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Comprehensive Clinical Nephrology

Comprehensive Clinical
Nephrology
SIXTH EDITION
John Feehally, DM, FRCP

Professor of Renal Medicine
The John Walls Renal Unit
Leicester General Hospital
Leicester, United Kingdom
Jürgen Floege, MD, FERA

Professor of Medicine
Director
Division of Nephrology and Clinical Immunology
RWTH University of Aachen
Aachen, Germany
Marcello Tonelli, MD, SM, MSc, FRCPC

Associate Vice President (Research)
Department of Medicine
University of Calgary
Calgary, Alberta, Canada
Richard J. Johnson, MD
Division Chief
Tomas Berl Professor of Nephrology
University of Colorado–Denver
Denver, Colorado, USA
For additional online content visit ExpertConsult.com
Edinburgh London New York Oxford Philadelphia St Louis Sydney 2019

© 2019, Elsevier Inc. All rights reserved.
First edition 2000
Second edition 2003
Third edition 2007
Fourth edition 2010
Fifth edition 2015
Cover Image
Three dimensional reconstruction of mouse glomeruli in which podocyte nuclei are labelled in green. The vas-
culature was labelled in red using CD31 antibody. Image was provided by Dr. Victor Puelles and Prof. Marcus
Moeller from RWTH Aachen University Clinic, Dep. of Nephrology and Clinical Immunology, Aachen, Germany.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechani-
cal, including photocopying, recording, or any information storage and retrieval system, without permission in
writing from the publisher. Details on how to seek permission, further information about the Publisher’s permis-
sions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright
Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
The contributions made by Charles Wingo, and Jeffrey Kopp are in the public domain.
Notices
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds or experiments described herein. Because of rapid advances in
the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.
To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for
any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise,
or from any use or operation of any methods, products, instructions, or ideas contained in the material
herein.
ISBN: 978-0-323-47909-7
E-ISBN: 978-0-323-54719-2
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Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1

CONTENTS
Preface, viii 17 Minimal Change Disease, 209

List of Contributors, ix Gabriel Cara-Fuentes, Eduardo H. Garin, Richard J. Johnson,
Dedication, xix Jürgen Floege
18 Primary and Secondary (Non-Genetic) Causes of Focal
and Segmental Glomerulosclerosis, 219
Gerald B. Appel, Vivette D. D’Agati
SECTION I Essential Renal Anatomy
19 Inherited Causes of Nephrotic Syndrome, 232
and Physiology Shazia Ashraf, Friedhelm Hildebrandt
20 Membranous Nephropathy, 240
1 Renal Anatomy, 1
David J. Salant, Daniel C. Cattran
Wilhelm Kriz, Marlies Elger
21 Membranoproliferative Glomerulonephritis and
2 Renal Physiology, 14
Cryoglobulinemic Glomerulonephritis, 254
Matthew A. Bailey, Robert J. Unwin
Sanjeev Sethi, An S. De Vriese, Fernando C. Fervenza
22 Glomerulonephritis Associated With Complement
Disorders, 263
SECTION II Investigation of Renal Disease H. Terence Cook, Matthew C. Pickering
23 Immunoglobulin A Nephropathy and IgA Vasculitis
3 Assessment of Glomerular Filtration Rate, 29
(Henoch-Schönlein Purpura), 270
Lesley A. Inker, Andrew S. Levey
John Feehally, Jürgen Floege
4 Urinalysis, 39
24 Anti–Glomerular Basement Membrane Disease and
Giovanni B. Fogazzi, Giuseppe Garigali
Goodpasture Disease, 281
5 Imaging, 53
Richard G. Phelps, A. Neil Turner
David T. G. Wymer, David C. Wymer
25 Renal and Systemic Vasculitis, 290
6 Renal Biopsy, 72
J. Charles Jennette, Ronald J. Falk
Peter S. Topham, Yipu Chen
26 Lupus Nephritis, 306
Shikha Wadhwani, David Jayne, Brad H. Rovin
27 Renal Amyloidosis and Glomerular Diseases With
SECTION III Fluid and Electrolyte Disorders Monoclonal Immunoglobulin Deposition, 320
Pierre Ronco, Pierre Aucouturier, Bruno Moulin
7 Disorders of Extracellular Volume, 80
28 Rare Glomerular Disorders, 333
David H. Ellison, Robert W. Schrier
Richard J. Glassock
8 Disorders of Water Metabolism, 94
29 Thrombotic Microangiopathies, Including Hemolytic
Tomas Berl, Jeff M. Sands
Uremic Syndrome, 343
9 Disorders of Potassium Metabolism, 111
Marina Noris, Piero L. Ruggenenti, Giuseppe Remuzzi
I. David Weiner, Stuart L. Linas, Charles S. Wingo
10 Disorders of Calcium, Phosphate,
and Magnesium Metabolism, 124
Bryan Kestenbaum, Pascal Houillier SECTION V Diabetic Kidney Disease
11 Normal Acid-Base Balance, 142
Biff F. Palmer 30 Pathogenesis, Clinical Manifestations, and Natural
12 Metabolic Acidosis, 149 History of Diabetic Kidney Disease, 357
Biff F. Palmer Sydney Tang, Kumar Sharma
13 Metabolic Alkalosis, 160 31 Prevention and Treatment of Diabetic
Alan Segal, F. John Gennari Kidney Disease, 376
14 Respiratory Acidosis, Respiratory Alkalosis, Li-Li Tong, Sharon Adler, Christoph Wanner
and Mixed Disorders, 170 32 Management of the Diabetic Patient With Chronic
Horacio J. Adrogué, Nicolaos E. Madias Kidney Disease, 385
Rosa M. Montero, David J. A. Goldsmith
SECTION IV Glomerular Disease

SECTION VI Hypertension
15 Introduction to Glomerular Disease: Clinical
Presentations, 184 33 Normal Blood Pressure Control and the Evaluation of
Jürgen Floege, John Feehally Hypertension, 396
16 Introduction to Glomerular Disease: Histologic William J. Elliott, William J. Lawton
Classification and Pathogenesis, 199 34 Primary Hypertension, 412
John Feehally, Jürgen Floege Richard J. Johnson, George L. Bakris, Bernardo Rodríguez-Iturbe
v
vi CONTENTS
35 Nonpharmacologic Prevention and Treatment of 54 The Kidney in Schistosomiasis, 655

Hypertension, 422 Rashad S. Barsoum, Tarek S. Fayad
Brian Rayner, Karen E. Charlton, Wayne Derman 55 Glomerular Diseases Associated With Infection, 664
36 Pharmacologic Treatment of Hypertension, 430 Cynthia C. Nast, Bernardo Rodríguez-Iturbe
Bryan Williams, Megan Borkum 56 Human Immunodeficiency Virus Infection and
37 Evaluation and Treatment of Hypertensive Emergencies the Kidney, 679
and Urgencies, 444 Jeffrey B. Kopp, Saraladevi Naicker
Pantelis A. Sarafidis, George L. Bakris
38 Endocrine Causes of Hypertension: Aldosterone, 453 SECTION XI Urologic Disorders
I. David Weiner, Charles S. Wingo
39 Other Endocrine Causes of Hypertension, 463 57 Nephrolithiasis and Nephrocalcinosis, 689
A. Mark Richards Wei Chen, Rebeca D. Monk, David A. Bushinsky
40 Neurogenic Hypertension, Including Hypertension 58 Urinary Tract Obstruction, 704
Associated With Stroke or Spinal Cord Injury, 473 Kevin M. Gallagher, Jeremy Hughes
Venkatesh Aiyagari, Mohamed Osman, Philip B. Gorelick 59 Urologic Issues for the Nephrologist, 717
Raj P. Pal, James E. Dyer, J. Kilian Mellon
SECTION VII Renovascular Disease

SECTION XII Tubulointerstitial and
41 Renovascular Hypertension and Ischemic Vascular Diseases
Nephropathy, 482
Barbara A. Greco, Kausik Umanath 60 Acute Interstitial Nephritis, 729
Jérôme A. Rossert, Evelyne A. Fischer
61 Primary Vesicoureteral Reflux and
SECTION VIII Pregnancy and Renal Disease Reflux Nephropathy, 738
Ranjiv Mathews, Tej K. Mattoo
42 Renal Physiology and Complications in Normal 62 Chronic Interstitial Nephritis, 748
Pregnancy, 502 Tetsuhiro Tanaka, Masaomi Nangaku
Shikha Aggarwal, Mark A. Brown 63 Endemic Nephropathies, 761
43 Pregnancy With Preexisting Kidney Disease, 522 Ramón Garcia-Trabanino, Richard J. Johnson
Kate Bramham, Mark A. Brown 64 Myeloma and the Kidney, 767
Ashley B. Irish
SECTION IX Hereditary and Congenital Diseases

of the Kidney SECTION XIII Renal Disease and Cancer
65 Onconephrology: Kidney Disease in
44 Autosomal Dominant Polycystic Kidney Disease, 532
Cancer Patients, 776
Vicente E. Torres, Peter C. Harris
Ala Abudayyeh, Mark A. Perazella
45 Other Cystic Kidney Diseases, 545
Lisa M. Guay-Woodford
46 Alport Syndrome and Other Familial Glomerular SECTION XIV Acute Kidney Injury
Syndromes, 560
Michelle N. Rheault, Clifford E. Kashtan 66 Pathophysiology and Etiology of
47 Inherited Disorders of Sodium and Water Handling, 575 Acute Kidney Injury, 786
Detlef Bockenhauer Leah Haseley, J. Ashley Jefferson
48 Fanconi Syndrome and Other Proximal 67 Acute Kidney Injury in the Tropics, 802
Tubule Disorders, 586 Emmanuel A. Burdmann, Vivekanand Jha, Visith Sitprija
John W. Foreman 68 Diagnosis and Clinical Evaluation of
49 Sickle Cell Diseases and the Kidney, 597 Acute Kidney Injury, 810
Claire C. Sharpe, Fatiu A. Arogundade Eric Judd, Paul W. Sanders, Anupam Agarwal
50 Congenital Anomalies of the Kidney and 69 Epidemiology and Prognostic Impact of
Urinary Tract, 607 Acute Kidney Injury, 820
John O. Connolly, Melanie M. Y. Chan, Guy H. Neild Neesh Pannu, Marcello Tonelli
70 Prevention and Nondialytic Management of Acute
Kidney Injury, 825
SECTION X Infectious Diseases and the Kidney Josée Bouchard, Etienne Macedo, Ravindra L. Mehta
71 Dialytic Management of Acute Kidney Injury and
51 Urinary Tract Infections in Adults, 626 Intensive Care Unit Nephrology, 838
Thomas Hooton Mark R. Marshall, Luis A. Juncos
52 Tuberculosis of the Urinary Tract, 639 72 Dialytic Management of Refractory Heart Failure, 852
R. Kasi Visweswaran, K. P. Jayakumar Edward A. Ross, Kevin Damman, Amir Kazory
53 Fungal Infections of the Urinary Tract, 650 73 Hepatorenal Syndrome, 859
Carol A. Kauffman Javier Fernández, Vicente Arroyo

CONTENTS vii
SECTION XV Drug Therapy in Kidney Disease 92 Diagnostic and Interventional Nephrology, 1062
W. Charles O’Neill, Haimanot Wasse, Stephen R. Ash
74 Principles of Drug Therapy, Dosing, and Prescribing 93 Hemodialysis: Principles and Techniques, 1073
in Chronic Kidney Disease and Renal Peter Kotanko, Martin K. Kuhlmann, Christopher Chan,
Replacement Therapy, 870 Nathan W. Levin
Matthew J. Cervelli, Graeme R. Russ 94 Hemodialysis: Dialysis Prescription and Adequacy, 1082
75 Common Issues in Prescribing in Kidney Disease and Martin K. Kuhlmann, Peter Kotanko, Nathan W. Levin
Renal Replacement Therapy, 880 95 Acute Complications During Hemodialysis, 1090
Matthew J. Cervelli, Graeme R. Russ Kevan R. Polkinghorne, Peter G. Kerr
76 Herbal and Over-the-Counter Medicines and 96 Peritoneal Dialysis: Principles, Techniques,
the Kidney, 894 and Adequacy, 1103
Mark S. Segal, Xueqing Yu †Bengt Rippe
97 Complications of Peritoneal Dialysis, 1114
Simon J. Davies, Martin E. Wilkie
SECTION XVI Chronic Kidney Disease and 98 Extracorporeal Therapies for Drug Overdose
the Uremic Syndrome and Poisoning, 1124
Nigel Suren Kanagasundaram, Andrew Lewington
77 Epidemiology of Chronic Kidney Disease 99 Plasma Exchange, 1132
and Dialysis, 903 Jeremy Levy
Morgan E. Grams, Stephen P. McDonald
78 Pathophysiology of Disease Progression in Proteinuric
and Nonproteinuric Kidney Disease, 913 SECTION XIX Transplantation
Ariela Benigni, Norberto Perico, Giuseppe Remuzzi
79 Retarding Progression of Kidney Disease, 924 100 Immunologic Principles in Kidney Transplantation, 1141
Samir V. Parikh, Nabil J. Haddad, Lee A. Hebert Karl L. Womer
80 Clinical Evaluation and Management of 101 Immunosuppressive Medications in Kidney
Chronic Kidney Disease, 935 Transplantation, 1154
Laurie A. Tomlinson, David C. Wheeler Kawther F. Alquadan, Karl L. Womer, Michael J. Casey
81 Cardiovascular Disease in Chronic Kidney Disease, 942 102 Evaluation and Preoperative Management of Kidney
Peter Stenvinkel, Charles A. Herzog Transplant Recipient and Donor, 1163
82 Anemia in Chronic Kidney Disease, 958 William R. Mulley, John Kanellis
Iain C. Macdougall, Kai-Uwe Eckardt 103 Kidney Transplantation Surgery, 1174
83 Other Blood and Immune Disorders in Adam D. Barlow, Michael L. Nicholson
Chronic Kidney Disease, 967 104 Prophylaxis and Treatment of Kidney
Matthias Girndt, Gunnar H. Heine Transplant Rejection, 1186
84 Bone and Mineral Disorders in James E. Cooper, Erik Stites, Alexander C. Wiseman
Chronic Kidney Disease, 979 105 Medical Management of the Kidney Transplant
Kevin J. Martin, Jürgen Floege, Markus Ketteler Recipient: Infections and Malignancies, 1198
85 Neurologic Complications of Phuong-Thu T. Pham, Joanna Schaenman, Phuong-Chi T. Pham
Chronic Kidney Disease, 996 106 Medical Management of the Kidney Transplant
Julian L. Seifter, Martin A. Samuels Recipient: Cardiovascular Disease and Metabolic
86 Gastroenterology and Nutrition in Abnormalities, 1213
Chronic Kidney Disease, 1002 Phuong-Thu T. Pham, Son V. Pham, Phuong-Anh T. Pham,
Gemma Bircher, Graham Woodrow Gabriel M. Danovitch
87 Dermatologic Manifestations of 107 Chronic Allograft Injury, 1226
Chronic Kidney Disease, 1013 Christian Morath, Martin Zeier
Pieter Evenepoel, Dirk R. Kuypers 108 Recurrent Disease in Kidney Transplantation, 1236
88 Acquired Cystic Kidney Disease and Malignant Steven J. Chadban, Melanie Wyld
Neoplasms, 1022 109 Outcomes of Renal Transplantation, 1247
Anja S. Mühlfeld, Peter Boor Jeremy R. Chapman
110 Pancreas and Islet Transplantation, 1258
Jonathan S. Fisher, Christopher L. Marsh
SECTION XVII Geriatric and Palliative Nephrology 111 Kidney Disease in Liver, Cardiac, Lung, and
89 Geriatric Nephrology, 1028 Hematopoietic Stem Cell Transplantation, 1272
Mitchell H. Rosner, Emaad Abdel-Rahman, Antonelli Pani Claire Kennedy, Colm C. Magee
SECTION XVIII Dialytic Therapies SECTION XX Palliative Nephrology

90 Approach to Renal Replacement Therapy, 1036 112 Palliative Nephrology, 1282
Hugh C. Rayner, Enyu Imai, Vijay Kher Edwina A. Brown, Fliss E. Murtagh
91 Vascular Access for Dialytic Therapies, 1050
Jan H. M. Tordoir Index, 1289

P R E FA C E
In the sixth edition of Comprehensive Clinical Nephrology, we continue of the information provided: yellow boxes for general information, blue
to offer a text for fellows, practicing nephrologists, and internists that boxes for necessary investigations, and green boxes for therapeutic
covers all aspects of the clinical work of the nephrologist, including interventions. By popular demand we continue to offer readers access
fluids and electrolytes, hypertension, diabetes, dialysis, and transplanta- to the images from the book. We are pleased to see them used in lectures
tion. We recognize that this single volume does not compete with mul- and seminars in many parts of the world.
tivolume or highly referenced online texts, and it remains our goal to This is the third edition that features access to a companion Expert
provide “comprehensive” coverage of clinical nephrology yet also ensure Consult website, with fully searchable text, a downloadable image library,
that inquiring nephrologists can find the key scientific issues and patho- and links to PubMed. New to this edition is an online question bank
physiology that underlie their clinical work. with more than 400 multiple-choice questions.
All chapters have been extensively revised and updated in response And finally, we welcome a new co-editor, Marcello Tonelli, who will
to the advice and comments that we have received from many readers bring great epidemiological expertise (and significantly lower the average
and colleagues. These revisions include latest developments, such as age of the editors).
new insights into complement mediated glomerular diseases, and the
latest data on epidemiology and consequences of acute kidney injury John Feehally
and renal replacement therapy. Also included is a chapter on the emerg- Jürgen Floege
ing problem of endemic nephropathies in low and middle income Marcello Tonelli
countries. This edition retains the consistent design of the algorithms, Richard J. Johnson
which are a popular feature of the book, to emphasize different aspects
viii
LIST OF CONTRIBUTORS
The editor(s) would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new
edition would not have been possible.
Emaad Abdel-Rahman, MBBS Kawther F. Alquadan, MD Matthew A. Bailey, PhD

Professor of Clinical Internal Medicine Assistant Professor of Medicine Reader in Renal Physiology
Division of Nephrology University of Florida The Centre for Cardiovascular Science
University of Virginia Health System Gainesville, FL, USA The University of Edinburgh
Charlottesville, VA, USA Edinburgh, UK
Gerald B. Appel, MD
Horacio J. Adrogué, MD Director George L. Bakris, MD
Professor of Medicine The Glomerular Kidney Center at Columbia Professor of Medicine, Director
Baylor College of Medicine University Medical Center; American Society of Hypertension
Chief, Clinical Nephrology and Professor of Medicine at Columbia Comprehensive Hypertension Center
Hypertension University Department of Medicine
Houston Methodist Hospital College of Physicians and Surgeons University of Chicago
Houston, TX, USA New York, NY, USA Chicago, IL, USA
Ala Abudayyeh, MD Fatiu A. Arogundade, MBBS, FMCP, Adam D. Barlow, MD, FRCS
University of Texas MD Anderson Cancer FWACP Consultant Transplant Surgeon
Center Associate Professor and Consultant Leeds Teaching Hospitals NHS Trust
Houston, TX; Nephrologist Leeds, UK
Section of Nephrology Department of Medicine
Department of Medicine Obafemi Awolowo University and Teaching Rashad S. Barsoum, MD, FRCP, FRCPE
Yale University School of Medicine Hospitals Complex Emeritus Professor of Medicine
New Haven, CT, USA Ile-Ife, Osun State, Nigeria Kasr-El-Aini Medical School
Cairo University
Sharon Adler, MD Vicente Arroyo, MD, PhD Cairo, Egypt
Professor of Medicine Director of the EASL-CLIF
Chief and Program Director Consortium-Efclif. Ariela Benigni, PhD
Division of Nephrology and Hypertension Barcelona, Spain IRCCS - Istituto di Ricerche Farmacologiche
Los Angeles Biomedical Research Institute at Mario Negri
Harbor University of California–Los Stephen R. Ash, MD, FACP Bergamo, Italy
Angeles Director of Dialysis, Department of
David Geffen School of Medicine Nephrology Tomas Berl, MD
Torrance, CA, USA Indiana University Health Arnett; Professor of Medicine
Chairman and Director Division of Renal Diseases and
Anupam Agarwal, MD Research and Development Hypertension, Department of Medicine
Professor and Director HemoCleanse, Inc. and Ash Access University of Colorado Denver
Division of Nephrology Technology, Inc. Denver, CO, USA
Marie S. Ingalls Endowed Chair in Lafayette, IN, USA
Nephrology Gemma Bircher, MSc, BSc (hons), RD
University of Alabama at Birmingham Shazia Ashraf, MS Dietetic Manager
Birmingham, AL, USA Division of Nephrology Renal Dietitians
Boston Children’s Hospital Leicester General Hospital
Shikha Aggarwal, MBBS (HONS) FRACP Harvard Medical School Leicester, England
Consultant Nephrologist Boston, MA, USA
Department of Nephrology Mater Hospital Detlef Bockenhauer, PhD
Sydney, Australia Pierre Aucouturier, PhD Professor of Paediatric Nephrology
Professor of Immunology at Pierre et Marie UCL Centre for Nephrology;
Venkatesh Aiyagari, MBBS, DM, FAHA Curie University Honorary Consultant
Professor Department of Biologic Immunology Great Ormond Street Hospital for Children
Department of Neurological Surgery and Pôle de Biologie Médicale et Pathologie NHS Foundation Trust
Neurology and Neurotherapeutics Hôpitaux Universitaires de l’Est Parisien London, UK
University of Texas Southwestern Medical Paris, France
Center
Dallas, TX, USA
ix
x LIST OF CONTRIBUTORS
Peter Boor, MD, PhD Daniel C. Cattran, MD, FRCPC John O. Connolly, PhD, FRCP
Pathologist Professor of Medicine Consultant Nephrologist
Institute of Pathology University of Toronto; University College London Centre for
Uniklinik RWTH Aachen Senior Scientist Nephrology
Aachen, Germany Toronto General Research Institute Royal Free London National Health Service
Toronto, ON, Canada Foundation Trust
Josée Bouchard, MD London, UK
Associate Professor of Medicine Matthew J. Cervelli, BPharm
Hôpital du Sacré-Coeur de Montréal, Clinical Pharmacist Specialist H. Terence Cook, MB, BS, FRCPath
Université de Montréal Royal Adelaide Hospital Professor of Renal Pathology
Montréal, Canada Adelaide, Australia Centre for Complement and Inflammation
Research
Kate Bramham Steven J. Chadban, PhD, Bmed(Hons), Department of Medicine
Clinical Lecturer in Renal Sciences FRACP Imperial College
Department of Renal Medicine Clinical Professor London, UK
Division of Transplantation and Nephrologist, and Transplant Physician
Mucosal Biology Royal Prince Alfred Hospital and University James E. Cooper, MD
King’s College London of Sydney Associate Professor
London, UK Sydney, Australia Department of Medicine
Renal Division
Edwina A. Brown, DM, FRCP Christopher Chan, MD University of Colorado,
Professor of Renal Medicine, Imperial Director of Nephrology – UHN Aurora, CO, USA
College London; R Fraser Elliott Chair in Home Dialysis
Consultant Nephrologist Professor of Medicine Vivette D. D’Agati, MD
Imperial College Renal and Transplant Deputy Physician in Chief of Economics Director of Renal Pathology at Columbia
Centre Toronto, ON, Canada University Medical Center and Professor
Hammersmith Hospital of Pathology at Columbia University
London, UK Melanie M. Y. Chan, MA, MRCP College of Physicians and Surgeons
Clinical Lecturer in Renal Medicine and New York, NY, USA
Mark A. Brown, MD, MB, BS Transplantation
Professor of Renal Medicine University College London Centre for Kevin Damman, MD, PhD
St. George Hospital and University of New Nephrology Cardiologist
South Wales Royal Free London National Health Service Department of Cardiology
Sydney, Australia Foundation Trust University Medical Center Groningen
London, UK Groningen, The Netherlands
Emmanuel A. Burdmann, MD, PhD
Associate Professor, Division of Nephrology Jeremy R. Chapman, MD, FRACP, FRCP Gabriel M. Danovitch, MD
University of São Paulo Medical School Director of Renal Medicine Distinguished Professor of Medicine
São Paulo, Brazil Centre for Transplant and Renal Research David Geffen School of Medicine at
Sydney University, Westmead Hospital University of California-Los Angeles;
David A. Bushinsky, MD Westmead, Australia Medical Director, Kidney Transplant
John J. Kuiper Distinguished Professor of Program
Medicine and of Pharmacology and Karen E. Charlton, PhD, Adv APD, Ronald Reagan Medical Center at University
Physiology RPHNutr of California-Los Angeles
Department of Medicine Associate Professor Los Angeles, CA, USA
University of Rochester School of Medicine School of Medicine, Faculty of Science,
and Dentistry Medicine and Health Simon J. Davies, MD, BSc, FRCP
Rochester, NY, USA University of Wollongong Professor of Nephrology and Dialysis
New South Wales, Australia Medicine
Gabriel Cara-Fuentes, MD Institute for Science and Technology in
Clinical Lecturer Wei Chen, MD Medicine
Pediatrics Nephrology Assistant Professor Keele University;
University of Michigan Department of Medicine Consultant Nephrologist
Ann Arbor, MI, USA University of Rochester School of Medicine Department of Nephrology
and Dentistry University Hospital of North Staffordshire
Michael J. Casey, MD, MS Rochester, NY, USA Staffordshire, UK
Associate Professor of Medicine
University of Florida Yipu Chen, MD Wayne Derman, MBChB, PhD, FFIMS
Gainesville, Florida, USA Professor of Medicine Professor
Division of Nephrology Institute of Sport and Exercise Medicine
Beijing Anzhen Hospital Division of Orthopaedic Surgery
Capital Medical University Stellenbosch University
Beijing, People’s Republic of China IOC Research Centre
Matieland, South Africa
LIST OF CONTRIBUTORS xi
An S. De Vriese, MD, PhD John Feehally, DM, FRCP Ramón García-Trabanino, MD, MSc, FASN
Division of Nephrology Professor of Renal Medicine Centro de Hemodiálisis
AZ Sint-Jan Brugge The John Walls Renal Unit San Salvador, El Salvador
Brugge, Belgium Leicester General Hospital Fondo Social de Emergencia para la Salud
Leicester, UK de Tierra Blanca
James E. Dyer, MBChB, BSc Hons Usulután, El Salvador
Clinical Research Fellow Javier Fernández, MD, PhD
Department of Urology Head of the Liver ICU Giuseppe Garigali, ScD
Leicester General Hospital Hospital Clinic Barcelona Clinical and Research Laboratory on
Leicester, UK University of Barcelona Urinary Sediment
Barcelona, Spain Unità Operativa di Nefrologia
Kai-Uwe Eckardt, MD Dialisi e Trapianto di rene Fondazione
Professor of Medicine Fernando C. Fervenza, MD, PhD IRCCS, Ca’ Granda Ospedale Maggiore
Department of Nephrology and Medical Division of Nephrology and Hypertension Policlinico
Intensive Care Mayo Clinic Milan, Italy
Charité-Universitätsmedizin Berlin Rochester, MN, USA
Berlin, Germany Eduardo H. Garin, MD
Evelyne A. Fischer, MD Professor, Paediatrics
David H. Ellison, MD Institut de Biologie de l’Ecole Normale University of Florida
Professor of Medicine and Physiology and Superieure Gainesville, FL, USA
Pharmacology Cell Division and Neurogenesis
Department of Medicine INSERM F. John Gennari, MD
Oregon Health and Science University and Paris, France Professor Emeritus
VA Portland Health Care System Department of Medicine
Portland, OR, USA Jonathan S. Fisher, MD, FACS University of Vermont College of Medicine
Surgical Director of Pancreas Burlington, VT, USA
Marlies Elger, PhD Transplantation
Department of Neuroanatomy Scripps Center for Organ Transplantation Matthias Girndt, MD
Medical Faculty Mannheim Scripps Clinic and Green Hospital Department of Internal Medicine II
University of Heidelberg La Jolla, CA, USA Martin-Luther-University Halle-Wittenberg
Mannheim, Germany Halle/Saale, Germany
Jürgen Floege, MD, FERA
William J. Elliott, MD, PhD Professor of Medicine; Richard J. Glassock, MD
Professor of Preventive Medicine Director, Division of Nephrology and Emeritus Professor of Medicine
Internal Medicine and Pharmacology; Clinical Immunology Department of Medicine
Chief, Division of Pharmacology; RWTH University of Aachen David Geffen School of Medicine at
Chair, Department of Biomedical Sciences Aachen, Germany University of California–Los Angeles
Pacific Northwest University of Health Los Angeles, CA, USA
Sciences Giovanni B. Fogazzi, MD
Yakima, WA, USA Honorary Director David J. A. Goldsmith, MA FRCP FASN
Clinical and Research Laboratory on FERN
Pieter Evenepoel, MD, PhD Urinary Sediment Nephrologist, Guy’s and St Thomas’ NHS
Professor, Nephrology and Renal U.O. di Nefrologia, Dialisi e Trapianto di Foundation Trust
Transplantation rene London, UK
University Hospital Leuven Fondazione
Leuven, Belgium IRCCS, Ca’ Granda Ospedale Maggiore Philip B. Gorelick, MD, MPH, FACP
Policlinico Professor
Ronald J. Falk, MD Milan, Italy Department of Translational Science and
Nan and Hugh Cullman Eminent Professor Molecular Medicine
and Chair of Medicine John W. Foreman, MD College of Human Medicine
Department of Medicine Professor and Chief, Division of Pediatric Michigan State University
University of North Carolina at Chapel Hill Nephrology Grand Rapids, MI;
Chapel Hill, NC, USA Department of Pediatrics Medical Director
Duke University Medical Center Mercy Health Hauenstein Neurosciences
Tarek S. Fayad, MD Durham, NC, USA Grand Rapids, MI, USA
Kasr El-Aini Medical School Kevin M. Gallagher, MBChB BMedSci MSc
Cairo University MRCSed
Cairo, Egypt MRC/Kidney Research UK/GSK Clinical
Research Fellow
Tissue Injury and Repair Group
University of Edinburgh
Edinburgh, UK

xii LIST OF CONTRIBUTORS
Morgan E. Grams, MD Charles A. Herzog, MD David Jayne, MD

Associate Professor Professor of Medicine Reader in Vasculitis
School of Medicine, Division of University of Minnesota; Department of Medicine
Cardiovascular and Clinical Division of Cardiology University of Cambridge
Epidemiology Department of Medicine Cambridge, UK
Welch Center for Prevention, Epidemiology Hennepin County Medical Center and
and Clinical Research University of Minnesota J. Ashley Jefferson, MD, FRCP
Johns Hopkins Bloomberg School of Public Minneapolis, MN, USA Associate Professor of Medicine
Health Division of Nephrology
Baltimore, MD, USA Friedhelm Hildebrandt, MD University of Washington
Division of Nephrology Seattle, WA, USA
Barbara A. Greco, MD Boston Children’s Hospital,
Associate Clinical Professor of Medicine Harvard Medical School J. Charles Jennette, MD
Department of Nephrology Boston, MA, USA Kennith M. Brinkhous Distinguished
Baystate Medical Center, Tufts; Professor and Chair of Pathology and
Western New England Renal and Transplant Thomas Hooton, MD Laboratory Medicine
Associates Professor of Clinical Medicine Department of Pathology and Laboratory
Springfield, MA, USA Division of Infectious Diseases Medicine
Department of Medicine University of North Carolina at Chapel Hill
Lisa M. Guay-Woodford, MD University of Miami Miller School of Chapel Hill, NC, USA
Professor and Director Medicine;
Center for Translational Science Chief of Medicine Vivekanand Jha, MD, DM, FRCP
Children’s National Health System and The Miami Veterans Administration Healthcare Professor
George Washington University System Department of Nephrology
Washington, DC, USA Miami, FL, USA Postgraduate Institute of Medical Education
and Research
Nabil J. Haddad, MD Pascal Houillier, MD, PhD Chandigarh, India;
Associate Professor of Clinical Medicine Professor of Physiology Executive Director
Division of Nephrology Department of Physiology George Institute for Global Health
Department of Internal Medicine Paris Descartes University New Delhi, India
The Ohio State University Medical Center Georges Pompidou Hospital
Columbus, OH, USA Paris, France Richard J. Johnson, MD
Peter C. Harris, PhD Jeremy Hughes, MA, MB, BS, PhD, FRCPE Tomas Berl Professor of Nephrology
Professor of Biochemistry/Molecular Professor of Experimental Nephrology University of Colorado–Denver
Biology and Medicine Medical Research Council Centre for Denver, CO, USA
Division of Nephrology and Hypertension Inflammation Research
Mayo Clinic University of Edinburgh; Eric Judd, MD, MS
Rochester, MN, USA Honorary Consultant Physician Assistant Professor
Edinburgh Royal Infirmary Division of Nephrology
Leah Haseley, MD Edinburgh, UK University of Alabama at Birmingham
Clinical Professor of Medicine Birmingham, AL, USA
Division of Nephrology Enyu Imai, MD, PhD
University of Washington Nakayamadera Imai Clinic Luis A. Juncos, MD
Seattle, WA, USA Takarazuka, Hyogo, Japan Chief of Nephrology
Central Arkansas
Lee A. Hebert, MD Lesley A. Inker, MD, MS Veterans Healthcare Systems;
Professor of Medicine William B. Schwartz Division of Nephrology Professor of Medicine
Department of Internal Medicine Tufts Medical Center; University of Arkansas for Medical Sciences
Division of Nephrology Associate Professor Medicine Little Rock, AR, USA
The Ohio State University Medical Center Tufts University School of Medicine
Columbus, OH, USA Boston, MA, USA Nigel Suren Kanagasundaram, MD, MB
ChB, FRCP
Gunnar H. Heine, MD Ashley B. Irish, MBBS, FRACP Honorary Clinical Senior Lecturer
Department of Internal Medicine IV Consultant Nephrologist Institute of Cellular Medicine
University of the Saarland Department of Nephrology and Renal Newcastle University;
Homburg/Saar, Germany Transplantation Consultant Nephrologist
Fiona Stanley Hospital Renal Services
Murdoch, Western Australia, Australia Newcastle upon Tyne Hospitals National
Health Service Foundation Trust
Newcastle upon Tyne, UK

LIST OF CONTRIBUTORS xiii
John Kanellis, PhD, MBBS(Hons), FRACP Jeffrey B. Kopp, MD Jeremy Levy, MD, PhD, FRCP
Nephrologist Branch Chief Consultant Nephrologist
Department of Nephrology Kidney Disease Branch Renal and Transplant Centre
Monash Medical Centre; NIDDK, NIH Imperial College Healthcare National Health
Department of Medicine Bethesda, MD, USA Service Trust
Monash University London, UK
Clayton, Australia Peter Kotanko, MD
Research Director Andrew Lewington, MD, BSc Med, FRCP,
Clifford E. Kashtan, MD Renal Research Institute FRCPE
Professor of Pediatrics New York, NY, USA Honorary Clinical Associate Professor
Department of Pediatrics Department of Medicine
Division of Pediatric Nephrology Wilhelm Kriz, MD University of Leeds;
University of Minnesota Medical School Department of Neuroanatomy, Medical Consultant
Minneapolis, MN, USA Faculty Mannheim Renal Physician
University of Heidelberg Department of Renal Medicine
Bryan Kestenbaum, MD, MS Mannheim, Germany St. James’s University Hospital
Professor Leeds, UK
University of Washington Jayakumar K. P., MD DNB (Med) DM
Kidney Research Institute DNB(Nephro) FISN Stuart L. Linas, MD
Seattle, WA, USA Professor Professor of Medicine
Department of Nephrology Division of Renal Diseases and
Carol A. Kauffman, MD Govt Medical College Hypertension
Professor of Internal Medicine Kottayam Kerala India University of Colorado School of Medicine
University of Michigan Medical School; and Chief of Nephrology
Chief, Infectious Diseases Martin K. Kuhlmann, MD Denver Health Medical Center
Veteran Affairs Ann Arbor Healthcare Director Denver, CO, USA
System Department of Internal Medicine
Ann Arbor, MI, USA Nephrology Iain C. Macdougall, BSc, MD, FRCP
Vivantes Klinikum im Friedrichshain Consultant Nephrologist and Professor of
Amir Kazory, MD Berlin, Germany Clinical Nephrology
Associate Professor of Medicine Department of Renal Medicine
Division of Nephrology, Hypertension, and Dirk R. Kuypers, MD, PhD King’s College Hospital
Renal Transplantation Professor London, UK
University of Florida Department of Nephrology and Renal
College of Medicine Transplantation Etienne Macedo, MD
Gainesville, FL, USA University Hospitals Leuven Assistant Adjunct Professor
Leuven, Belgium University of California San Diego
Claire Kennedy, MB BCh BAO, BMed Sci San Diego, CA, USA
Clinical Research Fellow William J. Lawton, MD, FACP
Beaumont Hospital and Royal College of Associate Professor Emeritus Nicolaos E. Madias, MD, FASN
Surgeons in Ireland Department of Internal Medicine Maurice S. Segal, MD, Professor of Medicine
Dublin, Ireland Nephrology-Hypertension Division Tufts University School of Medicine
University of Iowa Carver College of Physician, Division of Nephrology
Peter G. Kerr, PhD, MB, BS, FRACP Medicine St. Elizabeth’s Medical Center
Professor and Director Iowa City, IA, USA Boston, MA, USA
Department of Nephrology
Monash Medical Centre; Andrew S. Levey, MD Colm C. Magee, MD, MPH
Professor Chief, Division of Nephrology Consultant Nephrologist
Department of Medicine William B. Schwartz Division of Nephrology Beaumont Hospital;
Monash University Tufts Medical Center; Lecturer in Medicine
Clayton, Australia Dr. Gerald J. and Dorothy R. Friedman Royal College of Surgeons in Ireland
Professor of Medicine Dublin, Ireland
Markus Ketteler, MD, FERA Tufts University School of Medicine
Division of Nephrology Boston, MA, USA Christopher L. Marsh, MD, FACS
Klinikum Coburg GmbH Division Chief
Coburg, Germany Nathan W. Levin, MD Scripps Center for Organ Transplantation
Visiting Professor Scripps Clinic and Green Hospital
Dr. Vijay Kher, MD, DM, FAMS, FRCPE Mount Sinai Icahn school of Medicine La Jolla, CA, USA
Chairman New York, NY
Division of Nephrology & Renal Transplant
Medicine
Fortis Escorts Kidney and Urology Institute
Fortis Escorts Hospital
India

xiv LIST OF CONTRIBUTORS
Mark R. Marshall, MBChB, MPH(Hons), Rebeca D. Monk, MD Cynthia C. Nast, MD

FRACP Professor Professor of Pathology
Honorary Associate Professor Department of Medicine Department of Pathology
Faculty of Medical and Health Sciences University of Rochester School of Medicine Cedars-Sinai Medical Center
South Auckland Clinical School; and Dentistry Los Angeles, CA, USA
Clinical Director Rochester, NY, USA
Department of Renal Medicine A. Neil Turner, PhD, FRCP
Counties Manukau District Health Board Rosa M. Montero, MRCP MD AFHEA Professor of Nephrology
Auckland, New Zealand Honorary Clinical Senior Lecturer Department of Renal Medicine
King’s College Royal Infirmary;
Kevin J. Martin, MB, BCH, FASN London, UK Centre for Inflammation
Professor of Internal Medicine University of Edinburgh
Director Christian Morath, MD Edinburgh, Scotland
Division of Nephrology Division of Nephrology
St Louis University Heidelberg University Hospital Guy H. Neild, MD, FRCP, FRCPath
St Louis, MO, USA Heidelberg, Germany Professor of Nephrology (Emeritus)
University College London Centre for
Ranjiv Mathews, MD Bruno Moulin, MD, PhD Nephrology
Professor of Urology and Pediatrics; Professor of Nephrology and London, UK
Director of Pediatric Urology Transplantation
Division of Urology Hôpitaux Universitaires de Strasbourg Michael L. Nicholson, DSc, MD, FRCS
Department of Surgery Strasbourg, France Professor of Transplant Surgery
Southern Illinois University Department of Surgery
School of Medicine Anja S. Mühlfeld, MD University of Cambridge, Cambridge, UK
Springfield, IL, USA Consultant, Division of Nephrology and
Immunology Marina Noris, PhD
Tej K. Mattoo, MD, DCH, FRCP (UK), Uniklinikum RWTH Aachen University Head
FAAP Aachen, Germany Laboratory of Immunology and Genetics of
Professor and Acting Chair of Pediatrics Transplantation and Rare Diseases
Wayne State University School of Medicine; William R. Mulley, PhD, B.Med(Hons), Department of Molecular Medicine
Chief, Pediatric Nephrology and FRACP IRCSS–Istituto di Ricerche Farmacologiche
Hypertension Nephrologist, Department of Nephrology “Mario Negri,”
Children’s Hospital of Michigan Monash Medical Centre; Bergamo, Italy
Detroit, MI, USA Senior Lecturer
Department of Medicine W. Charles O’Neill, MD
Stephen P. McDonald, PhD FRACP Monash University Professor of Medicine
Director of Dialysis and Senior Staff Clayton, Australia Director of Ultrasonography
Specialist Renal Division, Department of Medicine
Central Adelaide Local Health Network Fliss E. Murtagh Emory University
Royal Adelaide Hospital (RAH); Professor of Palliative Care Atlanta, GA, USA
Executive Officer Wolfson Palliative Care Research Centre,
Australia and New Zealand Dialysis & Hull York Medical School, Mohamed Osman, MD
Transplant Registry University of Hull, Fellow, Neurocritical Care
SA Health and Medical Research Institute; Hull, UK Department of Neurological Surgery and
Clinical Professor Neurology and Neurotherapeutics
Adelaide Medical School Saraladevi Naicker, MD, PhD University of Texas Southwestern Medical
University of Adelaide Professor of Nephrology Center
Adelaide, Australia Division of Nephrology Dallas, TX, USA
Department of Internal Medicine
Ravindra L. Mehta, MD University of the Witwatersrand Raj P. Pal, BSc(Hons), MB ChB, MD, FRCS
Professor of Medicine Faculty of Health Sciences Department of Urology
University of California San Diego Johannesburg, South Africa Leicester General Hospital
San Diego, CA, USA Leicester, UK
Masaomi Nangaku, MD, PhD
J. Kilian Mellon, MD, FRCS (Urol) Professor and Head Biff F. Palmer, MD
Professor of Urology Division of Nephrology and Endocrinology Professor of Internal Medicine
Department of Urology The University of Tokyo School of Medicine Distinguished Teaching Professor
Leicester General Hospital Tokyo, Japan Department of Medicine
Leicester, UK University of Texas Southwestern Medical
Center
Dallas, Texas, USA

LIST OF CONTRIBUTORS xv
Antonelli Pani Son V. Pham, MD, FACC Giuseppe Remuzzi, MD, FRCP
Section of Nephrology and Dialysis Chief of Cardiology Director, Unit of Nephrology and Dialysis,
AO Brotzu Hospital South Texas Veterans Health Care System Azienda Socio-Sanitaria Territoriale Papa
Sardinia, Italy Assistant Clinical Professor of Medicine Giovanni XXIII;
University of Texas Health Science Center, Director, IRCCS -Istituto di Ricerche
Neesh Pannu, MD, SM San Antonio Farmacologiche “Mario Negri,” Bergamo,
Associate Professor San Antonio, TX, USA Italy;
Department of Medicine Chiara Fama Professor of Nephrology,
University of Alberta Richard G. Phelps, PhD, FRCP Department of Biomedical and Clinical
Edmonton, Alberta, Canada Senior Lecturer in Nephrology Sciences, University of Milan, Italy
MRC Centre for Inflammation Research
Samir V. Parikh, MD University of Edinburgh; Michelle N. Rheault, MD
Assistant Professor of Medicine Honorary Consultant Associate Professor
Department of Internal Medicine Renal Medicine Division of Paediatric Nephrology
Division of Nephrology Royal Infirmary of Edinburgh University of Minnesota
The Ohio State University Wexner Medical Edinburgh, UK Minneapolis, MN, USA
Center
Columbus, OH, USA Mark A. Perazella, MD A. Mark Richards, MD, PhD, DSc, MB, ChB
University of Texas MD Anderson Cancer Professor
Alice K. Pau, Pharm D Center Department of Medicine
Division of Clinical Research Houston, TX; University of Otago Christchurch
NIH-NIAID Section of Nephrology Christchurch, New Zealand;
Bethesda, MD, USA Department of Medicine Director
Yale University School of Medicine Cardiovascular Research Institute
Norberto Perico, MD New Haven, CN, USA National University of Singapore
IRCCS - Istituto di Ricerche Farmacologiche Singapore
Mario Negri Matthew C. Pickering, PhD, MB, BS
Bergamo, Italy Professor of Rheumatology †
Bengt Rippe, MD, PhD
Centre for Complement and Inflammation Formerly Professor
Phuong-Chi T. Pham, MD, FASN Research Department of Nephrology
Chief Department of Medicine University Hospital of Lund
Division of Nephrology and Hypertension Imperial College Lund, Sweden
Olive View–University of California Los London, UK
Angeles (UCLA) Medical Center; Bernardo Rodriguez-Iturbe, MD
Program Director Kevan R. Polkinghorne, PhD, MBChB, M Professor of Medicine
Olive View–UCLA Nephrology Fellowship Clin Epi, BHB, FRACP Department of Nephrology
Program Associate Professor Hospital Universitario and Universidad del
Los Angeles, CA, USA Department of Nephrology Zulia,
Monash Medical Centre; Maracaibo, Zulia, Venezuela
Phuong-Anh T. Pham, MD, FACC Associate Professor
Division of Cardiology Department of Medicine Pierre Ronco, MD, PhD
Interventional Cardiology Epidemiology and Preventative Medicine Professor of Nephrology
VA Nebraska-Western Iowa Health Care Monash University Pierre et Marie Curie University;
System Melbourne, Australia Department of Nephrology and Dialysis
Omaha, NE, USA Hôpital Tenon
Brian Rayner, MBChB, FCP, MMed, PhD Paris, France
Phuong-Thu T. Pham, MD, FASN Professor
Clinical Professor of Medicine Division of Nephrology and Hypertension Mitchell H. Rosner, MD
David Geffen School of Medicine at University of Cape Town Professor of Medicine
University of California-Los Angeles Cape Town, South Africa Division of Nephrology
Division of Nephrology; University of Virginia Health System
Director Hugh C. Rayner, MD, MA, DipMedEd, Charlottesville, VA, USA
Outpatient Services FRCP
Kidney Transplant Program Consultant Nephrologist Edward A. Ross, MD
Ronald Reagan Medical Center at University Department of Renal Medicine Chair and Professor, Department of Internal
of California-Los Angeles Heart of England National Health Service Medicine
Los Angeles, CA, USA Foundation Trust University of Central Florida
Birmingham, UK College of Medicine
Orlando, FL, USA
†
Deceased.

xvi LIST OF CONTRIBUTORS
Jérôme A. Rossert, MD, PhD Pantelis A. Sarafidis, MD, MSc, PhD Visith Sitprija, MD, PhD, FACP, FRCP,
Global Clinical Development Assistant Professor and Honorary FRACP, FRCPE
Vertex Pharmaceuticals Consultant in Nephrology Director
Boston, MA, USA Department of Nephrology Queen Saovabha Memorial Institute
Hippokration Hospital Bangkok, Thailand
Brad H. Rovin, MD Aristotle University of Thessaloniki
The Lee A. Hebert Distinguished Professor Thessaloniki, Greece Peter Stenvinkel, MD, PhD
of Nephrology Professor
Director Joanna M. Schaenman, MD, PhD Senior Lecturer, Department of Nephrology
Division of Nephrology Department of Medicine Karolinska Institute
The Ohio State University Wexner Medical Ronald Reagan UCLA Medical Center Karolinska University Hospital at Huddinge
Center Los Angeles, CA, USA Stockholm, Sweden
Columbus, OH, USA
Robert W. Schrier, MD Eric Stites, MD
Piero L. Ruggenenti, MD Professor Emeritus Assistant Professor
Assistant Professor Department of Medicine Division of Nephrology and Hypertension
Unit of Nephrology University of Colorado School of Medicine University of Colorado-Denver
Azienda Ospedaliera Papa Giovanni; Aurora, CO, USA Aurora, Colorado, USA
Head
Department of Renal Medicine Alan Segal, MD Tetsuhiro Tanaka
IRCSS–Instituto di Ricerche Farmacologiche Associate Professor Division of Nephrology and Endocrinology
“Mario Negri,” Division of Nephrology The University of Tokyo School of Medicine
Bergamo, Italy Department of Medicine, University of Tokyo, Japan
Vermont College of Medicine
Graeme R. Russ, PhD, MBBS, FRACP Burlington, VT, USA Sydney Tang
Royal Adelaide Hospital Chair of Renal Medicine and Yu Endowed
Adelaide, Australia Mark S. Segal, MD, PhD Professor in Nephrology
Professor and Chief Division of Nephrology
David J. Salant, MD, BCh J. Robert Cade Professor of Medicine Department of Medicine
Norman G. Levinsky Professor Division of Nephrology The University of Hong Kong
Renal Section Hypertension & Renal Transplantation Queen Mary Hospital
Department of Medicine University of Florida College of Hong Kong, China
Boston University School of Medicine Medicine
Boston, MA, USA Gainesville, FL USA Laurie A. Tomlinson, MBBS, PhD
Associate Professor
Martin A. Samuels, MD, DSc(hon), FAAN, Julian L. Seifter, MD Faculty of Epidemiology and Population
MACP, FRCP Brigham and Women’s Hospital Health
Miriam Sydney Joseph Professor of Boston, MA, USA London School of Hygiene and Tropical
Neurology Medicine
Harvard Medical School; Sanjeev Sethi, MD, PhD London, UK
Chair Division of Anatomic Pathology
Department of Neurology Mayo Clinic Marcello Tonelli, MD, SM, MSc, FRCPC
Brigham and Women’s Hospital; Rochester, MN, USA Associate Vice President (Research)
Senior Consultant, Neurology Department of Medicine
Massachusetts General Hospital Kumar Sharma, MD, FAHA University of Calgary
Boston, MA, USA Hillis Endowed Chair and Professor of Calgary, Alberta, Canada
Medicine
Paul W. Sanders, MD Chief Li-Li Tong, MD
Thomas E. Andreoli, M.D., Endowed Chair Division of Nephrology Associate Professor of Medicine
in Nephrology Vice Chair of Research, Department of Division of Nephrology and Hypertension
University of Alabama at Birmingham; Medicine Los Angeles Biomedical Research Institute at
Chief, Renal Section University of Texas Health San Antonio Harbor University of California–Los
Veterans Affairs Medical Center San Antonio, Texas, USA Angeles
Birmingham, AL, USA David Geffen School of Medicine
Claire C. Sharpe, MBBS PhD FRCP Torrance, CA, USA
Jeff M. Sands, MD Reader in Renal Sciences
Juha P. Kokko Professor of Medicine and King’s College Hospital; Peter S. Topham, MD, MB, ChB
Physiology Consultant Nephrologist Consultant Nephrologist
Renal Division King’s College Hospital John Walls Renal Unit
Department of Medicine London, UK University Hospitals of Leicester NHS Trust
Emory University Leicester, UK
Atlanta, GA, USA

LIST OF CONTRIBUTORS xvii
Jan H. M. Tordoir, PhD Shikha Wadhwani, MD Alexander C. Wiseman, MD

Vascular Surgeon Fellow in Glomerular Diseases Associate Professor
Director of the Vascular Laboratory Division of Nephrology Division of Renal Diseases and
Department of Surgery The Ohio State University Wexner Medical Hypertension
Maastricht University Medical Center Center University of Colorado;
Maastricht, The Netherlands Columbus, OH, USA Medical Director
Kidney and Pancreas Transplant Programs
Vicente E. Torres, MD, PhD Haimanot Wasse, MD, MPH University of Colorado Hospital
Professor of Medicine Professor and Vice Chair; Director of Aurora, CO, USA
Division of Nephroogy and Hypertension Interventional Nephrology
Mayo Clinic Rush University Medical Center Karl L. Womer, MD
Rochester, MN, USA Chicago, IN, USA Professor of Medicine
University of Florida
A. Neil Turner, PhD, FRCP I. David Weiner, MD Gainesville, FL, USA
Professor of Nephrology Professor of Medicine and Physiology and
MRC Centre for Inflammation Research Functional Genomics Graham Woodrow, MBChB, MD, FRCP
University of Edinburgh; Division of Nephrology Consultant Nephrologist
Honorary Consultant Hypertension and Renal Transplantation Renal Unit
Renal Medicine University of Florida College of Medicine St. James’s University Hospital
Royal Infirmary of Edinburgh Nephrology and Hypertension Section Leeds, UK
Edinburgh, UK North Florida/South Georgia Veterans
Health System Melanie Wyld, MBBS, MPH
Kausik Umanath, MD MS Gainesville, FL, USA Renal Department
Section Head Royal Prince Alfred Hospital Sydney
Clinical Trials Research David C. Wheeler, MBChB, MD Australia
Division of Nephrology and Hypertension Professor of Kidney Medicine University of Sydney
Henry Ford Hospital Centre for Nephrology Australia
Detroit, MN, USA University College London Medical School
London, UK David C. Wymer, MD
Robert J. Unwin, PhD, BM, FRCP, FSB Associate Professor Medicine and Radiology
CBiol Martin E. Wilkie, MD, FRCP Associate Chair Radiology
Professor of Nephrology and Physiology Consultant Renal Physician and Honorary Department of Radiology
UCL Centre for Nephrology Reader University of Florida
University College London Editor in Chief Gainesville, FL, USA
London, UK Peritoneal Dialysis International
Sheffield Kidney Institute David T.G. Wymer, MD
Christoph Wanner, MD Northern General Hospital Assistant Professor
Professor of Medicine Sheffield, UK Department of Radiology
Chief Mount Sinai Medical Center
Division of Nephrology Bryan Williams, MD Miami, FL, USA
University Hospital Würzburg Professor of Medicine
Würzburg, Germany Institute of Cardiovascular Science Xueqing Yu, MD, PhD
University College London Professor of Medicine;
R. Kasi Visweswaran, MD, DM, FRCP London, UK Director
(Edin) Institute of Nephrology
Professor Charles S. Wingo, MD The First Affiliated Hospital
Ananthapuri Hospitals and Research Center Professor of Medicine and Physiology and Sun Yat-Sen University
Thiruvananthapuram Functional Genomics Guangzhou, China
Kerala, India Division of Nephrology, Hypertension and
Renal Transplantation Martin Zeier, MD
University of Florida College of Medicine Division of Nephrology
Nephrology and Hypertension Section, Heidelberg University Hospital
North Florida/South Georgia Veterans Heidelberg, Germany
Health System
Gainesville, FL, USA

To our mentors in nephrology—especially Bill Couser, Stewart Cameron,
Karl M. Koch, and Kailash Jindal.
To our colleagues and collaborators, as well as others, whose research
continues to light the way
To our wives and families, who have once again endured the preparation of
this sixth edition with unfailing patience and support
To our patients with renal disease, for whom it is a privilege to care
John Feehally
Jürgen Floege
Marcello Tonelli
Richard J. Johnson

SECTION I Essential Renal Anatomy and Physiology
1
Renal Anatomy
Wilhelm Kriz, Marlies Elger
The complex structure of the mammalian kidney is best understood the renal sinus, finally divides into the interlobar arteries, which extend
in the unipapillary form that is common to all small species. Fig. 1.1 toward the cortex in the space between the wall of the pelvis (or calyx)
is a schematic coronal section through a unipapillary kidney, with a and the adjacent cortical tissue. At the junction between cortex and
cortex enclosing a pyramid-shaped medulla, the tip (papilla) of which medulla, the interlobar arteries divide and pass over into the arcuate
protrudes into the renal pelvis. The medulla is divided into an outer arteries, which also branch. The arcuate arteries give rise to the cortical
and an inner medulla; the outer medulla is further subdivided into an radial arteries (interlobular arteries), which ascend radially through the
outer and an inner stripe. cortex. No arteries penetrate the medulla.
Afferent arterioles supply the glomerular tufts and generally arise from
cortical radial arteries. As a result, the blood supply of the peritubular
STRUCTURE OF THE KIDNEY capillaries of the cortex and the medulla is exclusively postglomerular.
The specific components of the kidney are the nephrons, the collecting Glomeruli are drained by efferent arterioles. Two basic types of
ducts (CDs), and a unique microvasculature.1 The multipapillary kidney efferent arterioles can be distinguished: cortical and juxtamedullary.
of humans contains approximately 1 million nephrons, although this Cortical efferent arterioles, which derive from superficial and midcortical
number varies considerably. The number of nephrons is already estab- glomeruli, supply the capillary plexus of the cortex. The efferent arte-
lished during prenatal development; after birth, new nephrons cannot rioles of juxtamedullary glomeruli represent the supplying vessels of
be developed and a lost nephron cannot be replaced. the renal medulla. Within the outer stripe of the medulla, these vessels
divide into the descending vasa recta and then penetrate the inner stripe
Nephrons in cone-shaped vascular bundles. At intervals, individual vessels leave
A nephron consists of a renal corpuscle (glomerulus) connected to a the bundles to supply the capillary plexus at the adjacent medullary
complicated and twisted tubule that finally drains into a CD (Fig. 1.2 level.
and Table 1.1). Three types of nephron can be distinguished by the Ascending vasa recta drain the renal medulla. In the inner medulla,
location of renal corpuscles within the cortex: superficial, midcortical, the vasa recta arise at every level, ascending as unbranched vessels, and
and juxtamedullary nephrons. The tubular part of the nephron consists traverse the inner stripe within the vascular bundles. The ascending
of a proximal tubule and a distal tubule connected by a loop of Henle2 vasa recta that drain the inner stripe may join the vascular bundles or
(see later discussion). There are two types of nephrons: those with long may ascend directly to the outer stripe between the bundles. All the
loops of Henle and those with short loops. Short loops turn back in ascending vasa recta traverse the outer stripe as individual wavy vessels
the outer medulla or even in the cortex (cortical loops). Long loops with wide lumina interspersed among the tubules. Because true capil-
turn back at successive levels of the inner medulla. laries derived from direct branches of efferent arterioles are relatively
scarce, the ascending vasa recta form the capillary plexus of the outer
Collecting Ducts stripe. The ascending vasa recta empty into arcuate veins.
A CD is formed in the renal cortex when several nephrons join. A The vascular bundles represent a countercurrent exchanger between
connecting tubule (CNT) is interposed between a nephron and a corti- the blood entering and that leaving the medulla. In addition, the orga-
cal CD. Cortical CDs descend within the medullary rays of the cortex. nization of the vascular bundles results in a separation of the blood
Then they traverse the outer medulla as unbranched tubes. On entering flow to the inner stripe from that to the inner medulla. Descending
the inner medulla, they fuse successively and open finally as papillary vasa recta supplying the inner medulla traverse the inner stripe within
ducts into the renal pelvis (see Fig. 1.2 and Table 1.1). the vascular bundles. Therefore blood flowing to the inner medulla has
not been exposed previously to tubules of the inner or outer stripe. All
Microvasculature ascending vasa recta originating from the inner medulla traverse the
The microvascular pattern of the kidney is similarly organized in mam- inner stripe within the vascular bundles. Thus blood that has perfused
malian species1,3 (Fig. 1.3; see also Fig. 1.1). The renal artery, after entering tubules of the inner medulla does not subsequently perfuse tubules of
1
2 SECTION I Essential Renal Anatomy and Physiology
Coronal Section Through a Unipapillary Kidney Nephrons and the Collecting Duct System
Short-looped Long-looped Glomeruli Renal
nephron nephron artery 9
8
1
9 7
2
Cortex
Outer
medulla
Cortex 8
Inner
medulla 1
10 Medullary
7 ray
2
3
Collecting Renal
duct vein 3
Outer stripe 6
Fig. 1.1 Coronal section through a unipapillary kidney.
6
Outer
medulla Inner 11
TABLE 1.1 Subdivisions of the Nephron and stripe 4
Collecting Duct System
Section Subsections
Nephron
Renal corpuscle Glomerulus: term used most frequently Inner 12
4 5
to refer to entire renal corpuscle medulla
Bowman capsule
Proximal tubule Convoluted part
Straight part (pars recta), or thick
descending limb of Henle loop
Intermediate tubule Descending part, or thin descending 1. Renal corpuscle 7. Macula densa
2. Proximal convoluted tubule 8. Distal convoluted tubule
limb of Henle loop 3. Proximal straight tubule 9. Connecting tubule
Ascending part, or thin ascending limb 4. Descending thin limb 10. Cortical collecting duct
5. Ascending thin limb 11. Outer medullary collecting duct
of Henle loop
6. Distal straight tubule 12. Inner medullary collecting duct
Distal tubule Straight part, or thick ascending limb (thick ascending limb)
of Henle loop: subdivided into Fig. 1.2 Nephrons and the collecting duct system. Shown are
medullary and cortical parts; the short-looped and long-looped nephrons, together with a collecting duct
cortical part contains the macula (not drawn to scale). Arrows denote confluence of further nephrons.
densa in its terminal portion
Convoluted part
The intrarenal arteries and the afferent and efferent glomerular
Collecting Duct System arterioles are accompanied by sympathetic nerve fibers and terminal
Connecting tubule Includes the arcades in most species axons representing the efferent nerves of the kidney.1 Tubules have
Collecting duct Cortical collecting duct direct contact to terminal axons only when the tubules are located
Outer medullary collecting duct: around the arteries or the arterioles. Tubular innervation consists of
subdivided into an outer stripe and “occasional fibers adjacent to perivascular tubules.”4 The density of
an inner stripe portion nerve contacts to convoluted proximal tubules is low; contacts to straight
Inner medullary collecting duct: proximal tubules, thick ascending limbs of Henle loops, and CDs have
subdivided into basal, middle, and never been encountered. Afferent nerves of the kidney are believed to
papillary portions be sparse.5
Glomerulus (Renal Corpuscle)

The glomerulus comprises a tuft of specialized capillaries attached to
the inner stripe. However, the blood returning from either the inner the mesangium, both of which are enclosed in a pouch-like extension
medulla or the inner stripe afterward does perfuse the tubules of the of the tubule that represents the Bowman capsule (Figs. 1.4 and 1.5).
outer stripe. The capillaries together with the mesangium are covered by epithelial
The intrarenal veins accompany the arteries. Central to the renal cells (podocytes) forming the visceral epithelium of the Bowman capsule.
drainage of the kidney are the arcuate veins, which, in contrast to arcuate At the vascular pole, this is reflected to become the parietal epithelium
arteries, do form real anastomosing arches at the corticomedullary of the Bowman capsule. At the interface between the glomerular capil-
border. laries and the mesangium on one side and the podocyte layer on the

CHAPTER 1 Renal Anatomy 3
Microvasculature of the Kidney Renal Corpuscle and

Juxtaglomerular Apparatus
Arterial vessels Venous
and capillaries vessels
Cortical
radial artery Juxtaglomerular
AA MD EGM
apparatus
Afferent EA
arteriole
N
Cortex
Cortical
radial vein GC SMC
Vascular pole
Arcuate
vein PE
Outer To
stripe intrarenal PO
vein
Bowman
Efferent capsule M E F
arteriole GBM
Outer
medulla Arcuate
Inner artery
stripe US
Descending
vasa recta
Urinary pole
Ascending Proximal
vasa recta tubule
AA Afferent arteriole PE Parietal epithelium

MD Macula densa PO Podocyte
Inner
EGM Extraglomerular mesangium M Mesangium
medulla EA Efferent arteriole E Endothelium
N Sympathetic nerve terminals F Foot process
GC Granular cells GBM Glomerular basement
SMC Vascular smooth muscle cells membrane
US Urinary space
Fig. 1.4 Glomerulus and juxtaglomerular apparatus. (Modified
with permission from reference 1.)
the podocyte layer. This peripheral portion of the capillary wall repre-
Fig. 1.3 Microvasculature of the Kidney. Afferent arterioles supply sents the filtration area.
the glomeruli, and efferent arterioles leave the glomeruli and divide into
the descending vasa recta, which together with the ascending vasa Glomerular Basement Membrane
recta form the vascular bundles of the renal medulla. The vasa recta The GBM serves as the skeleton of the glomerular tuft. This membrane
ascending from the inner medulla all traverse the inner stripe within the
is a complexly folded sack with an opening at the glomerular hilum
vascular bundles, whereas most of the vasa recta from the inner stripe
of the outer medulla ascend outside the bundles. Both types traverse
(see Fig. 1.4). The outer aspect of this GBM sack is completely covered
the outer stripe as wide, tortuous channels. with podocytes. The interior of the sack is filled with the capillaries and
the mesangium. As a result, on its inner aspect, the GBM is in contact
with either capillaries or the mesangium. At any transition between
these two locations, the GBM changes from a convex pericapillary to a
other side, the glomerular basement membrane (GBM) is developed. concave perimesangial course; the turning points are called mesangial
The space between both layers of the Bowman capsule represents the angles. In electron micrographs of traditionally fixed tissue, the GBM
urinary space, which at the urinary pole continues as the tubule lumen. appears as a trilaminar structure, with a lamina densa bounded by two
On entering the tuft, the afferent arteriole immediately divides into less dense layers, the lamina rara interna and lamina rara externa (see
several primary capillary branches, each of which gives rise to an anas- Fig. 1.7). Studies with freeze techniques reveal only one thick, dense
tomosing capillary network representing a glomerular lobule. In contrast, layer directly attached to the bases of the epithelium and endothelium.7
the efferent arteriole is already established inside the tuft by confluence The major components of the GBM include type IV collagen, laminin,
of capillaries from each lobule.6 Thus the efferent arteriole has a sig- and heparan sulfate proteoglycans, as in basement membranes at other
nificant intraglomerular segment located within the glomerular stalk. sites. However, the GBM has several unique properties, notably a distinct
Glomerular capillaries are a unique type of blood vessel composed spectrum of type IV collagen and laminin isoforms. The mature GBM
of nothing but an endothelial tube (Figs. 1.6 and 1.7). A small stripe consists of type IV collagen made of α3, α4, and α5 chains and laminin
of the outer aspect of this tube directly abuts the mesangium; the major 11, made of α5, β2, and γ1 chains.8 Type IV collagen is the antigenic
part bulges toward the urinary space and is covered by the GBM and target in Goodpasture disease (see Chapter 16), and mutations in the

MD Peripheral Portion of a Glomerular Lobule
EA Glomerular
AA basement
Podocyte membrane
EGM
Foot
processes
Capillary
Mesangial Capillary
angle endothelium
PO
PE
Microfilaments
Mesangium
Mesangial
matrix
P
Fig. 1.5 Longitudinal section through a glomerulus (rat). At the Fig. 1.6 Peripheral portion of a glomerular lobule. This part shows
vascular pole, the afferent arteriole (AA), the efferent arteriole (EA), the a capillary, the axial position of the mesangium, and the visceral epithe-
extraglomerular mesangium (EGM), and the macula densa (MD) are lium (podocytes). At the capillary-mesangial interface, the capillary endo-
seen; PO, podocyte. At the urinary pole, the parietal epithelium (PE) thelium directly abuts the mesangium.
transforms into the proximal tubule (P). (Light microscopy; magnification
× 390.)
Mesangial cells. Mesangial cells are irregular in shape, with many
processes extending from the cell body toward the GBM (see Figs. 1.6
genes of the α3, α4, and α5 chains are responsible for Alport syndrome and 1.7). In these processes, dense assemblies of microfilaments are
(see Chapter 46). found, containing α-smooth muscle actin, myosin, and α-actinin.11
Current models depict the basic structure of the GBM as a three- The processes are attached to the GBM directly or through the inter-
dimensional network of type IV collagen.7 The type IV collagen monomer position of microfibrils The GBM represents the effector structure of
consists of a triple helix that is 400 nm in length, with a large, noncol- mesangial contractility. Mesangial cell–GBM connections are found
lagenous globular domain at its C-terminal end called NC1. At the N throughout the mesangium-GBM interface but are especially prominent
terminus, the helix possesses a triple helical rod 60 nm long: the 7S at the turning points of the GBM infoldings (mesangial angles). The
domain. Interactions between the 7S domains of two triple helices or folding pattern of the GBM is permanently challenged by the expansile
the NC1 domains of four triple helices allow type IV collagen monomers forces of the high intraglomerular perfusion pressure. Centripetal
to form dimers and tetramers. In addition, triple helical strands inter- mesangial cell contraction balances the expansile forces. Thus the folding
connect by lateral associations through binding of NC1 domains to pattern of the GBM, including the complex convolutions of glomerular
sites along the collagenous region. This network is complemented by capillaries, are maintained by mesangial cells.
an interconnected network of laminin 11, resulting in a flexible, non- Mesangial cells possess a great variety of receptors, including those
fibrillar polygonal assembly that provides mechanical strength and for angiotensin II (Ang II), vasopressin, atrial natriuretic factor, pros-
elasticity to the basement membrane and serves as a scaffold for align- taglandins, transforming growth factor β (TGF-β), and other growth
ment of other matrix components.9,10 factors (platelet-derived growth factor [PDGF], epidermal growth factor
The electronegative charge of the GBM mainly results from the [EGF], connective tissue growth factor [CTGF]).12
presence of polyanionic proteoglycans. The major proteoglycans of the Mesangial matrix. The mesangial matrix fills the highly irregular
GBM are heparan sulfate proteoglycans, including perlecan and agrin. spaces between the mesangial cells and the perimesangial GBM, anchoring
Proteoglycan molecules aggregate to form a meshwork that is kept well the mesangial cells to the GBM.6 Many common extracellular matrix
hydrated by water molecules trapped in the interstices of the matrix. proteins have been demonstrated within the mesangial matrix, including
collagen types IV, V, and VI and microfibrillar protein components such
Mesangium as fibrillin and the 31-kilodalton microfibril-associated glycoprotein. The
Three major cell types occur within the glomerular tuft, all of which matrix also contains several glycoproteins, most abundantly fibronectin.
are in close contact with the GBM: mesangial cells, endothelial cells,
and podocytes. The mesangial/endothelial/podocyte cell ratio is 2 : 3 : 1 Endothelium
in the rat. The mesangial cells and mesangial matrix establish the glo- Glomerular endothelial cells consist of cell bodies and peripherally
merular mesangium. located, attenuated, and highly fenestrated cytoplasmic sheets (see Figs.

GBM
MF
A B
Fig. 1.7 Glomerular capillary. (A)The layer of interdigitating podocyte processes and the glomerular base-
ment membrane (GBM) do not completely encircle the capillary. At the mesangial angles (arrows), both
deviate from a pericapillary course and cover the mesangium. Mesangial cell processes containing dense
bundles of microfilaments (MF), interconnect the GBM, and bridge the distance between the two mesangial
angles. (B) Filtration barrier. The peripheral part of the glomerular capillary wall comprises the endothelium
with open pores (arrowheads), the GBM, and the interdigitating foot processes (FPs). The GBM shows a
lamina densa bounded by the lamina rara interna and externa. The FPs are separated by filtration slits bridged
by thin diaphragms (arrows). (Transmission electron microscopy [TEM]; magnification: A, [× 8770]; B, [× 50,440].)
1.6 and 1.7). Glomerular endothelial pores lack diaphragms, which are that actually are also FPs.16 Thus the interdigitating FP pattern as it
encountered only in the endothelium of the final tributaries to the adheres to the GBM is completely homogeneous, forming a uniform
efferent arteriole.6 The round to oval pores have a diameter of 50 to cover of interdigitating filopodia.
100 nm. A negatively charged layer of membrane-bound and loosely In contrast to the cell body, which harbors a prominent endoplasmic
attached molecules (glycocalyx) covers the entire luminal surface, includ- reticulum and Golgi system and has well-developed endocytotic and
ing, as sieve plugs, the endothelial pores.13 Endothelial cells are active autophagic machinery, the cell processes apart from endocytotic ele-
participants in processes controlling coagulation and inflammation. ments contain only a few organelles. A sophisticated cytoskeleton accounts
Endothelial cells have receptors for vascular endothelial growth factor for the complex shape of the cells. In the cell body and the primary
(VEGF), angiopoietins, and TGFβ-1, among others. They synthesize processes, microtubules and intermediate filaments (vimentin, desmin)
and release PDGF-B, endothelin-1, and endothelium-derived relaxing dominate. Within the FPs, microfilaments (β-actin) form prominent
factor (EDRF), among others.14 U-shaped bundles arranged in the longitudinal axis of two successive
FPs in an overlapping pattern. Above, the bends of these bundles are
Visceral Epithelium (Podocytes) linked to the microtubules of the primary processes; peripherally, these
The visceral epithelium of the Bowman capsule comprises highly dif- bundles terminate in the dense cytoplasm associated with the sole plates,
ferentiated cells, the podocytes (Fig. 1.8; see also Fig. 1.6). Differentiated being part of the anchoring system of the FPs to the GBM (see later
podocytes are unable to replicate; therefore lost podocytes cannot be discussion). In addition, FPs have well developed sub-plasmalemmal
replaced in the adult. All efforts of the last decade to find progenitor cells actin network that has intimate contact to the anchor line of the SD
that might migrate into the tuft and replace lost podocytes have failed. and diffusely to the actin bundles. Multiple actin-associated proteins,
Podocytes have a voluminous cell body that floats within the urinary including α-actinin-4 and synaptopodin myosin (myo-1e), among many
space, separated from the GBM by a subpodocyte space.15 The cell others, establish the specific cytoskeleton in podocytes.19
bodies give rise to primary processes that fall apart into foot processes The luminal membrane contains a great variety of receptors (see
(FPs) that fix the cells to the capillaries, i.e. to the GBM. Sporadic FPs later discussion), and together with the luminal surface of the SD it is
also may arise directly from the cell body. The FPs of neighboring covered by a thick surface coat that is rich in sialoglycoproteins, includ-
podocytes regularly interdigitate with each other, leaving meandering ing podocalyxin and podoendin, accounting for the high negative surface
slits (filtration slits) between them that are bridged by a complex extra- charge of the podocytes.
cellular structure, the slit diaphragm (SD) that may be seen as a modified The abluminal cell membrane comprises a narrow band of lateral
adherens junction (Fig. 1.9; see also Figs. 1.6 to 1.8). Traditional scan- cell membrane extending from the SD to the GBM and, most important,
ning electron micrograph (SEM) pictures (see Fig.1.8A) do not convey the soles of the FPs abutting to the GBM. A complex anchoring system
the correct pattern of how FPs interdigitate and adhere to the GBM. connects the cytoskeleton of the FPs to the GBM. Two systems are
As seen by block-face SEM (see Fig. 1.8B), individual FPs may terminate known: (1) α3β1 integrin dimers interconnect the cytoplasmic focal
with a final branching and primary processes fall off into basal ridges adhesion proteins vinculin, paxillin, and talin with the α3, α4, and α5

adenosine monophosphate (cAMP) signaling stimulated by prostaglan-

din E2 (PGE2), dopamine, VEGF, isoproterenol, parathyroid hormone
(PTH), PTH-related peptide; and receptors for Ca2+ signaling stimulated
by numerous ligands, including angiotensin II, acetylcholine, PGF2,
arginine vasopressin (AVP), adenosine triphosphate (ATP), endothelin,
FP
and histamine.20 Among the transient receptor potential (TRP) cation
PP channels, TRPC5 and TRPC6 have received much attention.21-23 The
major target of this signaling orchestra is the cytoskeleton (see later
discussion). Other receptors, such as for TGF-β, fibroblast growth
factor (FGF-2), and other cytokines/chemokines, have been shown to
be involved in synthesis functions (GBM components) or in devel-
opment of podocyte diseases.20 Megalin is a multiligand endocytotic
receptor and the major antigen of Heymann nephritis in the rat,24
but is not present in humans.12 On the other hand, podocytes, by
paracrine and autocrine signaling, regulate the interplay with endo-
thelial and mesangial cells; during development they are responsible
A for building a glomerulus. VEGF, angiopoietins, and PDGF, among
others, are of crucial importance for the homeostatic maintenance of
the tuft.25
Function and Maintenance of the Filtration Barrier

Most glomerular diseases start in the glomerulus, beginning with the
breakdown of the filtration barrier. It is commonly accepted that the
physical forces associated with filtration represent crucial challenges
that account for the break down; they comprise filtration pressure and
filtrate flow.
B Filtration pressure and expansion. Traditionally, the high trans-
mural hydrostatic pressure gradients necessary for filtration have been
Fig. 1.8 Branching pattern of podocyte foot processes (rat). (A) considered the main challenge to the filtration barrier. Podocyte FPs
Scanning electron micrograph (SEM) showing the urinary side of the were considered a kind of pericyte process counteracting variations
podocyte cover of a glomerular capillary consisting of cell bodies, large
and derailments in perfusion pressures. This view has been challenged
primary processes (PP) and interdigitating foot processes (FP) separated
by the filtration slits. (B) Drawing of the basal aspect of the FP-branching
since we learned that the major way podocytes are lost (under any
pattern as seen by block-face SEM. A fully homogeneous branching circumstances) is by detachment from the GBM as viable cells. It seems
pattern of FPs attaches to the glomerular basement membrane (GBM) self-contradictory that FPs, which need their cytoskeleton to continually
that may be compared with a pattern of interdigitating filopodia con- adapt their pattern of attachment to the GBM (see later discussion),
nected by adherens junctions. The high degree of branching (not seen would simultaneously function as contractile pericyte-like processes,
from the luminal aspect) provides a high degree of adaptability to area counteracting the expansion of the GBM by increasing their tone. Con-
changes of the underlying GBM. (B, From reference 45, with permission.) sequently, it may be concluded that the principal burden for counter-
acting transmural pressure gradients (i.e., for developing wall tension)
falls instead on the GBM.26
chains of type IV collagen and laminin 521; and (2) β-α-dystroglycans As described earlier, the GBM is an elastic membrane that expands
interconnect the cytoplasmic adapter protein utrophin with agrin and or shrinks in surface area with increasing or decreasing transmural
laminin α5 chains in the GBM.9 hydrostatic pressure, respectively. Its expansion decreases with increasing
The junctional connection of podocyte FPs by the SD bridging the pressure and is limited.
filtration slits is complex and unique. The filtration slits have a constant Expansion of the GBM affords the immediate coordinated increase
width of approximately 30 to 40 nm: thus the SD has to connect the in the cover by interdigitated FPs; thus the FPs and the SD have to
FPs over a considerable distance. By transmission electron microscopy increase correspondingly (and vice versa when pressure decreases). The
(TEM), in routinely glutaraldehyde-fixed material, the SD shows up as ability for such acute adaptions has been previously shown in the iso-
a single dark line in cross sections and in an en-face view as a homog- lated perfused kidney. It is suggested that the changes in FP length
enous network of fibrillar structures interconnecting both membranes. occur by actin polymerization/depolymerization and the changes in
Combined tannic acid and glutaraldehyde–fixed tissue reveals, in en-face SD length by coordinated exocytotic and endocytotic processes of SD
view, a zipper-like structure with a row of pores approximately 14 × components.26,27
2 nm on either side of a central bar. The transmembrane proteins that An orchestrated connection between the mobility of the actin cyto-
establish the slit diaphragm (SD) and its connection to the actin cytoskeleton and the dynamics of the SD has been uncovered in great depth
skeleton of the FPs include nephrin, P-cadherin, FAT1, NEPH 1-3, by innumerable studies during the past two decades.28,29
podocin, and CD2AP, among others20 (see Fig. 1.9). Filtrate flow and shear stress. The flow of the filtrate through
Podocytes contain a great variety of surface receptors and ion chan- the filtration barrier represents by far the highest extravascular fluid
nels, many of which accumulate close to the SD; the schematic in Fig. flow in the body. It consists of the outflow from glomerular capillar-
1.9 shows some of them. They include receptors for cyclic guanosine ies, through the GBM, and into the Bowman space. This latter step
monophosphate (cGMP) signaling, stimulated by natriuretic peptides creates a problem: in contrast to the exit of filtrate from capillaries,
(atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and where flow presses the endothelium against the basement membrane,
C-type natriuretic peptide [CNP]) and nitric oxide; receptors for cyclic its entry into the Bowman space tends to separate the podocytes from

Glomerular Filtration Barrier
Cl−
Actin
NSCC
N M Ca2+
AT1
S PC
Ang II
TRPC6
Ez Podocin
Ca2+
U
Cas
Z
CD FAK ILK
Cat TPV TPV
β
α-Actinin 4 Nephrin β1 α3
NEPH 1-3 α
Laminin11 P-Cadherin
Dystroglycan
FAT1
Integrin
Agrin COLLAGEN IV (α3, α4, α5)
Capillary Capillary
endothelium endothelium
Fig. 1.9 Glomerular filtration barrier. Two podocyte foot processes (FPs) bridged by the slit membrane
(SM), the glomerular basement membrane (GBM) and the porous capillary endothelium, are shown. The
surfaces of podocytes and of the endothelium are covered by a negatively charged glycocalyx containing
the sialoprotein podocalyxin (PC). The GBM is mainly composed of type IV collagen (α3, α4, and α5), laminin
11 (α5, β2, and γ1 chains), and the heparan sulfate proteoglycan agrin. The SM represents a porous protein-
aceous membrane composed of (as far as is known) nephrin, NEPH 1-3, P-cadherin, and FAT1. The actin-
based cytoskeleton of the FPs connects to both the GBM and the SM. Regarding the connections to the
GBM, β1α3 integrin dimers specifically interconnect the talin, paxillin, vinculin (TPV) complex to laminin 11;
the β- and α-dystroglycans interconnect utrophin to agrin. The SM proteins are joined to the cytoskeleton
by various adapter proteins, including podocin, Zonula Occludens protein 1 (ZO-1; Z), CD2-associated protein
(CD), and catenins (Cat). Among the nonselective cation channels (NSCC), TRPC6 associates with podocin
(and nephrin, not shown) at the SM. Only the angiotensin II (Ang II) type 1 receptor (AT1) is shown as an
example of the many surface receptors. Cas, p130Cas; Ez, ezrin; FAK, focal adhesion kinase; ILK, integrin-
linked kinase; M, myosin; N, Na+-H+ exchanger regulatory factor (NHERF2); S, synaptopodin. (Modified from
reference 17.)
the GBM. The insight that the major way of losing podocytes in disease flow the SD is permanently under tension that counteracts the shear
is by detachment has brought the shear stress created by the filtrate stress to both sides of the slit.27
flow into discussion. Barrier function. Filtrate flow through the barrier occurs along an
The strength of the shear stress depends on the flow rate and the extracellular route, including the endothelial pores, GBM, and SD (see
geometry of the channel; the narrower the channel or the higher the Figs. 1.7 and 1.9). The barrier shows a high permeability for water,
flow velocity, the higher is the shear stress. In rats the filtrate flow small solutes, and ions, whereas the barrier is fairly tight for macro-
amounts to 30 nl/min, creating a shear stress to the FPs within the molecules, selective for size, shape, and charge.20 The charge selectivity
filtration slit as high as 8 Pa.30 Much lower values of shear stress to the of the barrier results from the dense accumulation of negatively charged
podocyte cell bodies may lead to detachment when podocytes come to molecules throughout the entire depth of the filtration barrier, most
lie within the urinary orifice.27 Moreover, a high sensitivity of podocytes importantly the surface coat of endothelial cells, and from the high
to shear stress has been shown in cell culture studies. content of negatively charged heparan sulfate proteoglycans in the GBM.
This led to a new view of the relevance of the SM (in addition to Most plasma proteins, including albumin, are negatively charged, and
its barrier function; see later discussion). Shear stress tends to lead to thus their repulsion is dominantly charge dependent.
deformations of the lateral walls of FPs, and thus widens the slit. The The size/shape selectivity seems to be established by the SD.13
interconnection of both opposite FPs by the SD at the narrowest site Uncharged macromolecules up to an effective radius of 1.8 nm pass
of the slit is ideally positioned to counteract these destabilizing forces. freely through the filter. Larger components are increasingly restricted
The SD uses the shear stress against one side of the slit to balance the (indicated by their fractional clearances, which progressively decrease)
shear stress against the opposite side. This means that during filtrate and are totally restricted at effective radii of more than 4 nm. Plasma

albumin has an effective radius of 3.6 nm; without the repulsion from
the negative charge, plasma albumin would pass through the filter in Tubular Epithelia
considerable amounts.
Studies by the group of Marcus Moeller proposed an electrophoretic Luminal Paracellular Transcellular
membrane transport transport
mechanism for the repulsion and exclusion of plasma proteins from the
glomerular filter.31,32 According to their hypothesis, the flow of the filtrate
through the charged filter creates a streaming potential. This electrical Tight
field is negatively charged on the urinary side of the glomerular filter junction
compared with the capillary side by approximately −0.05 mV/10 mm Hg
filtration pressure. Thus the negatively charged molecules (albumin) that Basolateral Lateral
approach the filter will be exposed to an electrophoretic force that drives membrane intercellular
them back toward the capillary lumen. The charm of this hypothesis space
consists of being independent of any structural pore preventing their
passage. The barrier actually consists of a strictly filtration-dependent
potential difference; without sufficient convective flow of filtrate, the
barrier will become permeable.31,32
Pathology. The hypothesis that the mechanical interconnection of
Basement
the FPs by the SD is the most vulnerable structure to the physical chal- membrane
lenges of filtration is supported by the pathologic changes. The loss of
Fig. 1.10 Tubular epithelia. Transport across the epithelium may
the SD connection between adjacent FPs represents the earliest failure follow two routes: transcellular, across luminal and basolateral mem-
that starts the detachment of podocytes.27 branes, and paracellular, through the tight junction and intercellular spaces.
This can be interpreted as the loss of local control of filtrate flow.
Unchanneled filtrate flow through such leaks will exert unbalanced
shear stress to the FPs, initiating locally the detachment of FPs. Repair luminal and basolateral cell membrane and through the cytoplasm and
of such leaks seems impossible in the face of ongoing filtrate flow, a paracellular pathway through the junctional complex and the lateral
accounting for the observation that the damage will proceed. intercellular spaces. The functional characteristics of paracellular trans-
Taken together, the layer of interdigitating FPs interconnected by port are determined by the tight junction, which differs markedly in
the SD regulates the entry of the filtrate flow into the Bowman space its elaboration in the various tubular segments. The transcellular trans-
by channeling the flow through the filtration slits. The geometry of the port is determined by the specific channels, carriers, and transporters
slits is maintained against the shear forces to both opposite FPs through included in the apical and basolateral cell membranes. The various
the interconnection of opposing FPs by the SD. Loss of the junctional nephron segments differ markedly in function, distribution of transport
connection is detrimental because it opens leaks for uncontrolled filtrate proteins, and responsiveness to hormones and drugs such as diuretics.
flow with the tendency to increase the leaks.33 The cell surface area of the plasmalemmal compartments carrying the
transport systems is extensively enlarged in many tubule cells, that is,
Parietal Epithelium by microvilli at the luminal membrane domain, by lamellar folds of
The parietal epithelium of the Bowman capsule consists of squamous the basolateral membrane interdigitating with those of the neighboring
epithelial cells resting on a basement membrane (see Figs. 1.4 and 1.5). cells (interdigitations), or by lamellar folds of the basal cell membrane
The flat cells are filled with bundles of actin filaments running in all invaginating into its own cells (invaginations).
directions. In contrast to the GBM, the parietal basement membrane
comprises several proteoglycan-dense layers that, in addition to type Proximal Tubule
IV, contain type XIV collagen. The predominant proteoglycan of the The proximal tubule reabsorbs the bulk of filtered water and solutes
parietal basement membrane is a chondroitin sulfate proteoglycan.34 (Fig. 1.11). The proximal tubule is generally subdivided into three seg-
ments (known as S1, S2, and S3) that differ considerably in cellular
Renal Tubule organization and, consequently, also in function.35 Generally, the proximal
The renal tubule is subdivided into several distinct segments: a proximal tubule has a prominent brush border and e xtensive interdigitation by
tubule (convoluted and straight portions), an intermediate tubule, a basolateral cell processes. This lateral cell interdigitation extends up to
distal tubule (straight and convoluted portion), a CNT, and the CD the leaky tight junction, thus increasing the tight junctional belt in
(see Figs. 1.1 and 1.3).1,2,34 The loop of Henle comprises the straight length and providing a greatly increased passage for the passive transport
part of the proximal tubule (representing the thick descending limb), of ions. Proximal tubule cells have large prominent mitochondria inti-
the thin descending and the thin ascending limbs (both thin limbs mately associated with the basolateral cell membrane where the Na+,K+–
together represent the intermediate tubule), and the thick ascending adenosine triphosphatase (Na+,K+-ATPase) is located; this machinery
limb (representing the straight portion of the distal tubule), which is the molecular mechanism initiating numerous secondary transcellular
includes the macula densa. The CNT connects the nephron to the CD transport processes. The luminal transporter for Na+ reabsorption spe-
system. cific for the proximal tubule is the Na+-H+ exchanger (NHE3) located
The renal tubules are outlined by an epithelium that comprises a in the plasma membrane of the apical microvilli and accounts for
single layer of cells anchored to a basement membrane. The epithelial reabsorption of most of the filtered sodium. Further, sodium-coupled
cells have multiple transport functions and show numerous structural transporters in the microvillous membrane are the sodium-glucose
adaptations to their special roles. They are connected apically by a cotransporters SGLT2 and SGLT1 and several sodium-phosphate cotrans-
junctional complex consisting of a tight junction (zonula occludens), porters. The abundance of channel protein aquaporin 1 in the apical
an adherens junction, and, at some sites, a desmosome. As a result of microvillous membrane and the basolateral cell membrane accounts
this organization, two different pathways through the epithelium exist for the high hydraulic permeability for water of this epithelium.
(Fig. 1.10): a transcellular pathway, including the transport across the An apical tubulovesicular compartment is part of the prominent

A B
Fig. 1.11 Tubules of the renal cortex. (A) Proximal convoluted tubule is equipped with a brush border
and a prominent vacuolar apparatus in the apical cytoplasm. The rest of the cytoplasm is occupied by a basal
labyrinth consisting of large mitochondria associated with basolateral cell membranes. (B) Distal convoluted
tubule also has interdigitated basolateral cell membranes intimately associated with large mitochondria. In
contrast to the proximal tubule, however, the apical surface is amplified only by some stubby microvilli.
(TEM; A, × 1530; B, × 1830.)
endosomal-lysosomal system and is responsible for the reabsorption reabsorption of divalent ions, notably of magnesium. The cells are
of macromolecules (polypeptides and proteins such as albumin) that heavily interdigitated by basolateral cell processes, associated with large
have passed the glomerular filter. The proximal tubule segment S3, mitochondria supplying the energy for the transepithelial transport.
including portions of S2, in addition, are engaged in many secretory The cells synthesize a specific protein, the Tamm-Horsfall protein, and
processes of toxic substances and drugs via organic anion transporters release it into the tubular lumen. This protein is thought to be important
and anorganic cation transporters. Proximal tubule cells are electrically for preventing the formation of kidney stones. A short distance before
coupled by gap junctions. the transition to the distal convoluted tubule, the thick ascending limb
contains the macula densa, which adheres to the glomerulus of the
Intermediate Tubule same nephron (see Juxtaglomerular Apparatus).
The intermediate tubule comprises the thin portion of the loop of
Henle displaying a flat epithelium and consists of a thin descending Distal Convoluted Tubule
and (only in long loops) a thin ascending limb (Fig. 1.12; see also Fig. The epithelium exhibits the most extensive basolateral interdigitation
1.2). The thin descending limb, like the proximal tubule, is highly per- of the cells and the greatest numerical density of mitochondria compared
meable for water (the channels are of aquaporin 1), whereas, beginning with all other nephron portions (see Fig. 1.11). Apically, the cells are
at the turning point, the thin ascending limb is impermeable to water. equipped with numerous solitary microvilli. The specific Na+ transporter
The latter has a highly interdigitated epithelium also along the tight of the distal convoluted tubule is the luminal Na2+Cl− cotransport system
junction, which is highly permeable to ions. (NCC), which can be inhibited by the thiazide diuretics. Magnesium
is reabsorbed via the transient receptor potential channel melastatin
Distal Straight Tubule (Thick Ascending subtype 6 (TRPM6) in the luminal membrane and, along the paracel-
Limb of the Loop of Henle) lular route, through the tight junctional proteins Claudin 16 and 19.
The thick ascending limb of the loop of Henle is often called the dilut-
ing segment. It is water impermeable but reabsorbs considerable amounts
of sodium and chloride, resulting in the separation of salt from water.
COLLECTING DUCT SYSTEM
The salt is trapped in the medulla (see Fig. 1.12), whereas the water is The CD system (see Fig. 1.2) includes the CNT and the cortical and
carried away into the cortex, where it may return into the systemic medullary CDs. The embryologic origin of the CNT, which is interposed
circulation. The specific transporter for Na+ reabsorption in this segment between the distal convoluted tubule and the CD, is unclear in whether
is the Na2+K2+2Cl− symporter (NKCC2), which is specifically inhibited it derives from the nephron anlage or the ureteral bud. Two nephrons
by loop diuretics such as furosemide. This transporter is inserted in may join at the level of the CNT, forming an arcade. Two types of cell
the luminal membrane, which is amplified by only solitary microvilli. establish the CNT: the CNT cell, which is specific to the CNT, and the
The tight junctions of the thick ascending limb are elongated by lateral intercalated (IC) cell, which is also present in varying amounts in the
interdigitation of the cells. They have a comparatively low overall per- distal convoluted tubule and in the CD. The CNT cells are similar to
meability; however, they contain the protein Claudin 16 for paracellular the CD cells in cellular organization. Both cell types share sensitivity

IC
P
F CD
CD
VR
AL
TL
F
C
DL TL
VR
C
A B
Fig. 1.12 Tubules in the medulla. (A) Cross section through the inner stripe of the outer medulla shows
a descending thin limb of a long Henle loop (DL), the medullary thick ascending limbs of Henle (AL), and a
collecting duct (CD) with principal (P) cells and intercalated (IC) cells. C, Peritubular capillaries; F, fibroblast.
(B) In the inner medulla cross section, thin descending and ascending limbs (TL), a collecting duct (CD), and
vasa recta (VR) are seen. (TEM; A, × 990; B, × 1120.)
to vasopressin (antidiuretic hormone [ADH]; see later discussion). The A and B cells, distinguished on the basis of structural, immunocyto-
amiloride-sensitive epithelial sodium channel (ENaC) and the epithelial chemical, and functional characteristics. Type A cells have been defined
calcium channel (TRPV5) are located in the apical membrane begin- as expressing an H+-ATPase at their luminal membrane; they secrete
ning in the distal convoluted tubule and extending into the CNT. protons. Type B cells express H+-ATPase at their basolateral membrane;
they secrete bicarbonate ions and reabsorb protons.38
Collecting Ducts With these different cell types, the CDs are the final regulators of
The CDs (see Fig. 1.12) may be subdivided into cortical and medullary fluid and electrolyte balance, playing important roles in the handling
ducts, and the medullary ducts into an outer and inner portion; the of Na+, Cl−, and K+ and in acid-base homeostasis. The responsiveness
transitions are gradual. Like the CNT, the CDs are lined by two types of the CDs to vasopressin enables an organism to live in arid condi-
of cell: CD cells (principal cells) and IC cells. The IC cells decrease in tions, allowing production of concentrated urine and, if necessary,
number as the CD descends into the medulla and are absent from the dilute urine.
inner medullary CDs.
The CD cells (Fig. 1.13A) increase in size toward the tip of the
papilla. The basal cell membrane amplifies by lamellar invaginations
JUXTAGLOMERULAR APPARATUS
into the cell (basal infoldings). The tight junctions have a large apico- The juxtaglomerular apparatus comprises the macula densa, the extra-
basal depth, and the apical cell surface has a prominent glycocalyx. glomerular mesangium, the terminal portion of the afferent arteriole
Along the entire CD, these cells contain an apical shuttle system for with its renin-producing granular cells (also often termed juxtaglo-
aquaporin 2 under the control of vasopressin, providing the potential merular cells), and the beginning portions of the efferent arteriole (see
to switch the water permeability of the CDs from zero to very low levels Fig. 1.4).
to permeable.36 A luminal amiloride-sensitive Na+ channel is involved The macula densa is a plaque of specialized cells in the wall of the
in the responsiveness of cortical CDs to aldosterone. The terminal por- thick ascending limb of Henle at the site where the limb attaches to
tions of the CD in the inner medulla express the urea transport system the extraglomerular mesangium of the parent glomerulus (Fig. 1.14A;
UTB1, which, in an antidiuretic hormone (ADH)-dependent fashion, see also Fig. 1.5). The most obvious structural feature is the narrowly
accounts for the recycling of urea, a process that is crucial in the urine- packed cells with large nuclei, which account for the name macula
concentrating mechanism.37,38 densa. The cells are anchored to a basement membrane, which blends
The second cell type, the IC cell (see Fig. 1.13B), is present in both with the matrix of the extraglomerular mesangium. The cells are joined
the CNT and the CD. There are at least two types of IC cells, designated by tight junctions with very low permeability and have prominent lateral

A B
Fig. 1.13 Collecting duct cells. (A) Principal cell (CD cell) of a medullary collecting duct. The apical cell
membrane bears some stubby microvilli covered by a prominent glycocalyx; the basal cell membrane forms
invaginations. Note the deep tight junction. (B) Intercalated cells, type A. Note the dark cytoplasm (dark cells)
with many mitochondria and apical microfolds; the basal membrane forms invaginations. (TEM; A, × 8720;
B, × 6970.)
GC
EGM
A B
Fig. 1.14 Juxtaglomerular apparatus. (A) Macula densa of a thick ascending limb of Henle. The cells
have prominent nuclei and lateral intercellular spaces. Basally, they attach to the extraglomerular mesangium
(EGM). (B) Afferent arteriole near the vascular pole. Several smooth muscle cells are replaced by granular
cells (GC) containing accumulations of renin granules. (TEM; A, × 1730; B, × 1310.)
intercellular spaces. The width of these spaces varies under different the Bowman capsule and the walls of both glomerular arterioles. As a
functional conditions.1 The most conspicuous immunocytochemical whole, the extraglomerular mesangium interconnects all structures of
difference between macula densa cells and other epithelial cells of the the glomerular entrance.6
nephron is the high content of neuronal nitric oxide synthase and The granular cells are assembled in clusters within the terminal
cyclooxygenase-2 in macula densa cells.39,40 portion of the afferent glomerular arteriole (see Fig. 1.14B), replacing
The basal aspect of the macula densa is firmly attached to the extra- ordinary smooth muscle cells. Granular refers to the specific cytoplasmic
glomerular mesangium, a solid complex of cells and matrix penetrated granules in which renin, the major secretion product of these cells, is
by neither blood vessels nor lymphatic capillaries. As with the mesangial stored. Granular cells are the main site of the body where renin is
cells proper, extraglomerular mesangial cells are heavily branched. Their secreted. Renin release occurs by exocytosis into the surrounding inter-
processes are interconnected by gap junctions, contain prominent bundles stitium. Granular cells are connected to extraglomerular mesangial cells,
of microfilaments, and are connected to the basement membrane of adjacent smooth muscle cells, and endothelial cells by gap junctions

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[150] Page 64.
[151] Imitation-coutume and imitation-mode.
[152] Americans should notice that what they are apt to call the
snobbishness of the English middle class—their anxiety to imitate
those whom they regard as social superiors—has its good result
in producing a discipline in which many of us are somewhat
grossly lacking. It may be better, in manners for instance, that
people should adopt a standard from questionable motives than
that they should have no standard at all. The trouble with us is the
prevalence of a sprawling, gossiping self-content that does not
know or care whether such things as manners, art and literature
exist or not.
CHAPTER XXX
FORMALISM AND DISORGANIZATION
The Nature of Formalism—Its Effect upon Personality—

Formalism in Modern Life—Disorganization,
“Individualism”—How it Affects the Individual—Relation
to Formalism—“Individualism” Implies Defective Sympathy
—Contemporary “Individualism”—Restlessness under
Discomfort—The Better Aspect of Disorganization.
Too much mechanism in society gives us something for which
there are many names, slightly different in meaning, as
institutionalism, formalism, traditionalism, conventionalism, ritualism,
bureaucracy and the like. It is by no means easy, however, to
determine whether mechanism is in excess or not. It becomes an
evil, no doubt, when it interferes with growth and adaptation, when it
suppresses individuality and stupefies or misdirects the energies of
human nature. But just when this is the case is likely not to be clear
until the occasion is long past and we can see the matter in the
perspective of history.
Thus, in religion, it is well that men should adhere to the creeds
and ritual worked out in the past for spiritual edification, so long as
these do, on the whole, fulfil their function; and it is hard to fix the
time—not the same for different churches, classes or individuals—
when they cease to do this. But it is certain that they die, in time, like
all tissue, and if not cleared away presently rot.
It has been well said that formalism is “an excess of the organ of
language.”[153] The aim of all organization is to express human
nature, and it does this through a system of symbols, which are the
embodiment and vehicle of the idea. So long as spirit and symbol
are vitally united and the idea is really conveyed, all is well, but so
fast as they are separated the symbol becomes an empty shell, to
which, however, custom, pride or interest may still cling. It then
supplants rather than conveys the reality.
Underlying all formalism, indeed, is the fact that it is psychically
cheap; it substitutes the outer for the inner as more tangible, more
capable of being held before the mind without fresh expense of
thought and feeling, more easily extended, therefore, and impressed
upon the multitude. Thus in our own architecture or literature we
have innumerable cheap, unfelt repetitions of forms that were
significant and beautiful in their time and place.
The effect of formalism upon personality is to starve its higher life
and leave it the prey of apathy, self-complacency, sensuality and the
lower nature in general. A formalized religion and a formalized
freedom are, notoriously, the congenial dwelling-place of depravity
and oppression.
When a system of this sort is thoroughly established, as in the
case of the later Roman Empire, it confines the individual mind as in
a narrow cage by supplying it with only one sort of suggestions. The
variation of ideas and the supplanting of old types by new can begin
only by individuals getting hold of suggestions that conflict with those
of the ruling system; and in the absence of this an old type may go
on reproducing itself indefinitely, individuals seeming no more to it
than the leaves of a tree, which drop in the autumn and in the spring
are replaced by others indistinguishable from them. It “breeds true”
on the same principle that wild pigeons, long kept to a fixed type by
natural limitations, are less variable than domestic species, in whose
recent past there have been elements of change.
Among the Hindoos, for instance, a child is brought up from
infancy in subjection to ceremonies and rites which stamp upon him
the impression of a fixed and immemorial system. They control the
most minute details of his life, and leave little room for choice either
on his part or that of his parents. There is no attempt to justify
tradition by reason: custom as such is obligatory.
Intolerance goes very naturally with formalism, since to a mind in
the unresisted grasp of a fixed system of thought anything that
departs from that system must appear irrational and absurd. The
lowest Chinaman unaffectedly despises the foreigner, of whatever
rank, as a vulgar barbarian, just as Christians used to despise the
Jews, and the Jews, in their time, the Samaritans. Tolerance comes
in along with peaceful discussion, when there is a competition of
various ways of thinking, no one of which is strong enough to
suppress the others.
In America and western Europe at the present day there is a great
deal of formalism, but it is, on the whole, of a partial and secondary
character, existing rather from the inadequacy of vital force than as a
ruling principle. The general state of thought favors adaptation,
because we are used to it and have found it on the whole beneficial.
We expect, for example, that a more vital and flexible form of
organization will supplant the rigid systems of Russia and the Orient,
and whatever in our own world is analogous to these.
But dead mechanism is too natural a product of human conditions
not to exist at all times, and we may easily find it to-day in the
church, in politics, in education, industry and philanthropy; wherever
there is a lack of vital thought and sentiment to keep the machinery
pliant to its work.
Thus our schools, high and low, exhibit a great deal of it. Routine
methods, here as everywhere, are a device for turning out cheap
work in large quantities, and the temptation to use them, in the case
of a teacher who has too much to do, or is required to do that which
he does not understand or believe in, is almost irresistible. Indeed,
they are too frequently inculcated by principals and training schools,
in contempt of the fact that the one essential thing in real teaching is
a personal expression between teacher and pupil. Drill is easy for
one who has got the knack of it, just because it requires nothing vital
or personal, but is a convenient appliance for getting the business
done with an appearance of success and little trouble to any one.
Even universities have much of this sort of cant. In literature, for
instance, whether ancient or modern, English or foreign, little that is
vital is commonly imparted. Compelled by his position to teach
something to large and diverse classes, the teacher is led to fix upon
certain matters—such as grammar, metres, or the biographies of the
authors—whose definiteness suits them for the didactic purpose,
and drill them into the student; while the real thing, the sentiments
that are the soul of literature, are not communicated. If the teacher
himself feels them, which is often the case, the fact that they cannot
be reduced to formulas and tested by examinations discourages him
from dwelling upon them.
In like manner our whole system of commerce and industry is
formal in the sense that it is a vast machine grinding on and on in a
blind way which is often destructive of the human nature for whose
service it exists. Mammon—as in the painting by Watts—is not a
fiend, wilfully crushing the woman’s form that lies under his hand, but
only a somewhat hardened man of the world, looking in another
direction and preoccupied with the conduct of business upon
business principles.
A curious instance of the same sort of thing is the stereotyping of
language by the cheap press and the habit of hasty reading. The
newspapers are called upon to give a maximum of commonplace
information for a minimum of attention, and in doing this are led to
adopt a small standard vocabulary and a uniform arrangement of
words and sentences. All that requires fresh thought, either from
reader or writer, is avoided to the greater comfort of both. The
telegraph plays a considerable part in this, and an observer familiar
with its technique points out how it puts a premium on long but
unmistakable words, on conventional phrases (for which the
operators have brief signs) and on a sentence structure so obvious
that it cannot be upset by mistakes in punctuation.[154] In this way
our newspapers, and the magazines and books that partake of their
character, are the seat of a conventionalism perhaps as destructive
of the spirit of literature as ecclesiasticism is of the spirit of
Christianity.
The apparent opposite of formalism, but in reality closely akin to it,
is disorganization or disintegration, often, though inaccurately, called
“individualism.”[155] One is mechanism supreme, the other
mechanism going to pieces; and both are in contrast to that harmony
between human nature and its instruments which is desirable.
In this state of things general order and discipline are lacking.
Though there may be praiseworthy persons and activities, society as
a whole wants unity and rationality, like a picture which is good in
details but does not make a pleasing composition. Individuals and
special groups appear to be working too much at cross purposes;
there is a “reciprocal struggle of discordant powers” but the
“harmony of the universe” does not emerge. As good actors do not
always make a good troupe nor brave soldiers a good army, so a
nation or a historical epoch—say Italy in the Renaissance—may be
prolific in distinguished persons and scattered achievements but
somewhat futile and chaotic as a system.
Disorganization appears in the individual as a mind without cogent
and abiding allegiance to a whole, and without the larger principles
of conduct that flow from such allegiance. The better aspect of this is
that the lack of support may stimulate a man to greater activity and
independence, the worse that the absence of social standards is
likely to lower his plane of achievement and throw him back upon
sensuality and other primitive impulses: also that, if he is of a
sensitive fibre, he is apt to be overstrained by the contest with
untoward conditions. How soothing and elevating it is to breathe the
atmosphere of some large and quiet discipline. I remember feeling
this in reading Lord Roberts’ Forty-one Years in India, a book
pervaded with one great and simple thought, the Anglo-Indian
service, which dominates all narrow considerations and gives people
a worthy ideal to live by. How rarely, in our day, is a book or a man
dominated by restful and unquestioned faith in anything!
The fact that great personalities often appear in disordered times
may seem to be a contradiction of the principle that the healthy
development of individuals is one with that of institutions. Thus the
Italian Renaissance, which was a time of political disorder and
religious decay, produced the greatest painters and sculptors of
modern times, and many great personalities in literature and
statesmanship. But the genius which may appear in such a period is
always, in one point of view, the fruitage of a foregoing and
traditional development, never a merely personal phenomenon. That
this was true of Renaissance art needs no exposition; like every
great achievement it was founded upon organization.
It is no doubt the case, however, that there is a spur in the
struggles of a confused time which may excite a few individuals to
heroic efforts and accomplishment, just as a fire or a railroad
disaster may be the occasion of heroism; and so the disorder of the
Renaissance was perhaps one cause of the men of genius, as well
as of the demoralization which they did not escape.
It looks at first sight as if formalism and disorganization were as far
apart as possible, but in fact they are closely connected, the latter
being only the next step after the former in a logical sequence—the
decay of a body already dead. Formalism goes very naturally with
sensuality, avarice, selfish ambition, and other traits of
disorganization, because the merely formal institution does not enlist
and discipline the soul of the individual, but takes hold of him by the
outside, his personality being left to torpor or to irreverent and riotous
activity. So in the later centuries of the Roman Empire, when its
system was most rigid, the people became unpatriotic, disorderly
and sensual.
In the same way a school whose discipline is merely formal, not
engaging the interest and good-will of the scholar, is pretty certain to
turn out unruly boys and girls, because whatever is most personal
and vital in them becomes accustomed to assert itself in opposition
to the system. And so in a church where external observance has
been developed at the expense of personal judgment, the individual
conforms to the rite and then feels free for all kinds of self-
indulgence. In general the lower “individualism” of our time, the
ruthless self-assertion which is so conspicuous, for example, in
business, is not something apart from our institutions but expresses
the fact that they are largely formal and unhuman, not containing and
enlarging the soul of the individual.
The real opposite of both formalism and disorder is that
wholesome relation between individuality and the institution in which
each supports the other, the latter contributing a stable basis for the
vitality and variation of the former.
From one point of view disorganization is a lack of communication
and social consciousness, a defect in the organ of language, as
formalism is an excess. There is always, I suppose, a larger whole;
the question is whether the individual thinks and feels it vividly
through some sort of sympathetic contact; if he does he will act as a
member of it.
In the writings of one of the most searching and yet hopeful critics
of our times[156] we find that “individualism” is identified primarily with
an isolation of sentiment, like that of the scholar in his study, the
business man in his office or the mechanic who does not feel the
broader meaning of his work. The opposite of it is the life of
shoulder-to-shoulder sympathy and coöperation, in which the desire
for separate power or distinction is lost in the overruling sense of
common humanity. And the logical remedy for “individualism” is
sought in that broadening of the spirit by immediate contact with the
larger currents of life, which is the aim of the social settlement and
similar movements.
This is, indeed, an inspiring and timely ideal, but let us hold it
without forgetting that specialized and lonesome endeavor, indeed
even individual pride and self-seeking, have also their uses. If we
dwell too exclusively upon the we-feeling and the loss of the one in
the many, we may lapse into a structureless emotionalism. Eye-to-
eye fellowship and the pride of solitary achievement are both
essential, each in its own way, to human growth, and either is
capable of over-indulgence. We need the most erect individual with
the widest base of sympathy.
In so far as it is true of our time that the larger interests of society
are not impressed upon the individual, so that his private impulses
coöperate with the public good, it is a time of moral disintegration. A
well-ordered community is like a ship in which each officer and
seaman has confidence in his fellows and in the captain, and is well
accustomed to do his duty with no more than ordinary grumbling. All
hangs together, and is subject to reason in the form of long-tried
rules of navigation and discipline. Virtue is a system and men do
heroic acts as part of the day’s work and without self-consciousness.
But suppose that the ship goes to pieces—let us say upon an
iceberg—then the orderly whole is broken up and officers, seamen
and passengers find themselves struggling miscellaneously in the
water. Rational control and the virtue that is habit being gone, each
one is thrown back upon his undisciplined impulses. Survival
depends not upon wisdom or goodness—as it largely does in a
social system—but upon ruthless force, and the best may probably
perish.
Here is “individualism” in the lowest sense, and it is the analogue
of this which is said, not without some reason, to pervade our own
society. Old institutions are passing away and better ones, we hope,
are preparing to take their place, but in the meantime there is a lack
of that higher discipline which prints the good of the whole upon the
heart of the member. In a traditional order one is accustomed from
childhood to regard usage, the authority of elders and the dominant
institutions as the rule of life. “So it must be” is one’s unconscious
conviction, and, like the seaman, he does wise and heroic things
without knowing it. But in our own time there is for many persons, if
not most, no authoritative canon of life, and for better or worse we
are ruled by native impulse and by that private reason which may be
so weak when detached from a rational whole. The higher morality, if
it is to be attained at all, must be specially thought out; and of the
few who can do this a large part exhaust their energy in thinking and
do not practise with any heartiness the truths they perceive.
We find, then, that people have to make up their own minds upon
their duties as wives, husbands, mothers and daughters; upon
commercial obligation and citizenship; upon the universe and the
nature and authority of God. Inevitably many of us make a poor
business of it. It is too much. It is as if each one should sit down to
invent a language for himself: these things should be thought out
gradually, coöperatively each adding little and accepting much. That
great traditions should rapidly go to pieces may be a necessary
phase of evolution and a disguised blessing, but the present effect is
largely distraction and demoralization.
In particular, we notice that few who have burdens to bear are
much under the control of submissive tradition, but every one asks
“Why must I bear this?” and the pain of trying to see why is often
worse than the evil itself. There is commonly no obvious reason, and
the answer is often a sense of rebellion and a bitterness out of which
comes, perhaps, recklessness, divorce, or suicide.
Why am I poor while others are rich? Why do I have to do work I
do not like? Why should I be honest when others are unscrupulous?
Why should I wear myself out bearing and rearing children? Why
should I be faithful to my husband or wife when we are not happy
together, and another would please me better? Why should I believe
in a good God when all I know is a bad world? Why should I live
when I wish to die? Never, probably, were so many asking such
questions as this and finding no clear answer. There have been
other times of analogous confusion, but it could never have
penetrated so deeply into the masses as it does in these days of
universal stir and communication.
How contemptible these calculations seem in comparison with the
attitude of the soldier, who knows that he must suffer privation and
not improbably death, and yet faces the prospect quite cheerfully,
with a certain pride in his self-devotion. In this spirit, evidently, all the
duties of life ought to be taken up. But the soldier, the seaman, the
fireman, the brakeman, the doctor and others whose trade leads
them into obvious peril have one great advantage: they know what
their duty is and have no other thought than to do it; there is no
mental distraction to complicate the situation. And as fast as
principles become settled and habits formed, people will be as heroic
in other functions as they are in these.
We may apply to many in our own time the words of Burckhardt in
describing the disorganization of the Renaissance: “The sight of
victorious egoism in others drives him to defend his own right by his
own arm. And, while thinking to restore his inward equilibrium, he
falls, through the vengeance which he executes, into the hands of
the powers of darkness.” That is, we think we must be as selfish as
other people, but find that selfishness is misery. I notice that many
men, even of much natural sympathy and fellow-feeling, have
accepted “every man for himself” as a kind of dogma, making
themselves believe that it is the necessary rule of a competitive
society, and practising it with a kind of fanaticism which goes against
their better natures. Perhaps the sensitive are more apt to do this
than others—because they are more upset by the spectacle of
“victorious egoism” around them. But the true good of the individual
is found only in subordinating himself to a rational whole; and in
turning against others he destroys himself.
The embittered and distracted individual must be a bad citizen.
There is the same kind of moral difference between those who feel
life as a rational whole, and so have some sort of a belief in God, as
there is between an army that believes in its commander and one
that does not. In either case the feeling does much to bring about its
own justification.
The fact that the breaking up of traditions throws men back upon
immediate human nature has, however, its good as well as its bad
side. It may obscure those larger truths that are the growth of time
and may let loose pride, sensuality and scepticism; but it also
awakens the child in man and a childlike pliability to the better as
well as the worse in natural impulse. We may look, among people
who have lost the sense of tradition, for the sort of virtues, as well as
of vices, that we find on the frontier: for plain dealing, love of
character and force, kindness, hope, hospitality and courage.
Alongside of an extravagant growth of sensuality, pride and caprice,
we have about us a general cult of childhood and womanhood, a
vast philanthropy, and an interest in everything relating to the welfare
of the masses of the people. The large private gifts to philanthropic
and educational purposes, and the fact that a great deal of personal
pride is mingled with these gifts, are equally characteristic of the
time.
And, after all, there is never any general state of extreme
disintegration. Such as our time suffers from in art and social
relations is chiefly the penalty of a concentration of thought upon
material production and physical science. In these fields there is no
lack of unified and cumulative endeavor—though unhuman in some
aspects—resulting in total achievement. If we have not Dante and
gothic architecture, we have Darwin and the modern railway. And as
fast as the general mind turns to other aims we may hope that our
chaotic material will take on order.
FOOTNOTES:
[153] The Poet. Emerson.
[154] See the article by R. L. O’Brien in the Atlantic Monthly,
Oct., 1904.
[155] Inaccurately, because the full development of the
individual requires organization
[156] Jane Addams.
CHAPTER XXXI
DISORGANIZATION: THE FAMILY
Old and New Régimes in the Family—The Declining Birth-Rate

—“Spoiled” Children—The Opening of New Careers to
Women—European and American Points of View—
Personal Factors in Divorce—Institutional Factors—
Conclusion.
The mediæval family, like other mediæval institutions, was
dominated by comparatively settled traditions which reflected the
needs of the general system of society. Marriage was thought of
chiefly as an alliance of interests, and was arranged by the ruling
members of the families concerned on grounds of convenance, the
personal congeniality of the parties being little considered.
We know that this view of marriage has still considerable force
among the more conservative classes of European society, and that
royalty or nobility, on the one hand, and the peasantry, on the other,
adhere to the idea that it is a family rather than a personal function,
which should be arranged on grounds of rank and wealth. In France
it is hardly respectable to make a romantic marriage, and Mr.
Hamerton tells of a young woman who was indignant at a rumor that
she had been wedded for love, insisting that it had been strictly a
matter of convenance. He also mentions a young man who was
compelled to ask his mother which of two sisters he had just met
was to be his wife.[157]
Along with this subordination of choice in contracting marriage
generally went an autocratic family discipline. Legally the wife and
children had no separate rights, their personality being merged in
that of the husband and father, while socially the latter was rather
their master than their companion. His rule, however—though it was
no doubt harsh and often brutal, judged by our notions—was
possibly not so arbitrary and whimsical as would be the exercise of
similar authority in our day; since he was himself subordinate not
only to social superiors, but still more to traditional ideas, defining his
own duties and those of his household, which he felt bound to carry
out. The whole system was authoritative, admitting little play of
personal choice.
Evidently the drift of modern life is away from this state of things.
The decay of settled traditions, embracing not only those relating
directly to the family but also the religious and economic ideas by
which these were supported, has thrown us back upon the
unschooled impulses of human nature. In entering upon marriage
the personal tastes of the couple demand gratification, and, right or
wrong, there is no authority strong enough to hold them in check.
Nor, if upon experience it turns out that personal tastes are not
gratified, is there commonly any insuperable obstacle to a dissolution
of the tie. Being married, they have children so long as they find it,
on the whole, agreeable to their inclinations to do so, but when this
point is reached they proceed to exercise choice by refusing to bear
and rear any more. And as the spirit of choice is in the air, the
children are not slow to inhale it and to exercise their own wills in
accordance with the same law of impulse their elders seem to follow.
“Do as you please so long as you do not evidently harm others” is
the only rule of ethics that has much life; there is little regard for any
higher discipline, for the slowly built traditions of a deeper right and
wrong which cannot be justified to the feelings of the moment.
Among the phases of this domestic “individualism” or relapse to
impulse are a declining birth-rate among the comfortable classes,
some lack of discipline and respect in children, a growing
independence of women accompanied by alleged neglect of the
family, and an increase of divorce.
The causes of decline in the birth-rate are clearly psychological,
being, in general, that people prefer ambition and luxury to the large
families that would interfere with them.
Freedom of opportunity diffuses a restless desire to rise in the
world, beneficent from many points of view but by no means
favorable to natural increase. Men demand more of life in the way of
personal self-realization than in the past, and it takes a longer time
and more energy to get it, the consequence being that marriage is
postponed and the birth-rate in marriage deliberately restricted. The
young people of the well-to-do classes, among whom ambition is
most developed, commonly feel poorer in regard to this matter than
the hand-workers, so that we find in England, for instance, that the
professional men marry at an average age of thirty-one, while miners
marry at twenty-four. Moreover, while the hand-working classes, both
on the farms and in towns, expect to make their children more than
pay for themselves after they are fourteen years old, a large family
thus becoming an investment for future profit, the well-to-do, on the
contrary, see in their children a source of indefinitely continuous
expense. And the trend of things is bringing an ever larger proportion
of the people within the ambitious classes and subject to this sort of
checks.
The spread of luxury, or even comfort, works in the same direction
by creating tastes and habits unfavorable to the bearing and rearing
of many children. Among those whose life, in general, is hard these
things are not harder than the rest, and a certain callousness of mind
that is apt to result from monotonous physical labor renders people
less subject to anxiety, as a rule, than those who might appear to
have less occasion for it. The joy of children, the “luxury of the poor,”
may also appear brighter from the dulness and hardship against
which it is relieved. But as people acquire the habit, or at least the
hope, of comfort they become aware that additional children mean a
sacrifice which they often refuse to make.
These influences go hand-in-hand with that general tendency to
rebel against trouble which is involved in the spirit of choice. In
former days women accepted the bearing of children and the
accompanying cares and privations as a matter of course; it did not
occur to them that anything else was possible. Now, being
accustomed to choose their life, they demand a reason why they
should undergo hardships; and since the advantages which are to
follow are doubtful and remote, and the suffering near and obvious,
they are not unlikely to refuse. Too commonly they have no
inwrought principles and training that dispose them to submit.
The distraction of choice grievously increases the actual burden
and stress upon women, for it is comparatively easy to put up with
the inevitable. What with moral strain of this sort and the anxious
selection among conflicting methods of nurture and education it
possibly costs the mother of to-day more psychical energy to raise
four children than it did her grandmother to raise eight.
It would be strange if children were not hospitable to the modern
sentiment that one will is as good as another, except as the other
may be demonstrably wiser in regard to the matter in hand. Willing
submission to authority as such, or sense of the value of discipline
as a condition of the larger and less obvious well-being of society, is
hardly to be expected from childish reasoning, and must come, if at
all, as the unconscious result of a training which reflects general
sentiment and custom. It is institutional in its nature, not visibly
reasonable.
But the child, in our day, finds no such institution, no general state
of sentiment such as exists in Japan and existed in our own past,
which fills the mind from infancy with suggestions that parents are to
be reverenced and obeyed; nor do parents ordinarily do much to
instil this by training. Probably, so great is the power of general
opinion even in childhood, they would hardly succeed if they tried,
but as a rule they do not seriously try. Being themselves accustomed
to the view that authority must appeal to the reason of the subject,
they see nothing strange in the fact that their children treat them as
equals and demand to know “Why?”
The fond attention which parents give to their children is often of a
sort to overstimulate their self-consequence. This constantly asking
them, What would you like? Shall we do this or that? Where do you
want to go? and so on, though amiable on our part, does the child
little good. The old practice of keeping children at a distance,
whatever its evils, was more apt to foster reverence.
Among hand-workers, especially in the country, the work being
more obvious and often shared by the whole family, the pressure of
necessary labor makes a kind of discipline for all, and the children
are more likely to see that there are rules and conditions of life
above their immediate pleasure. Social play, as we have seen, may
also do much for this perception. But this visible control of a higher
law has a decreasing part in modern life, especially with the well-to-
do classes, whose labors are seldom such as children may share, or
even understand.
In this, as in so many other respects, we are approaching a higher
kind of life at the cost of incidental demoralization. The modern
family at its best, with its intimate sympathy and its discipline of love,
is of a higher type than the family of an older régime. “I never,” said
Thackeray, “saw people on better terms with each other, more frank,
affectionate, and cordial, than the parents and the grown-up young
folks in the United States. And why? Because the children were
spoiled, to be sure.”[158] But where this ideal is not reached, there is
apt to be a somewhat disastrous failure which makes one regret the
autocratic and traditional order. Not merely is discipline lacking, but
the affection which might be supposed to go with indulgence is
turned to indifference, if not contempt. As a rule we love those we
can look up to, those who stand for the higher ideal. In old days
parents shared somewhat in that divinity with which tradition hedged
the great of the earth, and might receive a reverence not dependent
upon their personality; and even to-day they are likely to be better
loved if they exact respect—just as an officer is better loved who
enforces discipline and is not too familiar with his soldiers. Human
nature needs something to look up to, and it is a pity when parents
do not in part supply this need for their children.
In short, the child, like the woman, helps to bear the often grievous
burden of disorganization; bears it, among the well-to-do classes, in
an ill-regulated life, in lack of reverence and love, in nervousness
and petulance; as well as in premature and stunting labor among the
poor.
The opening of new careers to women and a resulting economic
independence approaching that of men is another phase of
“individualism” that has its worse and better aspects. In general it
has, through the fuller self-expression of women, most beneficial
reactions both upon family life and society at large, but creates some
trouble in the way of domestic reluctance and discontent.
The disposition to reject marriage altogether may be set aside as
scarcely existent. The marriage rate shows little decline, though the
average age is somewhat advanced. The wage-earning occupations
of women are mostly of a temporary character, and the great
majority of domestic servants, shop and factory girls, clerks,
typewriters and teachers marry sooner or later. There is no reason to
doubt that a congenial marriage continues to be the almost universal
feminine ideal.
A more real problem, perhaps, is found in the excessive
requirements, in the way of comfort and refinement, that young
women are said to cherish. In the United States their education, so
far as general culture is concerned, outstrips that of men, something
like three-fifths of our high school pupils being girls, while even in the
higher institutions the study of history, foreign languages and English
literature is largely given over to women. A certain sense of
superiority coming from this state of things probably causes the
rejection of some honest clerks or craftsmen by girls who can hardly
look for a better offer; and it has a tendency toward the cultivation of
refinement at the expense of children where marriage does occur. It
need hardly be said, however, that aggressive idealism on the part of
women is in itself no bad thing, and that it does harm only where ill-
directed. Hardly anything, for instance, would be more salutary than
the general enforcement by women of a higher moral standard upon
the men who wish to marry them.
And certainly nothing in modern civilization is more widely and
subtly beneficent than the enlargement of women in social function.
It means that a half of human nature is newly enfranchised,
instructed and enabled to become a more conscious and effective
factor in life. The ideals of home and the care of children, in spite of
pessimists, are changing for the better, and the work of women in
independent careers is largely in the direction of much-needed social
service—education and philanthropy in the largest sense of the
words. Any one familiar with these movements knows that much of
the intellectual and most of the emotional force back of them is that
of women. One may say that the maternal instinct has been set free
and organized on a vast scale, for the activities in which women
most excel are those inspired by sympathy with children and with the
weak or suffering classes.
To the continental European, accustomed to a society in which the
functions and conventions of men and women are sharply
distinguished and defined by tradition, it seems that Americans break
down a natural and salutary differentiation, making women
masculine and men feminine by a too indiscriminate association and
competition. No doubt there is some ground for distinct standards
and education, and in the general crumbling of traditions and sway of
a somewhat doctrinaire idea of equality some “achieved distinctions”
of value may have been lost sight of. Like other social
differentiations, however, this is one that can no longer be
determined by authority, but must work itself out in a free play of
experiment. As Mr. Ellis says, “The hope of our future civilization lies
in the development, in equal freedom, of both the masculine and
feminine elements in life.”[159]
Perhaps, also, the masculine element, as being on the whole more
rational and stable, should be the main source of government,
keeping in order the emotionality more commonly dominant in
women: and it may appear that this controlling function is ill-
performed in America. It should be remembered, however, that with
us the emancipation of women comes chiefly from male initiative and
is a voluntary fostering of das ewig Weibliche out of love and respect
for it. And also that most European societies govern women by
coercive laws or conventions and, in the lower classes, even by
blows. Americans have almost wholly foregone these extrinsic aids,
aiming at a higher or voluntary discipline, and if American women
are, after all, quite as well guided, on the whole, as those of Europe,
it is no mean achievement.
There are in general two sorts of forces, one personal and one
institutional, which hold people together in wedlock. By the personal I
mean those which spring more directly from natural impulse, and
may be roughly summed up as affection and common interest in
children. The institutional are those that come more from the larger
organization of society, such as economic interdependence of
husband and wife, or the state of public sentiment, tradition and law.
As regards affection, present conditions should apparently be
favorable to the strength of the bond. Since personal choice is so
little interfered with, and the whole matter conducted with a view to
congeniality, it would seem that a high degree of congeniality must,
on the whole, be secured. And, indeed, this is without much doubt
the case: nowhere probably, is there so large a proportion of couples
living together in love and confidence as in those countries where
marriage is most free. Even if serious friction arises, the fact that
each has chosen the other without constraint favors a sense of
responsibility for the relation, and a determination to make it succeed
that might be lacking in an arranged marriage. We know that if we do
not marry happily it is our own fault, and the more character and self-
respect we have the more we try to make the best of our venture.
There can hardly be a general feeling that marriage is one thing and
love another, such as may prevail under the rule of convenance.
Yet it is not inconsistent to say that this aim at love increases
divorce. The theory being that the contracting parties are to be made
happy, then, if they are not, it seems to follow that the relation is a
failure and should cease: the brighter the ideal the darker the fact by
contrast. Where interest and custom rule marriage those who enter
into it may not expect congeniality, or, if they do, they feel that it is
secondary and do not dream of divorce because it is not achieved.
The woman marries because her parents tell her to, because
marriage is her career, and because she desires a wedding and to
be mistress of a household; the man because he wants a household
and children and is not indifferent to the dowry. These tangible aims,
of which one can be fairly secure beforehand, give stability where
love proves wanting.
And while freedom in well-ordered minds tends toward
responsibility and the endeavor to make the best of a chosen course,
in the ill-ordered it is likely to become an impulsiveness which is
displayed equally in contracting and in breaking off marriage without
good cause. The conditions of our time give an easy rein to
undisciplined wills, and one index of their activity is the divorce rate.
Bad training in childhood is a large factor in this, neglected or spoiled
children making bad husbands or wives, and probably furnishing the

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Old and New Régimes in the Family—The Declining Birth-Rate