transplant recipients. In the absence of a renal biopsy, ischemic ATN can be diagnosed only when radiologic studies have excluded obstruction and confirmed allograft perfusion. ATN is uncommon following living-donor renal transplantation, and persistent oliguria despite adequate volume expansion

Clinical Aspects of Renal Transplantation

(diuretics) suggests a major surgical complication (renal vein 833 thrombosis, urine leak) that may warrant early surgical re-exploration. Management of ATN is supportive and includes judicious volume management, nutritional support, and renal replacement therapy as required. Calcineurin avoidance with substitution of CH 40 polyclonal antilymphocyte preparations has been advocated as a means of shortening the clinical course of postoperative ATN. The use of sorbitol-based ion exchange resins in the management of hyperkalemia should be avoided in the early postoperative period because of the risk of colonic dilation and perforation. Hemodialysis may exacerbate ischemic damage to the allograft and therefore is typically used only if medically imperative. Acute rejection is more common following ATN, and renal allograft biopsy is often required to exclude untreated acute rejection. Renal function in ischemic ATN typically recovers over 5 to 7 days but recovery may be delayed for several weeks. Hyperacute rejection is now a rare cause of primary renal allograft nonfunction. It is caused by preformed recipient antibodies directed against ABO blood group or HLA class I antigens. In classic hyperacute rejection, macroscopic changes are seen minutes after vascular anastomosis is established. Clinically, there is cyanosis and mottling of the kidney, anuria, and sometimes disseminated intravascular coagulopathy. Screening for recipient-donor ABO or class I major histocompatibility complex (MHC) incompatibility has ensured that hyperacute rejection is now uncommon. More commonly, antibody-mediated acute rejection occurring early in the post-transplant course is triggered by newly synthesized antibodies directed against donor alloantigens (humoral/antibody-mediated rejection). Pretransplant lymphocytotoxicity cross-match may miss low level antidonor alloantibodies generated by memory B cells. The diagnosis is made by renal biopsy and a positive repeat donorrecipient cross-match. Peritubular staining of capillaries for C4d has been proposed as a reliable marker of acute antibodymediated rejection. Early diagnosis of this condition is crucial and high-risk patients with DGF should have a renal allograft biopsy and repeat cross-match studies performed 3 to 5 days after transplantation. A regimen of plasmapheresis (to immediately remove donor-specific antibody [DSA]) and enhanced immunosuppression including MMF and tacrolimus (to suppress further production of DSA) is now yielding excellent results. Transplant renal artery or renal vein thrombosis usually occurs within 72 hours after transplantation and is the most common cause of graft loss in the first post-transplant week. Renal artery thrombosis presents with abrupt onset of anuria, rapidly rising plasma creatinine, but often little localized graft pain or discomfort. Radiologic studies show absent arterial and venous blood flow and transplant nephrectomy is indicated. Renal vein thrombosis has a similar presentation but

834 is often accompanied by allograft discomfort. Meticulous sur-

Renal Transplantation

gical technique and avoidance of hypovolemia can minimize the incidence of this devastating complication. The importance of ischemic injury in cadaveric renal transX plantation is emphasized by the impressive graft survival outcomes in living nonrelated donor transplantation, where ischemic times are short but HLA matching is often suboptimal. DGF is an independent predictor of long-term graft loss, and lowers the expected graft half-life by one third. Measures to limit the incidence and duration of DGF include optimization of the hemodynamic status of the donor and recipient. Avoidance of postoperative hypotension and minimization of exposure to nephrotoxins, especially radiocontrast material, is essential. No specific intervention, including the administration of dopamine or loop diuretics, has shown clinical benefit. DGF associated with ATN is likely to remain a significant problem in cadaveric kidney transplantation as the use of marginal donors increases. An algorithm for managing DGF is given in Figure 40-1.

High-risk recipient*

Low-risk recipient

Biopsy day 3–5

Biopsy day 7–10

Rejection

No rejection

No rejection

Acute AMR

Mild/moderate cellular

Severe cellular

Steroid pulse Plasmapheresis MMF + tacrolimus IgG

Steroid pulse

Steroid pulse or OKT3/ thymoglobulin

Rebiopsy in 5–10 days if DGF persists

Rebiopsy in 7–10 days if DGF persists

Figure 40-1. Algorithm for diagnostic biopsy of and treatment for persistent delayed graft function (DGF). *The presence of anti-donor HLA antibodies should prompt immediate biopsy in this high-risk setting. AMR, antibody-mediated rejection; MMF, mycophenolic mofetil.

Prerenal Dysfunction in the Early Post-Transplant Period

835

Table 40-3 shows the causes of allograft dysfunction during the early (1- to 12-week) post-transplant period. CH 40

Acute kidney injury (AKI) due to hypovolemia may develop as a result of a variety of factors including diminished oral intake, excessive diuresis from the transplanted kidney, or MMF-induced diarrhea. The effects of volume depletion are often compounded by CNI-induced renal vasoconstriction, which further impairs the GFR. Angiotensin-converting enzyme inhibitors (ACEIs) and NSAIDs also exacerbate prerenal ARF and should be avoided in the early post-transplant period. Management involves careful reduction of MMF dosage if diarrhea is problematic and either oral or intravenous volume expansion.

Acute Calcineurin Inhibitor Nephrotoxicity CNIs cause an acute reversible decrease in renal plasma flow and GFR mediated by afferent arteriolar vasoconstriction. This is manifested by blood concentration-dependent increases in plasma creatinine level that respond to dose reduction. On occasion, this may occur as a result of the introduction of a

Table 40-3

Causes of Allograft Dysfunction in the Early Postoperative Period

Prerenal Hypovolemia/hypotension Renal vessel thrombosis Drugs—ACE inhibitors, NSAIDs Transplant renal artery stenosis Intrarenal Acute rejection Acute CNI nephrotoxicity CNI-induced thrombotic microangiopathy Recurrence of primary disease Acute pyelonephritis Acute interstitial nephritis Postrenal Urinary tract obstruction/leakage ACE, angiotensin-converting enzyme; CNI, calcineurin inhibitor.


Hypovolemia

836 medication that interferes with CNI metabolism (see Table 40-1).


Conversely, drugs that induce the cytochrome P-450 system can lead to subtherapeutic drug levels with resultant acute rejection episodes. Histologic changes associated with CNI toxicity X include tubule and myocyte vacuolization. Several clinical findings suggest acute CNI nephrotoxicity: • Extrarenal toxicity such as severe tremor • Moderate increase in plasma creatinine ( 350 ng/mL or tacrolimus levels > 20 ng/mL) An algorithm for approaching this common clinical problem is shown in Figure 40-2. The threshold for biopsy should be low in patients at high risk of rejection given the risks associated with delayed treatment of undiagnosed acute rejection.

Exclude/treat hypovolemia, thrombotic microangiopathy, pyelonephritis Imaging studies to rule out urologic or vascular cause

Cr still elevated

CsA/tacrolimus trough blood concentration Normal/low

High (e.g., CsA > 350 ng/mL, tacrolimus > 20 ng/mL)

Empirical steroid pulse

Reduce CsA/tacrolimus

No response in 3–5 days

No improvement in 1–2 days

Biopsy

Specific intervention

Figure 40-2. Algorithm for management of allograft dysfunction in the early post-transplant period. Cr, creatinine; CsA, cyclosporine.

Acute Rejection

837


Acute rejection is the most common cause of graft dysfunction in the early post-transplant period and is strongly associated with development of chronic rejection and poorer allograft survival rates. An increase in serum creatinine (typically > CH 40 20%) is the cardinal sign of acute rejection. With current immunosuppression regimens, clinical symptoms (pain, fever, oliguria) are rare. Definitive diagnosis requires biopsy, but where there is a high likelihood of uncomplicated acute rejection, empirical treatment is sometimes instituted prior to biopsy. Uncomplicated acute cellular rejection is generally treated with a short course of high-dose intravenous corticosteroid (500–1000 mg methylprednisolone daily IV for 3–5 days). OKT3 or polyclonal antilymphocyte antibody preparations are reserved for steroid-resistant cases or when there is evidence of severe rejection (endothelialitis) on the initial biopsy (20–30% of cases). Treatment of acute rejection with OKT3 may be associated with an increase in plasma creatinine 3 to 4 days into the course due to a cytokine release syndrome. Following reversal of rejection, patient compliance with prescribed medications should be reviewed and if there are no contraindications, baseline immunosuppression should be adjusted. Acute rejection refractory to antibody therapy is associated with very poor allograft outcomes. Uncontrolled studies suggest that tacrolimus and MMF may be beneficial as “rescue” therapy in this setting. Acute rejection is less common after the first 6 months posttransplantation and, when occurs, may reflect either patient noncompliance or the inadvertent introduction of an inducer of the cytochrome P-450 system (see Table 40-1). Risk factors for noncompliance include younger age, immunosuppressiverelated side effects, lower socioeconomic status, minority status, and psychological stress or illness. Late acute rejection has a particularly deleterious effect on long-term graft outcome.

Thrombotic Microangiopathy Thrombotic microangiopathy (TMA) after renal transplantation is a rare but serious complication. Laboratory findings include rising plasma creatinine, thrombocytopenia, anemia, and the presence of schistocytes on the blood film. CNIs and, to a lesser extent, other factors (OKT3, viral infection, antiphospholipid syndrome) are associated with development of this syndrome. Onset is usually in the early post-transplant period. The long-term prognosis for graft function is often poor, and early diagnosis and intervention are essential. There are no prospective controlled trials of therapy in posttransplant TMA. Suggested measures include cessation of CNI therapy and tight control of blood pressure. There is no evidence to support the use of plasma exchange. Combination therapy

838 with MMF, corticosteroids, and sirolimus would appear to be the most prudent immunosuppresive regimen in such cases.

Acute Pyelonephritis Renal Transplantation

X Urinary tract infections (UTIs) may occur at any period but are most frequent shortly after transplantation. Risk factors for UTI include catheterization, ureteric stenting, and preexisting anatomic or neurologic abnormalities. UTIs are often heralded by fever, allograft pain and tenderness, and a raised peripheral blood white blood cell count. Diagnosis requires urine culture, but empirical antibiotic treatment should be started immediately if infection is suspected clinically. Renal function usually returns to baseline with antimicrobial therapy and volume expansion. Recurrent cases of pyelonephritis merit investigation to rule out underlying anatomic abnormalities.

Acute Allergic Interstitial Nephritis Acute interstitial nephritis is occasionally observed in the early postoperative course. Removal of the offending agent (often SMX-TMP) is indicated. A role for augmented steroid therapy is unclear.

Urine Leaks Urine leaks usually occur within weeks of transplantation. Causes include ureteric infarction due to perioperative disruption of its blood supply and breakdown of the ureterovesical anastomosis. The clinical features include abdominal pain and swelling with rising plasma creatinine levels secondary to reabsorption of solutes across the peritoneal membrane. If a perirenal drain is being used, a urine leak may present with high-volume drainage. Ultrasound often demonstrates a fluid collection (urinoma). Antegrade pyelography allows precise diagnosis and localization of proximal urinary leaks. Whenever urine leakage is suspected, a bladder catheter should be immediately inserted to decompress the urinary tract and most cases require urgent surgical exploration and repair.

Urinary Tract Obstruction Urinary tract obstruction can cause allograft dysfunction at any time after transplantation but is most common in the early postoperative period. The causes include the following: • • • • • •

Suboptimal ureterovesical anastomosis Ureteric blood clots Fibrosis of the ureter due to ischemia or rejection Prostatic hypertrophy Neurogenic bladder (diabetic neuropathy) Lymphocele

Late Allograft Dysfunction The causes and evaluation of late (>6 months post-transplant) renal allograft dysfunction in the months and years following renal transplantation are listed in Table 40-4.

Chronic Allograft Nephropathy Chronic allograft nephropathy (CAN) is characterized by a slow insidious decline in renal function at least 6 months after renal transplantation. It is typically associated with proteinuria and hypertension and, after censoring for death, is the most common cause of late renal allograft loss. Although alloimmune factors are important in the pathogenesis of CAN, other etiologic factors include ischemic injury, calcineurin toxicity, hypertension, and glomerular hyperfiltration. There is no specific treatment for CAN at this time. Hypertension and hyperlipidemia should be rigorously controlled, the former preferably with either an ACEI or ARB. The use of sirolimus or MMF in place of CNI may lead to a temporary improvement in GFR, however, there are no randomized, controlled trials supporting a long-term benefit from this strategy.

Table 40-4

Causes of Late Chronic Allograft Dysfunction

Prerenal Transplant renal artery stenosis Intrarenal Chronic allograft nephropathy Calcineurin inhibitor toxicity Chronic rejection (cellular or antibody mediated or both) Polyomavirus nephropathy Recurrence of primary disease New disease Postrenal Urinary tract obstruction


Ultrasonography demonstrates hydronephrosis; however, 839 dilation of the transplant urinary collecting system is frequently seen in the early postoperative period and serial scans may be required to confirm the diagnosis. Renal scintiscan with diuretic washout may be useful in equivocal cases. Open surgical repair is CH 40 usually required but endoscopic measures may suffice in certain circumstances. Obstruction in the early postoperative period due to an enlarged prostate should be managed with initial bladder catheter drainage and followed by elective prostatectomy.

840 Chronic Calcineurin Nephrotoxicity


Chronic nephrotoxicity associated with CNI is a welldocumented phenomenon in both renal and nonrenal organ transplantation. It is caused by chronic exposure to cyclosporX ine or tacrolimus and can occur even when drug levels are maintained within the normal therapeutic range. It is difficult to distinguish clinically from chronic allograft nephropathy, and often the two may coexist. The replacement of azathioprine by MMF, followed either by elimination or reduction of the CNI, is widely practiced. Many authorities advocate the reduction or removal of CNI-based immunosuppression in all patients; however, this runs the risk of triggering late acute rejection, which is associated with a poor prognosis.

Transplant Renal Artery Stenosis Transplant renal artery stenosis can arise at any time after transplantation. Retrospective studies report functionally significant stenosis in fewer than 10% of renal transplant recipients. Suggestive clinical signs include resistant hypertension, AKI following ACE inhibition, an audible renal bruit, and polycythemia. The diagnosis is made by renal angiography, magnetic resonance (MR) angiography, or duplex sonography. The clinical response rate to percutaneous angioplasty is approximately 40% to 75%; however, restenosis is common and may require repeat intervention or operative bypass. Particular care must be taken to avoid radiocontrast medium nephrotoxicity in the investigation and management of this condition.

Recurrent Disease in the Allograft Table 40-5 summarizes the conditions that recur after transplantation. With improvements in short- and long-term renal allograft survival rates, disease recurrence has assumed greater clinical importance. Several diseases such as focal segmental glomerulonephritis (FSGS), anti–glomerular basement membrane disease, and hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP) can occur early in the post-transplant course, but most diseases recur in the months and years following transplantation. The rates of disease recurrence vary depending on the primary diagnosis. Recurrence rates are highest with FSGS (especially the childhood variant) and membranoproliferative glomerulonephritis (MPGN), in which rates of over 80% are observed with type II disease and are associated with significant reductions in renal allograft survival. Recurrent diabetic nephropathy is common; however, the poorer outcomes in this patient subpopulation heretofore may have masked the true clinical significance of disease recurrence. Recurrence rates are less common with IgA nephropathy, the rapidly progressive glomerulonephritides, and lupus nephritis. Treatment strategies are broadly similar to those used in native real disease. Notably, even

Table 40-5

Recurrent Disease after Transplantation

Disease

Approximate Recurrence Rate

Time to Recurrence

Management

Living Donor Transplantation

Primary FSGS

40–50%

Hours to weeks

ACEI, steroids, ? plasmapheresis

No, if high risk of recurrence

IgA GN

35%

>2 months

ACE-I, ? fish oil Cytotoxics if cresentic GN

Yes

MPGN

30% type I 80–100% type II

Weeks

Type I: ? aspirin Type II: ? steroids

Type I: yes Type II: consider (1 week

Steroids, cytotoxics

Yes

HUS/TTP

Depends on cause: familial > classic HUS

Immediate and onward

Plasmapheresis

No, if familial HUS/TTP

ACEI, angiotensin-converting enzyme inhibitor; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; GBM, glomerular basement membrane; HUS, hemolytic uremic syndrome; IgA, immunoglobulin A; MMF, mycophenolate mofetil; MPGN, membranoproliferative glomerulonephritis; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura.

841

842 though less than 5% of all grafts are lost due to recurrent disease, this figure approaches 50% in cases of second graft loss when the first graft was lost due to primary disease recurrence.


X Polyomavirus Infection Reactivation of polyomavirus infection with shedding of infected urothelial cells (decoy cells) is estimated to occur in 10% to 60% of renal transplant recipients, but clinically significant disease occurs in less than 5%. The clinical features associated with infection of renal transplant patients include asymptomatic infection (most common), acute and chronic allograft dysfunction, and hemorrhagic cystitis. The acute graft dysfunction usually occurs secondary to interstitial nephritis, although ureteric stenosis has been described. The use of more powerful maintenance immunosuppression regimens incorporating MMF and tacrolimus have probably contributed to a rise in the incidence of clinically significant polyomavirus infection. The management of this condition is difficult and primarily involves progressive reduction in the immunosuppression burden in an attempt to augment host mechanisms of viral clearance. The long-term outlook for graft survival is often poor.

Clinical Outcomes and Allograft Survival Rates in Renal Transplantation Analysis of survival rates between the general dialysis population and transplanted patients is greatly affected by selection bias—in general, patients referred for transplantation are healthier and have better functional status than those patients felt to be unsuitable for transplantation. Comparisons between patients on the waiting list who do or do not receive a transplant demonstrate that, in the medium- to long-term, transplantation confers a significant survival benefit, particularly in diabetic patients. One-year survival rates of over 90% are now expected for both cadaveric and living-donor transplants. Long-term renal allograft survival rates have also steadily increased over the last 10 years and the expected graft half-life of a cadaveric transplant is now over 10 years.

MEDICAL MANAGEMENT OF THE TRANSPLANT RECIPIENT With the current low acute rejection rates and improvements in long-term graft survival, more emphasis is being placed on the general medical management of transplant patients. The management of common electrolyte, endocrine, and

cardiovascular complications after transplant is discussed in 843 the following sections.

Electrolyte Disorders Hypophosphatemia is common in the early post-transplant period due to residual hyperparathroidism. Clinical symptoms are uncommon but include muscle weakness and, in rare cases, respiratory muscle weakness. The target plasma phosphate level should be 2.5 to 4 mg/dL achieved by increasing dietary phosphate and oral phosphate repletion with or without vitamin D.

Hyperkalemia Mild hyperkalemia due to CNI-mediated impairment of tubule potassium secretion is common after renal transplant and may be exacerbated by poor allograft function, dietary indiscretion, and medications such as ACEIs or b-blockers. The hyperkalemia is usually not severe and improves with reduction in CNI dosage; treatment is often not required; exacerbating factors should be minimized.

Metabolic Acidosis A mild distal (hyperchloremic) renal tubular acidosis (RTA) is common after transplantation. This reflects tubule dysfunction caused by CNIs, rejection, or residual hyperparathyroidism. Oral bicarbonate replacement is given in severe cases.

Other Electrolyte Abnormalities Hypomagnesemia is common and due to a magnesuric effect of the CNIs. The effectiveness of supplementation is limited and magnesium supplement should be considered only when the serum level is below 1.5 mg/dL.

Bone Disorders after Renal Transplantation Hyperparathyroidism Hyperparathyroidism is seen in more than 50% of allograft recipients. Risk factors include the severity of pretransplant hyperparathyroidism and duration of renal replacement therapy. Laboratory findings include hypophosphatemia and mild to moderate hypercalcemia with an inappropriately high parathyroid hormone level. The condition usually resolves spontaneously and management in the interim consists of repletion of phosphate and the administration of vitamin D analogs if 1,25-vitamin D concentrations are low. Post-transplant subtotal parathyroidectomy is performed only for either severe acute

CH 40


Hypophosphatemia

844 symptomatic hypercalcemia or persistent, moderately severe hypercalcemia (e.g., calcium > 12 mg/dL for 12 months).

Osteoporosis Renal Transplantation

X Osteoporosis, defined as bone density more than 2.5 standard deviations below the mean of sex-matched, young adults, is observed in up to 60% of allograft recipients after transplantation, with most of the bone loss occurring in the first 6 months. Pathologic fractures of the appendicular skeleton are common after renal transplantation and diabetic recipients are at particular risk. Corticosteroid use is the primary cause of post-transplant osteoporosis, with hyperparathyroidism, hypophosphatemia, and vitamin D resistance acting as contributing factors. The diagnosis can be confirmed by dual x-ray absorptiometry (DEXA) scanning and all patients thought to be at high risk should be evaluated prospectively. Treatment strategies include 1000 mg/day of elemental calcium and 800 U/day of standard vitamin D (calcitriol, if GFR < 50 mL/min) accompanied by regular weight-bearing exercise. Emerging options include the minimization or elimination of corticosteroid use often in combination with T-cell mono- or polyclonal antibody administration. The use of bisphosphonates or sex hormone repletion is controversial. No prospective data exist showing a reduction in fracture incidence and these agents should only be used following consultation with an endocrinologist familiar with post-transplant bone disease.

Osteonecrosis Osteonecrosis (avascular necrosis), the most serious bone complication of renal transplantation, is seen 5% to 10% of renal transplant recipients. The most commonly affected site is the femoral head, and high-dose corticosteroid use is a risk factor. The principal symptom is pain and MR imaging is diagnostic. Treatment options include rest, core decompression, osteotomy, or joint replacement.

Gout The majority of cyclosporine-treated renal transplant recipients develop hyperuricemia, with less than 10% developing clinical symptoms. Acute attacks are treated with colchicine or an oral corticosteroid pulse. NSAIDs should be avoided. The use of azathioprine and allopurinol in combination for the treatment of hyperuricemia can result in severe bone marrow suppression and is best avoided.

Hypertension Hypertension occurs in up to 80% of kidney transplant recipients and can be attributed to the CNIs, weight gain,

Hyperlipidemia Hyperlipidemia is seen in 60% to 70% of kidney transplant recipients and may contribute not only to the high cardiovascular mortality rate observed but also to the development of CAN. The target low-density lipoprotein cholesterol should to be lower than 100 mg/dL and pharmacologic therapy is required to achieve this in the majority of patients. Other treatment options include steroid minimization and switching cyclosporine to tacrolimus. Statins are the cholesterol-lowering drug of choice despite concerns regarding rhabdomyolysis (see earlier). Bile acid sequestrants bind CNIs and should be taken separately.

Post-Transplant Malignancy The overall incidence of cancer in renal transplant recipients is greater than that in dialysis patients and the general population; for specific “transplant-associated” malignancies the risk is dramatically higher, but for the common malignancies (lung, breast, and prostate) the risk is similar. The cumulative amount of immunosuppression is the most important factor in increasing the risk of malignancy, and the long-term impact of more powerful immunosuppression regimens on cancer incidence is an emerging concern. The common post-tranplant malignancies are discussed here.

Skin and Anogenital Cancers Squamous cell carcinoma, basal cell carcinoma, and malignant melanoma are more common in renal transplant patients. Risk factors for skin cancer are the duration and cumulative dose of immunosuppression, exposure to ultraviolet light, and fair skin. Primary and secondary prevention is important: patients should be counseled on minimizing exposure to strong sunlight and to self-screen for skin lesions. Cancers of the vulva, uterine cervix, penis, scrotum, anus, and perianal region are more common than in the general population. These tumors tend to be multifocal and more aggressive and are associated with human papillomavirus infection. Prevention measures


allograft dysfunction, native kidney disease, and less com- 845 monly, transplant renal artery stenosis. Hypertension should be aggressively managed with a target blood pressure of less than 135/85 mm Hg and less than 125/75 mm Hg in those with proteinuria. ACEIs are typically avoided in the early post- CH 40 transplantation period. CCBs may offer some protection against CNI-mediated nephrotoxicity.

846 include yearly physical examination of the anogenital area and,

in women, yearly pelvic examinations and cervical histologic testing. Suspicious lesions should be excised, and patients should be closely followed for recurrence.


X

Post-Transplant Lymphoproliferative Disorder Post-transplant lymphoproliferative disorder (PTLD) is not a single disorder but rather a spectrum of tumors extending from benign polyclonal lymphoid proliferations to overtly malignant lymphomas. The cumulative incidence in renal transplant patients is 1% to 5%, with most occurring within 2 years of transplantation. More than 90% are non-Hodgkin lymphomas of recipient B-cell origin and the majority of cases are Epstein-Barr virus (EBV) associated. Risk factors include the following: • The combination of EBV-positive donor and EBV-negative recipient • Pediatric recipient (children are more likely to be EBV negative) • Degree of immunosuppressive burden (especially use of antilymphocyte antibodies) Thus, the clinical and histologic spectrum of PTLD at presentation is wide and its treatment can vary greatly. Extranodal involvement, including involvement of the renal allograft, is more common than in non–transplant associated lymphomas. The treatment involves the reduction of, or in the case of life-threatening disease, the elimination of, the immunosuppressive burden. Combination therapy involving surgical excision, chemotherapy, and radiotherapy are commonly employed.

Infectious Complications of Renal Transplantation The heightened risk of infection in renal transplant recipients is directly related to the intensity of immunosuppression and the exposure to potential pathogens. Given that immunosuppression alters the clinical presentation of lifethreatening infections, early and aggressive diagnostic workup followed by empirical antimicrobial therapy is essential if infectious illness is suspected. The spectrum of infection observed in renal transplant recipients changes over time. The majority of infections seen in the first month are related to the operative procedure itself (wound infection, urinary tract infection, etc.). Preventive measures include ensuring that donor and recipient are free of overt infection before transplant, good surgical technique, and

Cytomegalovirus CMV is one of the most important post-transplant pathogens and disease is typically observed 1 to 6 months after transplant. CMV infection is seen in 50% to 80% of patients; however, CMV disease implies both laboratory evidence of viral exposure (rising IgG titer or CMV antigen in body fluids) and symptoms of tissue invasion. The risk of CMV infection or disease is highest in the CMV-negative recipient of a CMV-positive kidney. OKT3/polyclonal therapy, particularly when prescribed for treatment of rejection, significantly increases the risk of subsequent CMV disease. Typical clinical features include fever, malaise, leukopenia, pneumonitis, hepatitis, and ulcerating lesions of the gastrointestinal tract. The gold standard diagnostic test is detection of CMV antigenemia by quantitative serum DNA PCR. Less sensitive alternatives include the centrifuged shell viral technique. Demonstration of shed virus in the urine or sputum correlates poorly with clinical outcomes and biopsy interpretation is complicated by the focal nature of the infection in many organs. CMV disease should be treated with reduction in immunosuppression and intravenous ganciclovir therapy for 2 to 4 weeks. Valganciclovir has greatly improved oral bioavailability compared to oral ganciclovir and is emerging as a possible replacement for intravenous ganciclovir in some situations. Foscarnet is reserved for CMV-resistant cases. Prevention of CMV disease is of great clinical importance and patients at highest risk of CMV should routinely receive CMV prophylaxis for up to 6 months; whether all low-risk patients need to receive prophylaxis is controversial.

Pneumocystosis The incidence of post-transplant Pneumocystis carinii infection has declined with the widespread use of SMX-TMP


SMX-TMP prophylaxis to prevent UTIs. After several weeks 847 of intensive immunosuppression, the risk of opportunistic infections with cytomegalovirus (CMV), EBV, Listeria monocytogenes, Pneumocystis carinii, and Nocardia sp. increases. Preventive measures include antiviral prophylaxis (for 3–6 CH 40 months after transplant) and SMX-TMP prophylaxis (for 6–12 months after transplant). Opportunistic infections after 6 to 12 months are uncommon unless the immunosuppressive burden is increased, for example, following the treatment of a late acute rejection. Exceptions include CMV retinitis and colitis, a higher incidence of respiratory syncytial virus (RSV) and influenza infections, and chronic manifestations of human papillomavirus infections.

848 prophylaxis. Alternative agents in sulfa-allergic patients

include dapsone and pyrimethamine, atovaquone, and aerosolized pentamidine.


X Immunization in Renal Transplant Recipients Important general rules concerning immunization in renal transplant patients are the following: • Immunizations should be completed at least 4 weeks before transplantation. • Immunization should be avoided in the first 6 months after transplantation. • Live vaccines are generally contraindicated after transplantation. Infections are a predictable complication of renal transplantation. Minimizing infection risk requires meticulous surgical technique, antiviral prophylaxis for the first 3 to 6 months, SMX-TMP prophylaxis for the first 6 to 12 months, and of course, avoidance of excessive immunosuppression.

Surgery in the Renal Transplant Recipient Allograft Nephrectomy This is an uncommon procedure. Indications for allograft nephrectomy include the following: • Allograft failure with symptomatic rejection (fever, malaise, and graft pain) • Allograft infarction due to thrombosis • Emphysematous pyelonephritis • Graft rupture Ongoing rejection in a failed allograft can sometimes be controlled with steroids, but prolonged immunosuppression of the ESRD patient is undesirable.

Nontransplant-Related Surgery or Hospitalization In-patient management of the renal transplant recipient hospitalized for nontransplant-related surgery should focus on the maintenance of adequate volume status, avoidance of nephrotoxic medicines (including NSAIDs and radiocontrast material), and the proper dosing of immunosuppressive drugs. If intravenous administration of corticosteroid is required, intravenous methylprednisolone can be used as maintenance therapy, prescribed at the same milligram-per-milligram dose as prednisone, with supplemental stress-dose hydrocortisone prescribed separately. Intravenous cyclosporine should be prescribed in slow infusion form at one third of the total daily oral dose, and intravenous tacrolimus given daily should be at one fifth of the total oral dose.

The Patient with the Failing Kidney

849

Pregnancy in the Renal Transplant Recipient Female and male fertility improves after successful renal transplantation. Pregnancy is generally considered safe for the mother, fetus, and renal allograft if the following criteria are met before conception: good general health for more than 18 months before conception, stable allograft function with a plasma creatinine level less than 2 mg/dL (preferably

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