Urinary Stones: Diagnosis, Treatment, and Prevention of Recurrence, Third Edition

Urinary Stones Diagnosis, Treatment, and Prevention of Recurrence

Albrecht Hesse, Ph.D. Professor of Experimental Urology Department of Urology University of Bonn Sigmund-Freud-Straße 25 DE–53105 Bonn, Germany E-Mail: [email protected] Harnsteinanalysezentrum Bonn Urinary Stone Analysis Centre Theaterplatz 14 DE–53177 Bonn, Germany E-Mail: [email protected] Hans-Göran Tiselius, M.D., Ph.D. Professor of Urology Division of Urology Department of Clinical Science, Intervention and Technology Karolinska Institutet Department of Urology Karolinska University Hospital SE–141 86 Stockholm, Sweden E-Mail: [email protected] Roswitha Siener, Ph.D. Associate Professor of Medical Nutrition Science Department of Urology University of Bonn Sigmund-Freud-Straße 25 DE–53105 Bonn, Germany E-Mail: [email protected] Bernd Hoppe, M.D. Professor of Pediatrics Head, Division of Pediatric Nephrology Department of Pediatrics University Hospital Cologne Kerpener Straße 62 DE–50924 Cologne, Germany E-Mail: [email protected]

Urinary Stones Diagnosis, Treatment, and Prevention of Recurrence Albrecht Hesse, Bonn Hans-Göran Tiselius, Stockholm Roswitha Siener, Bonn Bernd Hoppe, Cologne

Foreword by Hibbard E. Williams, Davis, California, USA 36 figures, 16 in color, 2009 3rd revised and enlarged edition

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Shanghai • Singapore • Tokyo • Sydney

Nachsorge bei Harnstein-Patienten: Ein Leitfaden für die ärztliche Praxis Herausgeber: A. Hesse, A. Jahnen, K. Klocke, A. Nolde, O. Scharrel ISBN 3–334–60832–8 © Gustav Fischer Verlag, Jena, 1994 1. Auflage Urinary Stones: Diagnosis, Treatment, and Prevention of Recurrence Editors: A. Hesse, H.-G. Tiselius, A. Jahnen ISBN 978–3–8055–6346– 8 © Gustav Fischer Verlag, Jena, 1997 1st edition Urinary Stones: Diagnosis, Treatment, and Prevention of Recurrence Editors: A. Hesse, H.-G. Tiselius, A. Jahnen ISBN 978–3–8055–7370–2, e-ISBN 978–3–318–00811–1 © S. Karger AG, Basel, 2002 2nd edition Library of Congress Cataloging-in-Publication Data Nachsorge bei Harnstein-Patienten. English. Urinary stones : diagnosis, treatment, and prevention of recurrence / Albrecht Hesse ... [et al.] ; foreword by Hibbard E. Williams. – 3rd rev. and enl. ed. p. ; cm. Rev. ed. of: Urinary stones : diagnosis, treatment, and prevention of recurrence / Albrecht Hesse, Hans-Göran Tiselius, Andrea Jahnen. 2nd rev. and enl. ed. 2002. Includes bibliographical references and index. ISBN 978-3-8055-9149-2 (soft cover : alk. paper) 1. Urinary organs – Calculi – Handbooks, manuals, etc. I. Hesse, A. (Albrecht) II. Title. [DNLM: 1. Urinary Calculi – Handbooks. WJ 39 N123u 2009a] RC916.N3313 2009 616.6‘22–dc22 2009016407 Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2009 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhard Druck, Basel ISBN 978–3–8055–9149–2 e-ISBN 978–3–8055–9150–8

Contents Foreword Preface to the first edition Preface to the second edition Preface to the third edition Introduction General aspects The emergency stone – Treatment of patients with acute renal colic Standard procedures – Treatment and care of patients with urinary stones Type of stone Calcium oxalate stones Uric acid stones Calcium phosphate stones Struvite stones Cystine stones 2,8-Dihydroxyadenine stones Xanthine stones Ammonium urate stones Appendix Interventional procedures Absorption/loading tests Risk indices Examination under standardized dietary conditions Analytical methods Unusual stone components/artifacts Tables 1–3: Calcium, oxalate and purine contents of foods Tables 4–6: Reference values for children Crystals in the urinary sediment (colored illustrations) References Subject index

VII VIII IX X 1 7 8 21 37 38 66 86 108 124 142 152 160 173 174 178 186 190 192 198 200 206 213 216 227

Foreword Renal stone disease is a most ancient and common affliction of man. Over a seventy-year life span, it is estimated that as many as 15% of some populations will develop renal stones. No age is spared and no country or ethnic group protected from this common clinical problem. Most, but not all, patients who develop a stone will eventually form others. Although very few individuals die as a direct result of stone disease, it does lead to substantial morbidity from pain, urinary tract infections and obstructive uropathy. In the past few decades, substantial progress has been made in understanding the basic pathophysiologic mechanisms of stone disease, which has subsequently led to rational and effective programs for both its treatment and prevention of recurrence. Diagnostic study protocols to identify underlying mechanisms have now become available in most countries, thereby allowing for an accurate categorization of patients with renal stone disease. This handbook to assist physicians in the diagnosis, treatment and prevention of stone disease has been developed by its three editors, each of whom has contributed significantly to our basic understanding of stone disease. Their handbook is oriented toward clinicians and health care professionals to help them quickly and effectively study and treat patients with stone disease and assist them in developing effective approaches to the prevention of further stone development. In addition, it is written in a manner that could make it very useful in explaining to patients the more important aspects of their disease. It is very well organized, making it simple to use as a reference work and its utility is strengthened by an outline format, which facilitates understanding of diagnostic studies and treatment plans. All of the major stone types are discussed in detail, including sections on the less frequent stones, such as those composed of xanthine and 2,8-dihydroxyadenine. Of particular value is the discussion of diagnostic studies to be performed in those patients for whom a stone is not available for analysis, an increasingly common event now that lithotripter use has made it more difficult to recover stones. With our ability to determine more accurately than ever the basic mechanisms of stone formation and, therefore, to develop more effective treatment programs, recurrent stone disease should become less and less common. The editors and authors of this text have made an important contribution to this effort with this handbook which should be of immense help to health care professionals who care for patients with renal stones in efficiently and effectively guiding them through the appropriate diagnostic studies and the development of safe plans for treatment and prevention. Their patients will be ultimate beneficiaries of this text. We are grateful to its editors and authors for such a useful and usable book. Hibbard E. Williams, M.D. Professor and Dean emeritus School of Medicine University of California, Davis, California, USA July 1996

VII

Preface to the first edition During the past 15 years, therapeutic procedures for urinary stone disease have undergone fundamental changes. Alternative methods of lithotripsy have made open surgery superfluous in most countries. Repeated treatment with extracorporeal shock wave lithotripsy (ESWL) is relatively free of side effects and, as a rule, does not interfere with kidney function. However, one should note that these modern methods of therapy serve only to treat the symptoms of the disease – the stone. The actual cause of stone formation – infection, malnutrition, metabolic abnormalities, etc. – frequently remains unnoticed, so that recurrence is bound to occur. With a yearly incidence rate of 0.5% in Europe, the number of recurrences approximates 80%. However, with detailed knowledge of the causes of urinary stone formation, recurrences can largely be prevented. To achieve this goal, there is a need for laboratory diagnostics, including stone and urine analyses. Furthermore, it is necessary to investigate the dietary (nutritional) habits of the patient so that they can be given comprehensive guidelines for their specific kind of stone disease. Finally, the most appropriate post-operative follow-up care must be provided including, if necessary, the use of drugs. The patient should be encouraged to take part in a two-year therapy with regular checks. This may spare the patient further and repeated illness and can reduce the costs of therapy quite considerably. The present book is a manual for physicians in charge who, in the course of practice, encounter urinary stone patients. It provides appropriate diagnostic procedures as well as general advice for recurrence prophylaxis. To start with, there is a survey of outpatient diagnosis and treatment of acute urinary stone disease as it occurs in emergency medicine. If no stone analysis is available, general and unspecific therapeutic measures may be used. If, however, the type of stone is known, the indication as described in the respective chapter should be applied. The layout of the book is arranged so that on the right-hand pages, concise and distinct information is presented, while on the left-hand pages the respective detailed explanation is given. We trust that this book serves as a useful and practical guide to all physicians treating their urinary stone patients. The authors July 1996

VIII

Preface to the second edition The first edition of our book and an unamended reprint stimulated great interest world-wide. Karger Publishers consequently asked us to prepare a second revised edition. We are pleased to comply with this request, and are grateful to the staff of the publishing house for their excellent cooperation. A recent epidemiological survey revealed that 5.5% of all men and 4% of all women in Germany already had urinary stones (prevalence). In the case of men, 10% of those aged 50 or above were stone formers. Acute disorders were recorded in 1.5% of the population in the year 2000 (incidence). The high incidence of this disease makes it clear that modern methods of lithotripsy (ESWL, PNL, URS) have led to the continued disregard of metabolic diagnosis and the prevention of recurrent stone formation. It is in the vital interest of both patients and health economics that prophylactic measures are undertaken for each stone patient in order to prevent recurrences. During the revision of this book due attention has been paid to the current literature (see references) as well as the European and international guidelines on urolithiasis. Certain special methods of metabolic clarification have been supplemented in the appendix. Detailed tables referring to the oxalate, calcium and uric acid content of food have been added. We assume that the reference values for urinary excretion derived from healthy children will help to improve the treatment of children with urinary stones. We trust that this book will prove to be helpful to both doctors and their patients. The authors September 2001

IX

Preface to the third edition ‘Urinary stones are thriving’ – that is certainly not a good slogan! Despite the progress in clinical stone treatment, the incidence of urolithiasis is rapidly increasing. The methods for stone removal – SWL, URS, PNL – have constantly improved, and each method has its preferred application depending on the location and size of the stones involved. However, increasing attention is being paid to the fact that urinary stones less than 1 cm in size can pass spontaneously. A conservative approach with stone expulsion therapy via increased diuresis in combination with physical exercise and – if necessary – medication with -adrenoreceptor antagonists, calcium channel blockers and/or non-steroidal anti-inflammatory agents has proved successful. Expulsion rates of up to 70% have been achieved for stones in this category. In recent years, the guidelines for urinary stone therapy of urological societies (AUA, EAU, DGU) have been updated by expert committees. While the spectrum of available therapeutic methods has remained similar, application of these methods in various countries differs greatly. SWL is still the most important method for active stone removal. Improved flexibility of the instruments and the more widespread use of laser therapy have enhanced the importance of endourologic procedures, also in the treatment of renal stones. The efficiency rates for complete stone removal of staghorn calculi are between 50 (SWL) and 80% (PNL). For ureteral stones, stone-free rates of more than 90% can be achieved with both URS and SWL. However, residual concrements or fragments may often remain in the body after stone removal, and when this material does not pass spontaneously directly after completion of the treatment, it can provide the nucleus for a new stone. From a physico-chemical point of view, no insignificant residual concrements can ever occur when the urine is constantly supersaturated. Regardless of any residual concrements, epidemiological studies have shown that 25% of stone patients are at risk of multiple stone formation. Accordingly, differentiation has been made between high- and low-risk patients in the guidelines. This differentiation is based on the stone case history, the results from the stone analysis, and a basic laboratory diagnostic examination. For the prevention of recurrences in high-risk patients, an elucidation of metabolic risk factors is vital and may be followed by a treatment appropriate for the stone type. Consistent metaphylaxis can prevent more than 50% of recurrences. Patients not only expect to be relieved from symptoms caused by stones, but they also wish to remain free from recurrences. This should be the benchmark against which any therapeutic regimen is measured. In the 3rd edition of Urinary Stones, the recommendations contained in the international and German guidelines relating to urinary stone therapy have been taken into account. Also the latest scientific progress in clinical and laboratory diagnosis, together with dietary therapy and medication, have been included. The current edition also relates more deeply to the specific situation of urolithiasis in childhood. Excellent cooperation with the Karger Verlag has enabled a fundamental revision of the previous edition with the result that state-of-the-art tools are now available for the prevention of recurrences. May everyone applying our recommendations enjoy great success with the treatment of their patients! The authors March 2009

X

Checklist General aspects

Introduction

CaOx

The emergency stone Introduction

Ua

Urinary stones Y belong to the group of biominerals Y are the final product of a multifactorial process

CaP

Y the stone is the symptom, not the disease itself

Symptoms of different abnormalities

Struvite

w

Y occur today with a prevalence of 4–10%, which is steadily increasing

Widespread disease

2,8-DHA

w

Cystine

Y regional differences are important to acknowledge

NH4Urate

Metaphylactic treatment is undoubtedly necessary

Appendix

w

Xanthine

Y the recurrence rate which depends on the stone composition is 50–100% in untreated patients and 10–15% in treated patients

1

Introduction

Formation of urinary stones The biomineralization resulting in a urinary stone has a multifactorial origin in which socio-economic, genetic and constitutional factors as well as diet, pharmacologic treatment and metabolic abnormalities might act in concert. A supersaturation of urine with the stone-forming salt(s) is of fundamental importance and a prerequisite for the necessary precipitation. The solubility of the different stone components depends on the urinary pH and the excretion of other urine constituents. Accordingly, a saturation of urine above the solubility product (SP) and the associated risk of crystallization are determined by the urinary concentration (mmol/l) of the solutes taking part in the crystal formation and the pH. When the SP has been exceeded, the supersaturation is metastable. At this level of supersaturation the crystals can grow and aggregate (agglomerate) but new crystal formation is not possible unless promoted in some way. In order to start the formation of new crystals, the supersaturation has to be further increased to a level termed the formation product (FP). The isolated findings of increased concentrations are not diagnostic for stone disease but might reflect only the concentration capacity of the kidney. Normal values of urine constituents are usually expressed as the total excretion during a 24h period or a fraction of a 24h period. In children the excretion values are normally expressed in mmol and mg/1.73 m2 body surface area/day, or in mmol and mg/kg body weight/day, respectively. In infants and small children spot urines are analyzed and the substance concentration in urine is related to creatinine. Normal values are age-related and additionally given in mmol/24h and in mmol/kg body weight/24h (Appendix, tables 4–6). There is often an overlap in terms of urine supersaturation between stone formers and normal subjects indicating that factors other than the supersaturation have to be considered in the process of stone formation. It is of note, however, that the urine composition obtained from 24h or similar collections might obscure term from peaks of supersaturation. Substances which inhibit the nucleation, growth and aggregation of crystals are thought to play an important role. Furthermore, anatomical and functional abnormalities might contribute either by fixation of crystals or by reducing their excretion. Such a retention of crystals is necessary for the development of a clinically significant crystalline deposit.

Solubility

ammonium urate

uric acid

cystine

phosphate

pH dependence of the urinary solubility of lithogenic substances

2

5

6

7

8

Urinary pH

General aspects

Introduction

CaOx

Formation of urinary stones Profession Mentality

Nutrition Constitution

Climate Race

Inheritance

Metabolic abnormalities

Genetic factors

Ua

Age Sex

Abnormal renal morphology

Disturbed urine flow

Urinary tract infection

CaP

P

excretion of crystallization promoters

pH

excretion of crystallization inhibitors

urinary volume

pH

2,8-DHA

P

Xanthine

Physico-chemical change in the state of supersaturation

P

NH4Urate

Abnormal crystalluria Crystal aggregation Crystal growth

P

Appendix

excretion of stone-forming constituents

Decreased

Cystine

Increased

Struvite

P

Urinary stone

3

Introduction

Location and form of urinary stones Urinary stones occur in all parts of the renal collecting system. The sites of occurrence and formation are not necessarily identical. In the industrialized part of the world, Y 97% of all urinary stones are localized in the: parenchyma (collecting ducts) papilla calices

pelvis pelvis + calices ureter

Y only 3% are found in the bladder and the urethra. The anatomy of the collecting system at the site of stone development is an important determinant for the shape of the stone inasmuch as there frequently is an adaptation to the surrounding structures.

Composition and occurrence of the different crystal phases in urinary stones Urinary stones belong to the group of biominerals. Different inorganic or organic substances with a crystalline or amorphous structure are the major constituents of the stones. Only about 1/3 of all urinary stones has a monomineral composition. There is frequently a structure with layers of varied composition or a homogeneous mixture of different crystal phases. Calcium oxalate is by far the most common stone constituent, and is considered to be the major mineral in at least 70% of all stones. Stone type

Chemical composition

Mineral

Major constituent, % of cases

Oxalates

Calcium oxalate monohydrate Calcium oxalate dihydrate Uric acid Uric acid dihydrate Ammonium urate (mono ammonium urate) Magnesium ammonium phosphate hexahydrate Carbonate apatite Calcium hydrogenphosphate dihydrate Protein Cystine Xanthine 2,8-Dihydroxyadenine Indinavir Silicates Sulfonamides

Whewellite Weddellite Uricite

74.0

Uric acid and urates Phosphates

Protein Genetically determined stones Drug stones

Struvite Dahllite Brushite

11.0 1.0 0.5 5.8 5.0 1.5 0.5 0.5

rare

It is important to consider that the relative distribution of various stone constituents is subject to pronounced geographical variations.

4

General aspects

Introduction

CaOx

Location and shape of urinary stones

Staghorn stone

Pelvic stone

Ua

Calix stone

CaP

Ureteral stone

Cystine

Struvite

Bladder stone

Calcium oxalate monohydrate Calcium oxalate dihydrate

Whewellite Weddellite

Phosphate

Carbonate apatite Calcium hydrogenphosphate dihydrate Tricalcium phosphate Calcium hydroxyl phosphate Magnesium ammonium phosphate hexahydrate

Dahllite Brushite Whitlockite Hydroxyapatite Struvite

Uric acid, Urate

Uric acid Uric acid dihydrate Ammonium urate (mono ammonium urate) Mono sodium urate monohydrate

Uricite – – –

Stones associated with inborn errors of metabolism

L-Cystine

– – –

Xanthine 2,8 -Dihydroxyadenine

Xanthine

Oxalate

NH4Urate

Mineral name

Appendix

Chemical name

2,8-DHA

Composition of the most important stone constituents

5

Checklist

Biochemical investigations

Treatment

Metaphylaxis General aspects

General aspects

CaP Struvite

21 f.

Cystine

H

2,8-DHA

Standard procedures – Treatment and care of patients with urinary stones

Xanthine

8 f.

NH4Urate

H

Appendix

The emergency stone – Treatment of patients with acute renal colic

Ua

CaOx

General aspects

7

General aspects – the emergency stone

The emergency stone Symptoms A urinary stone that obstructs the renal collecting system causes an emergency situation, either as an episode of renal colic or by infection of the obstructed urinary tract.

Renal colic The pain associated with urinary stones can be explained by two mechanisms: 1. Dilatation of the obstructed system with stretching of the pain receptors in the renal pelvis and calices. 2. Local irritation in the wall of the ureter or renal pelvis with edema and release of pain mediators. Differential diagnosis A. Renal colic due to other urologic diseases Y passage of a blood clot Y passage of necrotic tissue Y hydronephrosis caused by pyeloureteral junction (PUJ) obstruction, stricture, compression or abnormal angulation of the ureter B. Other kinds of abdominal pain Y gastrointestinal: appendicitis, terminal ileitis, diverticulitis, cholecystitis, cholelithiasis, duodenal or ventricular ulcerations, pancreatitis, infectious colitis, toxic colon Y vascular: infarction of the kidney, spleen or bowel due to arterial obstruction; aortic aneurysm Y gynecological: ovarian cysts, adnexitis, ectopic pregnancy, endometriosis, ischemia Y others: psoas abscess, retroperitoneal tumors, cardiac infarction, porphyria, intoxication with heavy metals, diabetes mellitus, pheochromocytoma, Addison’s disease C. Children Y symptoms in infants and smaller children may not be colicky abdominal pain, but high fever, vomiting, failure to thrive.

Obstructive pyelonephritis It needs to be emphasized that an obstruction of the renal collecting system is not always associated with renal colic. The combination of flank pain and fever, possibly together with fits of shivering, constitutes an alarming symptomatology. The presence of a urinary tract infection and a dilatation of the renal collecting system demonstrated with ultrasound call for emergency relief of the obstruction. In these cases treatment with antibiotics alone is not sufficient inasmuch as the progressive infection might lead to urosepsis, a condition which has a very high mortality (150%), even with late diversion of urine from the obstructed kidney.

8

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist Emergency stone

Y Clinical signs:

reduced blood pressure, abdominal distension, sparse peristalsis, pain on deep palpation over the stone or most commonly in the costovertebral angle

Y Associated symptoms:

nausea, vomiting, urgency, pollakisuria, oliguria

Ua

very restless Skin: pale, cold perspiration

CaP

Y Patient’s appearance:

With accompanying urinary tract infection:

dysuria, fever, signs of septicemia, anuria

infection, sepsis, anuria

Y Patient’s appearance:

impaired general condition, reduced consciousness

Y Clinical signs:

reduced blood pressure, abdominal distension, sparse or no peristalsis, pain on percussing over the kidney, often only diffuse back or abdominal pain

Y Associated symptoms:

fever, nausea, vomiting

Xanthine

Y Primary symptoms:

2,8-DHA

Symptoms of obstructive pyelonephritis

NH4Urate

w

Where? kidney, urinary bladder, flank, thigh, middle and lower abdomen, urethra, genital tract

Struvite

How? sudden start of attacks of cramp-like pain

colicky pain (not always obvious in infants)

Cystine

Y Primary symptoms:

CaOx

Symptoms of renal colic

Appendix

w

9

General aspects – the emergency stone

Emergency diagnostic work-up Laboratory diagnostics Urine examination Erythrocytes: Microhematuria is a general symptom of urinary stone colic, but may infrequently be absent. Leukocytes and nitrite: Each stone in the urinary tract can cause an obstruction of the urine flow and information on an associated urinary tract infection is required (caution: obstructive pyelonephritis). pH: When clinical presentation, microhematuria and ultrasonography indicate a stone as explanation of the colic, but the plain radiograph is without calcifications, a pH around 5.0 supports the suspicion of a stone composed of uric acid. Blood examination Creatinine: Information on the level of this variable is necessary before administrating intravenous contrast medium, especially in the case of patients with only one kidney or with known reduced renal function. In case of a suspected obstructive pyelonephritis, all those laboratory analyses are indicated that can be of value for the establishment of a correct diagnosis or for the appropriate monitoring of the severity of the disease (caution: acidosis, thrombocytopenia, coagulation abnormalities, renal failure, electrolyte disturbances).

10

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

Emergency diagnostics

Culture

Indicates

positive positive positive >7.0 5 mm

Ua

Y Pronounced dilatation of the collecting system with reduced function, due to an impacted stone. Risk of local inflammation (‘stone-bite’) Y Infection in an obstructed collecting system H particularly with ascending, obstructive pyelonephritis

Struvite

CaP

Y Patient’s compliance pain experience, tolerance frequency of colic episodes profession pediatric patient I

Cystine

If spontaneous passage cannot be expected: I

Xanthine

2,8-DHA

H 174 f.

NH4Urate

Active stone removal is necessary

Appendix

w

19

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

CaOx

Standard procedures

H

22 f.

Y Imaging

H

24 f.

Y Biochemical investigations

H

26 f.

H

27 f.

H

28 f.

CaP

Y Medical history

Ua

Stone episodes

Struvite

Biochemical investigations I

Minimal analytic program

Cystine

Y Examination of spot urine samples Y Blood examination

2,8-DHA

Y Stone analysis I

Quality standard Elucidation of the causes of stone formation

Xanthine

Y Examination of 24h urine Y Blood examination

H 190 f.

NH4Urate

Y Dietary history H Metabolic disturbances: Repeated examinations under standardized dietary conditions I

Special investigations Appendix

w

Y Procedures specific for the stone composition Y Loading examinations Y Metabolic studies

H 178 f.

21

General aspects – standard procedures

Careful medical history Common in patients with stones composed of:

22

Current age/Age at first stone: 1.010 g/cm3

low fluid intake

all stones

≥105 colonies/ml positive >2.5 mmol/l

>380 ␮mol/l 5.8 >7.0 ≤5.8 positive positive positive

2,8-DHA

erythrocytes

Common with stones composed of

Xanthine

erythrocytes WBC nitrite Urometer/Strips: density, specific gravity Urinary sediment: crystalluria see Appendix, p. 213 f.

Indicates

struvite, CaP struvite, CaP cystine CaOx, CaP

NH4Urate

Urine (spot urine sample) Test strips: pH value (measured several times a day)

Result

uric acid, CaOx xanthine

Appendix

Examination

Stone analysis: H only with physical methods: IR spectroscopy, X-ray diffraction

27

General aspects – standard procedures

Biochemical investigation II Quality standard General methods for elucidating the causes of stone formation When the existing stone has passed, it is important to start the search for risk factors and mechanism(s) that might have been responsible for the development of the stone. Quality standard under normal dietary conditions: Y Examination of a 24h urine collection (or urine sample collected during any other specified period of time) Y Examination of serum Y Dietary assessment H The patient has to: – collect a 24h urine sample (but analysis of urine should not be carried out until at least 10–20 days have passed after stone passage or removal) – measure a pH profile during the day – complete a diet record H The doctor has to: – give instructions for the appropriate: collection of a 24h urine sample management of test strips, urometer completion of a diet record – provide bottles for urine collection containing an appropriate preservative solution, either: 10 ml of 5% thymol in isopropanol (for a 2 l bottle), or: 20–30 ml of 6 mol/l hydrochloric acid (if uric acid can be omitted from the analytic program) Acidification of urine is necessary in order to prevent precipitation of calcium salts and to prevent oxidation of ascorbic acid to oxalate. If there is reason to suspect a metabolic or dietary abnormality (as a result of the dietary assessment), the biochemical investigation has to be repeated under standardized dietary conditions. H See Appendix, p. 190 f.: Y Examinations under standardized dietary conditions. Y Instructions for collecting a 24h urine sample.

28

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

Standard procedures

CaOx

Quality standard Y To be analyzed irrespective of stone composition!

Urate Citrate Oxalate Creatinine* Optional Magnesium Inorganic phosphate Ammonium Cystine

Ua >6.8 g/cm3 l mmol mmol mmol mmol mmol mmol mmol

35 >50 >0.8

mmol mmol mmol mmol

CaP

1.010 5.0 (>8.0 >4.0 0.5 7–13 13–18

H is defined as hypercalciuria)

Struvite

Compulsory pH (day profile) Density (morning urine) Volume Calcium

Levels at which treatment is justified (per 24h)

women men

Cystine

24h urine variable

2,8-DHA

Urea, sodium, potassium, chloride and phosphate are helpful to assess the dietary habits > = too high; < = too low; * = to check for the completeness of the collection

Optional PTH Blood gases

Reference values for children see H 206 f.

Xanthine

S-Urate S-Phosphate S-Creatinine

2.0–2.5 (1.12–1.32 119–380 0.81–1.29 25–100

mmol/l mmol/l) ␮mol/l mmol/l ␮mol/l

NH4Urate

Compulsory during first examination S-Calcium (ionized calcium)

Normal range

Depending on method pH: 7.35–7.45 pCO2: 35–45 mm Hg / pO2: 80–90 mm Hg HCO3–: 22–26 mmol/l / BE: 8 2 mmol/l

Appendix

Blood

29

General aspects – standard procedures

Evaluation of the results Whenever possible, the results of serum and urine analysis should be considered in view of the stone composition. H Stone composition is known: Procedures for investigation, treatment and metaphylaxis are found in the chapters dealing with the different types of stone. H Stone composition is so far unknown: Further procedures have to be based on the results of urine and serum analysis. One or several urine or serum variables are above or below the reference limits: Y might give a first indication of the stone composition (see table), Y leads to further diagnostic procedures, Y a specific therapy can be added to the general metaphylactic regimen. Further diagnostic procedures Biochemical findings

Procedure

Refer to page

U-Calcium >5 mmol/24h

Dietary assessment Calcium loading in selected patients

184

Dietary assessment

U-Urate >4 mmol/24h pH >6.8 in 24h urine constantly >5.8 in the day profile Reference values for children see

30

冧

Exclude infection When infection is excluded, NH4Cl-loading

H 206 f.

180

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

Evaluation of results

CaOx

Evaluation of the results f Stone composition is known: See the specific chapter.

Y Calcium phosphate stone

U-pH in day profile never 7 (urease-producing bacteria) U-Ammonium d U-Citrate f

Y Cystine stone

U-Cystine d

Y Xanthine stone

S-Urate f

Y Ammonium urate stone

U-pH 6.5–7 (infection) U-Ammonium d U-Phosphate f

CaP

U-pH normal or low U-Calcium d U-Oxalate d U-Citrate f U-Urate d U-Magnesium f

Struvite

Y Calcium oxalate stone

Cystine

U-pH in day profile R Climate Age

Struvite

Frequency: 70–75% Develop as a result of a multifactorial process

Lithogenic potential d

NH4Urate

Y Y

CaP

Ua

CaOx

Calcium oxalate stones

Appendix

Supersaturation with CaOx

Crystalluria

Ox = Oxalate CaOx = Calcium oxalate

Calcium oxalate stone

39

Type of stone – calcium oxalate stones

Specific notes for CaOx stone disease see General aspects, page

Medical history

22 f.

Lifestyle: Overweight, lack of physical activity, stress Pathophysiologic factors: Disturbances in the metabolism of calcium, oxalate and uric acid

Imaging

24 f.

Radiograms with calcifications Ultrasonography: Echogenic structures

Minimal program Urine analysis: pH low Envelope and dumb-bell shaped crystals in the sediment

26 f. 213 f.

Serum analysis: Calcium 12.5 mmol/l (5.0 meq/l) or normal Uric acid 1380 ␮mol/l (6.4 mg/100 ml) or normal

Establishment of the diagnosis by stone analysis: CaOx stone (whewellite, weddellite)

40

192 f.

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

CaOx

Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)

>2.5 mmol/l

H

Exclude HPT

H

42 f.

Urate

>380 ␮mol/l

H

Diet

H

56 f.

H

Medication

H

62 f.

Struvite

Calcium

CaP

Ua

Serum analysis

H

52 f.

Density

>1.010 g/cm3

H

Urine dilution

H

52 f.

Calcium

>5.0 mmol/24h

H

Diet

H

54 f.

Medication

H

58 f.

Diet

H

56 f.

Medication

H

64 f.

Diet

H

56 f.

Medication

H

62 f.

Diet

H

56 f.

Medication

H

62 f.

Oxalate

Urate

Citrate

>0.5 mmol/24h

>4.0 mmol/24h

4 mmol/24h 100 mg/day if only U-urate >4 mmol/24h (1–3 mg/kg body weight/day in children) Allopurinol 300 mg/day

Appendix

Y

NH4Urate

+

63

Type of stone – calcium oxalate stones

Risk factor: Hyperoxaluria 1. Secondary hyperoxaluria a) Enteric hyperoxaluria. The most common reason for enteric hyperoxaluria is the insufficient complex formation between calcium and oxalate seen in Crohn’s disease, conditions following bariatric surgery, pancreatic insufficiency and other diseases with malabsorption. The high intestinal concentration of fatty acids results in binding of calcium with ensuing lack of calcium for oxalate complex formation. Increased absorption of oxalate can also be the result of an insufficient intake of calcium. A reduced occurrence of intestinal oxalate-consuming bacteria (Oxalobacter formigenes) is another factor to consider. Hyperabsorption of oxalate might also occur for unknown reasons (oxalate absorption test, see Appendix, p. 178 f). b) Other causes of secondary hyperoxaluria Y intoxication with ethylene glycol and methoxyflurane Y ingestion of large doses of ascorbic acid (more than 2–4 g/day) Therapeutic possibilities: Y calcium administration (in patients with a low Ca excretion): Diet rich in calcium or calcium salt preparations (Cave: calcium salt preparations may contain vitamin D! Hence, calcium absorption and therefore calcium excretion may increase!). Neither diet nor calcium salt preparations are recommended in childhood. Y magnesium administration (complex-formation with oxalate) Y administration of alkaline citrate Y reduced intake of fat Y administration of MCT fat (medium chain fatty acids). This form of treatment can be attempted in patients with maldigestion or malabsorption of fat. MCT fats are absorbed without lipolysis and without the need of bile acids. The formation of calcium-soaps is thereby counteracted. MCT fats should be gradually increased. 2. Primary hyperoxaluria (Type I and II) H These patients should preferably be treated in specialized centers. In primary hyperoxaluria endogenous production of oxalate is increased, which leads to massive hyperoxaluria and hence recurrent urolithiasis or progressive nephrocalcinosis. Y administration of pyridoxine (vitamin B6): pyridoxine is an essential cofactor of all body aminotransferases. In PH I administration of vitamin B6 may lead to enhancement of AGT activity and thus lesser endogenous oxalate production. Pyridoxine is started with 5 mg/kg body weight/day, in order to exclude or demonstrate pyridoxine responsiveness (130% reduction of urinary oxalate excretion). If no response is reached, dosage will be increased stepwise to 20 mg/kg body weight/day. A trial of at least 3–6 months is warranted in all PH I patients to prove or disprove B6 responsiveness. Pyridoxine does not help in PH II, and in secondary hyperoxaluria. Y alkaline citrate: increased excretion of citrate results in increased inhibition of CaOx crystallization (recent results have indicated a much better prognosis in patients treated with alkaline citrate). Y the intake of calcium must be sufficient (in children age-dependent: 600–1,200 mg/day). A high intestinal concentration of calcium brings about a reduction of intestinal hyperabsorption of oxalate. Y magnesium forms a soluble complex with oxalate and is a therapeutic alternative to alkaline citrate.

64

Biochemical investigations

Treatment

Metaphylaxis

Medication

General aspects

Checklist

CaOx

Oxalate excretion 10.5 mmol/24h Secondary hyperoxaluria Therapeutic possibilities:

Ua

Calcium 500 mg/day (12.5 mmol/day) or more, taken together with meals (the urinary Ca excretion should be monitored) Preparations: Calcium effervescent tablets Cave: vitamin D-containing calcium supplements (hypercalciuria)

Magnesium

Y

MCT fats

Struvite

Dosage: 200–400 mg/day (8.25–16.5 mmol/day) Preparations: Magnesium citrate, magnesium oxide, magnesium hydroxide in patients with maldigestion or malabsorption of fat

Cystine

Primary hyperoxaluria H best treated in specialized centers Therapeutic possibilities: Y

Pyridoxine (Vit. B6) Dosage:

Preparation: Y

Pyridoxine is started with 5 mg/kg body weight/day If no response is reached, dosage will be increased stepwise to 20 mg/kg body weight/day (see left page) Pyridoxine

Magnesium Dosage: Adults: as above. Children: 6 mg (0.25 mmol) per kg body weight/day Preparations: as above

Alkaline citrate

NH4Urate

Y

Appendix

Dosage: Children: 0.10–0.15 g/kg body weight/day Preparations: Potassium citrate, sodium-potassium citrate, potassium-magnesium citrate, Shol’ Solution (see p. 58 f. and 61 f.) Y

2,8-DHA

Y

CaP

Dosage:

Xanthine

Y

Sufficient intake of calcium

65

Type of stone – uric acid stones

Uric acid stones Introduction Up to 15% of urinary stones are composed of uric acid. Most patients with uric acid stones are in an advanced period of life, with the majority of patients aged more than 60 years. Younger uric acid stone formers are often obese. Men fall ill two to four times more frequently than women. At physiologic pH values, urate is the end-product of purine metabolism, which is converted to poorly soluble uric acid at pH values !6.5 after renal excretion. As uric acid stones are formed only in an acid urine, the individual diet might be an important risk factor in uric acid stone formation. A diet rich in protein and purines with a high consumption of alcoholic beverages results in increased uric acid excretion and a low urinary pH value. 20–40% of gout patients subsequently form uric acid stones. These patients suffer from overproduction of uric acid which results in hyperuricosuria. Together with low urinary pH values, the risk for uric acid stone formation is increased. It needs to be emphasized that patients with ileostomy more commonly form uric acid stones than calcium oxalate stones because of the combined low pH and small urine volume and also because the colon seems to be important for the excessive oxalate absorption in enteric hyperoxaluria. Uric acid dihydrate is a special modification, which is formed in very acid urine (pH ! 5.5). Uric acid stones are the only type of stone that can be dissolved by medical agents. This chemolytic treatment is successful in 90% of uric acid stone patients.

66

Biochemical investigations

Checklist

Treatment

Metaphylaxis General aspects

Uric acid stones

Ua

CaOx

Uric acid stones

Uric acid

CaP Struvite Cystine

low urine pH + high concentration of uric acid

high urine pH + high concentration of urate + cation

f

f

High ion-activity product of uric acid

High ion-activity product of a urate salt (NH4, Na or K)

Uric acid stone

Urate stone

2,8-DHA

Y

Xanthine

Y

Occurrence: 3–15% Formed in acid urine Different from urate stones

NH4Urate

Y

Uric acid dihydrate

H 160 f.

Appendix

Y radiolucent Y susceptible to medicinal dissolution

67

Type of stone – uric acid stones

Specific notes for uric acid stone disease see General aspects, page

Medical history

22 f.

Pathophysiologic factors Metabolic abnormalities Pharmacologic influence on the excretion of uric acid

Imaging

24 f.

Radiolucent stone on plain films Visible on helical CT examination Contrast defect on the urogram Ultrasonography: Structure with a high density and a typical echo

Minimal program Urine analysis: pH constantly !6.0 Crystals with whetstone appearance or with right angles; fine crystalline ‘brick-meal’ in the sediment

26 f.

213 f.

Serum analysis: Urate 1380 ␮mol/l (6.4 mg/100 ml)

Establishment of the diagnosis by stone analysis: Uric acid and/or uric acid dihydrate stone

68

192 f.

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

CaOx

Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)

H

Diet

H

82 f.

Medication

H

84 f.

CaP

>380 ␮mol/l (6.4 mg/100 ml)

Struvite

Urate

Ua

Serum or plasma analysis

H

Urine dilution

H

80 f.

Density

>1.010 g/cm3

H

Urine dilution

H

80 f.

pH

in day profile 4.0 mmol/24h

2,8-DHA

4.0 mmol/24h 100 mg/day if only U-urate >4.0 mmol/24h 1–3 mg/kg body weight/24h in children Preparation: Allopurinol

Struvite

300 mg/day

Cystine

Dosage:

H uricosuric agents increase the excretion of urate and are contraindicated

2,8-DHA

Diet Y foodstuffs with a low content of purines ( H see Diet, p. 82, and Table 3 on the purine content of foods, p. 204 f.)

3. Urine dilution

Xanthine

f Goal: at least 2.0 l of urine/24h

NH4Urate

Fluid intake: at least 2.5 l/day in adults at least 1.0–2.0 l/m2 body surface area/day in children

Type of beverages

Appendix

preferably: alkalizing beverages Y mineral water rich in bicarbonate (11,500 mg HCO3–/l) Y citrus juices (diluted with water; be aware of the energy content)

77

Type of stone – uric acid stones

Metaphylactic treatment Methods aimed at dissolving uric acid stones also have a preventive effect against new crystal precipitation and therefore: Therapy = Metaphylactic treatment As a long-term objective, it is important to change living and dietary habits so that the need of medication can be reduced or even eliminated. In any case, the basic disease should always be considered and treated appropriately.

General measures Reduction of overweight is particularly important in cases of uric acid stone formation. Weight reduction should, however, be accomplished without extreme fasting, because this can lead to an increased excretion of uric acid. Y Normal weight: BMI (body mass index) 18.5–25.0 kg/m2 BMI = body weight in kg/height in m2 In addition to an adaptation of the energy intake, sufficient physical activity is necessary. Great losses of fluid due to extreme sweating or the use of laxatives must be avoided or compensated by additional intake of fluid. The risk of new stone formation increases markedly with a reduction in pH and therefore it is necessary to check the urinary pH level regularly. H All relevant serum and urine variables should be checked regularly: Serum: urate Urine: pH, urate

78

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

Long-term goal CaOx

w

Y Increased pH (6.5–6.8)

Ua

Y Reduced excretion of urate ! 4.0 mmol/24h ! 0.12 mmol/kg body weight/24h in children

Struvite

General measures

Cystine

Y Reduction of body weight (aim at normal body weight without extreme fasting) Y Sufficient physical activity Y Avoid excessive losses of fluid (sauna, sun-baths, extreme exercise, use of laxatives)

2,8-DHA

Y Reduce stress Y Allow for sufficient sleep

NH4Urate

Xanthine

Y Regular control of: G serum and urine variables

Appendix

w

CaP

Y Sufficient urine dilution at least 2.0 l/24h at least 1.0–2.0 l/m2 body surface area/24h in children

79

Type of stone – uric acid stones

Urine dilution The most important metaphylactic measure is a sufficient dilution of urine. The daily intake of fluid should be at a level that results in at least 2.0 l of urine. Depending on the degree of physical activity and surrounding temperature, it is necessary to drink at least 2.5 l/day, evenly distributed over the day. It is wise to drink again before or after each voiding. In order to counteract high urine concentrations that occur during the sleeping period, it is also important to drink just before going to bed. Therefore, in addition to the intake of other fluids: H During day-time: drink at least 2.5 dl every second hour (approx. 2 cups or 2 small glasses) During sleeping period: drink before going to bed and drink again before or after each voiding

Type of beverages Alkalizing beverages are preferable since they increase the urinary pH: Y Mineral water rich in hydrogen carbonate (11,500 mg HCO3–) Y Citrus juices have a considerable energy content (approx. 400 kcal/l) H if possible, dilute them before ingestion Also useful are urine-neutral beverages: They dilute urine without affecting its composition. Unsuitable beverages: Alcoholic beverages (especially beer) increase the urate excretion and acidify the urine.

80

Biochemical investigations

Treatment

Metaphylaxis

Urine dilution

General aspects

Checklist

CaOx

Goal: Urine dilution H at least 2.0 l of urine per day

Ua

f Fluid intake: at least 2.5 l/day in adults at least 1.0–2.0 l/m2 body surface area/day in children f

Type of beverages CaP

H preferable: alkalizing beverages Y HCO3– -rich mineral water Y citrus juices (diluted with water)

Struvite

H also suitable: urine-neutral beverages Y kidney tea, bladder tea, herbal tea and fruit tea Y mineral water with a low content of minerals

Cystine

H suitable in limited amounts: Y coffee Y black tea, green tea

Appendix

NH4Urate

Xanthine

2,8-DHA

H unsuitable: Y all alcoholic beverages (especially beer) Y sugar-sweetened soft drinks, including cola

81

Type of stone – uric acid stones

Diet Patients with uric acid stones do not need to follow a strict dietary regimen, but it is important that the food has a low purine content (max. 500 mg of uric acid/day or 3 mmol/day). Products from plants usually have a lower content of purine than animal products and have an alkalizing effect. In contrast, meat and fish have an acidifying effect due to their protein composition. Purine content of some foodstuffs: Uric acid

Meat Skin-free fish Neck sweet bread Liver Kidneys Poultry skin Herring with/without skin

Uric acid

mg/100 g

mmol/100 g

150 150 900 230–360 220–255 300 320/180

0.9 0.9 5.4 1.4–2.1 1.3–1.5 1.8 1.9/1.1

Chick peas Lentils Soy beans Sardines Anchovies Sprats

mg/100 g

mmol/100 g

160 200 350 350 160 500

1.0 1.2 2.1 2.1 1.0 3.0

See also Table 3 on the purine content of foods H 204 f. The diet is best composed of vegetables, salads, fruits, cereal products, eggs and dairy products. Furthermore, wholegrain cereals and cereal products should be preferred. It should be noted that alternative dietary components (e.g. soy products) are not purine free (see table below). In particular, products which are enriched with yeast to give taste contain considerable quantities of purine. Compare:

Soy beans Soy-knackwurst Tofu Buckwheat Whole-meal noodles

Uric acid

Uric acid

mg/100 g

mmol/100 g

220 100 70 150 50

1.3 0.6 0.4 0.9 0.3

H H

White beans Knackwurst

H H

Wheat Regular noodles

mg/100 g

mmol/100 g

180 110

1.1 0.7

90 30

0.5 0.2

It is recommended that the intake of protein should be restricted to 0.8 g/kg body weight/day. This goal can usually be achieved if the intake of meat, fish and sausages is reduced to 150 g/day. On 3 days/week meat and meat products should be avoided.

82

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

Diet

CaOx

Balanced mixed diet With consideration of the following points f

Ua

Purine intake Y restrict dietary products rich in purine H meat, meat products and fish (max. 150 g/day), legumes, including soy products

Struvite

Y prefer dietary products with a low content of purine H vegetables, salads, fruits, cereal products, eggs and dairy products

CaP

Y avoid dietary products extremely rich in purine H innards, sardines, anchovies, sprats, mackerel, skin from fish, poultry and pork

H ovo-lacto-vegetarian diet

Cystine

Caution: alternative dietary regimens which have a high content of purines.

Protein intake

NH4 Urate

Xanthine

Important general rule: Avoid excesses!

Appendix

w

2,8-DHA

Y restrict intake of protein to 0.8 g/kg bogy weight/day H max. 150 g of meat, meat products or fish per day H restrict meat and meat products to max. 4 meals per week

83

Type of stone – uric acid stones

Medical treatment Neutralization of urine Y Treatment with alkaline citrate or sodium bicarbonate Effect: Increases urinary pH by adjusting the acid-base balance Contraindications: Recurrent urinary tract infections, hypertension (control!), phosphate stones, renal insufficiency, metabolic alkalosis, hyperkalemia Side effects: Infrequent gastrointestinal disturbances Long-term administration of K-citrate or Na-K-citrate particularly to patients with reduced renal function can lead to hyperkalemia. In such cases a Ca-citrate preparation might be useful. H The regular intake of alkalizing beverages can enable a reduced dosage of alkaline citrate or sodium bicarbonate. The effects should be monitored by repeated measurements of the urinary pH. Reduction of uric acid excretion Y Treatment with allopurinol Effect: see p. 76 Contraindications: Be careful treating patients with reduced renal function. Relative contraindications: Pregnancy, liver disease Side effects: Increased excretion of xanthine (formation of xanthine stones has, however, been observed only with the extreme doses used to treat patients with Lesch-Nyhan syndrome); changes in blood cell formation; hypersensitivity reactions; interaction with anticoagulants and antihistaminics

84

Biochemical investigations

Treatment

Metaphylaxis

Medication

General aspects

Checklist

Alkaline citrate Dosage: Preparations:

According to pH 6.5–6.8 Sodium potassium citrate, potassium citrate, e.g. Uralyt U쏐, Blemaren쏐 N, Urocit-K쏐, Polycitra-K쏐

Ua

f Y

CaOx

Urinary pH constantly ^6.0

or

Sodium bicarbonate Dosage:

CaP

Y

According to pH 6.5–6.8

Y

Struvite

with reduced renal function:

Calcium citrate Dosage:

According to pH 6.5–6.8

Cystine

H Dose reduction is possible with a generous intake of alkalizing beverages.

Allopurinol Dosage:

if S-urate >380 ␮mol/l and U-urate >4.0 mmol/24h 100 mg/day if only U-urate >4.0 mmol/24h (1–3 mg/kg body weight/day in children) 300 mg/day

Xanthine

Y

2,8-DHA

Urate excretion 14.0 mmol/24h

Appendix

NH4 Urate

H Dose reduction is possible with a low purine diet.

85

Type of stone – calcium phosphate stones

Calcium phosphate stones Introduction Two different kinds of calcium phosphate stones occur depending on the urinary pH value. Carbonate apatite and other calcium phosphate/apatite stones develop in alkaline urine (pH 1 6.8) with high calcium and low citric acid concentrations. Inasmuch as calcium oxalate stones develop under similar conditions, carbonate apatite and calcium oxalate stones often occur as mixed stones. However, brushite stones (calcium hydrogen phosphate) develop in urine with a pH in the range of 6.5–6.8 and high concentrations of calcium and phosphate. When the pH value increases up to 6.8, brushite converts into carbonate apatite. Brushite stones grow rapidly with a correspondingly very high recurrence rate. So strong prophylactic treatment is highly important in brushite stone formers. Brushite stones are very hard, therefore disintegration by lithotripsy is more difficult than for other calcium stones.

86

Checklist

Biochemical investigations

Treatment

Metaphylaxis General aspects

Calcium phosphate stones

Y

Occur in different forms

Carbonate apatite (Dahllite) and other calcium phosphates/apatites

Cystine

w

Dahllite

Struvite

Brushite

CaP

Ua

CaOx

Calcium phosphate stones

Xanthine

Brushite (Calcium hydrogen phosphate dihydrate)

NH4 Urate

Occurrence: 1.5% are monomineral stones 0.5% are mixed stones most commonly together with a small fraction of CaOx Y brushite stones most commonly occur in a monomineral form

Appendix

w

2,8-DHA

Occurrence: 32% of all stones are mixed stones with different fractions of carbonate apatite 4.8% are monomineral stones Y most common in alkaline or infected urine Y occur together with CaOx or struvite

87

Type of stone – calcium phosphate stones

Specific notes for calcium phosphate stone disease see General aspects, page

Medical history

22 f.

Immobilization; infections in the urinary tract/other organs Pathophysiologic factors: Disturbances in the metabolism of calcium and phosphate Unexplained back pain H A renal stone as an accidental finding

Imaging

24 f.

Radiodense stones, sometimes of staghorn type Widespread intratubular calcifications and multiple stones Ultrasonography: Structure with a high density and a typical echo

Minimal program

26 f.

Urine analysis: pH 1 6.8 Test strips: sometimes positive for leukocytes and nitrite; pseudo-amorphous crystals in the sediment

冧

H Carbonate apatite/Whitlockite

pH 6.5–7.2 Test strips: negative for leukocytes and nitrite; pillar-like crystals in the sediment

冧

H Brushite

Serum analysis: Calcium sometimes 12.5 mmol/l (5.0 meq/l)

Establishment of the diagnosis by stone analysis: Carbonate apatite, brushite and other phosphates/apatites

88

192 f.

Biochemical investigations

Treatment

Metaphylaxis General aspects

Checklist

CaOx

Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)

>2.5 mmol/l

H

Exclude HPT (also refer to the chapter on CaOx stones)

H

42 f.

CaP

Calcium

Ua

Serum or plasma analysis

102 f.

Density

>1.010 g/cm3

H

Urine dilution

H

102 f.

Calcium

>8.0 mmol/24h

H

Diet

H

104 f.

Medication

H

106 f.

(also refer to the chapter on

H

54 f.

CaOx stones)

H

58 f.

Diet

H

104 f.

(chapter on struvite stones)

H

120 f.

Medication

H

106 f.

Phosphate >35 mmol/24h

H

Citrate

6.8

H

Exclude infection

H

92 f.

or

Treat infection

H

96 f.

in day profile never 1.010 g/cm3

H

Urine dilution

H

118 f.

pH

in day profile constantly >7.0

H

Exclude infection

H

112 f.

Treat infection

H

114 f.

Acidification therapy

H

122 f.

Ammonium

≥50 mmol/24h

H

Treat infection

H

114 f.

Phosphate

≥35 mmol/24h

H

Diet

H

120 f.

Medication

H

122 f.

2,8-DHA

Urine dilution

Xanthine

H

NH4Urate

0.5 mmol/24h

>4.0 mmol/24h

H

H

H

(also refer to the chapter CaOx stones) Diet

H

54 f.

Medication

H

58 f.

Diet

H

56 f.

Medication

H

64 f.

(also refer to the chapter CaOx stones)

NH4Urate

Oxalate

>8.0 mmol/24h

(also refer to the chapter Uric acid stones) Diet

H

82 f.

Medication

H

84 f.

Reference values for children see H 206 f.

127

Appendix

Calcium

138 f.

Cystine

70 ␮mol/24h

Cystine

H

2,8-DHA

Urine dilution

Xanthine

H

NH4Urate

6.5

H

Exclude infection

H

166 f.

Treat infection

H

168 f.

Diet

H

170 f.

Medication

H

170 f.

Exclude infection

H

166 f.

Urate

>4 mmol/24h

H

Ammonium

>50 mmol/24h

H

Phosphate Sodium Potassium

obviously decreased decreased decreased

(normal: 16–48 mmol/24h) (normal: 150–220 mmol/24h) (normal: 30–90 mmol/24h)

Reference values for children see H

2,8-DHA

Urine dilution

Xanthine

H

NH4Urate

380 ␮mol/l and U-urate >4 mmol/24h 100 mg/day if only U-urate >4 mmol/24h (1–3 mg/kg body weight/day in children) 300 mg/day

NH4Urate

Y

Appendix

q

meat, meat products and fish (max. 150 g/day), legumes, including soy products innards, sardines, anchovies, sprats, mackerel, skin from fish, poultry and pork

2,8-DHA

Y restrict: Y avoid:

Ua

Purine intake (see also Uric acid stones)

171

General aspects

Appendix

H

186 f.

Examination under standardized dietary conditions

H

190 f.

Analytical methods

H

192 f.

Unusual stone components/artifacts

H

198 f.

Tables 1–3: Calcium, oxalate and purine contents of foods

H

200 f.

Tables 4–6: Reference values for children

H

206 f.

Crystals in the urinary sediment (colored illustrations)

H

213 f.

CaP

Risk indices

Struvite

178 f.

Cystine

H

2,8-DHA

Absorption/loading tests

Xanthine

174 f.

NH4Urate

H

Appendix

Interventional procedures

Ua

CaOx

Appendix

173

Appendix – interventional procedures

Interventional procedures Extracorporeal shock-wave lithotripsy (SWL) During SWL treatment, disintegration is accomplished by focussing extracorporeally induced shock waves on the stone. The shock-wave sources might be electrohydraulic, electromagnetic or piezoelectric. Today most devices use electromagnetic sources. The shock waves are transmitted into the body through water, focused by a reflector or acoustic lens system, and the energy is released by reflection at the surface of the stone. The absorption of this energy is the basis for the disintegrating power. Demands on modern lithotripters: Y high efficiency (high energy density at the stone) with optimum focus (no damage to the surrounding tissues) and minimal pain (possible to complete the treatment with mild analgo-sedation) Y combined ultrasonographic and fluoroscopic imaging Indications: Y 80% of all stones: SWL mono-therapy Y 90% of all stones: SWL together with auxiliary measures Restrictions: Y spontaneous passage of fragments must be possible Y a urinary obstruction (below the stone) needs to be surgically corrected Y large staghorn stones (combination with PNL or chemolysis) Y avoidance in PH types I and II and in accompanying nephrocalcinosis Success rate: Y 60–75% of the stone patients are free of stones after 3 months; for ureteral stones the stone-free rate is above 90%. Attendant measures: Y Prevention of new aggregation by alkalization therapy, if the kind of stone indicates it (not with phosphate and ammonium urate stones) and urinary infection can definitely be excluded. In patients with residual gravel appropriate recurrence-preventive measures should be considered.

174

Loop extraction Under cytoscopic and preferably fluoroscopic control, a special ureteral catheter is inserted beyond the stone up to the renal pelvis where it is closed to form a loop (Zeiss loop catheter). In successful cases, the peristaltic activity of the ureter expels the catheter together with the stone. This passive extraction might occasionally take several days. The stone can also be extracted with a little basket, but such a procedure should only be carried out with a ureteroscope. Both Zeiss loop and basket extractions are only applicable for stones with diameters not greater than 5–6 mm.

CaP Appendix

NH4Urate

Indication: Y Distal ureteral stones which remain in position despite a size that should enable spontaneous passage.

Struvite

Complications: Y Ureter lesions or perforation up to 10%, most of which heal without complications with internal ureteral stenting. Y The development of late strictures is possible.

Cystine

Indication: Y Particularly in the case of impacted stones, but in the hands of an experienced endoscopist, the technique can be used for all ureteral stones. There is a high success rate and a low complication rate with ureteral stones. Both URS and SWL are considered as acceptable alternatives for removal of ureteral stones at all levels of the ureter.

2,8-DHA

An endoscope (semirigid or flexible), the diameter of which is adapted to the lumen of the ureter is inserted transurethrally into the ureter up to the stone under visual and radiographic control. General or regional anesthesia is usually necessary. The stone is extracted intact or disintegrated by mechanical vibration, by laser or by shock waves (electrohydraulic ultrasound). Today the most efficient technique to disintegrate ureteral stones has been reported with Holmium-YAG-laser devices.

Xanthine

Ureterorenoscopy (URS)

Ua

CaOx

General aspects

Interventional procedures

175

Appendix – interventional procedures

Percutaneous nephrolithotomy (PNL) Under regional or general anesthesia and with ultrasonographic or fluoroscopic control, the kidney is punctured and a track established through the renal parenchyma. Following dilatation to 20–30 Fr, a nephroscope can be introduced. The stone is extracted intact or disintegrated under vision by mechanical vibration or shock waves (electrohydraulic ultrasound or laser lithotripsy). The fragments can subsequently be removed with forceps or by suction. Indication: Y renal stones or occasionally proximal ureteral stones, particularly those with a diameter exceeding 20–25 mm Y in case of SWL failure Y for removal of disintegrated stones after SWL Y in combination with SWL in case of a large staghorn stone Y in case of urinary tract obstruction below the stone (infundibular stenosis, ureteral stenosis)

Retrograde intrarenal stone surgery (RIRS) Retrograde intrarenal stone surgery has been introduced for removal of stones in the renal pelvis or calices. The procedure is accomplished by a flexible ureteroscope and forceps or a laser device. The technique requires specific expertise but might be useful for removal of, for instance, stones in the caliceal diverticula as well as stone material residing in the lower calix.

176

Open surgery

Cystine

Open surgery has been abandoned almost completely due to the modern techniques SWL, URS and PNL.

CaP

Uric acid is the only salt that is very well soluble in alkaline urine. Alkalization can be attained by agents given orally or intravenously. The pH levels necessary for dissolving other kinds of stone can only be reached in vitro or in situ with irrigation through percutaneously or transurethrally inserted catheters. The risks of these methods are either local irritation of the mucosa or systemic effects if the solution is inappropriately used. Chemolitholysis is indicated for removal of residual gravel following SWL of stones caused by infection (soluble in acid solutions) and of uric acid and cystine stones (soluble in alkaline solutions). Solutions used for dissolution of uric acid stones are THAM (tris-hydroxymethyl-aminomethane; 0.3 or 0.6 mol/l). These solutions can also be used for contact dissolution of cystine stone material. In the latter case a combination with 2% acetylcysteine (0.12 mol/l in an alkaline solution, pH 8.5) might be successful. For infection stones the greatest chemolytic experience has been obtained with hemiacidrin (Renacidin쏐, 10%) or Suby’s solution.

Struvite

Chemolitholysis

Ua

CaOx

General aspects

Interventional procedures

Appendix

NH4Urate

Xanthine

2,8-DHA

Indication: Y stone removal with the simultaneous treatment of a urinary tract obstruction Y when all other options have been unsuccessful, particularly in case of acute obstructive pyelonephritis Y for removal of large staghorn stones

177

Appendix – absorption/loading tests

Absorption/loading tests [13C2]Oxalate absorption test* Hyperoxaluria is one of the most important risk factors for urinary stone formation. A small increase in oxalate easily results in exceeding the calcium oxalate formation product. Depending on the method of measurement and the definition of the upper normal limit, up to 46% of calcium oxalate stone patients exhibit hyperoxaluria. Hyperoxaluria can result from endogenous production, from excessive oxalate content of the diet or from intestinal hyperabsorption. For a causal therapy, it is important to discriminate between endogenous and absorptive hyperoxaluria. The [13C2]oxalate absorption test allows reliable determination of intestinal oxalate absorption. Because of the use of a stable isotope, this test may be repeated as often as required. Study design for the oxalate absorption test The assessment of oxalate absorption is performed under standardized conditions: 2,400 ml of liquid is distributed evenly over the day. Standard diet on the test days consists of normal foodstuffs; it contains 2,400 kcal, 93 g protein, 350 g carbohydrates, 96 g fat, 800 mg (20 mmol) calcium, 750 mg (31 mmol) magnesium and 63 mg (0.7 mmol) oxalate per day. Normal values: adults !10% (von Unruh et al., 2003; Voss et al., 2006) children !18.6% (Sikora et al., 2008)

* Von Unruh et al. (1998).

178

General aspects

Absorption/ loading tests

CaOx

[13C2]Oxalate absorption test

8 a.m.

Intake of 33.8 mg [13C2]oxalic acid as 50 mg of di-Na-salt in a capsule, soluble in gastric juice Breakfast Urine collection (+15 ml HCl, 25%) Lunch Urine collection (+15 ml HCl, 25%) Urine collection (+30 ml HCl, 25%)

9 a.m. 8 a.m. to 2 p.m. 2 p.m. 2 p.m. to 8 a.m. 8 p.m. to 8 a.m.

CaP

Day 2:

Median

Range

Median

Range

Women (n = 60) Men (n = 60) Total (n = 120)

6.80 7.75 6.85

1.7–20.0 1.8–18.5 1.7–20.0

Women (n = 60) Men (n = 60) Total (n = 120)

8.80 9.85 9.45

2.7–23.5 1.8–27.1 1.8–27.1

Girls (n = 12) Boys (n = 23) Total (n = 35)

9.6 10.6 10.4

1.9–18.6 4.3–26.2 1.9–26.2

Girls (n = 27) Boys (n = 33) Total (n = 60)

14.1 17.0 15.3

1.7–37.7 2.6–32.8 1.7–37.7

Xanthine

CaOx stone patients

NH4Urate

Healthy subjects

2,8-DHA

The quantitative determination of the [13C2]oxalate excreted in the urine fractions of Day 2 was performed by gas chromatography-mass spectroscopy. Adhering to the standardized conditions – especially the liquid supply and the supply of calcium and magnesium – the following values were determined:

Struvite

Urine collection (+30 ml HCl, 25%) Urine collection (+30 ml HCl, 25%)

Cystine

8 a.m. to 8 p.m. 8 p.m. to 8 a.m.

As borderline for an increased risk an absorption of 10% was defined. 46% of the calcium oxalate stone patients (n = 120) and 28% of the volunteers (n = 120) had an oxalate absorption of ≥10%.

179

Appendix

Day 1:

Ua

Procedure

Appendix – absorption/loading tests

Ammonium chloride loading test To demonstrate renal tubular acidosis (RTA) A urinary pH that over several days never falls below 5.8 in the day profile raises the suspicion of a latent RTA. Pathogenesis The reason for RTA is an insufficient secretion of H+-ions in the distal tubule. Also few H+-ions are available for the bicarbonate in exchange of acid anions. Instead, more chloride anions are reabsorbed, and this results in a hyperchloremic metabolic acidosis. A metabolic acidosis always causes a breakdown of apatite with increased mobilization of calcium and phosphate from the bone tissue. Thus, RTA always implies a great risk of calcium phosphate as well as of calcium oxalate stone formation. A proximal and a distal form of RTA is known. Only distal RTA is important for stone formation. The complete distal form is found in 0.5% of patients with stone disease. A limited acidification capacity without acidosis, the incomplete form of RTA, occurs in 3–5% of all stone patients.

180

Complete dRTA

Incomplete dRTA

Blood pH f Plasma HCO3– f S-Chloride d U-Calcium d U-Phosphate d U-Citrate f

Blood pH normal Plasma HCO3– normal S-Chloride normal U-Calcium d U-Phosphate normal U-Citrate f

General aspects

Absorption/ loading tests

CaOx

Ammonium chloride loading test

Ua

f pH never decreases below 5.8 in diurnal profile (exclude urease-positive infection!) f Demonstration of RTA NH4Cl loading test (see next page)

CaP

f Result pH falls to 5.4 pH does not fall below 5.4

Struvite

H no RTA

f

Cystine

Blood gas analysis f 7.35–7.45 35–45 mm Hg 80–90 mm Hg 22–26 mmol/l 8 2 mmol

2,8-DHA

: : : : :

low

normal

f

f

complete RTA

incomplete RTA

Xanthine

Plasma HCO3– and blood pH

NH4Urate

Result

pH pCO2 pO2 HCO3– BE

Appendix

normal values:

181

Appendix – absorption/loading tests

Ammonium chloride loading test The test can be carried out on an ambulatory basis. Y laboratory instruments: pH-meter – glass electrode (do not use test strips) Number of NH4Cl tablets or capsules per kg body weight (, 0.1 g NH4Cl/kg body weight) Body weight, kg

Number of tablets

Body weight, kg

Number of tablets*

40–41 42–44 45–47 48–51 52–54 55–57 58–61 62–64

12 13 14 15 16 17 18 19

65–67 68–70 71–74 75–77 78–80 81–84 85–87 88–90

20 21 22 23 24 25 26 27

* 1 tablet/capsule , 300 mg NH4Cl

182

General aspects

Absorption/ loading tests

Y

CaOx

Ammonium chloride loading test Material for the patient

9 a.m.

collect urine into first collecting bottle H drink 150 ml*

10 a.m.

collect urine into second collecting bottle H drink 150 ml*

11 a.m.

collect urine into third collecting bottle H drink 150 ml*

12 noon

collect urine into fourth collecting bottle H drink 150 ml*

1 p.m.

Struvite

breakfast + NH4Cl tablets H drink 150 ml*

Cystine

8 a.m.

CaP

Procedure

2,8-DHA

Y

Ua

NH4Cl tablets (number see opposite page) 5 small (0.5 l) collecting bottles (number the bottles!)

collect urine into fifth collecting bottle H lunch

Xanthine

* fruit tea or mineral water poor in HCO3– f Y

Immediately bring all collecting bottles to the laboratory Measure the pH value in all samples

Appendix

Y

NH4Urate

f

183

Appendix – absorption/loading tests

Calcium loading test* Hypercalciuria is the most frequent biochemical abnormality in patients with stone disease. When stone formation continues despite normal calcium intake or medical treatment, a special diagnostic work-up might be indicated. With the calcium loading test, three types of hypercalciuria can be distinguished. 1. Absorptive hypercalciuria: Excessive calcium absorption from the intestine. After exceeding the renal resorption maximum, the excessive calcium supply results in hypercalciuria: type I: independent of Ca intake type II: only with increased Ca intake 2. Renal hypercalciuria: Pathologically decreased Ca reabsorption in the distal tubules H renal leak. The renal Ca loss stimulates the production of parathyroid hormone leading to secondary hyperparathyroidism (HPT). 3. Resorptive hypercalciuria: Excessive bone reabsorption and increased intestinal Ca absorption because of primary hyperparathyroidism. If no metabolic disorder is discovered and the hypercalciuria cannot be assigned to one of these types, the disorder is called idiopathic hypercalciuria. This occurs in approximately 20% of the afflicted patients. If necessary, the test can be carried out on an ambulatory basis, but since the result highly depends on a correct handling of the samples, it is advisable to do it as an in-patient examination. The urinary excretion of substances of importance for stone formation is influenced by the diet. Since metabolic disorders may be concealed, simulated or enhanced by the individual diet, the calcium loading test should be performed under standardized dietary conditions.

* Modified according to Pak et al. (1975) and Heller et al. (2007).

184

General aspects

Absorption/ loading tests

Y

CaOx

Calcium loading test Material for the patient

Y

Ca-poor diet (no milk products) 6 p.m. last meal 8 p.m. 300 ml Ca-poor water 11 p.m. 300 ml Ca-poor water

second day:

7 a.m. 7–9.00 a.m.

Struvite

first day:

CaP

Procedure

Cystine

urination, 600 ml Ca-poor water first urine collecting period (blank value) collect urine into first collecting bottle 9 a.m. breakfast (1 sandwich, butter, jam, 2 cups of fruit tea) + 1,000 mg Ca tablets 9.00 a.m.–1 p.m. second urine collecting period (loading value) collect urine into second collecting bottle 11 a.m. 300 ml Ca-poor water

2,8-DHA

Y

Ua

2 (1 l) collecting bottles (numbered) 1.5 l Ca-poor water 1,000 mg Ca (effervescent tablets)

Analyses Calcium and creatinine are measured in first and second urine sample.

Xanthine

Interpretation of the result

normal absorptive hypercalciuria renal/resorptive hypercalciuria

blank value

loading value

up to 0.337 up to 0.337 ≥ 0.338

up to 0.563 ≥ 0.564 ≥ 0.564

NH4Urate

Divide: Ca (mmol/l)/creatinine (mmol/l)

Appendix

Y

renal hypercalciuria: cAMP increased resorptive hypercalciuria: parathyroid hormone increased k HPT

185

Appendix – risk indices

Risk indices Ion-activity product indices* Estimates of the ion-activity products of calcium oxalate and calcium phosphate The precipitation of calcium oxalate (CaOx) and calcium phosphate (CaP) is determined by the level of supersaturation with the respective salt. In order to get an idea of the level of supersaturation, information on the ion-activity product (AP) is necessary. Ion-activity products can be obtained from advanced calculation with computerized systems following analysis of a large number of urine variables. Two simplified indices are presented below by means of which approximate estimates of the ion-activity products of CaOx and CaP can be derived from the analysis of calcium, oxalate, citrate, magnesium, phosphate and pH. Moreover the volume is measured and expressed in liters. The urine variables used in the formulas should be in mmols excreted during the collection period. The APCaOx index approximately corresponds to 108 ! APCaOx and the APCaP index to 1015 ! APCaP. APCaOx and APCaP are the ion-activity products of CaOx and CaP as derived from calculations with the EQUIL2 program. Thereby fixed values were used for variables not included in the indices. The estimates of AP are valid in case the latter urine variables do not deviate too much from their fixed values. In order to avoid errors that might be due to samples with urine volumes that do not reflect the normal situation, standardized estimates have been formulated in which the 24h urine volume is set to 1.5 liters. Because it is often difficult to get a reliable assessment of pH in a long-term urine collection, the standardized APCaP index has the pH set to 7.0. In the clinical work-up an APCaOx index of !1.5–1.7 and an APCaP index of !50 should be the aim of treatment.

* Tiselius et al. (1997/2001).

186

General aspects

Risk indices

CaOx

Ion-activity products of CaOx, CaP and uric acid A ⴢ Calcium0.84 ⴢ Oxalate

APCaOx index =

Ua

Citrate0.22 ⴢ Magnesium0.12 ⴢ Volume1.03 B ⴢ Calcium1.07 ⴢ Phosphate0.70 ⴢ (pH – 4.5)6.8

APCaP index =

CaP

Citrate0.20 ⴢ Volume1.31

6

8

12

16

18

20

24

Factor A Factor B (! 10–3)

6.3 5.1

4.5 4.3

3.7 3.9

3.2 3.6

2.7 3.2

2.3 3.0

2.2 2.9

2.1 2.8

1.9 2.7

Cystine

4

Formula for estimating the ion-activity product of uric acid (APHU). APHU =

Curate ⴢ 10–pH ⴢ 0.53 (1 + 1.63 ⴢ 105 ⴢ 10–pH)

Appendix

NH4Urate

In this formula Curate is the concentration of urate. The solubility (SP) and formation (FP) products of uric acid are 2 ⴢ 10 –9 (mol/l)2 and 5 ⴢ 10 –9 (mol/l)2, respectively.

2,8-DHA

2

Xanthine

Collection period (h)

Struvite

Factors A and B are determined according to the duration of the collection period and take the following values:

187

Appendix – risk indices

Calcium oxalate crystallization risk – the BONN Risk Index (BRI) The BONN Risk Index is a successfully applied strategy in the evaluation and monitoring of the risk of calcium oxalate formation (Laube et al., 2000, 2004). This index is determined by in vitro crystallization experiments in samples of unprepared native urine. Method The determination of the BRI requires first the collection of a 24h urine without the addition of any preservatives. During the collection period, the urine should be stored at +4 ° C. When urine collection is complete, the urine’s calcium ion concentration, [Ca2+], has to be determined by a conventional calcium-selective electrode. To a well-stirred 200-ml aliquot of the 24h urine, 0.04 N ammonium oxalate solution is added step-by-step (0.25 ml/step; 1 step/min) until precipitation of calcium oxalate begins. This moment can be simply detected by an in-line laser probe or a dip-in photometer (␭ = 620 nm), as the number of suspended particles dramatically increases at this moment. The [Ca2+] measurement and the crystallization experiment have to be performed at a sample temperature of 37 ° C. From the [Ca2+] and the amount of ammonium oxalate added at the moment of detected crystallization (Ox2–), the BRI can be simply obtained by calculating BRI = [Ca2+]/(Ox2–). A BRI ; 1 l–1 is the best value to separate samples of stone formers and healthy persons, i.e., the overlap between both groups is minimized. Therefore, samples indicated by a BRI 1 1 l–1 are assumed to be ‘at risk’, whereas samples showing a BRI ^ 1 l–1 are assumed to be at ‘moderate risk’, or, samples with very low values ‘without risk’. Conclusion The particular advantage of the BRI approach is the fact that all urinary components contribute their individual effects in their native ratio to the experiment. Thus, BRI is an excellent marker of an imbalance between promoters and inhibitors at an individual level. In the case of an observed crystallization risk, the urine should be biochemically investigated in order to clarify, for example, the metabolic reasons for the enhanced risk. In comparison, the calculation of, for example, the relative supersaturation out of a biochemical data set provides a helpful strategy to evaluate an individual treatment scheme as the urinary concentrations of the major lithogenic constituents, which are the focus of therapeutic measures, are combined in a meaningful and easy-to-interpret manner.

188

General aspects

Risk indices

CaOx

Calcium oxalate crystallization risk – the BONN Risk Index (BRI) 2.5

‘high risk’

1.0

BRI = 1/l

‘low’ to ‘no risk’

0.5

CaP

1.5

Struvite

Ionized calcium (mmol/l)

2.0

Ua

Best-fit hyperbola (r = 0.88) Urines of healthy subjects, n = 157 Urines of stone formers, n = 139

BRI = 32.9/l

BRI = 0.044/l

0 Amount of titrated ammonium oxalate at the beginning of crystallization (mmol)

Mean and standard deviation of [Ca2+] and (Ox2–) values obtained from 24h urine samples of stone formers and healthy subjects. The [Ca2+] and (Ox2–) values are significantly (p ! 0.001) and highly hyperbolically (r = 0.87) related. Samples plotted on a line through the origin show the same BRI as is calculated as the quotient of [Ca2+] and (Ox2–). Circles indicate the maximum (32.9 l–1) and minimum (0.044 l–1) BRI values observed from a stone former and a healthy subject.

Appendix

NH4Urate

Short description Y Collection of a 24h urine, without preservatives (storage at +4 ° C) Y Determination of [Ca2+] with a calcium-selective electrode Y Triggering of calcium oxalate precipitation by addition of ammonium oxalate solution Y Detection of that moment with an in-line laser probe or a dip-in photometer; evaluation of (Ox 2–) Y Calculation of BRI = [Ca2+]/(Ox2–) ] BRI ` 1 l–1: sample ‘at risk’ ] BRI ^ 1 l–1: sample at ‘low risk’

2,8-DHA

Cystine

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0

Xanthine

0

189

Appendix – examination/diet

Examination under standardized dietary conditions The urine excretion of substances of importance for stone formation is influenced by the diet. Thus, metabolic disorders may be concealed, stimulated or enhanced. Since the examination under standardized dietary conditions needs an exact handling, it is necessary to do it on an in-patient basis. To clarify the metabolic situation, the patient should collect one or two 24h urine samples with their individual diet (control urine). Afterwards, one urine sample should be collected after 3 days on a standardized diet (standardized diet urine). During this period the metabolism is adapted to a steady state, so that abnormalities attributable to the diet are eliminated or at least minimized. By comparing the composition of the control urine and the standardized diet urine sample, it is possible to detect those abnormalities that depend on dietary habits. A recording of the diet should be carried out at the same time. Collection of a 24h urine Y Material for the patient: Two 2.5 l collecting bottles per day For urine preservation fill 10 ml of 5% thymol in isopropanol into each bottle. Y Collecting instructions 1. On the day of urine collection, void as usual after getting up in the morning and discard the urine. Note the time! 2. After that, all urine should be collected in the bottle (also during the night). Urinate before each defecation, so that no urine is lost. Always store the collecting bottles in a cool place! 3. At exactly the same time on the next morning, urinate and collect the urine for the last time. 4. When the collection is completed, bring the urine immediately to the laboratory.

190

General aspects

Examination/ Diet

Ua H

28 f.

H

28 f.

CaP

f 24h urine under individual diet H recording of the diet f Analyses according to the quality standard

CaOx

Control urine

Standardized diet urine

Struvite

f Three days standardized diet

f Analyses according to the quality standard

Cystine

f On the fourth day, collection of a 24h urine sample under the standardized diet

2,8-DHA

Interpretation of the results

184 f.

H Ammonium chloride loading test

H

180 f.

H [13C2]Oxalate absorption test

H

178 f.

H BONN Risk Index (BRI)

H

188 f.

NH4Urate

H

Appendix

H Calcium loading test

Xanthine

1. Normalization of abnormal urine variables under the standardized dietary conditions: H inappropriate dietary habits (arrange a contact with a dietitian) 2. No change of abnormal urine variables under the standardized dietary conditions: H indicates metabolic disorders! (further clarification by loading tests)

191

Appendix – analytical methods

Analytical methods Analysis of urinary stones Based on the guidelines for treatment and recurrence prevention of urolithiasis, the first measure after stone removal is analysis of the concrements (Straub et al., 2005; Tiselius et al., 2008). A specific diagnostic evaluation as well as successful prevention of recurrent stones should always be based on a valuable stone analysis. Different methods have been used for stone analysis, however, only a few meet the criteria for use in a routine laboratory and its accompanying quality control. Hence, only the last two of the following methods are recommended for stone analysis: – Chemical analysis – Microscopy – Scanning electron microscopy – X-ray diffraction – Infrared spectroscopy The chemical methods show a significant error rate and are not able to distinguish between different mineralogical phases. The exact microscopic examination of stone grain specimens requires very highly qualified laboratory personnel. For scanning electron microscopy very expensive equipment is required and the analysis is time-consuming. Hence, this method needs further research efforts. On the basis of the crystalline structure of the stone substances, a very exact stone analysis is obtained by X-ray diffraction (Hesse et al., 2005; Euler et al., 2008). However, the equipment is also very expensive and substances without a crystalline structure, such as proteins and amorphous phosphates, are not ascertained. Infrared spectroscopy is the most widely used method for stone analysis. Based on the different molecular structures of the stone substances, typical absorption spectra in the infrared spectrum range result, which correspond to a finger print of each single substance. More than two thirds of all urinary stones are composed of more than one substance, which can clearly be distinguished with this method (Hesse et al., 2005). Infrared spectroscopy equipment with the latest technology (FTIR-ATR) only needs a very tiny amount of a substance for analysis (!1 mg) and enables very fast and accurate analysis. For evaluation, reference spectra or a computed spectra library can be applied (Hesse and Sanders, 1988). Because of the necessary equipment stone analysis should be performed in qualified centers where adequate documentation for scientific evaluation can also be carried out (see figure on p. 193).

192

Urinary Stone Analysis Center Bonn

Patient name and date of birth (address)

CaOx

General aspects

Analytical methods

harnsteinanalysezentrum bonn

Ua

Prof. Dr. rer. nat. A. Hesse * Dr. med. R. M. Schaefer Dr. med. Ph. Lossin * Prof. Dr. med. D. Bach

Theaterplatz 14, D - 53177 Bonn - Bad Godesberg Phone: +49 228 95737 16 * Fax: +49 228 95737 21

CaP

Sender/Stamp/Date

no

Stone Lab

Sample received on:

Sample-No.:

Date of stone passage dd.mm.yy

Result in weight-%

Stone removal

Whewellite Weddellite Carbonatapatite (Dahllite) Brushite Struvite Uric acid (Uricit) Uric acid dihydrate Ammonium urate Cystine

spontaneous

operative

conservative

chemolitholytic

instrumental

lithotryptic

kidney right

kidney left

ureter right

ureter left

bladder

urethra

yes

no

Localization

Core-Shell-Analysis *Additional comments:

No. of stones/ gravel

overall

Stone colour white yellow black brown

=1 =2 =3 =4

core

shell

Cystine

other*

yes

2,8-DHA

urinary stone

Recurrence:

Stone surface green = 5 beige = 6 grey = 7

Xanthine

Type of stone:

Struvite

To fill in by the SENDER:

rough =1 smooth = 2 bizarre = 3

stone analysis by infrared spectroscopy

Appendix

stone analysis by infrared spectroscopy

NH4Urate

Date/Signature:

193

Appendix – analytical methods

In addition to routine analytic methods (Ca, Mg, uric acid, creatinine), some special methods are necessary. In the following, the most important of these methods are described.

Oxalate Method 1: Principle:

Enzymatic with oxalate oxidase (Sigma-Kit) Transformation of oxalate to carbon dioxide and hydrogen peroxide by oxalate oxidase. In the presence of peroxidase, hydrogen peroxide reacts with 3-methyl-2-benzothiozolinon and 3-dimethylamino benzoic acid forming an indamine dye-stuff. The intensity of the color as determined photometrically at 590 nm is directly proportional to the concentration of oxalate.

Method 2: Principle:

Ion chromatographic After separation from other constituents, oxalate is quantified on an anion exchange column by means of a conductivity detector. Robertson, W.G., Scurr, D.S., Smith, A., Orwell, R.L. (1982) The determination of oxalate in urine and urinary calculi by a new ion-chromatographic technique. Clin. Chim. Acta 126: 91–99

Literature:

Method 3: Principle:

Literature:

194

HPLC-enzyme-reactor An in-line enzyme reactor containing immobilized oxalate oxidase which converts oxalate to hydrogen peroxide is used. Hydrogen peroxide is analyzed with high sensitivity by amperometric detection. The determination limit for the method is 1.5 ␮mol/l, the mean recovery in urine is 102%. Hönow, R., Bongartz, D., Hesse, A. (1997) An improved HPLC-enzyme-reactor method for the determination of oxalic acid in complex matrices. Clin. Chim. Acta 261: 131–139

Urine and plasma glycolate, oxalate, sulfate, phosphate and citrate

Literature:

CaP

Inorganic phosphate

Literature:

Phosphate-molybdate reaction Reaction of phosphate with molybdate by forming molybdenum blue. The color intensity is proportional to the concentration of phosphate and is determined photometrically at 578 nm. Anner, B., Moosmayer, M. (1975) Rapid determination of inorganic phosphate in biological systems by highly sensitive photometric method. Analyt. Biochem. 65: 305

Appendix

Method: Principle:

Struvite

Enzymatic with citrate lyase Transformation of citrate by citrate lyase to oxaloacetic acid and acetate. In the presence of malate dehydrogenase, oxaloacetic acid and its decarboxylation product pyruvate are reduced to L-malate and L-lactate by NADH+H+. The required amount of NADH which is proportional to the concentration of citrate is determined photometrically at 340 nm. Moellering, H., Gruber, W. (1966) Determination of citrate with citrate lyase. Anal. Biochem. 17: 369–376 Welshman, S.G., McCambridge, H. (1973) The estimation of citrate in serum and urine using a citrate lyase technique. Clin. Chim. Acta 46: 243–246

Cystine

Method: Principle:

2,8-DHA

Citric acid

Xanthine

Literature:

Combined ion-chromatographic method Urine and plasma glycolate, oxalate, sulfate, phosphate and citrate concentration is simultaneously measured with an ion-chromatography system. Hoppe, B., Kemper, M.J., Hvizd, M.G., Sailer, D.E., Langman, C.B. (1998) Simultaneous determination of oxalate, citrate and sulfate in children’s plasma with ionchromatography. Kidney Int. 53: 1348–1352

NH4Urate

Method: Principle:

Ua

CaOx

General aspects

Analytical methods

195

Appendix – analytical methods

Ammonium Method: Principle: Literature:

Ion-selective electrode Determination of ammonium in strong alkaline milieu as ammonia. Classen, A., Weber, A., Miersch, W., Liappis, N., Hesse, A. (1987) Measurement and importance of ammonium concentration in urine of patients with urolithiasis. (Messung und Bedeutung der Ammoniumkonzentration im Harn bei Urolithiasis-Patienten.) Lab. Med. 11(4): 165–166

Xanthine, 2,8-Dihydroxyadenine Method: Principle: Literature:

High performance liquid chromatography (HPLC) Separation of purines, e.g. xanthine and 2,8-DHA, on C18-phase with sodium-phosphate-buffer. Hesse, A., Thon, A., Classen, A., Birwé, H. (1988) Diagnostic and therapy-control of inborn metabolic disorders by high performance liquid chromatography: 2,8-Dihydroxyadeninuria, Xanthinuria. Chromatographia 25: 205–209

Cystine/Cysteine Method 1: Principle: Literature:

Method 2:

Literature:

196

Amino acid analyzer Separation on ion exchange columns, detection with ninhydrine reaction. H only the total sum of cystine and cysteine is assessed. Liappis, N. (1973) Sex specific differences of urinary free amino acids in adults. (Geschlechtsspezifische Unterschiede der freien Aminosäuren im Harn von Erwachsenen.) Z. Clin. Chem. Clin. Biochem. 11(7): 297–285 High performance liquid chromatography H determination of both cystine and cysteine is possible; important to follow the treatment of patients with cystinuria. Birwé, H., Hesse, A. (1991) High-performance liquid chromatographic determination of urinary cysteine and cystine. Clin. Chim. Acta 199: 33–42

Appendix – unusual stones/artifacts

Unusual stone components/artifacts Drug stones During therapeutic measures, urinary stones may form as a result of the transformation of certain active drug components to insoluble metabolites. Y Chemotherapeutic agents Sulfamethoxazole and sulfadiazine are transformed into the poorly soluble metabolites N4 -actetyl-sulfamethoxazole or N4 -acetyl-sulfadiazine, respectively. These constituents have been found as the only stone components. Indinavir sulfate is a protease inhibitor of human immunodeficiency virus (HIV). Based on clinical trials the incidence of indinavir-associated urolithiasis is 3–14%. Y Analgesics Mefenamic acid is excreted in urine in glucoronic form. Concrements with 20% of mefenamic acid have been described. Y Antacids Antacids made of magnesium trisilicates may lead to the development of SiO2-containing concrements after long-time use.

Inappropriate handling of sample material Improper storage of stone material can result in its transformation to other compounds. Newberyite: (Magnesium-hydrogenphosphate-trihydrate) may form if struvite stones are kept in formalin. Dittmarite: (Magnesium-ammonium-phosphate-monohydrate) may form during the ageing process of struvite. Protein: Coagulum, fibrin

198

CaOx

General aspects

Unusual stones/ Artifacts

Artifacts

CaP Struvite

Paraffin, wax, material of suppositories Grain of seed Suture material, gauze Lead bullets Origin of artifacts Y unintentional material mix-up: e.g. instead of a dropped urinary stone, a piece of mud or plaster has been picked up. Y intentional artifacts: material brought along by the patient themselves (may be a completely different material than listed in the table above) Important: For identification and correct classification of unusual urinary stones or of artifacts, an exact stone analysis with physical methods (infrared spectroscopy, X-ray diffraction) is absolutely necessary. With chemical analyses, unusual stone components such as pharmaceutical agents and their metabolites might be impossible to discover.

Appendix

* Cave: Regular intake of silicate-containing drugs (see Drug stones, p. 198) may lead to the formation of silicate stones in vivo. Likewise calcite stones may form at high urinary pH values (18.0). In animals, silicate- and calcium carbonate-containing concrements often occur in specific species (Hesse and Neiger, 2009).

Cystine

Tridymite (quartz) – Gypsum Calcite, aragonite, vaterit

2,8-DHA

Silicon dioxide* Cholesterin (biliary calculus) Calciumsulfate-dihydrate Calcium carbonate*

Xanthine

Mineralogical name

NH4Urate

Chemical name

Ua

Relatively often, the following compounds are found as artifacts:

199

Appendix – tables

Tables Table 1: Calcium content of foods (mean, mg/100 g) I. Up to 150 mg Ca/100 g Butter Cream Sour cream Curd, cottage cheese Milk Yoghurt Ice cream

20 90 100 90 120 120 150

II. 150–400 mg Ca/100 g Evaporated milk Camembert/brie 60–70% fat 45% fat

250 300 400

III. Over 400 mg Ca/100 g Ewe’s cheese Chester, Edam, Gouda, Tilsit Hard cheese Emmental Parmesan Parmesello Powdered milk Milk protein concentrate 60% protein 80% protein Conversion factor (calcium): mg ! 0.02495 = mmol

200

600 800 1,200 1,300 1,600 900 1,900 1,400

General aspects

Tables

Oxalate content

CaOx

Table 2: Oxalate content of foods (mean, mg/100 g)* Sample

Soluble

Total

Ua

mg/100 g

6.8 2.6 16.2 54.2 13.9 36.9 1.4

Struvite

6.8 0.9 15.7 1.9 1.5 16.3 1.1

Cystine

3.5 6.8 6.8 29.2 295.4 2.4 72.1 20.5 21.6 27.0 1.7 23.0 3.1 7.5 8.5 1.8 4.9 18.9 19.8 0.3

2,8-DHA

1.8 1.9 0.7 0.9 138.9 1.5 7.1 3.3 3.2 3.1 0.6 2.4 0.5 0.5 0.3 0.2 0.9 3.4 4.9 0.3

Xanthine

Apple, Granny Smith, raw Apricot, raw Banana, raw Bramble, raw Carambola, raw Cherry, sweet, raw Elderberry, black, raw Fig, raw Gooseberry, red, raw Gooseberry, green, raw Grape, green, raw Kiwi fruit, raw Lemon, raw Lime, raw Mandarin, raw Orange, raw Pineapple, preserved, without sugar Raspberry, raw Red current, raw, red Watermelon, raw

CaP

I. Fruits

Appendix

Artichoke, boiled Asparagus, boiled Aubergine, raw Bean, preserved, white Bean, kidney, red Beet root, boiled Broccoli, boiled

NH4Urate

II. Vegetables and salads

* Hönow, R. and Hesse, A. (2002); Siener et al. (2006a, b).

201

Appendix – tables

Sample

Soluble

Total mg/100 g

II. Vegetables and salads Carrot, raw Leek, raw Lentil, dried Linseed, ground coarsely Mangold, raw Olive, green, canned Olive, black, canned Potato, boiled Potato, chips Radish, raw, red Rhubarb, raw Rice, raw Spinach, raw Tomato, raw Tomato ketchup

9.0 9.4 1.9 7.2 327 1.2 1.6 12.8 45.8 1.4 380 12.8 1,029 3.6 3.3

17.8 17.0 13.3 7.7 874 45.7 13.9 24.3 47.0 1.7 1,235 12.8 1,959 8.5 7.7

III. Beverages Apple juice, 100% Carrot juice, 100% Cherry juice, 100% Cranberry juice, 100% Grapefruit juice, 100% Grape juice, red, 100% Lemon juice, 100% Orange juice, 100% Pineapple juice, 100% Tomato juice, salted, filtered Black tea, 1.75 g/200 ml, 5 min, 70°C Camomile tea, 1.5 g/200 ml, 5 min, 70°C Fennel tea, 3.5 g/200 ml, 5 min, 70°C Fruit tea, 3 g/200 ml, 5 min, 70°C

202

0.19 2.8 1.17 0.4 0.12 1.2 0.3 0.1 1.4 3.6 4.0 0.3 1.3 0.6

0.9 4.6 1.17 0.4 0.12 2.1 0.6 0.2 1.4 4.1 – – – –

General aspects

Tables

Oxalate content Soluble

Total

CaOx

Sample

mg/100 g

6.3 0.6 1.0 – – 0.6 0.4

– – 1.1 567 0.05 – 0.4

60.0 76 90.8 2.4 26.8 41.2 22.3

159 136 623 28.5 55.7 85.2 182

89.9 82.2 26.0 35.9 36.8 10.5 123 11.8 7.1 131.2

383.3 143.0 90.8 167.4 56.5 26.4 3,800 24.5 37.9 457.4

CaP

Green tea, 1.75 g/200 ml, 5 min, 70°C Peppermint tea, 1.25 g/200 ml, 5 min, 70°C Beer Cacao powder, oil removed Coke, Coca-Cola Coffee, 30 g/l Milk, 1.5% fat

Ua

III. Beverages

Cystine 2,8-DHA

Dill, raw Parsley, leaves Pepper, black, ground Pepper, white, ground Peppermint, leaves Sage, leaves Thyme, dried

Struvite

IV. Spices and herbs

NH4Urate Appendix

Almond, slices Buckwheat Crisp bread Hazel nut, chopped Pistachio, chopped Rolled oats, whole corn Sesame seed, dried Sunflower seed, peeled Wholemeal bar, with chocolate Wheat bran

Xanthine

V. Nuts and cereals

Conversion factor (oxalate): mg ! 0.01111 = mmol

203

Appendix – tables

Table 3: Purine content of foods (mg uric acid/100 g) Over 150 mg uric acid/100 g Cereals Buckwheat

150

Pulses Peas, green Lentils, dried Soy beans

150 200 220

Meat Veal Beef, fillet Pork, fillet Game

150 150 170 150–170

Poultry Chicken roasted Leg Skin

160 300

Innards Veal

Beef Pork

Kidney Liver Neck sweet bread (thymus gland) Liver Kidney Liver

Wolfram, G. (2006)

204

210 260 900 360 255 300

General aspects

Tables

CaOx

Purine content

190 320 200 260 170 180 350

CaP

Fish Herring, without skin with skin Trout, with skin Anchovies Salmon Tuna in oil Sardines in oil

Ua

Over 150 mg uric acid/100 g

Appendix

NH4Urate

Xanthine

2,8-DHA

Cystine

Struvite

Conversion factor (uric acid): mg ! 0.0059485 = mmol

205

Appendix – tables

Table 4: Reference values for urinary excretion and molar creatinine ratios (solute:creatinine) of specific urinary lithogenic and stone inhibitory substances in children Parameter Age

Ratio solute:creatinine

Urinary excretion

Calcium 7 years

mol/mol