Table Of ContentDiabetes and
Kidney Disease
Diabetes and
Kidney Disease
EDITED BY
Gunter Wolf MD, MHBA
Professor and Chairman
Department of Internal Medicine III
University of Jena
University Hospital
Jena, Germany
A John Wiley & Sons, Ltd., Publication
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Library of Congress Cataloging-in-Publication Data
Diabetes and kidney disease / edited by Gunter Wolf.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-470-67502-1 (hardback : alk. paper)
I. Wolf, Gunter, 1961–
[DNLM: 1. Diabetic Nephropathies. WK 835]
LC Classification not assigned
616.4'62–dc23
2012036995
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may
not be available in electronic books.
Cover image: Courtesy of Hermann J. Kissler, Christiane Rüster, Utz Settmacher
Cover design by Garth Stewart
Set in 8/12 pt Stone Serif by Toppan Best-set Premedia Limited
1 2013
Contents
Contributors, vii 10 Diabetes, pregnancy and the kidney, 129
Preface, x Helmut Kleinwechter and Ute Schäfer-Graf
11 Diabetic nephropathy in children, 143
Kai D Nüsken and Jörg Dötsch
Part I Introduction and
12 Diabetes, the kidney and
Pathophysiology
retinopathy, 153
1 History of diabetic nephropathy: Hans-Peter Hammes
a personal account, 3
Eberhard Ritz
Part III Prevention and Therapy
2 Epidemiology of chronic kidney disease
in diabetes, 14 13 Reducing progression of diabetic
Andrea Icks and Michael Koch nephropathy by antihyperglycemic
3 Genetic risk factors for diabetic treatment, 171
nephropathy, 29 Christoph Hasslacher
Carsten A. Böger and Peter R. Mertens 14 Dosage of antihyperglycemic drugs in
4 Pathophysiology of diabetic patients with renal insuffi ciency, 186
nephropathy, 45 Alexander Sämann and Ulrich A. Müller
Ivonne Loeffl er 15 Reducing progression of diabetic
5 Histology of human diabetic nephropathy by antihypertensive
nephropathy, 62 treatment, 202
Kerstin Amann and Christoph Daniel Anita Hansen, Ivo Quack and
6 Natural history and diagnosis of diabetic Lars Christian Rump
kidney disease, 70 16 Treatment of the patient with end-stage
Bethany Karl and Kumar Sharma diabetic nephropathy, 215
Muriel Ghosn and Fuad N. Ziyadeh
17 Combined pancreas and kidney
Part II Special Situations, Risk Factors
transplantation or kidney alone
and Complications
transplantation for patients with diabetic
7 Cardiovascular disease in diabetic nephropathy, 232
nephropathy: pathophysiology and Hermann J. Kissler, Christiane Rüster
treatment, 85 and Utz Settmacher
Martin Busch
8 Statin therapy in patients with diabetic
Index, 253
nephropathy, 101
Color plate section can be found facing
Christoph Wanner
page 54
9 Diabetes mellitus, bone and kidney, 116
Thomas Neumann and Gabriele Lehmann
v
Contributors
Kerstin Amann MD Hans-Peter Hammes MD
Professor of Nephropathology Section Head, Endocrinology
Department of Pathology 5th Medical Department
Universität Erlangen- Nürnberg UMM– University of Heidelberg
Erlangen, Germany Mannheim, Germany
Carsten A. Bö ger MD Anita Hansen MD
Department of Internal Medicine II Medical Faculty
Nephrology Department of Nephrology
University Medical Center Regensburg Heinrich-Heine University Dü sseldorf
Regensburg, Germany Düsseldorf, Germany
Martin Busch MD Christoph Hasslacher
Consultant, Nephrologist and Lecturer Professor of Internal Medicine
Department of Internal Medicine III Diabetesinstitut Heidelberg
Jena University Hospital, Jena, Germany St. Josefskrankenhaus
Heidelberg, Germany
Christoph Daniel PhD
Nephropathology, Department of Pathology Andrea Icks MD DPH MBA
Universität Erlangen -Nürnberg Institute of Biometrics and Epidemiology
Erlangen, Germany German Diabetes Center;
Senior Lecturer
Jörg D ötsch MD Department of Public Health
Professor of Pediatrics Faculty of Medicine
University Hospital of Cologne Heinrich-Heine University
Department of Pediatric and Adolescent Düsseldorf, Germany
Medicine
Cologne, Germany Bethany Karl DO
Nephrology Fellow
Muriel A. Ghosn MD Center for Renal Translational Medicine
Medical Chief Resident University of California
Department of Internal Medicine CA, USA
American University of Beirut
Beirut, Lebanon
vii
Contributors
Hermann J. Kissler MD Thomas Neumann MD
Visceral Surgery Fellow Consultant Rheumatologist
Department of General, Visceral and Department of Internal Medicine III
Vascular Surgery Jena University Hospital
Jena University Hospital Jena, Germany
Jena, Germany
Kai D. N üsken MD
Helmut Kleinwechter MD Division of Pediatric Nephrology
Specialist in Diabetology Department of Pediatric and Adolescent
Diabetologikum Kiel Medicine
Diabetes Center and Diabetes Education University Hospital of Cologne
Center Cologne, Germany
Kiel, Germany
Ivo Quack MD
Michael Koch MD Medical Faculty
Head Department of Nephrology
Center of Nephrology Mettmann, Germany; Heinrich-Heine University Dü sseldorf
Clinic of Urology and Nephrology Düsseldorf, Germany,
Niederberg Hospital Velbert, Germany
Eberhard Ritz MD
Gabriele Lehmann MD Professor of Nephrology
Department of Internal Medicine III Department Internal Medicine
Jena University Hospital Division of Nephrology
Jena, Germany Nierenzentrum
Carola Ruperto University Hospital
Ivonne Loeffl er PhD Heidelberg, Germany
Postdoctoral Research Fellow
Department of Internal Medicine III Lars Christian Rump MD
Jena University Hospital Professor of Medicine
Jena, Germany Department of Nephrology
Heinrich-Heine University Dü sseldorf
Peter R. Mertens MD Düsseldorf, Germany
Professor of Medicine
Director Christiane Rü ster MD
Department of Nephrology and Attending Physician, Nephrologist
Hypertension, Diabetes and Endocrinology Department of Internal Medicine III
Otto-von-Guericke University Magdeburg Jena University Hospital
Magdeburg, Germany Jena, Germany
Ulrich A. Mü ller MD MSc Alexander Sä mann MD
Department of Medicine III Department of Medicine III
Jena University Hospital Jena University Hospital
Jena, Germany Jena, Germany
viii
Contributors
Ute Sch äfer-Graf MD, PhD Christoph Wanner MD
Specialist in Perinatology and Diabetology Professor of Medicine
Berlin Diabetes and Pregnancy Center Department of Medicine
Department of Gynecology and Obstetrics Division of Nephrology
St. Joseph Hospital University of Wü rzburg
Berlin, Germany Würzburg, Germany
Utz Settmacher MD Fuad N. Ziyadeh MD FASN FACP
Professor of Surgery Professor of Medicine and Biochemistry
Chairman Chairman, Department of Internal Medicine
Department of General, Visceral and American University of Beirut
Vascular Surgery Beirut, Lebanon
Jena University Hospital
Jena, Germany
Kumar Sharma MD FAHA
Director
Center for Renal Translational Medicine
Professor of Medicine
University of California
CA, USA
ix
Preface
In 1801 the English physician Erasmus Darwin more complex relationship between the kidney
(1731–1802) recognized some patient with dia- and diabetes. All the contributors to this book
betes whose urine could be coagulated by heat, are experts in their fi elds. It covers a wide range
indicating proteinuria, and associated this of topics from epidemiology, pathophysiology
fi nding with dropsy and general swelling. In and genetics to concrete treatment recommen-
1936, the seminal discovery by Kimmelstiel and dations and algorithms for the practicing physi-
Wilson showed the morphologic changes by cian. Furthermore, the reader will also fi nd
the description of glomerular lesions in diabet- chapters on topics normally not found in stand-
ics with nephropathy. Today, diabetic renal ard books on diabetic nephropathy, such as
disease is now worldwide the major cause of diabetic nephropathy in children, the relation-
end-stage renal failure. Besides the uncountable ship between retinal and renal diabetic com-
individual suffering of patients with diabetic plications and diabetes, bone, and the kidney.
nephropathy, there is an increasing economical Therefore, the book is not only for the expert
burden for such patients. Patients with diabetic nephrologists and diabetologists, but also for
renal disease have a very high cardiovascular general internists and primary care physicians.
morbidity and mortality. The spectrum of The authors have put an enormous amount of
patients with diabetes and renal disease has work into this book. They would be happy if
completely been changed: 25 year ago diabetic this contribution could help to better care for
nephropathy was a feature of patients with type patients with diabetes and renal affections.
1 diabetes, type 2 diabetes was considered a rela- Many thanks to Wiley -Blackwell (especially Jen-
tively rare even a “normal” process of aging. nifer Seward) for agreeing to start this ambigu-
Now, the increasing pandemic of patients with ous projects and for the continuous help while
type 2 diabetes makes this group the largest suf- carrying it out.
fering from diabetic nephropathy, albeit the
incidence of patients with type 1 diabetes has Professor Dr. Gunter Wolf MD, MHBA
also increased in recent years. The current book Department of Internal Medicine III
provides an up- to-date review of many aspects, University of Jena
not only of diabetic nephropathy but of the Jena, Germany
x
Mesangial expansion and
Glomerular basement hemodynamic changes
membrane (GBM) Mesangial matrix Glomerulo- Tubular
Mesangial cell sclerosis epithelial ceTllusbular basement
VED and
Hyper-permeability LUMEN membrane (TBM)
ROS
ECM
Endothelial cell TGF-β1
Thickening of
Foot processes
GBM
VEGF MCP1/Cytokines Thickening TUBULE
Ang II of TBM
Inflammation
Podocyte Attenuated
(glomerular epithelial cell) tubular reabsorption
Podocyte pathology of albumin resident
(effacement, apoptosis) fibroblast
Tubuloepithelial
hypertrophy
EMT TGF-β1
Tubular atrophy
Tubulointerstitial fibrosis
Albuminuria
ininnetr erglstoitimaelrular Progression of diabetic nephropaTutihbnyufllaominmteartsitoitnial ECM Masmt cyaeoclfltiibvraotbedlast
Plate 4.1 Involvement of different renal cell types in pathogenesis of diabetic nephropathy (DN). Multiple factors
contribute to the pathogenesis of DN. Via “crosstalking ” the glomerular cell types (mesangial cells, glomerular
endothelial cells, and podocytes) are involved in thickening of the glomerular basement membrane and mesangial
expansion as well as via upregulation of various mediators, such as transforming growth factor (TGF)- β1, vascular
endothelial growth factor, angiotensin II, reactive oxygen species (ROS), and MCP -1, in glomerular infl ammation,
glomerulosclerosis, and vascular endothelial dysfunction (VED). In addition to some of these glomerular changes
and the pathology of podocytes, tubules also contribute to the development of albuminuria, a hallmark of DN.
Increased extracellular matrix (ECM) production by the renal interstitial cell types (tubular cells, resident fi broblasts,
activated myofi broblasts, and mast cells) leads to tubulointerstitial fi brosis, another characteristic feature of DN.
See text for details.Reproduced from D’ Agati V, e t al. RAGE, glomerulosclerosis and proteinuria: roles in podocytes
and endothelial cells.Trends Endocrinol Metab 2010; 21:50–6.
Diabetes and Kidney Disease, First Edition. Edited by Gunter Wolf.
© 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.
Loss of epithelial adhesion
Disruption of
basement membrane
adhesion molecules Induction of
mesenchymal markers
de novoα-SMA
metastable cell
synthesis
Tubule Tubule
Stress
Cytokines
Extracellular
TGF-β1 Matrix
basement MMP2
membrane TGF-β1 2) EMT
epithelial cells
1) Proliferation
resident fibroblast
TGF-β1 Fibronectin
Collagen I
Blood Blood
vessel vessel Collagen III
3) EndMT
Loss of
VE-cadherin and CD31
Induction of
endothelial cells mesenchymal markers interstitial myofibroblast
de novoα-SMA synthesis
Tubulointerstitial
4) Infiltration of circulating bone
fibrosis
Blood marrow-derived fibrocytes
vessel
bone marrow-derived fibrocyte
Plate 4.2 Hypothesis of progression of tubulointerstitial fi brosis by EMT and EndMT. Interstitial myofi broblasts
responsible for synthesis of ECM and contribution to fi brosis have been proposed to be derived from more
sources: (1) proliferation/activation of resident fi broblasts, (2) epithelial- to-mesenchymal transition (EMT), (3)
endothelial-to-mesenchymal transition (EndMT), and/or (4) infi ltration of circulating bone marrow- derived fi bro-
cytes. Initiated by external stimuli (e.g., hyperglycemia, cytokines, extracellular matrix) tubular or endothelial cells
lose their cell- cell contacts and start to express mesenchymal markers (e.g. α -smooth muscle actin, vimentin) and
undergo EMT and EndMT, respectively. The initially metastable cells, which coexpress tubular/endothelial and
mesenchymal markers, disengage themselves from cell connective and transdifferentiate to interstitial myofi brob-
lasts. These mesenchymal cells derived from epithelium or endothelium in the tubulointerstitium contribute to
progression of DN. Modifi ed and supplemented according to Kizu A, e t al. Endothelial -mesenchymal transition
as a novel mechanism for generating myofi broblasts during diabetic nephropathy. A m J Pathol 2009; 175:1371–3,
and Barnes JL, e t al. Myofi broblast differentiation during fi brosis: role of NAD(P)H oxidases. K idney Int
2011;79:944–56.
