Evidence-Based Nephrology

This book covers the management of all major renal diseases from an evidence-based and patient-centred approach. With contributions from leading international experts who have a real understanding of evidence-based medicine it provides recommendations on treatment regimens to adopt for individual patients that are most strongly supported by the evidence.

The inclusion of the latest observational and epidemiological data, as well as randomized controlled trial evidence ensures that the book properly reflects the current state of evidence available for nephrological practice. It will be a useful aid to all clinicians, including those caring for transplant and pediatric patients, as it covers the major clinical questions encountered by nephrologists.

This reference is an invaluable source of evidence-based information distilled into guidance for clinical practice which will be welcomed by practitioners, trainees and associated health professionals.

• Language: English
• Publisher: Wiley
• Release date: Aug 31, 2011
• ISBN: 9781444358230

Book preview

Contents

List of contributors

Foreword

Introduction

Why a trial (evidence)-based book

Why a systematic review-based book

Why a book which GRADEs evidence

Why evidence-based nephrology is a work in progress

References

Part 1 Epidemiology of Kidney Disease

1 Epidemiology of Chronic Kidney Disease

William M. McClellan & Friedrich K. Port

Introduction

Definition of chronic kidney disease

Functional and etiologic diagnoses for CKD

Prognostic importance of the stage of CKD

Complications of CKD and CKD stages

Descriptive epidemiology of CKD

Survival after initiation of RRT

References

2 Chronic Disease Surveillance and Chronic Kidney Disease

Diane L. Frankenfield & Michael V. Rocco

Definition of surveillance

US ESRD surveillance systems

ESRD Network and treatment center quality improvement activities

Other national ESRD surveillance systems

Other ESRD surveillance systems

Practice-based screening and quality management for CKD

Summary

References

3 Risk Factors for Progression of Chronic Kidney Disease

Eberhard Ritz, Danilo Fliser, & Marcin Adamczak

Evidence for progression of primary and secondary chronic kidney diseases

Assessment of CKD progression

Prevention of progression of CKD

References

4 Epidemiology and Screening for Chronic Kidney Disease

Sylvia Paz B. Ramirez

Epidemiology of chronic kidney disease as a basis for a population-based system for surveillance and screening for kidney disease

Impact of natural history of CKD on screening

Impact of other factors on development of a surveillance and screening system

High-risk populations for CKD

Cost-effectiveness analyses for CKD screening

Discussion and recommendations for future research

References

5 Prediction of Risk and Prognosis: Decision Support for Diagnosis and Management of Chronic Kidney Disease

Benedicte Stengel, Marc Froissart, & Jerome Rossert

Estimation of GFR

Assessment of proteinuria

Mortality and ESRD risk associated with CKD

References

Part 2 Acute Kidney Injury

6 Definition, Classification, and Epidemiology of Acute Kidney Disease

Eric A. J. Hoste, Ramesh Venkataraman, & John A. Kellum

Introduction

From acute kidney failure to acute kidney injury

Epidemiology of AKI

Outcomes in AKI

Limitations of the RIFLE criteria

Biomarkers of renal tubular injury

Conclusions

References

7 Pre-Renal Failure and Obstructive Disease

Kevin W. Finkel

Introduction

Diagnosis

Treatment

Cardiorenal syndrome

Obstructive nephropathy

References

8 Hepatorenal Syndrome

Andrés Cárdenas & Pere Ginès

Pathogenesis

Clinical features

Clinical diagnosis

Management

Prevention

References

9 Acute Tubular Necrosis

Jay L. Koyner & Patrick T.Murray

Introduction

Diagnosis

Pathophysiology

Outcomes

Preventive strategies

Pharmacologic therapy of established ATN

Summary

References

10 Radiocontrast Nephropathy

Brendan J. Barrett & Patrick S. Parfrey

Introduction

Definition of contrast-induced nephropathy

Burden of disease

Risk stratification of patients

Preventive interventions

Conclusions and recommendations

References

11 Miscellaneous Etiologies of Acute Kidney Injury

Kamalanathan K. Sambandam & Anitha Vijayan

Introduction

Acute interstitial nephritis

AKI associated with multiple myeloma

Crystalline nephropathies

Atheroembolic renal disease

Renal artery and vein thromboses

References

12 RenalReplacement Therapy inAcuteKidney Injury

Steven D. Weisbord & Paul M. Palevsky

Introduction

Prescription and delivery of RRT

Mechanistic considerations in RRT

Summary

Acknowledgment

References

Part 3 Primary Glomerulonephritis

13 Management of Idiopathic Nephrotic Syndrome in Adults: Minimal Change Disease and Focal Segmental Glomerulosclerosis

Alain Meyrier

Definitions

Renal function: progression to chronic kidney disease

MCD

Management

FSGS

Plasmapheresis

Pregnancy

References

14 Membranous Nephropathy

Fernando C. Fervenza & Daniel C. Cattran

Introduction

Natural history

Clinical manifestations

Predicting factors

Response measurements

Treatment

References

15 IgA Nephropathy in Adults and Children

Jonathan Barratt, John Feehally, & Ronald Hogg

Introduction

Natural history

Prognostic factors

Methods

Recommendations

Immunosuppressive treatments

References

16 Membranoproliferative Glomerulonephritis

Richard J. Glassock

Introduction

Classification

Clinical features and natural history

Evidence base for treatment decisions

Summary and recommendations

References

Part 4 Secondary Diseases of the Kidney

Hypertensive Renal Disease

17 Hypertension: Classification and Diagnosis

Bernardo Rodriguez-Iturbe & Crispín Marin Villalobos

Introduction

Determination of blood pressure in different settings

Classification of hypertension

Hypertension as a cause and consequence of kidney disease

Evaluation of the hypertensive patient

References

18 Management of Essential Hypertension

Eberhard Ritz, Danilo Fliser, & Marcin Adamczak

Evidence for hypertensive renal damage

Diagnosis of hypertensive renal damage

Prevention and treatment

References

19 Management of Hypertension in Chronic Kidney Disease

Aimun Ahmed, Fairol H. Ibrahim, & Meguid El Nahas

Hypertension and risk of developing chronic kidney disease

Hypertension and risk of progression of CKD

Mechanisms of hypertension in CKD

Guidelines for management of hypertension

Guidelines for management of hypertensive CKD

Risk stratification of CKD and CVD risk: the CKD-CVD complex

References

20 Diagnosis and Management of Renovascular Disease

Jörg Radermacher

Introduction

Pathophysiology of renal artery stenosis

Patients who should be screened for renal artery stenosis

Screening methods for renal artery stenosis

Quantification of stenosis and estimation of functional relevance

Exclusion of renoparenchymatous disease

Correction of renal artery stenosis versus drug treatment

Improving short-and long-term results of correction of renal artery stenosis

Cholesterol embolism and radiocontrast toxicity

Conclusions

References

21 Diabetes Mellitus

Piero Ruggenenti & Giuseppe Remuzzi

Introduction

The epidemics of type 2 diabetes and related renal and cardiovascular disease

Diabetic renal disease

The cardio-renal syndrome

Protecting target organs in people with diabetes and kidney disease

Inhibition of the RAAS

Role of calcium channel blockade: class effects of dihydropyridine and nondihydropyridine calcium antagonists

Role of intensified blood pressure control

Preventing kidney disease in people with diabetes

Conclusions

References

22 Lupus Nephritis

Arrigo Schieppati, Erica Daina, & Giuseppe Remuzzi

Definition and epidemiology of lupus nephritis

Diagnosis and monitoring lupus nephritis

Renal pathology

Outcome

Treatment of lupus nephritis

Conclusions

References

23 Infection-Related Nephropathies

Monique E. Cho & Jeffrey B. Kopp

Introduction

HIVAN and collapsing glomerulopathy

Pathogenesis of HIV-associated collapsing glomerulopathy

Treatment

HIV-associated glomerulonephritis

Thrombotic microangiopathy

Drug-induced nephrotoxicity in HIV-1 infection

References

24 Hepatitis B Virus

M. Aamir Ali, Scott D. Cohen, & Paul L. Kimmel

Hepatitis B virus

HBV infection and renal disease

HBV-associated membranous nephropathy

HBV-associated MPGN

Treatment

HBV and PAN

HBV and essential mixed cryoglobulinemia

HBV and IgAN

HBV and FSGS

HBV and ESRD

Conclusions

References

25 Infection-Related Nephropathies: Hepatitis C Virus

Dirk R. J. Kuypers

Introduction

Glomerular disease associated with HCV infection

Role of HCV infection in MPGN with type II mixed cryoglobulinemia

Clinical manifestations

Renal pathology

Treatment

References

26 Polyomavirus-Associated Nephropathy

Fabrizio Ginevri & Hans H. Hirsch

Introduction

Definitions

Pathogenesis of PVAN

Risk factors

Clinical management

Perspective

References

Toxic Nephropathies

27 Toxic Nephropathies: Nonsteroidal Anti-Inflammatory Drugs

Wai Y. Tse & Dwomoa Adu

Introduction

Cyclooxygenases in the kidney

Clinical syndromes associated with nonselective and COX-2-selective NSAIDs

Conclusions

References

28 Toxic Nephropathies: Environmental Agents and Metals

Richard P. Wedeen

Introduction

Heavy metals

Solvent nephropathy

References

29 The Kidney in Pregnancy

Phyllis August & Tiina Podymow

Renal anatomy and physiology in pregnancy

Assessment of renal function in pregnancy

Kidney disease in pregnancy

Therapy of end-stage renal disease during pregnancy

Hypertensive disorders of pregnancy

Conclusions

References

Part 5 Chronic Kidney Disease, Chronic Renal Failure

30 Progression of Kidney Disease: Diagnosis and Management

Anil K. Agarwal, Nabil Haddad, & Lee A. Hebert

Introduction

GFR loss and risk of natural progression

Proteinuria magnitude and risk of natural progression

Monitoring kidney disease progression

Therapy of natural progression

References

31 Treatment of Anemia in Chronic Kidney Disease, Stages 3–5

Robert N. Foley

Introduction

Evaluation of anemia in CKD

Hemoglobin targets in CKD

Use of ESAs

Iron therapy

References

32 Dyslipidemia in Chronic Kidney Disease

Vera Krane & Christoph Wanner

Introduction

Types of dyslipidemia in different stages of chronic kidney disease and renal replacement therapy

Dyslipidemia and impact on CVD

Cardiovascular end point studies on lipid-lowering therapy in CKD patients

Renal end point studies of lipid-lowering therapy in CKD patients

Treatment guidelines

References

33 Chronic Kidney Disease and Hypertension

Sangeetha Satyan & Rajiv Agarwal

CKD burden in the general population

Misclassification of HTN with BP monitoring in clinic

Role of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers in CKD and HTN

BP level and progression of nephropathy

Goal BP in CKD and HTN

Choice of antihypertensive therapy in CKD and HTN

Conclusions

References

34 Recognition and Management of Mineral and Bone Disorder of Chronic Kidney Disease and End-Stage Renal Disease

Donald A. Molony

Definition of MBD in CKD

In the development of CKD, when does MBD begin?

Epidemiology and definition of vitamin D deficiency

Does vitamin D supplementation improve other aspects of health and survival in the non-CKD population?

What is the evidence then that vitamin D replacement in patients with CKD results in meaningful clinical patient-centered outcomes?

25(OH)-Vitamin D

Hyperphosphatemia

Treatment strategies for hyperphosphatemia

Phosphate-restricted diet

Phosphate binders

Metal salts as phosphate binders

Non-met al-based phosphate binders

Calcium-based phosphate binders: are they safe?

Sevelamer

Meta-analyses comparing sevelamer and other binders

Hyper-and hypoparathyroidism

Treatments for secondary hyperparathyroidism of CKD

Calcimimetic therapy

Bisphosphonates

References

35 Preparation for Dialysis

Mark G. Parker & Jonathan Himmelfarb

Timeliness of nephrology referral and outcomes

Modality selection

Vascular access planning for hemodialysis

Peritoneal access planning for peritoneal dialysis

Summary

References

Part 6 Chronic Kidney Disease Stage 5: Hemodialysis

36 When to Start Dialysis andWhether the First Treatment Should Be Extracorporeal Therapy or Peritoneal Dialysis

Raymond T. Krediet

When to start dialysis

PD or HD as initial renal replacement therapy

References

37 Modalities of Extracorporeal Therapy: Hemodialysis, Hemofiltration, and Hemodiafiltration

Kannaiyan S. Rabindranath & Norman Muirhead

Introduction

Principles of extracorporeal RRT modalities

Review of current clinical practice guidelines

Availability of evidence

Evidence from nonrandomized studies

Evidence from systematic reviews of RCTs

Extracorporeal RRT modalities

Critique of the evidence and guidelines

Conclusions

References

38 Dialysis Delivery and Adequacy

Peter Kotanko, Nathan W. Levin, & Frank Gotch

Introduction

Kinetic modeling

Dialysis delivery

eKt/V and spKt/V

Dialysis dosing target

Impact of residual renal urea clearance on eKt/V and estimated nPCR

Standard Kt/V

Use of approximation equations

The NCDS and HEMO studies

Dialysis adequacy: current recommendations

The Frequent Hemodialysis Network trial

References

39 General Management of the Hemodialysis Patient

Robert Mactier & David C. Wheeler

Introduction

Hyperkalemia

Metabolic acidosis

Hypertension

Dialysis-related hypotension

Nutrition

Dyslipidemia

Conclusion

References

40 Infections in Hemodialysis

Behdad Afzali & David J. A. Goldsmith

Introduction

Susceptibility to infection in patients receiving HD: immunodeficiency

Infections related to vascular access

Management of access-related infections in HD

Treatment of access-related infections

Conclusions

References

41 Non-Access-Related Nosocomial Infections in Hemodialysis

Brett W. Stephens & Donald A. Molony

Introduction

Background

Epidemiology

Dialysis-related infections

Water quality

Dialyzer reuse

Guidelines and recommendations

Summary

References

42 Vascular Access for Hemodialysis

Kevan R. Polkinghorne

Introduction

Screening and vascular access survival

Pharmacological approaches to preventing AVF and AVG failure: RCTs

Conclusions

References

Part 7 Chronic Kidney Disease Stage 5: Peritoneal Dialysis

43 Selection of Peritoneal Dialysis as Renal Replacement Therapy

Norbert Lameire, Raymond Vanholder, & Wim Van Biesen

Introduction

Factors driving modality selection

PD in special patient groups

References

44 Small Solute Clearance in Peritoneal Dialysis

Sharon J. Nessim & Joanne M. Bargman

Introduction

Recommended targets and monitoring of PD adequacy

Strategies for optimizing peritoneal solute clearance

Strategies for preserving RRF

Conclusions

References

45 Salt andWater Balance in Peritoneal Dialysis

Cheuk-Chun Szeto & Philip Kam-Tao Li

Influence of salt and water removal

Assessment and monitoring of salt and water balance

Tests of peritoneal transport

Classification, diagnosis, and management of UF failure

Measures augmenting salt and water removal in PD patients

Acknowledgments

References

46 Impact of Peritoneal Dialysis Solutions on Outcomes

David W. Johnson & John D. Williams

Introduction

Neutral pH, lactate-buffered, low-GDP fluids

Neutral pH, bicarbonate (± lactate)-buffered, low-GDP fluids

Icodextrin

Amino acid dialysates

Conclusions

References

47 Prevention and Treatment of Peritoneal Dialysis-Related Infections

Giovanni F. M. Strippoli, Kathryn J. Wiggins, David W. Johnson, Sankar Navaneethan, Giovanni Cancarini, & Jonathan C. Craig

Introduction

Definitions

Available guidelines for prevention and treatment of exit site and tunnel infection and peritonitis

Available evidence for prevention and treatment of exit site and tunnel infections and peritonitis

Conclusions

References

Part 8 Transplantation

48 Evaluation and Selection of the Kidney Transplant Candidate

Bryce Kiberd

Introduction

Cardiovascular disease

Cerebral vascular disease

Peripheral vascular disease

Pulmonary disease

Cancer

Infections

Liver disease

Gastrointestinal disease

Systemic disease

Recurrent disease

Urological issues

Obesity

Compliance and adherence

References

49 Evaluation and Selection of the Living Kidney Donor

Connie L. Davis

Introduction

The overall evaluation process

Immediate surgical risk: assessment of cardiopulmonary and coagulation systems

Mortality

Renal evaluation

Other testing

Other issues

Consent

References

50 Predictors of Transplant Outcomes

Krista L. Lentine, Robert M. Perkins, & Kevin C. Abbott

Introduction

Definitions

Infections after kidney transplantation

Cardiovascular disease and posttransplantation outcomes

Summary

References

51 The Early Course: Induction, Delayed Function, and Rejection

Paul A. Keown

Introduction

Definitions

Guidelines

Available evidence

Conclusion

References

52 Maintenance Immunosuppression

Yves Vanrenterghem

Introduction

Tacrolimus–mycophenolate mofetil–corticosteroids: the current standard of maintenance immunosuppression

Maintenance immunosuppression without corticosteroids

Maintenance immunosuppression without CNIs

References

53 Chronic Allograft Nephropathy

Bengt C. Fellström, Alan Jardine, & Hallvard Holdaas

Definition

The course of CAN

Immunological injury

Clinical factors and progression of CAN

BK virus nephropathy

Prevention and treatment

Overall impact of CAN

Summary and conclusion

References

Part 9 Disorders of Electrolytes (Acute and Chronic)

54 Overview of Electrolyte and Acid–Base Disorders

L. Lee Hamm & Michael Haderlie

Introduction to evidence-based electrolyte disorders section

Normal physiology of acid–base homeostasis

Diagnosis of acid–base disorders

Metabolic acidosis

Treatment of metabolic acidosis

Treatment of other causes of metabolic acidosis

Metabolic alkalosis

Summary

References

55 Hyponatremia

Chukwuma Eze & Eric E. Simon

Introduction

Clinical manifestations

Incidence, morbidity, and mortality

Treatment

Summary of recommendations for various entities

References

56 Potassium Disorders

John R. Foringer, Christopher Norris, & Kevin W. Finkel

Introduction

Hyperkalemia

Hypokalemia

References

57 Metabolic Evaluation and Prevention of Renal Stone Disease

David S. Goldfarb

Introduction

Urologic aspects of stone disease

Guidelines on evaluation and management of stone formers

Evaluation of stone formers

Calcium stones

Nonspecific prevention of stone recurrence

Calcium phosphate stones

Struvite stones

Uric acid stones

Cystinuria

References

Part 10 Pediatrics

Themes Across Renal Disease and Renal Failure

58 Growth, Nutrition, and Pubertal Development

Lesley Rees

Phases of normal growth and influence of renal disease

Prevalence, severity, and natural history of growth disorders in chronic kidney disease

Chronic kidney failure

Dialysis

Posttransplantation

Final height

Available guidelines

Evidence for benefits of interventions on nutrition and growth

Effect of height on long-term outcome

Conclusions

References

59 Hypertension, Cardiovascular Disease, and Lipid Abnormalities in Children with Chronic Kidney Failure

Elke Wühl & Franz Schaefer

Introduction

Hypertension

Measurement of BP in children and selection of appropriate normative data

Efficacies of strategies for prevention and treatment of hypertension in children

CVD in children with CKF

Efficacies of strategies for prevention of CVD in children

Lipid abnormalities in pediatric kidney disease

Efficacies of strategies for prevention and treatment of lipid abnormalities in children

Conclusions

References

60 Bones Across Kidney Disease and Kidney Failure

Mary B. Leonard

Introduction

Histomorphometry of renal osteodystrophy in children

PTH assays and bone turnover in pediatric CKD

Treatment of renal

Glucocorticoid-induced osteoporosis in pediatric CKD

Quantitative assessment of bone status in children

Summary

References

61 Anemia

Susan Furth & Sandra Amaral

Introduction: causes of anemia in chronic kidney disease

Sequelae of anemia in CKD

Treatment

References

Management of Renal Failure/Transplants

62 Renal Transplantation

Pierre Cochat & Justine Bacchetta

Epidemiology and outcomes for patient and graft

Donor and recipient factors affecting outcome

Evidence for efficacy of primary immunosuppression regimens for both induction and maintenance

Evidence for efficacy of treatment of acute rejection

Epidemiology, outcomes, and management of chronic rejection and allograft nephropathy

Epidemiology, outcomes, and management of infectious diseases

Epidemiology, outcomes, and management of disease recurrence

Epidemiology, outcomes, and management of malignancy

Evidence for effects of treatment adherence on graft outcome

Conclusions

References

63 Peritoneal Dialysis in Children

Jaap W. Groothoff & Maruschka P. Merkus

Introduction

Searching for evidence

Patient survival and causes of death

Technique survival

Comorbidity

Hospitalization

Clinical implications with respect to choice of RRT

Use and placement of PD catheter

PD-associated infections

Adequacy of Dialysis

References

64 Pediatric Hemodialysis

Stuart L. Goldstein

Introduction

Physiology of hemodialysis: pediatric issues

Hemodialysis adequacy

Target dry weight assessment and ultrafiltration management

Nutrition management

Vascular access

Evidence table

References

Specific Pediatric Renal Disease

65 Urinary Tract Infection, Vesicoureteric Reflux, and Urinary Incontinence

GabrielleWilliams, Premala Sureshkumar, Patrina Caldwell, & Jonathan C. Craig

Introduction

Urinary tract infection

Vesicoureteric reflux

Urinary incontinence

Conclusions

References

66 Epidemiology and General Management of Childhood Idiopathic Nephrotic Syndrome

Nicholas J. A. Webb

Introduction

Epidemiology

SSNS

General management of nephrotic syndrome

Thrombosis

Edema

Evidence-based recommendations

References

67 Management of Steroid-Sensitive Nephrotic Syndrome

Elisabeth M. Hodson, Jonathan C. Craig, & Narelle S. Willis

Introduction

Treatment of the first episode of nephrotic syndrome with corticosteroids

Treatment of the first episode of nephrotic syndrome with corticosteroids and cyclosporine

Treatment of relapsing SSNS with corticosteroids

Corticosteroid-sparing agents in frequently relapsing and steroid-dependent SSNS

Conclusions

References

68 Steroid-Resistant Nephrotic Syndrome

Annabelle Chua & Peter Yorgin

Introduction

Treatment of SRNS: methods

Calcineurin inhibitor therapy

Corticosteroid therapy

Purine synthesis inhibitors

Alkylating agents

Other antineoplastic and immunosuppressant medications

Combination therapy

Nonimmunosuppressant therapy

Pheresis-based therapies

Antibody therapy

Bone marrow transplantation

Conclusions

References

Other Pediatric Renal Diseases

69 Henoch-Schonlein Nephritis and Membranoprolifertive Glomerulonephritis

Sharon Phillips Andreoli

Introduction

Etiology, epidemiology, and natural history of HSP nephritis

Etiology, epidemiology, and natural history of MPGN

References

70 Cystinosis

William G. van’t Hoff

Introduction and clinical course

Treatment

Recommendations for optimal management

References

Index

This edition first published 2009, © by Blackwell Publishing Ltd

BMJ Books is an imprint of BMJ Publishing Group Limited, used under licence by Blackwell Publishing which was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing programme has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell.

Registered office

John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex,

PO19 8SQ, UK

Editorial office

9600 Garsington Road, Oxford, OX4 2DQ, UK

The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA

For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell

The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought.

The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data

Data available

ISBN: 978-1-4051-3975-5

List of contributors

Kevin C. Abbott MD, MPH

Walter Reed Army Medical Center

Washington, DC, USA

Marcin Adamczak MD

Department of Nephrology

Endocrinology and Metabolic Diseases

Medical University of Silesia

Katowice, Poland

Dwomoa Adu MD, FRCP

Department of Nephrology

Queen Elizabeth Hospital

Birmingham, United Kingdom

Behdad Afzali MD

Department of Nephrology and Transplantation

Guy’s Hospital

London, United Kingdom

Anil K. Agarwal MD

Department of Internal Medicine

The Ohio State University Medical Center

Columbus, Ohio, USA

Rajiv Agarwal MD

Division of Nephrology

Department of Medicine

Indiana University School of Medicine,

Indianapolis, Indiana, USA

Aimun Ahmed MD

Sheffield Kidney Institute

Sheffield, United Kingdom

M. Aamir Ali MD

Division of Renal Diseases and Hypertension

Department of Medicine

George Washington University Medical Center

Washington, DC, USA

Sandra Amaral MD, MHS

Division of Pediatric Nephrology

Emory Healthcare & Children’s Healthcare of Atlanta, Atlanta, Georgia, USA

Sharon Phillips Andreoli MD

Bryon P. and Frances D. Hollett Professor of Pediatrics

Director of the Division of Pediatric Nephrology

James Whitcomb Riley Hospital for Children

Indianapolis, Indiana, USA

Phyllis August MD, MPH

Weill Medical College of Cornell University

Ithaca, New York, USA

Justine Bacchetta MD

Département de Pédiatrie & Inserm

Hôpital Edouard-Herriot

Hospices Civils de Lyon & Université Lyon

Lyon, France

Joanne M. Bargman MD

Department of Medicine

Division of Nephrology

University of Toronto

Toronto, Canada

Jonathan Barratt MD

Department of Infection

John Walls Renal Unit

Leicester General Hospital

Leicester, United Kingdom

Brendan J. Barrett MBBS, PhD

Division of Nephrology and Clinical Epidemiology

Faculty of Medicine

Memorial University of Newfoundland

St. John’s, Newfoundland, Canada

Patrina Caldwell MBBS, PhD

Centre for Kidney Research

The Children’s Hospital at Westmead

Westmead, Australia

Giovanni Cancarini MD

Section and Division of Nephrology

Department of Experimental and Applied

Medicine

University and Spedali Civili

Brescia, Italy

Andrés Cárdenas MD, MMSc

Liver Unit

Institut de Malalties Digestives i Metaboliques

Hospital Clinic

University of Barcelona

Barcelona, Spain

Daniel C. Cattran MD, FRCP

University of Toronto

Toronto, Ontario, Canada

Monique E. Cho MD

Kidney Disease Section

National Institute of Diabetes and Digestive and Kidney Diseases

National Institutes of Health

US Department of Health and Human Services

Bethesda, Maryland, USA

Annabelle Chua MD

Section of Pediatric Nephrology

Texas Children’s Hospital

Baylor College of Medicine

Houston, Texas, USA

Pierre Cochat MD

Département de Pédiatrie

Hôpital Edouard-Herriot

Lyon, France

Scott D. Cohen MD

Division of Renal Diseases and Hypertension

Department of Medicine

George Washington University Medical Center

Washington, DC, USA

Jonathan C. Craig MD, PhD

School of Public Health

University of Sydney

Deptartment of Nephrology

The Children’s Hospital at Westmead

Sydney, Australia

Erica Daina MD

Mario Negri Institute for Pharmacological

Research

Negri Bergamo Laboratories

Bergamo, Italy

Connie L. Davis MD

Division of Nephrology

Department of Medicine

University of Washington School of Medicine

Seattle, Washington, USA

Allison Eddy MD

Children’s Hospital & Regional Medical Center

Seattle, Washington, USA

Meguid El Nahas PhD, FRCP

Sheffield Kidney Institute

Northern General Hospital

Sheffield, United Kingdom

Chukwuma Eze MD

Good Samaritan Hospital

Dayton, Ohio, USA

John Feehally MD

University of Leicester

The John Walls Renal Unit

Leicester General Hospital

Leicester, United Kingdom

Bengt C. Fellström MD, PhD

Department of Medical Sciences

Nephrology Unit

University Hospital

Uppsala, Sweden

Fernando C. Fervenza MD, PhD

Division of Nephrology and Hypertension

Mayo Clinic College of Medicine

Rochester, Minnesota, USA

Kevin W. Finkel MD

Division of Renal Diseases and Hypertension

University of Texas Medical

School at Houston

Houston, Texas, USA

Danilo Fliser MD

Department of Internal Medicine

Division of Nephrology

Medical School Hannover

Hannover, Germany

Robert N. Foley MB, MSc

Chronic Disease Research Group

University of Minnesota

Minneapolis, Minnesota, USA

John R. Foringer MD

Division of Renal Diseases and Hypertension

University of Texas Medical School at Houston

Houston, Texas, USA

Diane L. Frankenfield MD

Centers for Medicare & Medicaid Services

Office of Clinical Standards and Quality

Baltimore, Maryland, USA

Marc Froissart MD, PhD

Paris-Descartes University School of Medicine

Georges Pompidou European Hospital

INSERM U652

Paris, France

Susan Furth MD, PhD

Pediatrics and Epidemiology Welch Center for Prevention

Epidemiology and Clinical Research

Johns Hopkins Medical Institutions

Baltimore, Maryland, USA

Pere Ginés MD

Liver Unit

Institut de Malalties Digestives i Metaboliques

Hospital Clinic

University of Barcelona

Barcelona, Spain

Fabrizio Ginevri MD

Pediatric Nephrology Unit

Istituto G. Gaslini

Genova, Italy

Richard J. Glassock MD

David Geffen School of Medicine

University of California Los Angeles

Los Angeles, California, USA

David S. Goldfarb MD

Nephrology Division

NYU Medical Center

Professor of Medicine and Physiology

NYU School of Medicine

New York, USA

David J. A. Goldsmith MD

Department of Nephrology and Transplantation

Guy’s Hospital

London, United Kingdom

Stuart L. Goldstein MD

Baylor College of Medicine

Medical Director

Renal Dialysis Unit and Pheresis Service

Houston, Texas, USA

Frank Gotch MD

University of California San Francisco

San Francisco, California, USA

Jaap W. Groothoff MD, PhD

Department of Pediatric Nephrology

Emma Children’s Hospital

Academic Medical Center

Amsterdam, The Netherlands

Nabil Haddad MD

Department of Internal Medicine

The Ohio State University Medical Center

Columbus, Ohio, USA

Michael Haderlie MD

Department of Medicine

Tulane University School of Medicine

New Orleans, Louisiana, USA

L. Lee Hamm MD

Department of Medicine

Tulane University School of Medicine

New Orleans, Louisiana, USA

Lee A. Hebert MD

Department of Internal Medicine

The Ohio State University Medical Center

Columbus, Ohio, USA

Jonathan Himmelfarb MD

Kidney Research Institute

Division of Nephrology

University of Washington Medical School

Seattle, Washington, USA

Hans H. Hirsch MD, MS

Transplantation Virology & Molecular Diagnostics

Institute for Medical Microbiology

University of Basel

Basel, Switzerland

Elisabeth M, Hodson MD

Cochrane Renal Group

Centre for Kidney Research

The Children’s Hospital at Westmead

Westmead, Australia

Ronald Hogg MD

Division of Pediatric Nephrology

Children’s Health Center

St. Joseph’s Hospital and Medical Center

Phoenix, Arizona, USA

Hallvard Holdaas MD

Department of Nephrology

Rikshospitalet

Oslo, Norway

Byron P. Hollett MD

Department of Pediatrics

James Whitcomb Riley Hospital for Children

Indiana University Medical Center

Indianapolis, Indiana, USA

Frances D. Hollett MD

Department of Pediatrics

James Whitcomb Riley Hospital for Children

Indiana University Medical Center

Indianapolis, Indiana, USA

Eric AJ Hoste MD, PhD

The Clinical Research, Investigation and Systems

Modeling of Acute Illness (CRISMA)

Laboratory, Department of Critical Care Medicine

University of Pittsburgh School of Medicine

Pittsburgh, PA

Intensive Care Unit

Ghent University Hospital

Ghent, Belgium

Fairol H. Ibrahim MD

Sheffield Kidney Institute

Northern General Hospital

Sheffield, United Kingdom

Alan Jardine MD

Nephrology & Transplantation

BHF Cardiovascular Research Centre

University of Glasgow

Glasgow, United Kingdom

David W. Johnson MD

Department of Renal Medicine

University of Queensland at Princess Alexandra

Hospital

Brisbane, Australia

Bertram L. Kasiske MD

University of Minnesota

Department of Medicine

Hennepin County Medical Center

Minneapolis, Minnesota, USA

John A Kellum MD

The Clinical Research, Investigation, and Systems

Modeling of Acute Illness (CRISMA)

Laboratory, Department of Critical Care Medicine

University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania, USA

Paul A. Keown MD

Departments of Medicine and Pathology and

Laboratory Medicine

University of British Columbia

Vancouver, BC, Canada

Byrce Kiberd MD

Department of Medicine

Dalhousie University

Halifax, Nova Scotia, Canada

Paul L. Kimmel MD, FACP, FASN

Division of Renal Diseases and Hypertension

Department of Medicine

George Washington University

Medical Center

Washington, DC, USA

Jeffrey B. Kopp MD

Kidney Disease Section

National Institute of Diabetes and Digestive and

Kidney Diseases

National Institutes of Health

US Department of Health and Human Services

Bethesda, Maryland, USA

Peter Kotanko MD

Krankenhaus der Barmherzigen Brüder

Department of Internal Medicine

Graz, Austria

Jay L. Koyner MD

Section of Nephrology

University of Chicago

Chicago, Illinois, USA

Vera Krane MD

Department of Medicine

Division of Nephrology

University of Würzburg

Würzburg, Germany

Raymond T. Krediet MD, PhD

Academic Medical Center

Amsterdam, The Netherlands

Dirk R. J. Kuypers MD, PhD

Department of Nephrology and Renal

Transplantation

University Hospitals Leuven

University of Leuven

Leuven, Belgium

Norbert Lameire MD

Renal Division

Department of Internal Medicine

University Hospital Ghent

Ghent, Belgium

Krista L. Lentine MD, MS

Center for Outcomes Research and Division of

Nephrology

Saint Louis University School of Medicine

St. Louis, Missouri, USA

Mary B. Leonard MD, MSCE

Department of Pediatrics

The Children’s Hospital of Philadelphia

Department of Biostatistics and Epidemiology

University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania, USA

Nathan W. Levin MD

Renal Research Institute

New York, USA

Philip Kam-Tao Li MD, FRCP, FACP

Honorary Professor of Medicine

Chief of Nephrology and Consultant

Department of Medicine & Therapeutics

Prince of Wales Hospital

The Chinese University of Hong Kong

Hong Kong, China

Alison Macleod BMedBiol, MB, ChB, MD,

FRCP

Department of Medicine and Therapeutics

University of Aberdeen

Aberdeen, United Kingdom

Robert Mactier MD

Glasgow Royal Infirmary

Scotland, United Kingdom

Crispé;n Marin Villalobos MD

Nephrology Section

Hospital Universitario and Universidad del Zulia

School of Medicine

Maracaibo, Venezuela

William M. McClellan MD

Renal Division

Emory University School of Medicine

Atlanta, Georgia, USA

Maruschka P. Merkus PhD

Department of Pediatric Nephrology

Emma Children’s Hospital

Academic Medical Center

Amsterdam, The Netherlands

Alain Meyrier MD

Service de Nephrologie

Hôpital Georges Pompidou

Paris, France

Malot G. Minnick-Belarmino PhD

Chronic Kidney Disease in Children

Study Welch Center for Prevention

Baltimore, Maryland, USA

Donald A. Molony MD

Division of Renal Disease and Hypertension

University of Texas

Houston Medical School

Houston, Texas, USA

Norman Muirhead MD

Division of Nephrology

University of Western Ontario

London, Ontario, Canada

Patrick T. Murray MD

Section of Nephrology

University of Chicago

Chicago, Illinois, USA

Sankar Navaneethan MD, MPH

Department of Medicine

Unity Health System

Rochester, New York, USA

Sharon J. Nessim MD

Department of Medicine

Division of Nephrology

University of Toronto

Toronto, Canada

Christopher Norris MD

Division of Renal Diseases and Hypertension

University of Texas Medical School at Houston

Houston, Texas, USA

Paul M. Palevsky MD

Renal-Electrolyte Division

Department of Medicine

University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania, USA

Patrick S. Parfrey MD

Division of Nephrology and Clinical Epidemiology

Faculty of Medicine, Memorial University of Newfoundland

St. John’s, Newfoundland, Canada

Mark G. Parker MD

Maine Medical Center

Portland, Maine, USA

Robert M. Perkins MD

Department of Medicine/Nephrology Service

Medigan Army Medical Center

Ft. Lewis, Washington, USA

Tiina Podymow MD

McGill University Montreal, Quebec, Canada

Kevan R. Polkinghorne MD

Department of Nephrology

Monash Medical Centre

Melbourne, Australia

Friedrich K. Port MD

Arbor Research Collaborative for Health

Ann Arbor, Michigan, USA

Kannaiyan S. Rabindranath MD

Renal Unit

Churchill Hospital

Oxford, United Kingdom

Jörg Radermacher MD

Department of Nephrology

Klinikum Minden

Minden, Germany

Sylvia Paz B. Ramirez MD, MPH, MBA

Arbor Research Collaborative for Health

Ann Arbor, USA

Lesley Rees MD, FRCP, FRCPCH

Consultant Paediatric Nephrologist

Great Ormond St Hospital for Children NHS Trust

London, United Kingdom

Giuseppe Remuzzi MD, FRCP

Clinical Research Center for Rare Diseases

Mario Negri Institute for Pharmacological

Research

Bergamo, Italy

Eberhard Ritz MD

Department of Internal Medicine

Division Nephrology

Ruperto Carola University

Heidelberg, Germany

Michael V. Rocco MD

Wake Forest University School of Medicine

Department of Internal Medicine

Section on Nephrology,

Winston-Salem, North Carolina, USA

Bernardo Rodriguez-Iturbe MD

Nephrology Section

Hospital Universitario and Universidad del Zulia

School of Medicine

Maracaibo, Venezuela

Jerome Rossert MD

Paris-Descartes University School of Medicine

Georges Pompidou European Hospital

INSERM U872

Paris, France

Richard L. Roudebush MD

Division of Nephrology

Department of Medicine

Indiana University School of Medicine

Indianapolis, Indiana, USA

Piero Ruggenenti MD

Unit of Nephrology

Azienda Ospedaliera Ospedali Riuniti di Bergamo

Bergamo, Italy

Kamalanathan K. Sambandam MD

Renal Division

Washington University School of Medicine

St. Louis, Missouri, USA

Sangeetha Satyan MD

Division of Nephrology

Department of Medicine

Indiana University School of Medicine

Indianapolis, Indiana, USA

Franz Schaefer MD

Division of Pediatric Nephrology

Center for Pediatric and Adolescent Medicine

University of Heidelberg

Heidelberg, Germany

Arrigo Schieppati MD

Division of Nephrology and Dialysis

Mario Negri Institute for Pharmacological

Research

Negri Bergamo Laboratories

Bergamo, Italy

Eric E. Simon MD

Department of Medicine

Tulane University School of Medicine

New Orleans, Louisiana, USA

Benedicte Stengel MD

Université Paris-Sud

INSERM U780

Villejuif, France

Brett W. Stephens MD

Division of Renal Disease and Hypertension

University of Texas

Houston Medical School

Houston, Texas, USA

Giovanni F. M. Strippoli MD

Centre for Kidney Research

The Children’s Hospital at Westmead

Westmead, Australia

Cochrane Renal Group

University of Sydney

School of Public Health

Sydney, Australia

Premala Sureshkumar MD

Centre for Kidney Research

The Children’s Hospital at Westmead

Westmead, Australia

Cheuk-Chun Szeto MD, FRCP

Department of Medicine & Therapeutics,

Prince of Wales Hospital

The Chinese University of Hong Kong

Hong Kong, China

Robert Daniel Toto MD

Nephrology Division

University of Texas Southwestern Medical Center

Dallas, Texas, USA

Wai Y. Tse BSc, FRCP, PhD

Department of Neprology

Derriford Hospital

Plymouth, United Kingdom

Wim van Biesen MD

Renal Division

Department of Internal Medicine

University Hospital Ghent

Ghent, Belgium

Raymond Vanholder MD

University of Ghent

Associate Head of the Nephrology

Division of the Ghent University Hospital

Ghent, Belgium

Yves Vanrenterghem MD

Department of Nephrology

University Hospital Gasthuisberg

Leuven, Belgium

William G. van’t Hoff BSc, MD, FRCPCH, FRCP

Nephro-Urology Unit

Great Ormond Street Hospital for Children

London, United Kingdom

Ramesh Venkataraman MD

The Clinical Research, Investigation, and Systems

Modeling of Acute Illness (CRISMA)

Department of Critical Care Medicine

University of Pittsburgh School of Medicine

Pittsburgh Pennsylvania, USA

Anitha Vijayan MD

Renal Division

Washington University School of Medicine

St. Louis, Missouri, USA

Christoph Wanner MD, PhD

Department of Medicine

Division of Nephrology

University of Würzburg

Würzburg, Germany

Nicholas J. A. Webb DM, FRCP, FRCPCH

Department of Nephrology

Royal Manchester Children’s Hospital

Manchester, United Kingdom

Richard P. Wedeen MD

Universily of Medicine and Dentistry of New Jersey

The New Jersey Medical School

New Jersey, New Jersey, USA

Steven D. Weisbord MD, MSc

Renal-Electrolyte Division

Department of Medicine

University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania, USA

David C. Wheeler MD

Royal Free and University College Medical School

London, United Kingdom

Kathryn J. Wiggins MD

The University of Melbourne

Department of Medicine at St. Vincent’s Hospital

Melbourne, Australia

Gabrielle Williams MPH, PhD

Centre for Kidney Research

The Children’s Hospital at Westmead

Westmead, Australia

University of Sydney

Sydney, Australia

John D. Williams MD

Department of Nephrology

Cardiff University

Cardiff, United Kingdom

Narelle S. Willis

Centre for Kidney Research

Cochrane Renal Group

The Children’s Hospital at Westmead

Westmead, Australia

Elke Wühl MD

Division of Pediatric Nephrology

Center for Pediatric and Adolescent Medicine

University of Heidelberg

Heidelberg, Germany

Peter Yorgin MD

Section of Pediatric Nephrology

Loma Linda University Children’s Hospital

Loma Linda, California, USA

Foreword

The evidence-based approach to health care is assuming a greater role in informing patient care worldwide. This approach arises from a convergence of factors, including the easy availability of evidence-based resources that synthesize the evidence, as exemplified by the Cochrane database, the desire of practitioners to attain best practices in the face of an almost overwhelming volume of new biomedical information, and the realization that, in an environment of limited health care resources, the best evidence of effectiveness should be central to the determination of which specific treatments warrant full investment. On the most immediate level, best evidence should inform the rational care of individual patients by the practitioner. On a broader level, best evidence should also influence specific decisions by society on the provision of specific health care services. In each case, evidence forms one of the two main components of a medical decision, as described by David Eddy [1,2].

Because the term evidence-based medicine was first coined by Sackett and colleagues more than 15 years ago, the emphasis in evidence-based medicine has been on evidence as it informs the choices of individual patients and of practitioners caring for these individuals, where the choices are determined by the evidence and by the individual preferences of the patients but not, strictly speaking, bythe relative value or cost-effectiveness of these interventions [3,4]. Although cost-effectiveness determinations naturally evolve from a consideration of the evidence, we have chosen in this first evidence-based medicine-centered textbook in nephrology to address the evidence principally from the perspectives of the patient and the individual practitioner, not the policy maker. It is our hope that this evidence-based nephrology textbook will provide a resource for practitioners, and therefore we have focused on the primary clinical evidence and, where available, systematic reviews of this evidence. Health economic assessments are considered in this text only insofar as such analyses and the policy choices they have engendered may influence the various current national and international management guidelines, such as the National Kidney Foundation?s Kidney Disease Outcomes Quality Initiative and the European Best Practice Guidelines.

What then is the potential for an evidence-based approach to nephrology for the individual practitioner and patient?Asnotedby Eddy [1], ?different value judgments are unavoidable. Yet, a thorough and judicious assessment of the best evidence will promote treatment decisions that are: less arbitrary, better informed, more individualized, more transparent, and more broadly acceptable. The first contribution of evidence-based medicine is to change the anchor for the decision from the beliefs of experts to evidence of effectiveness.? An important consequence of a comprehensive examination of the evidence broadly covering all clinical topics in nephrology as necessitated by this textbook is the exposure of the scope of evidence that informs the diagnosis and management of patients in our field, the laying bare, so to speak, of what is known and what is not known. Recently, Strippoli and coworkers evaluated the number of randomized controlled trials in nephrology compared to other fields in internal medicine [5]. They found that the number of randomized trials in nephrology was substantially lower than for other internal medicine subspecialties. In this evidence-based nephrology textbook, evidence from high-quality observational studies is considered in many cases in conjunction with the randomized controlled trials evidence, a reflection of the current state of the best available evidence that informs the practice of nephrology.

The examination of the totality of evidence should have the following principal outcomes. An explicit acknowledgment of the limited scope of the evidence, specifically, that it is rather incomplete in many areas, should permit a responsible challenge of opinion-based (even expert opinion) practice recommendations and should, thus, reduce the reliance on dogma. Identifying those areas of disease management for which there is only poor-grade evidence should suggest a research agenda. Because evidence-based medicine has traditionally emphasized patient-centered research, it is anticipated that an evidence-based approach will be more robustly patient centered.

In the spirit of evidence-based medicine, we have embarked on this book with the following goals in mind. First, we wish to provide the student of nephrology with a single convenient source of clinical evidence that has been passed through an evidence-based filter. Second, we wish to provide a forum for the reasonable inclusion of data of multiple types as these determine best practice in nephrology, including high-quality observational and epidemiological data, in particular where high-quality experimental data are lacking. Third, by uncovering the areas where evidence is lacking, we hope to help inform the hierarchy of need for clinical trials. We hope that this textbook reflects current best evidence and that it is sufficiently comprehensive to cover the major clinical questions encountered by nephrologists, including those caring for the transplant patient and the pediatric patient. In compiling a textbook we have had to make some editing choices for clarity and organization. There may be areas, we hope very few, that have not been covered as comprehensively as the majority of topics in this text. We have included very little discussion of some topics that are covered extensively in traditional nephrology textbooks, including discussions of the mechanisms of disease and/or pathophysiology that emerge from in vitro studies, unless a discussion of these is likely required to understand clinical evidence on treatment of the relevant renal disorder. Thus, the treatment of electrolyte disorders that typically occupies one-third of most textbooks in nephrology is confined to one rather brief section, as clinical trials evidence is entirely lacking for much of the dogma on this topic.

Figure 1 The spectrum of clinical uncertainty.

By definition a textbook is likely to be less up to date than an evidence-based medicine website that can undergo comprehensive updating in realtime. The latter type of resource, as exemplified by the Cochrane database, requires a large investment of intellectual resources, and for this reason the promise of a truly comprehensive constantly updated review of all topics in nephrology has not been fully achieved to date. In the absence of such resources, we hope that this textbook, Evidence-Based Nephrology, will fill a substantial portion of this void. Furthermore, unlike the Cochrane database, which is almost exclusively focused on questions of therapy, we have also included comparisons of many of the current evidence-based guidelines and we have included a discussion ofthe evidence as it relates to diagnosis, prognosis, and risk identification. We begin with a discussion of the sources of this evidence and the qualities that differentiate high-quality evidence from that of lower quality. We acknowledge that inclusion of nonexperi mental evidence does not permit robust conclusions in the absence of a significant degree of clinical uncertainty. This general concept of a spectrum of clinical uncertainty, in which all clinical decisions are made along a continuum from higher degrees of uncertainty to lower degrees of uncertainty, is illustrated in Figure 1.

It is our hope that this evidence-based nephrology textbook will, by moving the practice of nephrology toward the right-hand end of this spectrum, result in better clinical decisions. In the true spirit of evidence-based medicine, we hope that this text will thus push the specialty toward greater reliance on less biased evidence and make explicit the fact that we will never be able to manage patients without some uncertainty.

We also wish to acknowledge, along with the benefits we have enumerated above, some of the risks of an evidence-based approach in developing a textbook. In sum, we do believe the practice of nephrology is far better off with an evidence-based approach based on the principles that we have tried to exemplify in compiling this text as the starting point of an understanding of our field. To the material detailed in the various chapters, we hope or rather expect that our evidence-based medicine-centered learners and readers will add, through their own judicious application of evidence-based medicine principles, their own new knowledge as it emerges from the medical literature. Additionally, we acknowledge that an evidence-based medicine text might be most up to date when first published but that new information will always emerge between editions; hence, a textbook like this can at best be only one of several resources for the evidence-based medicine practitioner. We hope this effort will provide a core resource for the evidence-based nephrology practitioner who is otherwise limited by time constraints from researching every question that may arise daily in the care of patients.

Donald A. Molony, MD

Jonathan C. Craig, MD

References

1 Eddy DM. Clinical decision making: from theory to practice?anatomy of a decision. JAMA 1990; 263: 441?443.

2 Tunis SR, Eddy D. Reflections on science, judgment and value in evidence-based decision making: a conversation with David Eddy. Health Affairs 2007; 26: 500?515.

3 Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical Epidemiology: a Basic Science for Clinical Medicine, 2nd edn. Little Brown & Co., Boston, 1992; 173?186.

4 Guyatt G, EBM Working Group. Evidence based medicine. A new approach to teaching the practice of medicine. JAMA 1992; 268: 2420?2425.

5 Strippoli GF, Craig JC, Schena FP. The number, quality, and coverage of randomized controlled trials in nephrology. J Am Soc Nephrol 2004; 15(2): 411?419.

Introduction: Trials, Systematic Reviews, Grading Evidence, and Implications for Nephrology Research

Jonathan C. Craig

Why a trial (evidence)-based book

Readers of this book will be very familiar with the usual rationale for why randomized controlled trials (RCTs) should be central to routine clinical care [1]. Fundamentally, health care is about improving health outcomes, and an RCT is the study design which best estimates the true effects of interventions. Clearly, to practice good health care, other types of questions need to be addressed, diagnostic and prognostic questions in particular, and for these questions other study designs are needed. Inevitably in a book like this, some prioritization is needed, and because treatment questions are critical, results of relevant RCTs have been highlighted in all chapters.

The recent history of RCTs is interesting and was begun not in health care but in agricultural science by R. A. Fisher in 1935 [2]. Like many advances in biomedical science, innovators and leaders are always needed, and this came in the form of two eminent English scientists, Major Greenwood and Bradford Hill. Major Greenwood, as head of the Medical Research Council’s (MRC) Statistical Committee, was able to convince the Therapeutic Trials Committee of the MRC in the 1930s to 1940s of the importance of RCTs. Bradford Hill took over Major Greenwood’s position in 1945, and under his supervision the MRC’s randomized trial of streptomycin was conducted in 1946 and published in 1948 [3]. Richard Doll, another major figure in the development of clinical trials during the 20th century, reflected upon the impact of this landmark study. The expert judgment of the Professor in deciding whether an intervention worked or not was rejected in favor of am explicit, quantitative, methodologically robust study design, the randomized trial [4].

The history of RCTs has also been marked by critics who typically suggest that observational studies are more real world, and because they are larger, follow patients for longer time periods, are more inclusive, they are at least as valid as RCTs for evaluating whether interventions work, and they are probably more valid [5–10]. This debate occurred during the so-called outcomes research movement in the 1980s, but it was comprehensively decided in favor of trial-based evaluation of interventions, given that for the past 20 years major research funders, guidelines groups, regulators, and purchasers of health care had almost universally accepted the trial as the most valid study design to evaluate the effects of interventions, with observational studies a clear second [11]. Recently, this debate has been reignited, largely it would seem, to lower the barrier for new drugs and devices for the purposes of approval and subsidization [12].

The fundamental flaw of observational studies is that the allocation of interventions to patients is not random [13–16]. Consequently, any difference in outcomes between the patients who did and those who did not receive the intervention may be due to differences in patient characteristics, and unfortunately these differences can never be reliably and completely adjusted for, despite regression analysis, propensity scores, and the other statistical methods. A large-scale empirical comparison of the results of trials and observational studies was commissioned by the National Health Service and published as a Health Technology Assessment report [17]. The conclusion was clear. Most of the time, the results of observational studies and trials are concordant, but sometimes they are not, and the results of trials cannot be predicted with certainty based upon observational studies. There are many examples, tightness of glucose control in type 2 diabetics being a recent one. Contraryto observational studies, which have consistently shown tight glucose control improves macrovascular and microvascular outcomes, the ACCORD [18] and ADVANCE [19] studies showed no improvement in macrovascular outcomes, and in ACCORD, an increasedall-causemortalitywasreported.Studieslikethesereaffirm the importance of proper evaluation of interventions in RCTs, even though they are expensive and take time. The conduct of trials will become increasingly important when the marginal gains in health care become smaller and the potential harms and costs, greater.

Why a systematic review-based book

Decisions on treatment should be based upon all, and not just some, relevant RCTs. Currently, the Cochrane Renal Group has a register of RCTs in kidney disease that contains the records of about 10,000 trials and 12,000 publications arising out of those trials. The registry steadily increases at about 2000 trials/year. A simple Medline search would find only about two-thirds of these trials, because of problems in classification of the disease category and study design in the Medline coding. Also, about one-fourth of all trials in the registry come from handsearching, mainly from abstract compilations from the major nephrology and transplantation meetings. These studies may never be published (publication bias) or may be published relatively late (publication delay bias). Why systematic reviews of RCTs should form the basis of treatment recommendations and not just narrative reviews or a single trial chosen by an expert is beyond the scope of this introduction, but I will summarize the key points.

For clinicians it is easier to look at one systematic review than the many trials that are summarized in that review. Second, many trials are relatively underpowered, and a formal quantitative synthesis of the results may find a statistically significant benefit (or harm) that none of the component studies found. Meta-analysis provides a summary estimator of treatment effects, where appropriate, and this is necessary to inform practice, to ensure that benefits numerically exceed harms. Third, the variabilities in populations and interventions in a systematic review may increase the applicability of the findings. For example, interleukin 2 receptor antagonists have a remarkably homogeneous effect in reducing acute rejection despite the variability in baseline immunosuppression used [20]. Critics of meta-analyses argue that like should only be kept with like, and that apples and oranges should never be combined. Actually, it is often only in a context of a meta-analysis that there can be formal testing of whether treatment effects vary according to prior beliefs. Fourth, systematic reviews may minimize and/or highlight the various publication biases that might occur. One publication bias, the tendency for so-called negative studies not to be published, can be minimized if a comprehensive search of the grey literature (meeting abstract compilations, etc.) is conducted. The opposite bias, duplication bias, is where one study, typically one that is favorable to an intervention, is published multiple times and this is not disclosed to readers. Some salami slicing is reasonable, when studies are extremely large and report many outcomes. Many is not, particularly when the net effect is to mislead clinicians into thinking an intervention is more effective than it really is because of multiple, undisclosed publications. Finally, systematic reviews can highlight an outcomes reporting bias. It has been shown that trialists frequently change their primary outcomes during the trial, and this tends to favor the intervention under evaluation [21,22]. Trialists may only report what is improved with an intervention and not what is most important to a patient or what they said they would do at the inception of a study. These observations have led to calls for public disclosure of trial protocols. Systematic reviews can highlight these potential biases by demonstrating discrepancies in the number of trials reporting important outcomes. For example, many trials of calcineurin inhibitors did not report diabetes, acute rejection, or graft survival [23].

Why a book which GRADEs evidence

Most evidence-based textbooks and guidelines only evaluate the study design. Randomized trials become the proxy for evidence, when the reality is much more complex. What about when the trials are poorly done? What about when the wrong outcomes are measured? What about when the benefits are evaluated but the harms are not? Recently, the GRADE group, an open, multidisciplinary, international group of researchers and policy makers, developed a comprehensive approach to evidence, which forms the basis of this book [24–26]. Many of the chapters in this book have one or more evidence profile tables, with the simple two-tier (strong or recommend, weak or suggest) recommendations developed by GRADE. Full details of the process are provided elsewhere, but in short, GRADE begins with a systematic review of the available evidence. The overall evidence supporting an intervention, against the comparator intervention, is assessed. Domains considered are the study design (RCTs, observational studies, etc.), study quality (for RCTs this would include allocation concealment, blinding, intention to treat, loss to follow-up), consistency (are all the studies reporting the same results or are they different, and are the differences unexplained), and directness. Directness concerns whether the results of the trials can be generalized to the patient group being considered for the intervention and whether the outcomes being assessed are relevant or of a surrogate or unimportant nature. These four domains are considered in evaluating the overall strength of the evidence for the intervention being evaluated. Importantly, both benefits and harms are given equal consideration, and so even if there was high-quality evidence of the benefits of an intervention, if the quality of data for the adverse effects was very low, then the overall quality of evidence would also be rated as very low. Conceptually, evidence is rated as high quality when the evidence is so robust that no new studies could be justified because the benefits and harms are clear. The GRADE framework is a net clinical benefit, a benefit–harm framework, informed by the quality of the evidence. The evidence profile is then converted into a treatment recommendation after considering the quality of the evidence, values and preferences, local applicability considerations, and the benefit–harm trade-off in the patient group being considered for treatment. Conceptually, a strong recommendation would be equivalent to a recommendation that most clinicians and patients would follow if well-informed.

Clearly, judgment is required, but GRADE requires that such judgments be explicit and incorporate all of the relevant domains. GRADE reinforces the notion that, although trials are essential for evidence-based health care, they are insufficient. Observational studies are often needed to quantify the baseline risk values of individuals for outcomes that are averted by an intervention and to quantify the harms of rare events. GRADE also reinforces the importance of systematic reviews as the first step in the recommendation process.

Why evidence-based nephrology is a work in progress

More and better trials are needed

It has been shown that the number of trials in kidney disease lags behind all other specialties, and the standard quality reporting domains of allocation concealment, blinding, and intention to treat analysis are low and not improving [27]. Nephrology patients deserve the same quality of evidence-based care as patients with cancer. This can only occur when the standard of clinical care is for participation in a trial of a new promising intervention versus the current standard of care that is large enough to answer the question and in which simple outcomes that matter to patients are measured in all participants, both benefits and harms. This model of a large, simple trial, which has been adopted so successfully in cardiology and oncology, is a long way from the current model in nephrology [28]. The typical current model is a small trial (presumablybecause of large per-patient recruitment costs or a lack of a cohesive recruiting network) and one that sometimes compares a new intervention against a nonstandard, clinically inferior intervention [29]. Superiority is typically demonstrated, but such trials have questionable ethics and give results with uncertain policy relevance where the best standard care is expected to be the comparator. Trials may also be short term (months), and not all patient-relevant outcomes are reported, suggesting outcomes reporting bias in which only favorable outcomes are reported. In nephrology trials, the generic call for mandatory registration of trials and study protocols, and for complete reporting of all outcomes, both harmful and beneficial, should be heeded [21,22]. The nephrology community needs to follow the example of other disciplines and develop a consensus on what outcomes should be reported in trials and what definitions should be used [30].

More and better systematic reviews are needed

To date, the nephrology community has summarized in systematic reviews only about 1000 of the available 10,000 trials. In short, we are only about 10% of the way towards the goal of up-to-date systematic reviews of all RCTs. Readers of this book will notice that not all chapters have tabulated evidence summaries based on the GRADE methods. Reasons for this are many but include the absence of existing systematic reviews in areas of high clinical importance.

Although the focus on interventions is justifiable, ideally we need systematic reviews of all diagnostic tests used in nephrology and, some would argue, we equally need systematic reviews of prognosis studies. This can only be achieved with much larger-scale cooperation across the peak nephrology bodies and among researchers and clinicians than has occurred to date. Until this occurs, and the relevant reviews are done, unnecessarily duplicative and unethical studies will continue, and needed studies will go undone. Research will be dominated by commercial interests and not patient needs.

More and better recommendations are needed

Not all authors in this book have used the GRADE system. This is to be expected, given the absence of existing systematic reviews and lack of familiarity with the GRADE process, which is still in development.

One critical lack is an almost complete absence of evidence about the values and preferences of patients with chronic kidney disease, which is needed to inform and assign weights to recommendations. Researchers tend to assume that they can correctly assign priorities to outcomes that reflect the values held by patients but, when evaluated, this has not been the case for other chronic diseases. A qualitative research agenda needs to be developed around patient perspectives of research and health care in nephrology.

In conclusion, this book has been deliberately ambitious. If readers are better informed by better evidence compared to their pre-reading state, then the goal of the book will have been achieved. A bonus will be if this book prompts a better evidence base that will make whatever subsequent editions of this book that appear more comprehensive, valid, and useful to clinical decision makers [31].

References

1 Collins R, Peto R, Gray R, Parish S. Large-scale randomised evidence: trials and overviews. In: Maynard A, Chalmers I, editors. Non-Random Reflections on Health Services Research. BMJ Books, London, 1998; 197–230

2 Mathews JR. Quantification and the Questfor Medical Certainty. Princeton University Press, Princeton, 1995.

3 MRC Streptomycin in Tuberculosis Trials Committee. Streptomycin treatment for pulmonary tuberculosis. BMJ 1948; ii: 769–782.

4 Doll R. Controlled trials: the 1948 watershed. BMJ 1998; 317: 1217–1220.

5 Greenfield S. The state of outcome research: are we on target– N Engl J Med 1989; 320: 1142–1143.

6 Clinton JJ. Outcomes research: a way to improve medical practice. JAMA 1991; 266: 2057.

7 Cross design synthesis: a new strategy for studying medical outcomes (editorial). Lancet 1992; 340: 944–946.

8 Wennberg JE, Barry MJ, Fowler FJ, Mulley A. Outcomes research, PORTs, and health care reform. Ann N Y Acad Sci 1993; 703: 52–62.

9 Lu-Yao GL, McLerran D, Wasson J, Wennberg JE. An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 1993; 269: 2633–2636.

10 Welch WP, Miller ME, Welch HG, Fisher ES, Wennberg JE. Geographic variation in expenditures for physicians’ services in the United States. N Engl J Med 1993; 328: 621–627.

11 Hill SR, Mitchell AS, Henry DA. Problems with the interpretation of pharmacoeconomic analyses: a review of submissions to the Australian Pharmaceutical Benefits Scheme. JAMA 2000; 283: 2116–2121.

12 Vandenbroucke JP. Observational research, randomised trials, and two views of medical science. PLoS Med 2008; 5:e67.

13 Miettinen OS. The need for randomization in the study of intended effects. Stat Med 1983; 2: 267–271.

14 Colditz GA, Miller JN, Mosteller F. How study design affects outcomes in comparisons of therapy. II. Medical. Stat Med 1989; 8: 441–454.

15 Miller JN, Colditz GA, Mosteller F. How study design affects outcomes in comparisons of therapy. II. Surgical. Stat Med 1989; 8: 455–466.

16 Davey Smith G, Phillips AN, Neaton JD. Smoking as independent risk factor for suicide: illustration of an artifact from observational epidemiology. Lancet 1992; 340: 709–712.

17 Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F et al. Evaluating non-randomised intervention studies. Health Technol Assess 2003; 7: 1–173.

18 Effects of intensive glucose lowering in type 2 diabetes.