Management of Acute Kidney Problems

Management of Acute Kidney Problems

Achim Jörres Claudio Ronco John A. Kellum (Eds.)

Management of Acute Kidney Problems

Achim Jörres, MD Professor of Medicine Deputy Director Chief, Department of Nephrology and Medical Intensive Care Charité University Hospital Campus Virchow-Klinikum Augustenburger Platz 1 13353 Berlin Germany [email protected]

John A. Kellum Jr., MD, FACP, FCCM Professor of Critical Care Medicine, University of Pittsburgh School of Medicine Department Critical Care Medicine 3550 Terrace Street, 606 Scaife Hall Pittsburgh, PA 15261 USA [email protected]

Claudio Ronco, MD St. Bortolo Hospital Director, Department of Nephrology Dialysis and Transplantation Viale Rodolfi, 16 36100 Vicenza Italy [email protected]

ISBN: 978-3-540-69413-7     e-ISBN: 978-3-540-69441-0 DOI: 10.1007/978-3-540-69441-0 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2009926256 © Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is ­concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant ­protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: Frido Steinen-Broo, eStudio Calamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

To Dinah, Marc, and Ann-Kristin; you are always at the center of my heart and my thoughts. Achim To my wife, Paola, who gives true meaning to all my efforts. Claudio To my sister, Janine, whose tireless care at the bedside of critically ill patients has made a world of difference and reminds me that all intensive care nurses are our great unsung heroes. John

Preface

Acute kidney disease (from injury to failure) is an important clinical area particularly in the intensive care unit setting. As many as two thirds of critically ill patients experience an episode of acute kidney injury during the course of their illness, and about 5% of patients admitted to an intensive care unit will eventually require renal replacement therapy. In these patients, in-hospital mortality is extremely high, exceeding 50%, with acute kidney failure constituting a significant independent risk factor for death. As intensive care practitioners are often the initial or even sole providers of care to seriously ill patients at risk for acute kidney injury, it is their responsibility to ensure that adequate measures to prevent its occurrence are taken. Moreover, it is their task to diagnose and evaluate incipient acute kidney disease, to initiate optimal supportive care, and where possible, definitive treatment of this disorder. It is the editors’ hope that this book will provide a reference for clinicians practicing in the intensive care unit, to help guide their care of patients with acute kidney disease. In addition, we would like to address clinicians from many other fields who are regularly involved in the care of patients at risk for acute kidney injury. To that end we have brought together a group of international authors to cover the most recent information on definition, epidemiology, pathophysiology, and clinical causes of acute kidney injury and failure. Their understanding is a fundamental prerequisite for the prevention of this disorder. Moreover, the earlier parts of this book present differential diagnostic approaches for patients with acute kidney disease and a detailed outline of important measures for its clinical management and the prevention of complications. The subsequent parts are dedicated to the diagnosis and management of acute kidney disease in specific patient groups and in particular disorders. Finally, the various key aspects related to the adequate delivery of acute renal replacement therapy are detailed in the final parts of the book. The chapters included in this book are derived from clinical experience and report the evidence for current clinical practice extracted from consensus statements or systematic analyses of the literature. We are truly indebted to the authors for their timely and expert contributions. We very much hope that the present book will be a tool for clinicians and a reference for investigators, students, and fellows. The enormous effort of putting together such compilation of information and references should stimulate all colleagues to use this book as a starting point for good clinical practice that will certainly be enriched day by day in the coming

vii

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Preface

months and years, by the expanding body of literature that the field of acute kidney disease requires and also as a resource for continuous progress toward better care for our patients. Berlin, Germany Vicenza, Italy Pittsburgh, Pennsylvania, USA

Achim Jörres Claudio Ronco John A. Kellum

Contents

Part I  Definition and Classification of Acute Kidney Failure 1.1

Definition and Classification of Acute Kidney Injury . . . . . . . . . . . . . Vijay Karajala and John A. Kellum

3

1.1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2 What Is Acute Kidney Injury? Current Controversies . . . . . . . . 1.1.3 Renal “Failure” or Renal “Success” . . . . . . . . . . . . . . . . . . . . . . 1.1.4 Oliguria and Anuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.5 Prerenal Azotemia and Acute Tubular Necrosis . . . . . . . . . . . . . 1.1.6 Limitations of Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.7 Renal Failure Defined by RIFLE Criteria . . . . . . . . . . . . . . . . . . 1.1.8 The Concept of Acute Kidney Injury: A Paradigm Shift . . . . . . 1.1.9 Validation Studies Using RIFLE . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.10 Conceptual Development and Future Directions . . . . . . . . . . . . 1.1.11 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 3 4 4 4 5 5 6 6 8 8 8

Part II  Overview of Pathophysiology, Etiology and Epidemiology 2.1

2.2

Mechanisms of Acute Kidney Injury and Repair . . . . . . . . . . . . . . . . Joseph V. Bonventre

13

2.1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2 Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4 Paracrine Effects of Bone Marrow–Derived Stem Cells . . . . . . 2.1.5 Other Mechanisms to Limit or Stop Inflammation . . . . . . . . . . . 2.1.6 Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13 14 15 17 17 18 18 19

Uremic Toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Griet Glorieux, Wim Van Biesen, Norbert Lameire, and Raymond Vanholder

21

2.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2 Interfering Factors Due to Renal Replacement Therapy . . . . . . 2.2.3 Biochemical Alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21 21 22

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2.2.4 2.2.5 2.2.6 2.2.7

2.3

2.4

Factors Responsible for the Uremic Syndrome . . . . . . . . . . . . . Major Low-Molecular-Weight Uremic Retention Products . . . . Middle Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Influencing Plasma Concentration of Uremic Solutes . . . . . . . . . . . . . . . . . . . . . . . . 2.2.8 Conclusions and Therapeutic Implications . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23 24 27

Prerenal Acute Kidney Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eric A. J. Hoste

33

2.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3 Causes of Prerenal Acute Kidney Failure . . . . . . . . . . . . . . . . . . 2.3.4 Diagnosis of Prerenal Acute Kidney Injury . . . . . . . . . . . . . . . . 2.3.5 Epidemiology of Prerenal Acute Kidney Failure . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33 34 34 35 35 36

Intrinsic Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Norbert Lameire

39

Epidemiology of AKI in the ICU Focusing on Non-ATN Etiologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2 Clinical Evaluation of the Critically Ill Patient with AKI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.3 Summary of General Therapeutic Principles of AKI in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28 28 28

2.4.1

2.5

2.6

40 41 50 51

Urinary Tract Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angela D’Angelo and Dorella Del Prete

53

2.5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2 Causes of Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.3 Renal Damage Induced by Urinary Tract Obstructions . . . . . . . 2.5.4 Clinical Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.5 Diagnostic Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.6 Instrumental Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.7 Radiologic Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.8 Renal Function After the Removal of an Obstruction . . . . . . . . 2.5.9 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

53 54 56 57 58 58 59 60 60 61

Epidemiology of Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . Tariq Ali and Paul Roderick

63

2.6.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2 Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.3 Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63 64 67 71 71

Contents

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2.7

Economic Impact of Acute Kidney Failure . . . . . . . . . . . . . . . . . . . . . Joseph F. Dasta and Sandra L. Kane-Gill

75

2.7.1 2.7.2

75

Quantifying Costs in the Intensive Care Unit . . . . . . . . . . . . . . . Overview of Studies Reporting Costs Associated with Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . 2.7.3 Clinical Studies of Costs Associated with AKI . . . . . . . . . . . . . 2.7.4 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75 78 80 80

Part III  Diagnostic Evaluation and Procedures 3.1

3.2

Clinical and Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert J. Anderson

83

Objectives to Understand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2 Presenting Manifestations of AKI . . . . . . . . . . . . . . . . . . . . . . . 3.1.3 Causes of AKI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4 Evaluation of AKI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83 83 83 86 87 91 91

Kidney Function Tests and Urinalysis . . . . . . . . . . . . . . . . . . . . . . . . . Sean M. Bagshaw

95

Objectives to Understand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 3.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 3.2.2 Overview of Kidney Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 3.2.3 Assessment of Kidney Function . . . . . . . . . . . . . . . . . . . . . . . . . 96 3.2.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 3.3

Renal Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Vicki E. Noble, Andrew Liteplo, and David F. M. Brown 3.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2 Ultrasound Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.4 Scanning Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.5 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.4

109 110 110 111 111 115 116

Management of Acute Kidney Problems: Indications for Renal Biopsy in Acute Renal Disease . . . . . . . . . . . . . 117 Alan D. Salama 3.4.1 3.4.2 3.4.3 3.4.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal Biopsy in Acute Renal Failure . . . . . . . . . . . . . . . . . . . . . Complications of Biopsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biopsy Processing and Adequacy . . . . . . . . . . . . . . . . . . . . . . . .

117 119 120 121

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3.4.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 3.4.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Part IV  Prevention and Conservative Therapy of Acute Kidney Failure 4.1

Volume Resuscitation and Management . . . . . . . . . . . . . . . . . . . . . . . . 125 Jean-Louis Vincent and Barbara Ceradini 4.1.1 4.1.2 4.1.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk of Hypervolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Potential Errors in Fluid Management in the Patient with, or at Risk of, Acute Renal Failure . . . . . . . . . . 4.1.4 How to Assess Fluid Status? . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5 Types of Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.7 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2

131 134 135 137 138 138

Acid–Base Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 John A. Kellum 4.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2 The Henderson–Hasselbalch Equation . . . . . . . . . . . . . . . . . . . . 4.3.3 Water and Physical Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.4 Strong Ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.5 Regulation of Plasma Strong Ion Difference . . . . . . . . . . . . . . . 4.3.6 Pathophysiology of Strong Ion Imbalance . . . . . . . . . . . . . . . . . 4.3.7 Weak Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.8 Unmeasured Anions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.4

126 127 128 129 129 130

Management of Electrolyte Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 131 Michael Oppert 4.2.1 Sodium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Potassium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3 Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.4 Phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.3

125 125

139 139 140 141 141 142 143 144 145 145

Monitoring and Management of Systemic Hemodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Non Wajanaponsan and Michael R. Pinsky 4.4.1 4.4.2 4.4.3 4.4.4

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal Hemodynamic Management Perspective . . . . . . . . . . . . . Renal Perfusion Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemodynamic Management and Resuscitation . . . . . . . . . . . . .

147 147 147 148

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4.4.5 4.4.6 4.4.7 4.4.8

Evaluation for Preload Responsiveness . . . . . . . . . . . . . . . . . . . Vasopressor Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inotropic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Improve Patient Outcome with Optimizing Oxygen Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5

150 150 152 153 153 153

Treatment of Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Annette Beyea and Howard L. Corwin References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

4.6

Metabolic Alterations and Nutrition in AKI . . . . . . . . . . . . . . . . . . . . 161 Wilfred Druml 4.6.1 4.6.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Metabolic Environment and Nutritional Requirements in Patients with AKI . . . . . . . . . . . . . . . . . . . . . . 4.6.3 Energy Metabolism and Energy Requirements . . . . . . . . . . . . . 4.6.4 Carbohydrate Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.5 Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.6 Protein and Amino Acid Metabolism/Protein Requirements . . . . . . . . . . . . . . . . . . . . . . . 4.6.7 Metabolism and Requirements of Micronutrients . . . . . . . . . . . 4.6.8 Electrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.9 Metabolic Impact of Renal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.10 Nutrient Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.11 Enteral Nutrition (Tube Feeding) . . . . . . . . . . . . . . . . . . . . . . . . 4.6.12 Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.13 Complications of Nutritional Support . . . . . . . . . . . . . . . . . . . . . 4.6.14 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7

161 162 162 163 163 163 164 164 164 165 165 166 167 167 168

Glucose, Insulin, and the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Miet Schetz, Ilse Vanhorebeek, Jan Gunst, and Greet Van den Berghe 4.7.1 4.7.2 4.7.3 4.7.4 4.7.5 4.7.6 4.7.7

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyperglycemia and Insulin Resistance in the Critically Ill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carbohydrate Metabolism and Transport in the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetic Nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adverse Effects of Acute Hyperglycemia in the Critically Ill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tight Glycemic Control with Intensive Insulin Therapy in Acute Illness . . . . . . . . . . . . . . . . . . . . . . . . . Tight Glycemic Control with Intensive Insulin Therapy and Acute Kidney Injury . . . . . . . . . . . . . . . . .

169 169 169 170 171 171 172

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4.7.8

Possible Mechanisms of Renoprotection by TGC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 4.7.9 Conclusion (Take Home Message) . . . . . . . . . . . . . . . . . . . . . . . 176 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 4.8

Bleeding and Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Herwig Gerlach and Susanne Toussaint 4.8.1 4.8.2

Basics of Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Vascular Endothelium as Central Regulator of Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3 Physiologic Anticoagulation and Fibrinolysis . . . . . . . . . . . . . . 4.8.4 Bleeding Disorders in Acute Care Patients . . . . . . . . . . . . . . . . . 4.8.5 Thromboembolic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.6 Sepsis-Associated Hemostatic Disorders . . . . . . . . . . . . . . . . . . 4.8.7 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9

181 185 187 189 190 192 195 195

Neurological Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Raf Brouns and Peter Paul De Deyn 4.9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2 Central Nervous System Complications . . . . . . . . . . . . . . . . . . . 4.9.3 Peripheral Nervous System Complications . . . . . . . . . . . . . . . . 4.9.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

197 198 203 204 204

4.10 Gastrointestinal Complications of Acute Kidney Injury . . . . . . . . . . 209 Susie Q. Lew, Marie L. Borum, and Todd S. Ing 4.10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10.2 Uremic Fetor, Dysgeusia, Anorexia, Dyspepsia, Hiccups, Nausea, and Vomiting . . . . . . . . . . . . . . . . 4.10.3 Stomatitis and Salivary Gland Inflammation . . . . . . . . . . . . . . . 4.10.4 Uremic Lesions in the Alimentary Tract . . . . . . . . . . . . . . . . . . . 4.10.5 Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10.6 Upper Gastrointestinal Hemorrhage . . . . . . . . . . . . . . . . . . . . . . 4.10.7 Diseases of the Small Intestines . . . . . . . . . . . . . . . . . . . . . . . . . 4.10.8 Diseases of the Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10.9 Pancreatic Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10.10 Hepatic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10.11 Cholecystitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10.12 Acid–Base and Electrolyte Abnormalities . . . . . . . . . . . . . . . . . 4.10.13 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

209 209 211 211 212 212 215 215 216 217 217 217 218 218

4.11 Cardiovascular Complications of Acute Kidney Injury . . . . . . . . . . . 221 W. Van Biesen and R. Vanholder 4.11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 4.11.2 Differential Diagnosis of Acute Cardiorenal Dysfunction . . . . . 221

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4.11.3 Cardiovascular Complications of Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 4.11.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 4.12 Acute Kidney Injury: Specific Interventions and Drugs . . . . . . . . . . . 229 John R. Prowle and Rinaldo Bellomo 4.12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.12.2 Contrast-Induced Nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . 4.12.3 Nephrotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.12.4 Specific Interventions for AKI . . . . . . . . . . . . . . . . . . . . . . . . . . 4.12.5 Secondary Prevention and Treatment of AKI . . . . . . . . . . . . . . . 4.12.6 Specific Situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.12.7 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

229 230 230 230 233 235 236 236

4.13 Drug Dosing in Acute Kidney Injury and  During Renal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 241 A. Mary Vilay and Bruce A. Mueller 4.13.1 Drug Dosing in Acute Kidney Injury and During Renal Replacement Therapy . . . . . . . . . . . . . . . . . . 241 4.13.2 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 4.14 Anesthesia in Patients with Kidney Failure . . . . . . . . . . . . . . . . . . . . . 253 Dinah Jörres and Achim Jörres 4.14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.14.2 Preoperative Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.14.3 Postoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.14.4 Prevention of Perioperative Acute Kidney Failure . . . . . . . . . . . 4.14.5 Management of High-Risk Patients . . . . . . . . . . . . . . . . . . . . . . 4.14.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

253 253 256 256 256 257 257

Part V  Long-Term Outcome of Acute Kidney Injury 5.1

Long-Term Outcome of Acute Kidney Injury . . . . . . . . . . . . . . . . . . . 261 Michael Joannidis and Philipp G.H. Metnitz 5.1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2 ICU and Hospital Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3 Factors Predicting Hospital Survival . . . . . . . . . . . . . . . . . . . . . 5.1.4 Long-Term Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.5 Recovery of Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.6 Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

261 261 262 262 264 264 265 265

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Part VI  Diagnosis and Management of Specific Disorders 6.1

Acute Kidney Injury in Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 Robert W. Schrier, Shweta Bansal, and Wei Wang 6.1.1.

Hemodynamics and Hormones During Sepsis and Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. Sodium and Water Balance During Sepsis . . . . . . . . . . . . . . . . . 6.1.3. Early Renal Vasoconstriction in Septic AKI . . . . . . . . . . . . . . . . 6.1.4. Role of Oxygen Radicals and Cytokines in Renal Tubular and Vascular Injury During Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.5. Prospective Randomized Clinical Studies in Sepsis . . . . . . . . . . 6.1.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brief Review of Renal Neurohormonal Regulation . . . . . . . . . . Clinical Aspects in the Management of AHFS and Cardiogenic Shock . . . . . . . . . . . . . . . . . . . . . . . . 6.2.4 Mechanical Circulatory Support in Cardiogenic Shock and its Effects on Renal Function . . . . . . . . 6.2.5 Role of Continuous Renal Replacement Therapy in Cardiogenic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

281 281 282 283 284 284 284

Acute Kidney Problems in Congestive Heart Failure . . . . . . . . . . . . . 287 Andrew Davenport 6.3.1 6.3.2 6.3.3 6.3.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congestive Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiorenal Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Deterioration in Renal Function During Management of Acute Decompensated Heart Failure . . . . . . . . 6.3.5 Risk of Rhabdomyolysis with Statins . . . . . . . . . . . . . . . . . . . . . 6.3.6 Cholesterol Embolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.7 Radiocontrast Nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.8 Special Circumstances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.9 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4

274 275 278 278

Kidney in Acute Heart Failure and Cardiogenic Shock . . . . . . . . . . . 281 Vijay Karajala and John A. Kellum 6.2.1 6.2.2 6.2.3

6.3

271 272 273

287 288 289 289 291 292 292 293 294 295

Hepatorenal Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Dietrich Hasper and Thomas Berg 6.4.1 6.4.2

Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

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6.4.3 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4.5 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5

Malignant Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Bert-Jan H. van den Born and Gert A. van Montfrans 6.5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.2 Histopathologic Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.3 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.4 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.5 Clinical Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.6 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.7 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.6

305 306 306 308 309 310 314 314

Toxic Nephropathy Due to Drugs and Poisons . . . . . . . . . . . . . . . . . . . 317 Pieter Evenepoel 6.6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.2 Pathophysiologic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.3 Common Nephrotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6.5 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.7

298 299 303 303

317 319 321 326 326 326

Toxic Nephropathy Due to Radiocontrast Media . . . . . . . . . . . . . . . . 329 Peter A. McCullough 6.7.1

Definition of Toxic Nephropathy After Iodinated Contrast Medium . . . . . . . . . . . . . . . . . . . . . . . . 6.7.2 Consensus Statements on Contrast-Induced Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.3 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.4 Classes of Iodinated Contrast . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.5 Importance of Volume Expansion . . . . . . . . . . . . . . . . . . . . . . . . 6.7.6 Dialysis and Hemofiltration . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.7 Pharmacologic Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.8 Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.9 Biomarkers for Contrast-Induced AKI . . . . . . . . . . . . . . . . . . . . 6.7.10 Future Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7.11 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.8

329 329 330 332 332 333 333 333 333 334 334 334

Acute Glomerulonephritis, Vasculitis, and Pulmonary Renal Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 Jai Prakash 6.8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 6.8.2 Causes of ARF Due to Glomerulonephritis/Vasculitis . . . . . . . . 337

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6.8.3 Causes of ARF Due to Glomerulonephritis . . . . . . . . . . . . . . . . 6.8.4 Acute Renal Failure in Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . 6.8.5 Pathogenesis of ARF in Glomerulonephritis/Vasculitis . . . . . . . 6.8.6 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.8.7 Acute Renal Failure in Patients with Underlying Glomerulonephritis . . . . . . . . . . . . . . . . . . . . . 6.8.8 Acute Renal Failure Complicating Nephrotic Syndrome . . . . . . 6.8.9 Treatment and Prognosis of Glomerulonephritis/ Vasculitis – Associated Acute Renal Failure . . . . . . . . . . . . . . . 6.8.10 The Pulmonary Renal Syndromes . . . . . . . . . . . . . . . . . . . . . . . 6.8.11 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9

338 339 340 340 341 341 342 343 344 345

Hemolytic Uremic Syndrome/ Thrombotic Thrombocytopenic Purpura . . . . . . . . . . . . . . . . . . . . . . . 349 Marina Noris, Miriam Galbusera, and Giuseppe Remuzzi 6.9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9.2 Acquired Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9.3 Genetic (TMA Associated with Congenital Defects) . . . . . . . . . 6.9.4 Idiopathic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9.5 Treatment Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9.6 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9.7 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

349 349 356 359 359 360 360 361

6.10 Acute Tubulointerstitial Nephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 David J. Border and Richard J. Baker 6.10.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.2 Historical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.4 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.5 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.6 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.7 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.8 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.9 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.10 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.10.11 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

365 365 366 366 366 368 368 369 369 370 370 371

6.11 Myoglobinuric Acute Kidney Failure . . . . . . . . . . . . . . . . . . . . . . . . . . 373 Mehmet Sükrü Sever and Raymond Vanholder 6.11.1 6.11.2 6.11.3 6.11.4 6.11.5

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

373 374 376 376 378

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6.11.6 Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.11.7 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.11.8 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

378 379 380 380

6.12 Tropical Infections and Acute Kidney Injury . . . . . . . . . . . . . . . . . . . 383 Rashad S. Barsoum 6.12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.12.2 Pathogenetic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.12.3 Clinical Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.12.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.12.5 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.12.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

383 386 388 388 388 389 389

6.13 AIDS and Acute Kidney Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 Hassane Izzedine 6.13.1 Epidemiology: Incidence and Risk Factors . . . . . . . . . . . . . . . . 6.13.2 Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.13.3 Intrinsic Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.13.4 Underlying Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.13.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.13.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

393 394 395 398 399 399 400

6.14 Acute Kidney Injury in Oncological Disorders and Tumor Lysis Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Claudio Ronco 6.14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.14.2 Negative Impact of AKI on Prognosis for Cancer Patients . . . . 6.14.3 Causes of AKI in Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . 6.14.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.14.5 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

403 403 404 409 410 410

6.15 Kidney Failure Following Cardiovascular Surgery . . . . . . . . . . . . . . . 413 Michael Haase and Anja Haase-Fielitz 6.15.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15.2 Epidemiology and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15.3 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15.4 Pathomechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15.5 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15.6 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15.8 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

413 413 414 415 417 422 423 424 424

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6.16 Burns and Acute Kidney Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Filippo Mariano, Ezio Nicola Gangemi, Daniela Bergamo, Zsuzsanna Hollo, Maurizio Stella, and Giorgio Triolo 6.16.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.16.2 Pathophysiology of Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.16.3 Renal and Electrolyte Abnormalities . . . . . . . . . . . . . . . . . . . . . 6.16.4 Acute Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.16.5 Renal Replacement Therapy in Burn Patients . . . . . . . . . . . . . . 6.16.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

429 429 431 432 434 435 435

6.17 Acute Kidney Transplant Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 Ralf Schindler 6.17.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.17.2 Clinical Approach and Diagnostic Procedures . . . . . . . . . . . . . . 6.17.3 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

439 440 443 443

6.18 Acute Kidney Failure During Pregnancy and Postpartum . . . . . . . . . 445 Duska Dragun and Michael Haase 6.18.1 Introduction and Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.18.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.18.3 Preeclampsia/Eclampsia/HELLP Syndrome . . . . . . . . . . . . . . . 6.18.4 Thrombotic Microangiopathies . . . . . . . . . . . . . . . . . . . . . . . . . . 6.18.5 SLE and Antiphospholipid Syndrome . . . . . . . . . . . . . . . . . . . . 6.18.6 Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.18.7 Therapeutic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.18.8 Prenatal and Obstetric Management . . . . . . . . . . . . . . . . . . . . . . 6.18.9 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

445 446 447 449 449 450 450 454 455 456

6.19 Acute Kidney Failure in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 Michael Zappitelli and Stuart L. Goldstein 6.19.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.19.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.19.3 Etiology and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.19.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.19.5 Specific Patient Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.19.6 Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.19.7 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

459 459 460 461 465 465 466 466

Part VII  Temporary Replacement of Kidney Function 7.1

Indications to Start Kidney Replacement Therapy . . . . . . . . . . . . . . . 471 Nathalie Neirynck and An S. De Vriese 7.1.1 7.1.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 Electrolyte Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472

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7.1.3 Acid–Base Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.4 Fluid Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.5 Azotemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2

Principles of Extracorporeal Therapy: Haemodialysis, Haemofiltration and Haemodiafiltration . . . . . . . . . . 481 Mathavakkannan Suresh and Ken Farrington 7.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.2 A Brief History of Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.3 Physiological Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.4 Membrane and Dialysers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.5 Dialysis Fluid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.6 The Dialysis Machine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.7 Anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.8 Haemodialysis/Filtration Techniques . . . . . . . . . . . . . . . . . . . . . 7.2.9 Adequacy of Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.10 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7.3

481 481 482 483 484 485 486 486 488 489 489

Membranes for Dialysis and Hemofiltration . . . . . . . . . . . . . . . . . . . . 491 Detlef H. Krieter and Christoph Wanner 7.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2 Classification of Dialysis Membranes . . . . . . . . . . . . . . . . . . . . 7.3.3 Dialysis Membrane Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.4 Dialysis Membrane Biocompatibility . . . . . . . . . . . . . . . . . . . . . 7.3.5 Dialysis Membrane Biocompatibility and Clinical Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.6 Dialysis Membrane Permeability and Clinical Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.7 Dialysis Membrane Requirements in Acute Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.8 Future Trends in Dialysis Membranes: The Bioartificial Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.9 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7.4

472 472 475 477 478

491 492 492 496 498 499 499 502 502 502

Dialysates and Substitution Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Isabelle Plamondon and Martine Leblanc 7.4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2 Fluids for CRRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.3 Choice of Buffer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.4 Citrate Anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.5 Influence of CRRT Prescription . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.6 Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.7 High Volume Hemofiltration . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.8 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

507 508 509 510 511 512 512 512 512

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Contents

Intermittent Hemodialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 Christophe Vinsonneau and Mourad Benyamina 7.5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.2 Operational Characteristics of IHD . . . . . . . . . . . . . . . . . . . . . . 7.5.3 Advantages and Limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.4 Different Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.5 Specificity of IHD Use in ICU . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.6 Preferential Indication for IHD . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.7 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7.6

Continuous Renal Replacement Therapies . . . . . . . . . . . . . . . . . . . . . 525 Shigehiko Uchino and Claudio Ronco 7.6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.2 Historical Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.3 CRRT Techniques and Nomenclature . . . . . . . . . . . . . . . . . . . . . 7.6.4 Indications and Timing of Starting CRRT . . . . . . . . . . . . . . . . . 7.6.5 Nonrenal Indications of CRRT . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.6 Complications/Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.7 CRRT Versus IRRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.8 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7.7

515 516 517 518 518 521 522 522

525 526 526 531 531 532 533 533 534

Extended Daily Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537 Danilo Fliser and Jan T. Kielstein 7.7.1

Extended Dialy Dialysis: Back to the Roots of Renal Replacement Therapy in Critically Ill Patients . . . . . . . . . 7.7.2 What Led to the Revival of EDD in the ICU? . . . . . . . . . . . . . . 7.7.3 Clinical Experience with EDD Therapy of Critically Ill Patients with AKI . . . . . . . . . . . . . . . . . . . . . . . . 7.7.4 Quantifying the Dose of EDD and Survival with EDD . . . . . . . 7.7.5 Technical Modifications of the EDD Technique . . . . . . . . . . . . . 7.7.6 The Genius Batch Dialysis System . . . . . . . . . . . . . . . . . . . . . . . 7.7.7 Removal of Drugs and Toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7.8 Economic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7.9 EDD: The “Hybrid” Approach in Terms of Techniques and Specialties . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7.10 Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7.11 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.8

537 538 538 540 541 541 542 542 542 543 543 543

Quantifying the Dose of Acute Kidney Replacement Therapy . . . . . . 547 Zaccaria Ricci and Claudio Ronco 7.8.1 7.8.2 7.8.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547 Meaning and Different Approaches to RRT Dose . . . . . . . . . . . 547 RRT Dose Adequacy: Does It Exist? . . . . . . . . . . . . . . . . . . . . . 549

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7.8.4

RRT Dose Delivery: Continuous, Intermittent, Hybrid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.8.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.8.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.9

551 554 555 555

Anticoagulation for Acute Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559 Andrew Davenport 7.9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.9.2 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.9.3 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

559 571 572 572

7.10 Vascular Access for Acute Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577 Bernard Canaud, Leila Chenine, Delphine Henriet, and Hélène Leray-Moragués 7.10.1 7.10.2 7.10.3 7.10.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How to Choose a CVC for Acute Dialysis? . . . . . . . . . . . . . . . . How to Insert, Care and Manage a Dialysis CVC? . . . . . . . . . . . How to Evaluate and to Improve Dialysis CVC Performances? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.10.5 How to Improve CVC Outcomes in Intensive Care Unit Setting? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.10.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.10.7 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

577 578 582 584 584 586 586 587

7.11 Principles and Practice of Acute Peritoneal Dialysis . . . . . . . . . . . . . . 591 Wai-Kei Lo, Sing-Leung Lui, and Terence Pok-Siu Yip 7.11.1 7.11.2 7.11.3 7.11.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Advantage of PD for ARF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disadvantages of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcome of Using PD in Acute Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.11.5 Forms of PD Available . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.11.6 Types of Peritoneal Dialysis Catheters for Acute Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.11.7 Implantation Technique of Cuffed Silicone PD Catheters . . . . . . . . . . . . . . . . . . . . . . . . . 7.11.8 The Peritoneal Dialysate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.11.9 The Dialysis Prescription . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.11.10 Complications of Acute Peritoneal Dialysis . . . . . . . . . . . . . . . . 7.11.11 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

591 592 592 593 594 595 595 596 596 597 600 600 600

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Contents

7.12 Choosing a Therapy Modality for Acute Renal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603 Achim Jörres and Dinah Jörres 7.12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.12.2 The “Evidence-Base”: Clinical Studies Comparing Outcomes of CRRT and IRRT . . . . . . . . . . . . . . . . . 7.12.3 The Clinical Choice of Treatment Modalities . . . . . . . . . . . . . . . 7.12.4 Diffusive Versus Convective Treatment Strategies . . . . . . . . . . . 7.12.5 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

603 604 605 606 607 607

7.13 Acute Kidney Replacement Therapy in Children . . . . . . . . . . . . . . . . 609 Jordan M. Symons 7.13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.13.2 Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.13.3 Intermittent Hemodialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.13.4 Continuous Renal Replacement Therapy . . . . . . . . . . . . . . . . . . 7.13.5 Summary/Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.13.6 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

609 609 611 613 615 615 615

7.14 Stopping Acute Kidney Replacement Therapy . . . . . . . . . . . . . . . . . . 617 Josée Bouchard, Roy Mathew, and Ravindra L. Mehta 7.14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 7.14.2 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 Part VIII  Extracorporeal Therapies for Nonrenal Indications 8.1

Extracorporeal Therapies and Immunomodulation During Sepsis . . . . . . . . . . . . . . . . . . . . . . . . 629 Jörg C. Schefold and Achim Jörres 8.1.1 8.1.2 8.1.3 8.1.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Immunopathogenesis of Sepsis: A Role for an Extracorporeal Intervention? . . . . . . . . . . . . . . . . Continuous Renal Replacement Techniques and EBT in Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . High-Volume Hemofiltration . . . . . . . . . . . . . . . . . . . . . . . . . . .

629 629 630 631

Contents

xxv

8.1.5

High Cutoff Dialysis/Hemofiltration and High-Flux Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1.6 Plasmapheresis/Plasma Separation . . . . . . . . . . . . . . . . . . . . . . . 8.1.7 Adsorption: Hemoperfusion and Plasma Separation/Adsorption . . . . . . . . . . . . . . . . . . . . . . . 8.1.8 Direct Hemoperfusion/Adsorption . . . . . . . . . . . . . . . . . . . . . . . 8.1.9 Coupled Plasma Filtration Adsorption . . . . . . . . . . . . . . . . . . . . 8.1.10 Plasma Filtration/Selective Adsorption . . . . . . . . . . . . . . . . . . . 8.1.11 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1.12 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2

632 633 633 633 634 634 634

Extracorporeal Liver Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637 Gesine Pless and Igor Maximilian Sauer 8.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.2 Artificial Liver Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.3 Bioartificial Liver Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.5 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8.3

632 632

637 638 640 642 643 644

Extracorporeal Removal of Drugs and Toxins . . . . . . . . . . . . . . . . . . . 647 James F. Winchester, Nikolas B. Harbord, Pallavi Tyagi, and Herman Rosen 8.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.2 Criteria and Considerations for Extracorporeal Therapy . . . . . . 8.3.3 Principles of Extracorporeal Removal of Drugs and Toxins . . . 8.3.4 Extracorporeal Modalities – Hemodialysis . . . . . . . . . . . . . . . . . 8.3.5 Extracorporeal Modalities – Hemofiltration and Hemodiafiltration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.6 Extracorporeal Modalities – Hemoperfusion . . . . . . . . . . . . . . . 8.3.7 Extracorporeal Modalities – Peritoneal Dialysis . . . . . . . . . . . . 8.3.8 Extracorporeal Modalities – Plasma Exchange and Exchange Transfusion . . . . . . . . . . . . . . . . . . . . . 8.3.9 Specific Drugs/Poisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.10 Take Home Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

647 648 648 651 651 652 652 652 654 656 656

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661

Contributors

Tariq Ali  Kent and Canterbury Hospital, Ethelbert Road, Canterbury, Kent CT1 3NG, UK [email protected] Robert J. Anderson  Department of Medicine, University of Colorado, Health Science Center, 4200 East 9th Avenue., Denver, CO 80262, USA [email protected] Sean M. Bagshaw  Division of Critical Care Medicine, University of Alberta Hospital, University of Alberta, 3C1.12 Walter C. Mackenzie Centre, ­8440–112 Street, Edmonton, Alberta T6G 2B7, Canada [email protected] Shweta Bansal  University of Colorado, School of Medicine, 4200 East 9th Avenue C281, Denver, CO 80262, USA [email protected] Richard J. Baker  Department of Renal Medicine, St James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK [email protected] Rashad S. Barsoum  Cairo University, Cairo Kidney Center, 3 Hussein El-Memar Street, Antique Khana, P.O. Box 91, Bab El-Louk, Cairo 11513, Egypt [email protected] Rinaldo Bellomo  Department of Intensive Care, Austin Hospital, Studley Rd, Heidelberg, Victoria 3084, Australia [email protected] Mourad Benyamina  Burn ICU, Department of Emergency Medicine and ICU, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris Descartes University, Paris, France Thomas Berg  Hepatology & Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany [email protected] Daniela Bergamo  Department of Internal Medicine, Division of Nephrology and Dialysis, CTO Hospital, Turin, Italy

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Annette Beyea  Departments of Medicine and Anesthesiology, DartmouthHitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA Joseph V. Bonventre  Brigham and Women’s Hospital, Renal Division, 75 Francis Street, Boston, MA 02115, USA [email protected] David J. Border  Department of Renal Medicine, York Hospital, Wigginton Road, York YO31 8HE, England, [email protected] Marie L. Borum  Division of Gastroenterology and Liver Diseases, George Washington University, 2150 Pennsylvania Avenue, NW, Suite 3-408, Washington, DC 20037, USA [email protected] Josée Bouchard  Department of Medicine, Division of Nephrology, University of California, San Diego, CA 92103, USA [email protected] Raf Brouns  Memory Clinic, Department of Neurology, Middelheim General Hospital, Antwerp, Belgium and Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Belgium David F. M. Brown  Department of Emergency Medicine, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114-2696, USA [email protected] Bernard Canaud  Nephrology, Dialysis & Intensive Care Unit, Renal Research and Training Institute, Lapeyronie University Hospital, CHU Montpellier, 34295 Montpellier, France [email protected] Barbara Ceradini  Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, 808, route de Lennik, 1070-Brussels, Belgium Leila Chenine  Nephrology, Dialysis & Intensive Care, Lapeyronie Hospital, Montpellier Cedex, France Howard L. Corwin  Departments of Medicine and Anesthesiology, DartmouthHitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA [email protected] Angela D’Angelo  Università di Padova, CNR, Via Giustiniani, 2 35128 Padova, Italy [email protected] Joseph F. Dasta  The Ohio State University, College of Pharmacy, University of Texas, College of Pharmacy, P.O. Box 967, Hutto, TX 78634-0967, USA [email protected] Andrew Davenport  Royal Free Hospital, Pond Street, London NW3 2QG , UK [email protected]

Contributors

Contributors

xxix

Peter Paul De Deyn  Department of Neurology and Memory Clinic, Middelheim General Hospital, Lindenreef 1, 2020 Antwerp, Belgium [email protected] An S. De Vriese  The Renal Unit, AZ Sint-Jan AV, Ruddershove, 10, 8000 Brugge, Belgium [email protected] Dorella Del Prete  Universitá di Padova, CNR, Via Giustiniani 2, 35128 Padova, Italy Wilfred Druml  Department of Medicine III, Division of Nephrology, Vienna General Hospital, Währinger Gürtel 18–20, 1090 Vienna, Austria [email protected] Duska Dragun  Department of Nephrology and Intensive Care Medicine, Charité Campus Virchow-Klinikum, 13343 Berlin, Germany Pieter Evenepoel  Department of Nephrology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium [email protected] Ken Farrington  Renal Unit, Lister Hospital, Corey Mill Lane, Stevenage, SG 14AB, UK [email protected] Donald A. Feinfeld  Division of Nephrology & Hypertension, Department of Medicine, Beth Israel Medical Center, 350 17th Street, 18BH20, New York, NY 10003, USA Danilo Fliser  Division of Renal and Hypertensive Disease, Department of Internal Medicine, Saarland University Centre, Kirrberger Strasse, 66421 Homburg/Saar, Germany [email protected] Miriam Galbusera  Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Mario Negri Institute for Pharmacological Research, 24125 Bergamo, Italy Ezio Nicola Gangemi  Department of Plastic Surgery, Burns Unit, CTO Hospital, Turin, Italy [email protected] Herwig Gerlach  Department of Anesthesia, Intensive Care Medicine, and Pain Management, Vivantes–Klinikum Neukölln, Klinik fuer Anaesthesie, Operative Intensivmedizin und Schmerztherapie, Rudower Strasse 48, 12313 Berlin, Germany [email protected] Griet Glorieux  Nephrology Unit, Department of Internal Medicine, University Hospital, Gent University, De pintelaan 185, 9000 Gent, Belgium Stuart L. Goldstein  Baylor College of Medicine, Medical Director, Renal Dialysis Unit and Pheresis Service, Texas Children’s Hospital, 6621 Fannin Street, MC 3-2482, Houston, Texas 77054, USA [email protected]

xxx

Jan Gunst  Department of Intensive Care Medicine, University Hospitals, University of Leuven, Herestraat 49, 3000 Leuven, Belgium [email protected] Michael Haase  Department of Nephrology and Intensive Care Medicine, Charité Campus Virchow-Klinikum, 13343 Berlin, Germany [email protected] Anja Haase-Fielitz  Department of Nephrology and Intensive Care Medicine, Charité University Medicine, Humboldt University Berlin, Berlin, Germany Nikolas B. Harbord  Albert Einstein College of Medicine, Bronx, New York, USA Dietrich Hasper  Nephrology & Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353, Berlin, Germany [email protected] Delphine Henriet  Nephrology, Dialysis & Intensive Care Unit, Renal Research and Training Institute, Lapeyronie University Hospital, CHU Montpellier, 34295 Montpellier, France Zsuzsanna Hollo  Department of Area of Medicine, Division of Nephrology and Dialysis, CTO Hospital, Turin, Italy Eric A. J. Hoste  Department of Intensive Care Medicine, 2K12-C, Gent University Hospital, De pintelaan 185, 9000 Gent, Belgium [email protected] Todd S. Ing  Department of Nephrology, Loyola University Medical Center, 2160 First Avenue, Maywood, IL 60153, USA [email protected] Hassane Izzedine  Department of Nephrology, La Pitié-Salpêtrière Hospital, 47-80 Boulevard de l’Hôpital, Assistance Publique-Hopitaux de Paris, Pierre et Marie Curie University, 75013 Paris, France [email protected] Michael Joannidis  Medical Intensive Care Unit, Department of General Internal Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria Achim Jörres  Department of Nephrology and Medical Intensive Care, Charite University Hospital Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany [email protected] Dinah Jörres  Department of Anaesthesiology and Intensive Care Medicine, Charité University Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany [email protected] Sandra L. Kane-Gill  University of Pittsburgh School of Pharmacy, 918 Salk Hall, 3501 Terrace St., Pittsburgh, PA 15261, USA [email protected]

Contributors

Contributors

xxxi

Vijay Karajala  CRISMA Laboratory, Department of Ciritical Care Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA [email protected] John A. Kellum  Department of Critical Care Medicine, University of Pittsburgh, 608 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA [email protected] Jan T. Kielstein  Division of Nephrology and Hypertension, Department of Internal Medicine, Medical School Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany [email protected] Detlef H. Krieter  University Hospital Würzburg, Department of Medicine, Division of Nephrology, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany [email protected] Norbert Lameire  Nephrology Unit, Department of Internal Medicine, University Hospital, Gent University, 4K4, NDT-COMGAN Office, De pintelaan 185, 9000 Gent, Belgium [email protected] Martine Leblanc  University of Montreal, Nephrology and Critical Care, Maisonneuve-Rosemont Hospital, 5415 boulevard de l’Assomption, Montreal, QC H1T 2M4, Canada [email protected] Hélène Leray-Moragués  Nephrology, Dialysis & Intensive Care Unit, Renal Research and Training Institute, Lapeyronie University Hospital, CHU Montpellier, 34295 Montpellier, France Susie Q. Lew  Division of Renal Diseases and Hypertension, George Washington University, 2150 Pennsylvania Avenue, NW, Suite 1-200, Washington, DC 20037, USA [email protected] Andrew Liteplo  Department of Emergency Medicine, Zero Emerson #3B, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, USA Wai-Kei Lo  Department of Medicine, Tung Wah Hospital, 12 Po Yan Street, Hong Kong [email protected] Sing-Leung Lui  Department of Medicine, Tung Wah Hospital, 12 Po Yan Street, Hong Kong [email protected] Filippo Mariano  Department of Internal Medicine, Division of Nephrology and Dialysis, CTO Hospital, Via G. Zurreti 29, 10126 Turin, Italy [email protected] Roy Mathew  Division of Nephrology, Department of Medicine, University of California, San Diego, CA 92103, USA [email protected]

xxxii

Peter A. McCullough  Division of Nutrition and Preventive Medicine, William Beaumont Hospital, 4949 Coolidge Highway, Royal Oak, MI 48073, USA [email protected] Ravindra L. Mehta  Division of Nephrology, Department of Medicine, University of California, San Diego, CA 92103, USA [email protected] Philipp G.H. Metnitz  Department of Anesthesiology and General Intensive Care, University Hospital of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria [email protected] Bruce A. Mueller  Department of Clinical, Social and Administrative Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109–1065, USA [email protected] Nathalie Neirynck  The Renal Unit, University Hospital Gent, Gent, Belgium Vicki E. Noble  Department of Emergency Medicine, Zero Emerson #3B, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, USA [email protected] Marina Noris  Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Mario Negri Institute for Pharmacological Research, 24125 Bergamo, Italy Michael Oppert  Nephrology & Medical Intensive Care, Charité Campus ­Virchow-Klinikum, 13343 Berlin, Germany [email protected] Michael R. Pinsky  Department of Critical Care Medicine, University of Pittsburgh, 606 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA [email protected] Isabelle Plamondon  University of Montreal, Nephrology and Critical Care, Maisonneuve-Rosemont Hospital, Montreal, P.Q., Canada Gesine Pless  Klinik für Allgemein-, Visceral- und Transplantationschirurgie, Experimentelle Chirurgie und Regenerative Medizin, Charité – Campus Virchow, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany Jai Prakash  Department of Nephrology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India [email protected]; [email protected] John R. Prowle  Department of Intensive Care, Austin Hospital, Melbourne, Victoria 3084, Australia Ana Reiter  Department of Anesthesiology and General Intensive Care, University Hospital of Vienna, Vienna, Austria Giuseppe Remuzzi  Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Mario Negri Institute for Pharmacological Research, Bergamo, Via Gavazzeni, 11, 24125 Bergamo, Italy [email protected]

Contributors

Contributors

xxxiii

Zaccaria Ricci  Department of Pediatric Cardiosurgery, Bambino Gesù Hospital, Piazza S. Onofrio 4, 00100 Rome, Italy [email protected] Paul Roderick  Public Health Sciences and ­Medical Statistics, C Floor, South Academic Block, Southampton General Hospital, Southampton SO166YD, UK [email protected] Claudio Ronco  Department of Nephrology, Dialysis and Transplantation, S. Bortolo Hospital, Viale Rodolfi 37, 36100 Vicenza, Italy [email protected] Herman Rosen  Division of Nephrology and Hypertension, Beth Israel Medical Center, New York, NY 10003, USA Alan D. Salama  Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK [email protected] Igor Maximilian Sauer  Department of Surgery, Charité Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany [email protected] Jörg Christian Schefold  Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13343 Berlin, Germany [email protected] Miet Schetz  Department of Intensive Care Medicine, University Hospitals, University of Leuven, Herestraat 49, 3000 Leuven, Belgium [email protected] Ralf Schindler  Department of Nephrology and Intensive Care Medicine, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany [email protected] Robert W. Schrier  University of Colorado School of Medicine, 4200 East Ninth Avenue, B173, Biomedical Research Building, Room 723, Denver, CO 80262, USA [email protected] Maurizio Stella  Department of Plastic Surgery, Burns Unit, CTO Hospital, Turin, Italy Mathavakkannan Suresh  Renal Unit, Lister Hospital, Corey Mill Lane, Stevenage, SG 14AB, UK Mehmet Sükrü Sever  Department of Internal Medicine/Nephrology, Istanbul School of Medicine, Millet caddesi, Çapa Topkapi TR 34390, Istanbul, Turkey [email protected] Jordan M. Symons  Division of Nephrology, Children’s Hospital and Regional Medical Center, Department of Pediatrics, University of Washington School of Medicine, 4800 Sand Point Way NE, Seattle, WA 98105–0371, USA [email protected]

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Susanne Toussaint  Department of Anesthesia, Intensive Care Medicine, and Pain Management, Vivantes – Klinikum Neukölln, Klinik fuer Anaesthesie, Operative Intensivmedizin und Schmerztherapie, Rudower Strasse 48, 12313 Berlin, Germany [email protected] Giorgio Triolo  Department of Internal of Medicine, Division of Nephrology and Dialysis, CTO Hospital, Turin, Italy Pallavi Tyagi  Private Practice, Singapore Shigehiko Uchino  Intensive Care Unit, Department of Anesthesiology, Jikei University School of Medicine, 3-19-18, Nishi-Shinbashi, Minato-ku, Tokyo 105–8471, Japan [email protected] Wim Van Biesen  Renal Division, Department of Internal Medicine, University Hospital Gent, ICU De pintelaan 185, 9000 Gent, Belgium [email protected] Greet Van den Berghe  Department of Intensive Care Medicine, University Hospitals, University of Leuven, Herestraat 49, 30000 Leuven, Belgium [email protected] Bert-Jan H. Van den Born  Department of Internal and Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands [email protected] Gert A. van Montfrans  Department of Internal and Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Raymond Vanholder  Renal Division, Department of Internal Medicine, University Hospital Gent, De pintelaan 185, 9000 Gent, Belgium [email protected] Ilse Vanhorebeek  Department of Intensive Care Medicine, University Hospitals, University of Leuven, Herestraat 49, 3000 Leuven, Belgium [email protected] A. Mary Vilay  Critical Care Nephrology Research Fellow and Clinical Instructor, Department of Clinical, Social and Administrative Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109–1065, USA [email protected] Jean-Louis Vincent  Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, 808, route de Lennik, 1070-Brussels, Belgium [email protected] Christophe Vinsonneau  Department of Intensive Care, Cochin Port-Royal University Hospital, René Descartes University, 75014 Paris, France [email protected] Non Wajanaponsan  Department of Critical Care Medicine, University of Pittsburgh, 606 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA Wei Wang  University of Colorado, School of Medicine, 4200 East Ninth Avenue C281, Denver, CO 80262, USA

Contributors

Contributors

xxxv

Christoph Wanner  University Hospital Würzburg, Department of Medicine, Division of Nephrology, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany [email protected] James F. Winchester  Division of Nephrology & Hypertension, Department of Medicine, Beth Israel Medical Center, 350 East 17th Street, 18BH20, New York, NY 10003, USA [email protected] Terence Pok-Siu Yip  Department of Medicine, Tung Wah Hospital, 12 Po Yan Street, Hong Kong [email protected] Michael Zappitelli  McGill University Health Center, Montreal Children’s Hospital, 2300 Tupper, Room E-222, Montreal, Quebec, H3J 2S6 Canada [email protected]

Part Definition and Classification of Acute Kidney Failure

II

Definition and Classification of Acute Kidney Injury

1.1

Vijay Karajala and John A. Kellum

Core Messages

›› Appreciation for the clinical meaning of even

›› ››

››

small changes in kidney function has radically changed the way patients are being cared for. Analogous to chronic kidney disease (CKD) in the outpatient arena, acute kidney injury (AKI) is associated with both short- and long-term adverse outcomes in hospitalized patients. The RIFLE classification has been validated in multiple studies and may be utilized as a prognostic tool. Evaluation of the epidemiology of AKI has been hampered by the lack of a standard definition and classification system. New studies involving multiple, different populations are clarifying the incidence and prevalence of this syndrome. However, the condition appears to be common (approximately 30–50% of critically ill patients) and is associated with a large increase in the risk of death (3–5-fold increase). As new treatments for AKI emerge, RIFLE classifications will undoubtedly be used to reference recommendations for prevention and treatment.

J. A. Kellum (*) Department of Critical Care Medicine, University of Pittsburgh, 608 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA e-mail: [email protected]

1.1.1  Introduction Acute kidney injury (AKI) is a common condition in hospitalized patients. A standardized definition of AKI is critical to enable clinicians to consistently identify the disorder. Until recently, no consensus definition existed. This chapter describes the new nomenclature of AKI as well as the validated consensus-based RIFLE criteria. To illustrate the difficulty associated with a lack of standardization in the definition of renal dysfunction, most chapters and review articles on “acute renal failure” begin with words such as “Depending on the definition used and population studied, incidence in critically ill patients is approximately 1–25%.” Indeed, there have been more than 35 definitions of acute renal failure in the literature [1–5], and the lack of a standard consensus definition has also been a major impediment to the progress of clinical and basic research in this field [6].

1.1.2 What Is Acute Kidney Injury? Current Controversies The term “acute renal failure” was introduced by Homer W. Smith [7] in the chapter “Acute Renal Failure Related to Traumatic Injuries” in his textbook “The Kidney: Structure and Function in Health and Disease” (1951). Since then the term acute renal failure has been widely used in the medical literature. The excretion of water-soluble solutes and urine production are the result of glomerular filtration, and clinicians have generally equated these functions of the kidney to the glomerular filtration rate (GFR). As a result, most definitions of renal acute failure use indirect estimates

A. Jörres et al. (eds.), Management of Acute Kidney Problems, DOI: 10.1007/978-3-540-69441-0_1.1, © Springer-Verlag Berlin Heidelberg 2010

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of GFR (serum creatinine [SCr]), solute clearance (blood urea nitrogen [BUN]), and/or urine output over time. However, this paradigm has serious limitations.

1.1.3 Renal “Failure” or Renal “Success” Fluid and electrolytes problems are commonly faced in the intensive care unit (ICU) setting. Urine output is an important physiological sign, and fluid imbalance is common in the critically ill due to their inability to drink fluids, excess volume losses, obligatory volume losses, and not least, renal dysfunction. Measurement of BUN and SCr are routinely performed in ICUs to assess renal function. An increase in BUN and SCr is known as azotemia (from “azote” – an old name for nitrogen). Azotemia and oliguria (i.e., decreased urine output) or anuria (i.e., no urine output) together form the cardinal features of renal failure. Before examining the pathological state of this condition, it will be useful to review the normal renal physiology. The normal kidney functions to remove nitrogenous waste and other solutes, as well as regulate fluid, electrolyte, and acid–base balance. Although it does each of these with remarkable efficiency, there are limits to what the kidney can do when stressed. For example, in the face of severe extracellular fluid depletion, GFR is reduced. This reduction is sometimes called “single-nephron” GFR to distinguish it from the loss of nephrons that occurs with renal disease (e.g., diabetic nephropathy), but it actually refers to all nephrons. The reduced GFR means that a greater fraction of salt and water can be absorbed, and thus, less will enter the tubules. Of course, less tubular filtrate means less urine and less nitrogen excretion. This physiology has also given rise to the observation that some cases of azotemia and oliguria actually represent a perfectly normal response (not failure) and thus “acute renal success” [8].

1.1.4  Oliguria and Anuria Urine output when severely decreased can be both a reasonably sensitive and functional index for the kidney as well as a biomarker of tubular function or injury;

V. Karajala and J. A. Kellum

however, this relationship between urine output and renal function/injury is complex. For example, oliguria may be more profound when tubular function is intact. Volume depletion and hypotension are profound stimuli for vasopressin secretion. As a consequence, the distal tubules and collecting ducts become fully permeable to water. Concentrating mechanisms in the inner medulla are also aided by low flow through the loops of Henle, and thus urine volume is minimized and urine concentration maximized (> 500 mOsm/kg). Conversely, when the tubules are injured, maximal concentrating ability is impaired and urine volume may even be normal (i.e., non-oliguric renal failure). Also, in critically ill patients, large doses of diuretics are commonly used, and urine output which would otherwise be used to categorize renal failure loses its diagnostic value in these patients (i.e., poor negative predictive value). Thus, urine output may be adequate in the presence of renal failure and does not necessarily correlate with the severity of renal injury. Furthermore, changes in urine output or GFR are neither essential nor adequate for the accurate diagnosis of renal pathology.

1.1.5 Prerenal Azotemia and Acute Tubular Necrosis Conventionally, acute renal failure is categorized in terms of physiology into prerenal or postrenal (effecting kidney function secondary to conditions “outside” the kidney, otherwise called “functional” renal failure) and renal (directly injuring the kidney, so-called structural renal failure or acute tubular necrosis [ATN]). This classification was proposed to enhance understanding of the pathophysiology. In reality, however, the mechanisms are not clearly understood, and these mechanisms often overlap and have limited relevance to clinical practice. The entity “prerenal” is considered as any “before the kidney” process affecting kidney function: for example, acute myocardial infarction and low cardiac output syndrome causing low perfusion states or a patient with major volume loss. This prerenal concept assumes that there is no intrinsic structural kidney injury. However, several logical questions have been posed. It is very difficult to know when functional renal failure becomes structural renal failure. It is also

1.1  Definition and Classification of Acute Kidney Injury

unclear from this definition how much structural injury is necessary to consider it “intrarenal”. Although in clinical practice we utilize urine studies (urine creatinine, urine electrolytes, fractional excretion of sodium, tubular casts, etc.) to classify patients as either with prerenal or renal conditions, this urinalysis-based approach has limited validation [9]. Intact tubular function, particularly early on, may be seen with various forms of renal disease. A high volume osmolality coupled with low urine Na+ in the face of oliguria and azotemia is strong evidence of intact tubular function. Sepsis, the most common condition associated with renal failure in the ICU [10], may alter function without characteristic changes in urine indices. In early post mortem studies of patients who died in ICU with acute renal failure (ARF) and sepsis, the histopathology of the kidney was often normal in ARF. In a recent systematic review of six histopathological studies of septic renal failure, only 22% of patients showed evidence of ATN [11]. Finally, it may be quite tempting to extrapolate the prerenal/renal paradigm to a benign and malignant azotemia, but as we and others have argued elsewhere [9, 12, 13], pure prerenal physiology is unusual in hospitalized patients and its effects are not necessarily benign. So classification of a case as benign “prerenal” azotemia will lead to incorrect management decisions.

1.1.6  Limitations of Biomarkers GFR has traditionally been used as the performance index for renal function. However, without knowing what the maximal GFR (renal reserve) would be in a given patient, measurements of GFR will not yield an accurate estimate of the global renal function. A noninvasive method of measuring real-time GFR has yet to be developed, and we still continue to rely on SCr and BUN as surrogate markers of GFR. However, there are significant limitations when these markers are used. BUN can vary independently of renal function for a variety of reasons, including gastrointestinal bleeding, steroid use, and nutritional status. Thus, changes in BUN do not reliably convey the degree of uremia in any given patient. Similarly, SCr is a marker of late-stage disease. In some cases, SCr levels might not increase until a substantial amount of functioning renal mass (up to 50%)

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has been lost. There are many renal and nonrenal factors that can markedly affect the SCr concentration independent of GFR, including age, sex, muscle mass, metabolism, drugs, and volume status [14, 15]. Furthermore, as GFR decreases, tubular secretion of creatinine increases. Thus, SCr can underestimate the degree of GFR decline during the evolution of ARF. Finally, changes in SCr reflect changes in the GFR only in a steady state, and no single creatinine value correlates to a given GFR across all patients. By definition, AKI is not a steady state, and the SCr may lead to falsely high or low GFR estimates [15].

1.1.7 Renal Failure Defined by RIFLE Criteria Over the last few years the case for a consensus definition and a classification system for ARF has repeatedly been made [16, 17]. The major aim of such a system would be to bring one of the major intensive care syndromes to a standard of definition and a level of classification similar to that achieved by two other common ICU syndromes (i.e., sepsis and acute respiratory distress syndrome). Furthermore, the need to classify the severity of the syndrome rather than only consider the most severe form was emphasized. Following such advocacy and through the persistent work of the Acute Dialysis Quality Initiative (ADQI) group, such a system was developed through a broad consensus of experts [1]. The characteristics of this system are summarized in Figure 1.1.1. The acronym RIFLE stands for the increasing severity classes Risk, Injury, and Failure, and the two outcome classes Loss and End Stage Kidney Disease. The three severity grades are defined on the basis of the changes in SCr or urine output where the worst of each criterion is used. The two outcome criteria, Loss and End-Stage Kidney Disease, are defined by the duration of loss of kidney function. Since its publication, the RIFLE classification system has received much attention, with more than 100,000 electronic hits for its publication site and more than 80 citations in 2 years. It has also spawned several investigations of its predictive ability, internal validity, robustness, and clinical relevance in a variety of settings.

6

V. Karajala and J. A. Kellum

Fig. 1.1.1  RIFLE criteria

GFR Criteria

Urine Output (UO) Criteria

Increased Creatinine (Cr) x 1.5

UO < .5ml/kg/h x 6Hr

High Sensitivity

RISK Cr x 2

UO < .5ml/kg/h x 12 hr

Cr x 3 Acute Cr 0.5

UO 4 weeks

ESRD

A recent study by Levy et al. [21] examined outcomes for over 1,000 patients enrolled in the control arm of two large sepsis trials. The early improvement (within 24 h) in cardiovascular (p = 0.001), renal (p < 0.0001), or respiratory (p = 0.046) function was significantly related to survival. This study suggests that outcomes for patients with severe sepsis in the ICU are closely related to early resolution of AKI. While rapid resolution of AKI may simply be a marker of good prognosis, it may also indicate a window of therapeutic opportunity to improve outcome in such patients. AKIN has also put forth a conceptual framework for AKI that may aid in future studies (Figure 1.1.2).

1.1.9  Validation Studies Using RIFLE Over 76,000 patients have been enrolled in studies to validate the RIFLE criteria as a means of classifying patients with AKI. One of the earliest studies by Abosaif et al. [22] studied 247 patients admitted to ICU with a SCr > 150 µmol/l. These investigators found that the ICU mortality was greatest among patients classified as RIFLE class F, with 74.5% mortality, compared with

1.1  Definition and Classification of Acute Kidney Injury Fig. 1.1.2  Conceptual model of acute kidney injury (AKI) (Adapted from www.AKINet.org)

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Complication

Normal

Risk

Antecedent Stage

50% among those who were class I, 38.3% in those who were class R. In a significantly larger single-center multi-ICU study, Hoste and colleagues [20] evaluated RIFLE as an epidemiological and predictive tool in 5,383 critically ill patients. They found that AKI occurred in a staggering 67% of patients, with 12% achieving a maximum class of R, 27% class I, and 28% class F. Of the 1,510 patients who reached class R, 56% progressed to either I or F. Patients with a maximum score of class R had a mortality rate of 5.5%. Furthermore, RIFLE class I (hazard ratio of 1.4) and class F (hazard ratio of 2.7) were independent predictors of mortality after controlling for other variables known to predict outcome in critically ill patients. Uchino and colleagues [2] focused on the predictive ability of RIFLE classification in a cohort of 20,126 patients admitted to a teaching hospital for > 24 h over a 3-year period. The authors used the electronic laboratory database to classify patients into RIFLE class R, I, and F, and followed then to hospital discharge or death. Nearly 10% of patients achieved a maximum RIFLE class R, 5% class I, and 3.5% class F. There was a nearly linear increase in hospital mortality with increasing RIFLE class with patients who were class R having more than three times the mortality rate of patients without AKI. Patients who were class I had close to twice the mortality of those who were class R, and patients who were class F had ten times the mortality rate of hospitalized patients without AKI. The investigators performed multivariate

Damage

GFR

AKI

Kidney Failure

Death

Outcome

logistic regression analyses to test whether RIFLE classification was an independent predictor of hospital mortality. They found that class R carried an odds ratio for hospital mortality of 2.5, class I of 5.4, and class F of 10.1. Ali and coworkers [6] studied the incidence of AKI in northern Scotland, a geographical population base of 523,390. The annual incidence of AKI was 2,147 per million population. Sepsis was a precipitating factor in 47% of patients. RIFLE classification was useful for predicting recovery of renal function (p < 0.001), requirement for renal replacement therapy (p < 0.001), length of hospital stay for survivors (p < 0.001), and in-hospital mortality (p = 0.035). Although subjects with AKI no longer had statistically significantly higher mortality at 3 and 6 months. Another study by Ostermann and Chang [23] analyzed 41,972 patients admitted to 22 ICUs in the United Kingdom and Germany between 1989 and 1999 as part of the Riyadh Intensive Care Program database. AKI defined by RIFLE occurred in 15,019 patients (35.8%): 7,207 (17.2%) who were class R, 4,613 (11%) class I, and 3,199 (7.6%) class F. Hospital mortality rates were RIFLE class R 20.9%, class I 45.6%, and class F 56.8%, compared with 8.4% among patients without AKI. Independent risk factors for hospital mortality were age (odds ratio 1.02); APACHE II score on admission to ICU (odds ratio 1.10); presence of preexisting end-stage disease (odds ratio 1.17); mechanical ventilation (odds ratio 1.52); RIFLE class R (odds ratio 1.40), class I

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(odds ratio 1.96), and class F (odds ratio 1.59); maximum number of failed organs (odds ratio 2.13); admission after emergency surgery (odds ratio 3.08); and nonsurgical admission (odds ratio 3.92). Interestingly, renal replacement therapy for AKI was not an independent risk factor for hospital mortality. Finally, in a recent systematic review by Ricci et al. [18], the authors analyzed data for more than 71,000 patients from published reports from August 2004 to June 2007 that have utilized RIFLE criteria. They identified 24 studies in which RIFLE classification was used for classification. In 13 studies that had mortality as an outcome, mortality was 6.9% in non-AKI patients compared with 31.2% in AKI patients. Mortality was 18.9%, 36.1%, and 46.5% in RIFLE class R, class I, and class F groups, respectively. They also noted that with respect to non-AKI patients, there appeared to be a stepwise increase in relative risk (RR) for death going from class R to F: 2.40, 4.15, and 6.15, respectively. The mortality with AKI seemed more pronounced among cardiovascular patients with class F versus nonAKI (RR = 13.85, p = 0.01); however, the 95% confidence interval (95% CI) in this group was quite large (95% CI, 1.8–106.7).

1.1.10 Conceptual Development and Future Directions The goal of a standard definition and classification of renal failure is now close to being realized. Further refinement of RIFLE definitions and classifications is ongoing. Recently, AKIN proposed to include an increase in SCr ³ 0.3 mg/dl within 48 h under the RIFLE R classification even if that increase failed to reach the 50% cutoff. In a recent study, Bagshaw et al. [24] compared this modification to the original RIFLE criteria. This study included 120,123 patients enrolled from January 2000 to December 2005 from 57 ICUs from the Australian New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD). This study found that compared with RIFLE criteria, the AKIN modification slightly increased the number of patients with AKI, by a modest 2%; furthermore, the modification did not significantly increase the predictive ability of RIFLE for mortality.

V. Karajala and J. A. Kellum

The use of functional markers (urine output and SCr) will be replaced or augmented in the near future by injury markers. Several potential urine and plasma markers have been identified, but no single biochemical marker so far provides the levels of sensitivity and specificity necessary to be clinically useful across the full spectrum of ARF, and these markers are reviewed elsewhere [14, 25]. In the future, biomarkers will likely identify this disorder before functional decline, and new therapies may be introduced earlier in the course of the disease, possibly mitigating and/or potentiating the recovery of this disorder. Until, then, the “tried and true” markers of urine output and serum creatinine, categorized by RIFLE criteria, will be the best we can provide.

1.1.11  Conclusions Even small changes in kidney function in hospitalized patients are associated with both short- and long-term adverse outcomes. The RIFLE classification provides a uniform definition for the whole range of AKI. It has been validated in multiple studies and may be utilized as a prognostic tool. The RIFLE classification for AKI is quite analogous to the Kidney Disease Outcomes Quality Initiative for chronic kidney disease (CKD) staging, which is well known to correlate disease severity with cardiovascular complications and other morbidities. CKD stages have also been linked to specific treatment recommendations, which have proven extremely useful in managing this disease. As the epidemiology of AKI becomes clearer and as new treatments emerge (both made all the more possible by standards for diagnosis and classification), RIFLE classifications will undoubtedly be used to reference recommendations for prevention and treatment. Indeed this was the ultimate purpose that RIFLE criteria was intended to serve.

References   1. Bellomo, R. et al., Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus

1.1  Definition and Classification of Acute Kidney Injury Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care, 2004. 8(4): p. R204–12.   2. Uchino, S., The epidemiology of acute renal failure in the world. Curr Opin Crit Care, 2006. 12(6): p. 538–43.   3. Bellomo, R., J.A. Kellum, and C. Ronco, Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med, 2007. 33(3): p. 409–13.   4. Hoste, E.A. and J.A. Kellum, Incidence, classification, and outcomes of acute kidney injury. Contrib Nephrol, 2007. 156: p. 32–8.   5. Kellum, J.A. et al., Developing a consensus classification system for acute renal failure. Curr Opin Crit Care, 2002. 8(6): p. 509–14.   6. Venkataraman, R. and J.A. Kellum, Defining acute renal failure: the RIFLE criteria. J Intensive Care Med, 2007. 22(4): p. 187–93.   7. Smith, H.W., Acute renal failure related to traumatic injuries; in The Kidney: Structure and Function in Health and Disease. 1951, Oxford University Press, Cary.   8. Thurau, K. and J.W. Boylan, Acute renal success. The unexpected logic of oliguria in acute renal failure. Am J Med, 1976. 61(3): p. 308–15.   9. Bagshaw, S.M., C. Langenberg, and R. Bellomo, Urinary biochemistry and microscopy in septic acute renal failure: a systematic review. Am J Kidney Dis, 2006. 48(5): p. 695–705. 10. Uchino, S. et al., Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA, 2005. 294(7): p. 813–8. 11. Langenberg, C. et al., The histopathology of septic acute kidney injury: a systematic review. Crit Care, 2008. 12(2): p. R38. 12. Kellum, J.A., Prerenal azotemia: still a useful concept? Crit Care Med, 2007. 35(6): p. 1630–1. 13. Bagshaw, S.M. et al., A systematic review of urinary findings in experimental septic acute renal failure. Crit Care Med, 2007. 35(6): p. 1592–8.

9 14. Bonventre, J.V., Diagnosis of acute kidney injury: from classic parameters to new biomarkers. Contrib Nephrol, 2007. 156: p. 213–9. 15. Dennen, P. and C.R. Parikh, Biomarkers of acute kidney injury: can we replace serum creatinine? Clin Nephrol, 2007. 68(5): p. 269–78. 16. Bellomo, R., J. Kellum, and C. Ronco, Acute renal failure: time for consensus. Intensive Care Med, 2001. 27(11): p. 1685–8. 17. Kellum, J.A., R.L. Mehta, and C. Ronco, Acute dialysis quality initiative (ADQI). Contrib Nephrol, 2001 132: p. 258–65. 18. Ricci, Z., D. Cruz, and C. Ronco, The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney Int, 2008. 73(5): p. 538–46. 19. Mehta, R.L. et al., Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care, 2007. 11(2): p. R31. 20. Hoste, E.A. et al., RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care, 2006. 10(3): p. R73. 21. Levy, M.M. et al., Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med, 2005. 33(10): p. 2194–201. 22. Abosaif, N.Y. et al., The outcome of acute renal failure in the intensive care unit according to RIFLE: model application, sensitivity, and predictability. Am J Kidney Dis, 2005. 46(6): p. 1038–48. 23. Ostermann, M. and R.W. Chang, Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med, 2007. 35(8): p. 1837–43; quiz 1852. 24. Bagshaw, S.M., C. George, and R. Bellomo, A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant, 2008. 23(5): p. 1569–74. 25. Nickolas, T.L., J. Barasch, and P. Devarajan, Biomarkers in acute and chronic kidney disease. Curr Opin Nephrol Hypertens, 2008. 17(2): p. 127–132.

Part Overview of Pathophysiology, Etiology and Epidemiology

II

Mechanisms of Acute Kidney Injury and Repair

2.1

Joseph V. Bonventre

Core Messages

›› Injection of mesenchymal stem (stromal) cells

›› The pathogenesis of acute kidney injury (AKI) ››

››

››

is complex and varies to some extent based on the particular cause. Inflammation contributes to this pathophysiology in a variety of contexts. Inflammation can result in reduction in local blood flow to the outer medulla, with adverse consequences on tubule function and viability. Both the innate and adaptive immune responses are important contributors to inflammation. With ischemia/reperfusion, endothelial cells express a number of adhesion molecules which have counterreceptors on leukocytes. A number of vasoactive mediators that are released with injury, such as nitric oxide, may also affect leukocyte–endothelial interactions. There is obstruction of the microvasculature as well as enhanced vasoconstriction. Tubule epithelial cells generate proinflammatory and chemotactic cytokines. In response to bilateral ischemia/reperfusion injury, mouse kidneys produce D series resolvins and protectins which reduce intrarenal inflammation and limit injury.

J. V. Bonventre Brigham and Women’s Hospital, Renal Division, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected]

››

is protective against renal injury as assessed by serum creatinine measured 24 h after ischemia. The mechanism of such protection may be through intrarenal paracrine effects to decrease inflammation or by systemic immune modu­ lation. The epithelial cells that replace the lost cells derive from surviving tubular epithelial cells.

2.1.1  Introduction The mechanisms involved in kidney injury and repair are complex. In this chapter, I will briefly summarize various components of this complexity. There are many potential causes of acute kidney injury (AKI), and each has its own characteristics, but I will focus on overriding themes, recognizing that the importance of some mechanisms may be dependent on the factors leading to the development of acute kidney dysfunction. The kidney is particularly susceptible to ischemia and toxins with resultant vasoconstriction, endothelial damage, and activation of inflammatory processes. This susceptibility derives in part from the vascular–tubular structural associations in the outer medulla of the kidney which lead to enhanced susceptibility to compromise of blood flow to critical nephron structures that are present there. In addition, because the nephron concentrates many substances as glomerular filtrate is reabsorbed from the tubular lumen, the concentrations of these substances may reach thresholds of toxicity to the surrounding epithelial cells. It is increasingly recognized that AKI is frequently superimposed on chronic renal disease and may be an important precipitant for progression to end-stage

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renal disease. The interplay between chronic and acute kidney disease contributes to additional complexity in understanding the mechanisms. The kidney is robust in its ability to repair itself, but often this ability is not manifest in our patients. To better understand how to facilitate recovery from AKI, it is important to understand the processes of repair under circumstances where repair is effective. This has led to a great deal of excitement in the area of stem cell biology as it relates to the kidney. We will discuss injury in the first part of this chapter and repair in the second.

2.1.2  Injury In response to a variety of insults, including ischemia and many toxins, there are many common features of

the epithelial cell response. The processes of injury and repair to the kidney epithelium are depicted schematically in Fig. 2.1.1. Injury results in rapid loss of cytoskeletal integrity and cell polarity. There is shedding of the proximal tubule brush border, loss of polarity with mislocalization of adhesion molecules and other membrane proteins such as Na+,K+-ATPase and b-integrins [50]. Cells die by apoptosis and necrosis [42]. With severe injury, viable and nonviable cells are desquamated leaving regions where the basement membrane remains as the only barrier between the filtrate and the peritubular interstitium. This allows for backleak of the filtrate, especially under circumstances where the pressure in the tubule is increased due to intratubular obstruction resulting from cellular debris in the lumen interacting with proteins such as fibronectin which enter the lumen [51]. Many cellular factors are involved with injury of the epithelial cell. Some of

Ischemia/ Reperfusion Necrosis

Apoptosis

Toxins

Normal Epithelium

Loss of polarity

Cell death

Differentiation & Reestablishment of polarity

Proliferation

Adhesion molecules Na +/K +- ATPase

Shedding of viable and dead cells

Dedifferentiation, Migration of Viable Cells

Fig. 2.1.1  Injury and repair to the epithelial cell of the kidney with ischemia/reperfusion. One of the first things to happen to the proximal epithelial cell after injury to the kidney is loss of the brush border and loss of the polarity of the epithelial cell with mislocation of adhesion molecules and Na+,K+-ATPase and other proteins. If the insult is severe, there is cell death by either necrosis or apoptosis. In addition, because of the mislocation of adhesion molecules, viable epithelial cells lift off the basement membrane and are found in the urine. The desquamated cells and

cellular debris can interact with luminal proteins to physically obstruct the tubule lumen. If provided with the proper nutrients and oxygen supply, the kidney can then initiate a repair process. Viable epithelial cells dedifferentiate and migrate over the basement membrane. The source of these cells appears to be the kidney itself and not the bone marrow. Cells replacing the epithelium may derive from differentiated epithelial cells or from a subpopulation of progenitor cells within the tubule. The cells then differentiate and reestablish the normal polarity of the epithelium

2.1  Mechanisms of Acute Kidney Injury and Repair Table 2.1.1  Proximate cellular causes of injury • ATP depletion • Increased intracellular free Ca2± concentration • Phospholipase activation • Protease activation including caspases • Endonuclease activation • Mitochondrial injury with cytochrome C leakage • Reactive oxygen species • Increased mitochondrial and plasma membrane permeability • Decreased protein synthesis • Endoplasmic reticulum swelling • Clumping of nuclear chromatin

these are summarized in Table 2.1.1. The endothelium likely also plays an important role in the injury, since blood flow and hence oxygen and nutrient delivery to the epithelial cell, as well as waste product removal, depends critically on the integrity of the vasculature. In turn, the integrity of the vasculature depends critically on a normal functioning endothelium. Damage to endothelial cells and subsequent distortion of peritubular capillary blood flow are characteristics of ischemic injury [2]. The damage to the endothelium may then result in impaired blood flow and lead to epithelial cell injury. Diminished blood flow may be particularly problematic in the outer medulla where endothelial edema may be particularly prone to result in stasis, given the confined space. Furthermore, in this region of the kidney, the oxygen tension is low at baseline due to countercurrent exchange in the vasa recta [8]; hence, impaired flow is particularly likely to lead to proximal tubule cell death. The epithelium is likely not to just be an innocent bystander in the process of kidney injury. Activation and damage to the epithelium results in the generation of inflammatory and vasoactive mediators, which can feed back on the vasculature to worsen the vasoconstriction and inflammation. Furthermore, there is activation of innate immunity which may play a critical role in the acute and chronic sequelae of initiation of injury. Inflammation contributes in a critical way to injury in AKI [7].

2.1.3  Inflammation The innate immune response. Both the innate and adaptive immune responses are important contributors to the pathobiology of ischemic injury. The innate

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component is responsible for the early response to infection or injury and is foreign-antigen independent. Toll-like receptors (TLRs), which are important for the detection of exogenous microbial products [1] and development of antigen-dependent adaptive immunity [22], also recognize host material released during injury [21]. TLRs are present in epithelial cells and up-regulated in response to endogenous ligands which are released by damaged tissue. TLRs can mediate a strong proinflammatory response, which, in many organs, includes activation and maturation of dendritic cells, the most potent antigen-presenting cells of the immune system [39]. Dendritic cells then activate naïve T cells to be antigen-specific, hence triggering the adaptive immune response. With ischemia/reperfusion in rats there was an increase in the number of dendritic cells that differentiated from peripheral blood monocytes, as well as a higher production of interleukin-12 (IL-12), greater expression of major histocompatibility complex (MHC) class II, and greater production of interferon-g (IFN-g) by T cells stimulated by dendritic cells [48]. Furthermore, it has been demonstrated that hypoxia in vitro and ischemia/reperfusion in vivo result in differentiation of dendritic cells that is comparable to allogeneic stimulation [36]. The role of TLRs was evaluated using an ischemia/ reperfusion model in TLR2−/− and TLR2+/+ mice [27]. Significantly fewer granulocytes were present in the interstitium of the kidney 1 day post ischemia/reperfusion in the TLR2−/− mice, and fewer macrophages were present 1–5 days after ischemia/reperfusion. Kidney homogenate cytokines KC, MCP-1, IL-1b, and IL-6 were also significantly lower in the TLR2−/− animals as compared with the TLR+/+ mice. Hence the absence of TLR2 clearly had an antiinflammatory effect on the response to ischemia/reperfusion. This antiinflammatory effect was associated with a functional protection as measured by serum creatinine at 1 day post ischemia/reperfusion and blood urea nitrogen and tubular injury score 1 and 5 days post ischemia/reperfusion. In a study of the role of TLR4 in ischemia/reperfusion injury of the kidney, Wu et al. [49] found that TLR4 expression by tubular epithelial cells is up-regulated by ischemia in vivo or in vitro. TLR4−/− animals were protected against ischemic injury, and injury was not significantly enhanced by a bone marrow transplant with marrow from TLR4+/+ mice, indicating that the protection afforded the TLR4−/− animals was due to prevention of TLR4 signaling in intrinsic kidney cells.

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Additional tubule contributions to inflammatory injury. Both the S3 segment of the proximal tubule and the medullary thick ascending limb (MTAL) are located in the outer stripe of the outer medulla. This region of the kidney is marginally oxygenated under normal conditions, and after an ischemic insult, oxygenation is further compromised because the return in blood flow is delayed. Both segments of the nephron contribute to the inflammatory response in AKI [5]. The distal tubule is physically closely associated with the proximal tubule and the vasa recta in the outer medulla. The distal cells are more adapted to the hypoxic environment of the medulla. Hence, with the increasing hypoxia associated with AKI, these cells are able to survive the insult more effectively than the S3 segment cells of the proximal tubule. This does not mean, however, that the distal cells are not involved in an important way in the overall response to ischemia including the modulation of inflammatory pathways. The distal tubule cells adaptively increase the production of survival factors, including growth factors, which may enhance the survival of the adjacent proximal tubule cells [17]. The tubule epithelial cells are known to generate proinflammatory and chemotactic cytokines such as TNF-a, MCP-1, IL-8, IL-6, IL-1b, and TGF-b, MCP1, IL-8, RANTES, and ENA-78 [7]. Proximal tubular epithelia may respond to T lymphocyte activity through activation of receptors for T cell ligands [28]. When CD40 on the proximal tubule cell is ligated in response to interaction with CD154, MCP-1 and IL-8 production is enhanced, as is TRAF6 recruitment and MAPK activation [28]. CD40 also induces RANTES production by human renal tubular epithelia, an effect which is amplified by production of IL-4 and IL-13 by T helper 2 (Th2) cells, a subpopulation of T cells [11]. B7-1 and B7-2 can be induced on proximal tubule epithelial cells in vivo and in vitro. After B7-1 and B7-2 induction, proximal tubule epithelial cells costimulate CD28 on T lymphocytes resulting in cytokine production [34]. Leukocyte–endothelial interactions. With ischemia/reperfusion, endothelial cells up-regulate integrins, selectins, and members of the immunoglobulin superfamily, including intercellular adhesion molecule-1 (ICAM-1) [24] and vascular cell adhesion molecule (VCAM). Interrupting the production of ICAM-1 either with antibodies or by genetic changes, results in protection of the mouse against ischemic injury [23, 24]. We proposed that this up-regulation of ICAM-1 was related

J. V. Bonventre

to the up-regulation of the proinflammatory cytokines TNF-a and IL-1b, which we measured to be increased by ischemia/reperfusion. A number of vasoactive compounds may also affect leukocyte–endothelial interactions. Vasodilators, such as nitric oxide (NO), also can have effects that decrease inflammation. NO inhibits adhesion of neutrophils to TNF-a-activated endothelial cells [30]. A normal endothelium appropriately regulates vascular tone and vascular permeability, limits adhesion and transmigration of inflammatory cells, and minimizes activation of the pro-coagulation pathways. With injury to the endothelium that characterizes many forms of kidney disease including AKI, there is enhanced leukocyte–endothelial cell adhesion, and activation of platelets and the local coagulation pathway. There is increasing vascular permeability and interstitial edema [41]. Activated platelets bind avidly to leukocytes, forming platelet–leukocyte complexes which roll on the endothelium and produce cytokines which further enhance the inflammatory response [46]. Inhibition of platelet-activating factor protects against ischemia/reperfusion injury in the rat [23]. It has been known for quite some time now that there is less flow to the outer medulla in the postischemic kidney [45]. Enhanced platelet–leukocyte–endothelial interactions can physically impede blood flow especially in the setting of tissue edema [6]. Furthermore, these interactions will additionally activate both leukocytes and endothelial cells and contribute to the generation of local factors that promote vasoconstriction especially in the presence of other vasoactive mediators, resulting in compromised local blood flow and impaired tubule cell metabolism [38]. Due to the anatomical relationships of vessels and tubules in the outer medulla these leukocyte–endothelial interactions impact the outer medulla to a greater extent than in the cortex. Neutrophils, Lymphocytes, and Macrophages. There has been some controversy about the relative importance of various subgroups of leukocytes to AKI. We found a robust influx of neutrophils early after reperfusion in the mouse. To evaluate whether prevention of neutrophil infiltration could be responsible for the protection observed in the ICAM-/-mice, we treated normal mice with antineutrophil serum to reduce absolute neutrophil counts to 1.020

abnormal 500

1.5 15 >1