Main IgA Nephropathy Today

IgA Nephropathy Today

A further step towards unraveling this mysterious disease Primary IgA nephropathy has first been described as a new disease entity almost 40 years ago. This disorder, considered to be an immune-complex-mediated glomerulonephritis, is characterized by granular deposition of IgA (mainly IgA1) and C3 in the glomerular mesangial areas and is defined as nephropathy showing proliferative changes in the glomerular mesangial cells and increases in the mesangial matrices. Apart from being one of the most common types of chronic glomerulonephritis, it is also the most frequent case of end-stage renal disease. But even though continuing efforts have gradually clarified various aspects of the pathogenesis of the disease, specific treatment is not yet available. In this publication, international nephrologists and basic scientists report the most recent data on IgA nephropathy. Starting with clinical reviews on topics such as the clinico-pathological classification, new treatment approaches, and the role of renal biopsies, the focus then shifts towards basic reviews on, for example, candidate genes, the pathogenic role of IgA receptors or immune complex formation. Updates on clinical and basic advances, discussing among other things the influence of obesity or various therapeutic approaches, make up the second part of the book. Presenting up-to-date information on this still mysterious disease, the publication at hand constitutes a valuable source of information for nephrologists, general practitioners, residents and interns.
Categories: Medicine
Year: 2007
Edition: 1
Publisher: Karger
Language: english
Pages: 267
ISBN 10: 3805582862
ISBN 13: 9783805582865
Series: Contributions to nephrology 157
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IgA Nephropathy Today

Contributions to Nephrology
Vol. 157

Series Editor

Claudio Ronco, Vicenza

IgA Nephropathy
Today

Volume Editor

Yasuhiko Tomino, Tokyo

24 figures, 5 in color, and 10 tables, 2007

Basel · Freiburg · Paris · London · New York ·
Bangalore · Bangkok · Singapore · Tokyo · Sydney

Contributions to Nephrology
(Founded 1975 by Geoffrey M. Berlyne)

Yasuhiko Tomino
Division of Nephrology
Department of Internal Medicine
Juntendo University School of Medicine
2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan)

Library of Congress Cataloging-in-Publication Data
International Symposium on IgA Nephropathy (11th : 2006 : Tokyo, Japan)
IgA nephropathy today / volume editor, Yasuhiko Tomino.
p. ; cm. – (Contributions to nephrology, ISSN 0302-5144 ; v. 157)
“11th International Symposium on IgA Nephropathy, October 5–7, 2006,
Tokyo, Japan”–Foreword.
Includes bibliographical references and index.
ISBN-13: 978–3–8055–8286–5 (hard cover : alk. paper)
1. IgA glomerulonephritis–Congresses. I. Tomino, Yasuhiko, 1949– II.
Title. III. Series.
[DNLM: 1. Glomerulonephritis, IGA–etiology–Congresses. 2.
Glomerulonephritis, IGA–therapy–Congresses. W1 CO778UN v.157 2007 / WJ
353 I6085i 2007]
RC918.I35I585 2006
616.6⬘1–dc22
2007011107

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and
Index Medicus.
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dosage set forth in this text are in accord with current recommendations and practice at the time of publication.
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All rights reserved. No part of this publication may be translated into other languages, reproduced or
utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying,
or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
ISSN 0302–5144
ISBN 978–3–8055–8286–5

Contents

IX Foreword
Tomino, Y. (Tokyo)
Chairman’s Reviews

1 Pathogenesis of IgA Nephropathy
Tomino, Y. (Tokyo)

8 Treatment for IgA Nephropathy
Tomino, Y. (Tokyo)
Clinical Reviews of IgA Nephropathy

13 International IgA Nephropathy Network Clinico-Pathological
Classification of IgA Nephropathy
Feehally, J.; Barratt, J. (Leicester); Coppo, R. (Turin); Cook, T. (London);
Roberts, I. (Oxford); on behalf of the International IgA Nephropathy Network

19 IgA Nephropathy: A Clinical Overview
Julian, B.A. (Birmingham, Ala.); Wyatt, R.J. (Memphis, Tenn.);
Matousovic, K. (Prague/Pilsen); Moldoveanu, Z.; Mestecky, J.;
Novak, J. (Birmingham, Ala.)

27 Angiotensin Antagonists and Fish Oil for Treating
IgA Nephropathy
Coppo, R.; Amore, A.; Peruzzi, L.; Mancuso, D.; Camilla, R. (Turin)

V

37 Treatment of IgA Nephropathy: Corticosteroids, Tonsillectomy,
and Mycophenolate Mofetil
Kawamura, T. (Tokyo)

44 Interpretation of Renal Biopsies in IgA Nephropathy
Cook, H.T. (London)
Basic Reviews of IgA Nephropathy

50 Altered Expression of Lymphocyte Homing Chemokines
in the Pathogenesis of IgA Nephropathy
Buren, M.; Yamashita, M. (Cleveland, Ohio); Suzuki, Y.; Tomino, Y. (Tokyo);
Emancipator, S.N. (Cleveland, Ohio)

56 IgA Nephropathy: Current Views of Immune Complex Formation
Mestecky, J. (Birmingham, Ala.); Suzuki, H.; Yanagihara, T. (Birmingham, Ala./Tokyo);
Moldoveanu, Z.; Tomana, M. (Birmingham, Ala.); Matousovic, K. (Birmingham, Ala./
Prague/Pilsen); Julian, B.A.; Novak, J. (Birmingham, Ala.)

64 Pathogenic Role of IgA Receptors in IgA Nephropathy
Monteiro, R.C. (Paris)

70 The Mucosa-Bone-Marrow Axis in IgA Nephropathy
Suzuki, Y.; Tomino, Y. (Tokyo)

80 Searching for IgA Nephropathy Candidate Genes: Genetic Studies
Combined with High Throughput Innovative Investigations
Schena, F.P.; Cerullo, G.; Torres, D.D.; Zaza, G.; Cox, S. (Bari);
Bisceglia, L. (San Giovanni Rotondo); Scolari, F. (Brescia); Frascà, G. (Ancona);
Ghiggeri, G.M. (Genoa); Amoroso, A. (Turin); on behalf of the European IgA
Nephropathy Consortium
Clinical Advances (Update)

90 Clinicopathological Influence of Obesity in IgA Nephropathy:
Comparative Study of 74 Patients
Tanaka, M.; Tsujii, T.; Komiya, T.; Iwasaki, Y.; Sugishita, T.; Yonemoto, S.;
Tsukamoto, T.; Fukui, S.; Takasu, A.; Muso, E. (Osaka)

94 A Multicenter Prospective Cohort Study of Tonsillectomy and Steroid
Therapy in Japanese Patients with IgA Nephropathy: A 5-Year Report
Miyazaki, M.; Hotta, O. (Sendai); Komatsuda, A. (Akita); Nakai, S. (Osaka);
Shoji, T. (Nagoya); Yasunaga, C. (Kitakyusyu); Taguma, Y. (Sendai); Japanese
Multicenter Study Group on the Treatment of IgA Nephropathy (JST-IgAN)

99 Tonsillectomy and Corticosteroid Therapy with Concomitant
Methylprednisolone Pulse Therapy for IgA Nephropathy
Suwabe, T.; Ubara, Y.; Sogawa, Y.; Higa, Y.; Nomura, K.; Nakanishi, S.; Hoshino, J.;
Sawa, N.; Katori, H.; Takemoto, F.; Hara, S.; Ohashi, K.; Takaichi, K. (Tokyo)

Contents

VI

104 Impact of Annual Urine Health Check-Up System to Obtain Clinical
Remission in Patients with IgA Nephropathy
Ieiri, N.; Hotta, O.; Taguma, Y. (Miyagi)

109 Sequential Immunosuppressive Therapy in Progressive
IgA Nephropathy
Rasche, F.M.; Keller, F.; von Müller, L.; Czock, D. (Ulm); Lepper, P.M. (Berne)

114 Prospective Trial of Combined Therapy with Heparin/Warfarin and
Renin-Angiotensin System Inhibitors in Progressive IgA Nephropathy
Ishii, T.; Kawamura, T.; Tsuboi, N.; Ogura, M.; Utsunomiya, Y.; Hosoya, T. (Tokyo)
Basic Advances (Update)

120 Downregulation of the ␤1,3-Galactosyltransferase Gene in
Tonsillar B Lymphocytes and Aberrant Lectin Bindings to
Tonsillar IgA as a Pathogenesis of IgA Nephropathy
Inoue, T.; Sugiyama, H.; Kikumoto, Y.; Fukuoka, N.; Maeshima, Y.; Hattori, H.;
Fukushima, K.; Nishizaki, K. (Okayama); Hiki, Y. (Toyoake); Makino, H. (Okayama)

125 Development of IgA Nephropathy-Like Disease with High
Serum IgA Levels and Increased Proportion of Polymeric IgA
in ␤-1,4-Galactosyltransferase-Deficient Mice
Nishie, T. (Kanazawa); Miyaishi, O. (Aichi); Azuma, H. (Osaka);
Kameyama, A. (Ibaraki); Naruse, C.; Hashimoto, N.; Yokoyama, H. (Kanazawa);
Narimatsu, H. (Ibaraki); Wada, T.; Asano, M. (Kanazawa)

129 IgA Nephropathy: Characterization of IgG Antibodies Specific for
Galactose-Deficient IgA1
Suzuki, H. (Birmingham, Ala./Tokyo); Moldoveanu, Z.; Hall, S.; Brown, R.;
Julian, B.A. (Birmingham, Ala.); Wyatt, R.J. (Memphis, Tenn.);
Tomana, M. (Birmingham, Ala.); Tomino, Y. (Tokyo); Novak, J.;
Mestecky, J. (Birmingham, Ala.)

134 IgA Nephropathy and Henoch-Schoenlein Purpura Nephritis:
Aberrant Glycosylation of IgA1, Formation of IgA1-Containing
Immune Complexes, and Activation of Mesangial Cells
Novak, J.; Moldoveanu, Z.; Renfrow, M.B.; Yanagihara, T.; Suzuki, H.; Raska, M.;
Hall, S.; Brown, R.; Huang, W.-Q.; Goepfert, A. (Birmingham, Ala.); Kilian, M.;
Poulsen, K. (Aarhus); Tomana, M. (Birmingham, Ala.); Wyatt, R.J. (Memphis, Tenn.);
Julian, B.A.; Mestecky, J. (Birmingham, Ala.)

139 Patients with IgA Nephropathy Respond Strongly Through Production
of IgA with Low Avidity Against Staphylococcus aureus
Shimizu, Y.; Seki, M.; Kaneko, S.; Hagiwara, M.; Yoh, K.; Yamagata, K. (Tsukuba);
Koyama, A. (Ami)

Contents

VII

144 Transferrin Receptor Engagement by Polymeric IgA1 Induces
Receptor Expression and Mesangial Cell Proliferation:
Role in IgA Nephropathy
Tamouza, H.; Vende, F.; Tiwari, M.; Arcos-Fajardo, M.; Vrtovsnik, F.; Benhamou, M.;
Monteiro, R.C.; Moura, I.C. (Paris)

148 IgA Fc Receptor I Is a Molecular Switch that Determines
IgA Activating or Inhibitory Functions
Kanamaru, Y.; Blank, U.; Monteiro, R.C. (Paris)

153 The Role of PDGF-D in Mesangioproliferative Glomerulonephritis
Floege, J.; van Roeyen, C.; Boor, P.; Ostendorf, T. (Aachen)

159 Analysis of Innate Immune Responses in a Model of
IgA Nephropathy Induced by Sendai Virus
Yamashita, M.; Chintalacharuvu, S.R. (Cleveland, Ohio); Kobayashi, N. (Tokyo);
Nedrud, J.G.; Lamm, M.E. (Cleveland, Ohio); Tomino, Y. (Tokyo);
Emancipator, S.N. (Cleveland, Ohio)

164 Roles of Bone Marrow, Mucosa and Lymphoid Tissues in
Pathogenesis of Murine IgA Nephropathy
Aizawa, M.; Suzuki, Y.; Suzuki, H.; Pang, H.; Kihara, M.; Yamaji, K.; Horikoshi, S.;
Tomino, Y. (Tokyo)

169 Concluding Remarks
Glassock, R.J. (Los Angeles, Calif.)
Abstracts

174 Clinical Reviews of IgA Nephropathy
180 Basic Reviews of IgA Nephropathy
185 Clinical Advances (Update)
215 Basic Advances (Update)
243 Closing Remarks
244 Author Index
249 Subject Index

Contents

VIII

Foreword

Almost 40 years have passed since Dr. Jean Berger first described primary
IgA nephropathy as a new disease entity. This disease may lead to end-stage
renal disease (ESRD) with its enormous economic impact on healthcare everywhere. Since the pathogenesis of IgA nephropathy is still obscure, specific
treatment is not yet available. However, efforts by many investigators around
the world have gradually clarified various aspects of the pathogenesis and treatment of this disease.
The objectives of the 11th International Symposium on IgA nephropathy
(October 5–7, 2006) are (1) to discuss the most up-to-date findings on pathogenesis and treatment of IgA nephropathy and (2) to build friendship among us.
This symposium is truly a small specialized meeting with the participation of
international nephrologists and basic scientists involved in the large topic of
IgA nephropathy. This article is a summary of the topics presented in the 11th
International Symposium on IgA nephropathy.
This symposium was made possible by the generosity of our sponsors.
Thanks go to the members of the Organizing and Scientific Committees, my colleagues in the Division of Nephrology at Juntendo University and the sponsors.
Autumn 2006
Yasuhiko Tomino, MD, PhD
President, 11th International Symposium on IgA Nephropathy
Professor, Division of Nephrology, Department of Internal Medicine
Dean, Juntendo University School of Medicine, Tokyo, Japan

IX

Acknowledgments

We sincerely thank the people mentioned below for their collaboration
with the 11th International Symposium of IgA Nephropathy in Tokyo, and with
the editing of this book. In addition, we especially appreciate the excellent and
dedicated assistance by Mr. Makishima and Dr. Hidaka.
Medical Toyu Co. Ltd.
Nobukazu Kai
Syunta Aramaki
Shigehiro Makishima
Nana Harada
Hiroyuki Miyazawa
Michiko Kai

Juntendo University School of
Medicine
Satoshi Horikoshi
Isao Ohsawa
Toshinao Tsuge
Noriyoshi Kobayashi
Hitoshi Suzuki
Teruo Hidaka
Masao Kihara
Eri Izumida
Hirofumi Ohba
Rei Kuze
Terumi Shibata
Kazutaka Yoshida

X

Chairman’s Reviews
Tomino Y (ed): IgA Nephropathy Today.
Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 1–7

Pathogenesis of IgA Nephropathy
Yasuhiko Tomino
Division of Nephrology, Department of Internal Medicine,
Juntendo University, Tokyo, Japan

Abstract
IgA nephropathy is generally considered to be an immune-complex-mediated or aggregated (polymerized) IgA (IgA1)-mediated glomerulonephritis. Since the pathogenesis of IgA
nephropathy is still obscure, it is important to determine the initiation and progression of this
disease using the spontaneous animal model. The ddY mouse strain can serve as a spontaneous animal model for IgA nephropathy. Genetic factors are considered to be involved in
the initiation and progression of IgA nephropathy. It has been hypothesized that susceptibility genes for IgA nephropathy can be detected by a genome-wide scan using this model. The
peak marker D10MIT 86 on chromosome 10 is located on the region syntenic to human
6q22–23 with IGAN1, which is responsible for familiar IgA nephropathy. There are several
developmental and/or exacerbating factors in this disease. Among them, the loss of glomerular epithelial cells (podocytes) and interstitial mast cell infiltration are important factors for
progression of glomerulosclerosis and tubulointerstitial injury in patients with IgA
nephropathy.
Copyright © 2007 S. Karger AG, Basel

Determination of Pathogenesis of IgA Nephropathy using
ddY Mice, a Spontaneous Animal Model for IgA Nephropathy

Although the etiology and pathogenesis of IgA nephropathy are still
obscure, much is known about serum IgA and mesangially deposited IgA (fig. 1).
IgA is the most common immunoglobulin produced by lymphocytes and plasma
cells lining the mucosal membranes, and is the main immunoglobulin directed
against bacterial or viral antigens in exogenous secretions. Imai et al. [1]
reported that the ddY mouse strain can serve as a spontaneous animal model for
IgA nephropathy, since these mice show mesangioproliferative glomerulonephritis with severe glomerular IgA deposition. In these mice, at over 40 weeks of age

Antibody

Antigen
Trigger ? Genetic ?

Alteration of molecules
in the hinge
region of IgA (IgA1)

Virus, fungus,
bacteria, food,
IgG, IgM, IgA1,
fibronectin, laminin
Genetic factors

Antigen antibody-dependent

Antigen antibody-independent
Aggregated IgA1
(nephritogenic IgA1)

IgA (IgA1)-IC

• Pinocytosis
• Charge
• Cytokine
• Complement

Receptors

• Fc␣R, novel Fc␣R
• Fc␣␮R
• ASGPR
• plgR
• Transferrin R

IgA deposition in mesangial areas/cells

Fig. 1. Initiation of IgA nephropathy.

marked deposition of IgA and C3 occurs in the glomerular mesangial areas, in
association with an increase in the levels of IgA and macromolecular IgAimmune complex in the serum [1, 2]. IgA nephropathy is generally considered to
be an immune-complex-mediated or aggregated (polymerized) IgA (IgA1)mediated glomerulonephritis. However, the antigens or stimulators that produce
the aggregated (polymerized) IgA involved in this disease are still obscure.
Several antigens originating in the respiratory, intestinal and/or biliary tracts and
some dietary antigens have been implicated. Previous studies revealed that
murine retroviral gp70 is involved in the pathogenesis of lupus nephritis in systemic lupus erythematosus (SLE)-prone NZB, NZB ⫻ NZWF1, BXSB and
MRL/Mp-lpr/lpr mice [3, 4]. Takeuchi et al. [5] reported that the murine retroviral envelope glycoprotein, gp70, is deposited in the glomerular mesangial areas
in ddY mice over 24 weeks, in the same way as IgG and IgA. Gp70 is also present in various lymphoid tissues. Thus, they suggested that gp70 derived from
lymphoid tissues circulates as immune complexes and is deposited in the
glomerular mesangial areas. It may be one of the pathogenic antigens involved in
renal disease of ddY mice. We examined the deposition of the major retroviral
envelop glycoprotein, gp70, in glomeruli of ddY mice by immunofluorescence
[6]. Positive staining of gp70 was not observed in glomeruli of our strain of
ddY mice at any age examined using two different anti-gp70 antisera and three

Tomino

2

different staining conditions, whereas deposition of IgA, IgG and IgM was manifest in mice aged over 40 weeks. It appears that gp70 deposition may not be sine
qua non for the pathogenesis of IgA nephropathy, and that ddY mice may have a
heterogenous genetic background, resembling the situation in humans.
Genetic factors are considered to be involved in the initiation and progression of IgA nephropathy on the basis of racial differences in prevalence and
familial aggregation. It has been hypothesized that susceptibility genes for IgA
nephropathy can be detected by a genome-wide scan using this model [7]. First,
serial renal biopsies were performed at 20, 40 and 60 weeks of age in 361 ddY
mice. The ddY mice were classified into three groups on the basis of onset of
glomerular injury as follows: early onset at 20 weeks (31.9%), late onset at 40
weeks (37.9%) and quiescence at 60 weeks (30.2%). The severity of glomerular
lesions in both onset groups correlated with the intensity of glomerular IgA
deposition but not with serum IgA levels. A genome-wide scan using 270
microsatellite markers identified three chromosomal regions on chromosomes
1, 9 and 10, which were significantly associated with the glomerular injuries.
Surprisingly, the peak marker D10MIT86 on chromosome 10 is located on the
region syntenic to human 6q22–23 with IGAN1, which might be responsible for
familial IgA nephropathy [7]. In addition, D1MIT16 on chromosome 1 was
located very close to the locus of the selectin gene, which is a known candidate
for human IgA nephropathy. It appears that the three-group ddY mouse model
can be a useful tool for identifying susceptibility genes and also for examining
their roles in the pathogenesis of IgA nephropathy.

Mechanisms of Progression in IgA Nephropathy

Factors previously reported to be associated with disease progression
include male sex, age, prolonged duration, nephrotic range proteinuria, hypertension and glomerular sclerosis in patients with IgA nephropathy. Other developmental and/or exacerbating factors for patients with IgA nephropathy are:
(1) complement activation; (2) blood coagulation activity and/or its inhibition in
plasma; (3) activity of cytokines/growth factors; (4) activity of reactive oxygen
species (ROS); (5) activation of adhesion molecules; (6) apoptosis; (7) podocyte
injury (loss) and (8) interstitial mast cell infiltration (fig. 2). Among them,
podocyte injury and interstitial mast cell infiltration from our data are reviewed
in this chapter.
Loss of Glomerular Epithelial Cells (Podocytes)
It is widely assumed that glomerular mesangial cell proliferation and
mesangial expansion represent major pathological mechanisms underlying

Pathogenesis of IgA Nephropathy

3

IgA deposition in mesangial areas/cells
(activation)

Cell infiltration
Genetic factors

Cytokine, chemokine and growth factor
ROS (reactive oxygen species)
Complement (local production)
Platelet aggregation/blood coagulation
Adhesion molecule

Repair
?

Mesangial expansion
Podocyte damage
Chemokine
Cytokine
Transferrin
Complement
FcRn (IgG)

?

Cell proliferation
Result
Glomerulo-tubular cross-talk

Cause

Apoptosis

Proteinuria
Interstitial damage
Tubulo-interstitial cross-talk

Tubular
damage

Macrophage, lymphocyte,
mast cell, fibroblast

ESRF

Fig. 2. Progression of IgA nephropathy.

progression to glomerular sclerosis. Marked glomerular mesangial expansion is
accompanied by a further increase in total glomerular volume. Broadening of
the podocyte foot processes is associated with a reduction in the number of
podocytes per glomerulus and an increase in the surface area covered by the
remaining podocytes. Podocyte loss appears to contribute to progression of IgA
nephropathy. Hypotheses concerning the cause of podocyte loss are: (a)
glomerular hypertrophy and hypertension may cause podocyte injury, and (b)
mesangial expansion beyond some critical point can presumably cause closure
of capillary loops and obliteration of the podocytes [8]. Morphological studies
on experimental models of progressive glomerular disease have identified the
detachment of podocytes from the glomerular basement membrane (GBM) as a
critical step in the development and progression of glomerulosclerosis. Several
molecular mechanisms for the detachment have been proposed, including
reorganization of the actin cytoskeleton in podocytes, apoptosis of podocytes
and oxidation of the GBM [9]. To predict progression in patients with IgA
nephropathy, we analyzed glomerular lesions except for sclerosis, adhesion
and/or crescents in 34 patients with this disease by morphometric analysis.
Levels of urinary protein excretion, creatinine clearance (Ccr), serum creatinine
(sCr) and mean blood pressure at the time of renal biopsy were used as clinical
parameters. The slope of 1/sCr was also used as a prognostic parameter. Renal

Tomino

4

specimens were obtained by echo-guided biopsy. In PAS-stained light microscopic renal sections, three mid sections of open glomeruli were selected and
photographed. Stereologic estimation was performed as follows: absolute values of glomerular volume (V(G)), glomerular surface area (S(G)), podocyte
and nonpodocyte cell number per glomerulus [N(G(pod)) and N(G(Non-pod))],
glomerular surface area covered by one podocyte [S(G)/N(G(pod))] and
glomerular volume occupied by one nonpodocyte cell [V(G)/N(G(Non-pod))].
There was a significant correlation between the levels of urinary protein excretion and the change of podocyte injury parameters [N(G(pod)) and
S(G)/N(G(pod))] or N(G(Non-pod)). N(G(pod)) was negatively correlated but
S(G)/N(G(pod)) and N(G(Non-pod)) were positively correlated with urinary
protein excretion. S(G)/N(G(pod)) and N(G(Non-pod)) were correlated with
mean blood pressure. N(G(pod)), S(G)/N(G(pod)), N(G(Non-pod)), urinary
protein excretion and mean blood pressure were significantly correlated
with the slope of 1/sCr. High specificity was observed for N(G(pod)),
S(G)/N(G(pod)) and mean blood pressure. High sensitivity was also observed
for N(G(Non-pod)) and urinary protein excretion. It appears that podocyte
injury might provide additional prognostic information in patients with IgA
nephropathy [10]. Further examinations are warranted to calculate the number
of podocytes by electron microscopy to detect the outcome in patients with IgA
nephropathy.
Interstitial Mast Cell Infiltration
Mast cells (MC) are derived from hematopoietic progenitors and migrate
into inflammatory lesions. Human MC can be classified into two types according to their protease composition: those containing only tryptase (MC(T)) and
those containing both tryptase and chymase (MC(TC)) [11]. MC(T) may play a
role in immunological responses, whereas MC(TC) seem to play roles in angiogenesis and tissue remodeling. The role of MC in renal inflammatory and
fibrotic processes has recently attracted considerable attention. Although the
mechanism of the protection provided by MC is poorly understood, hormonal
mediators released from MC are thought to protect against interstitial fibrosis.
Heparin, e.g., is one of the molecules released by the secretory granules of MC
and is well known for its anticoagulant activity and inhibition of the production
of TGF-␤.
MC have been observed in the renal interstitium of patients with primary
glomerular diseases. Their levels increase with progression of tubulointerstitial
fibrosis in patients with IgA nephropathy. Kurusu et al. [12] reported that the
number of MC in non-fibrotic tubulointerstitial fields can be a predictor of the
renal prognosis of patients with IgA nephropathy. In vitro studies have revealed
that MC also produce inflammatory mediators other than histamine, such as

Pathogenesis of IgA Nephropathy

5

fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF).
Accordingly, MC are assumed to contribute to the development of renal interstitial fibrosis in humans. Angiotensin II (Ang II) is closely involved in the
pathogenesis of renal fibrosis and is generated by chymases as well as by
angiotensin converting enzyme (ACE). It has been suggested that ACE works
mainly in intravascular areas, while chymases work mainly in extravascular
areas. Human MC have one ␣-chymase, which generates Ang II by cleaving the
terminal His and Leu residues from Ang I, whereas rodents express various
kinds of ␤-chymase [13]. Rat ␤-chymase destroys Ang II by cleaving it between
Tyr4 and Ile5, but the mouse ␤-chymase MC protease 4 (mMCP-4) generates
Ang II in the same way as human ␣-chymase [14]. Sakamoto-Ihara et al. investigated whether human MC contribute to renal fibrosis through local activation
of the renin-angiotensin system by assessing their numbers in renal biopsy
specimens from patients with IgA nephropathy or minimal change nephrotic
syndrome (MCNS). In patients with IgA nephropathy and MCNS, the numbers
of tryptase-positive MC (MC(T)) and MC positive for both tryptase and chymase (MC(TC)) were examined histopathologically. sCr, mean blood pressure
and the severity of glomerular and tubulointerstitial lesions were also determined. MC(TC) numbers differed between IgA nephropathy patients and
MCNS patients. IgA nephropathy patients had more MC(TC) than MC(T). MC
were found around but not in the conglomerate of Ang II-positive infiltrating
cells. In IgA nephropathy patients with the most severe pathology, the number
of Ang II-positive cells was correlated with that of MC(TC) and MC(T). It
appears that chymase-dependent Ang II synthesis due to human MC may be
involved in the inflammatory and fibrotic processes of IgA nephropathy
(submitted).

References
1
2

3

4
5
6

Imai H, Nakamoto Y, Asakura K, et al: Spontaneous glomerular IgA deposition in ddY mice: An
animal model of IgA nephritis. Kidney Int 1985;27:756–761.
Tomino Y, Nakamura T, Ebihara I, et al: Altered steady-state of mRNA coding for extracellular
matrices in renal tissues of ddY mice, an animal model for IgA nephropathy. J Clin Lab Anal
1991;5:106–113.
Yoshiki T, Mellors RC, Strand M, et al: The viral envelope glycoprotein of murine leukemia virus
and the pathogenesis of immune complex glomerulonephritis of New Zealand mice. J Exp Med
1974;140:1011–1027.
Izui S, MaConahey PJ, Theofilopoulos AN, et al: Association of circulating retroviral gp70-anti-gp70
immune complexes with murine systemic lupus erythematosus. J Exp Med 1979;149:1099–1116.
Takeuchi E, Doi T, Shimada T, et al: Retroviral gp70 antigen in spontaneous mesangial glomerulonephritis of ddY mice. Kidney Int 1989;35:638–646.
Shimizu M, Tomino Y, Abe M, et al: Retroviral envelope glycoprotein(gp 70) is not a prerequisite
for pathogenesis of primary immunoglobulin A nephropathy in ddY mice. Nephron 1992;62:
328–331.

Tomino

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7

8
9

10

11
12
13
14

Suzuki H, Suzuki Y, Yamanaka T, et al: Genome-wide scan in a novel IgA nephropathy model
identifies a susceptibility locus on murine chromosome 10, in a region syntenic to human IGAN1
on chromosome 6q22–23. J Am Soc Nephrol 2005;16:1289–1299.
Pagtaluman ME, Miller PL, Jumping-Eagle S, et al: Podocyte loss and progressive glomerular
injury in type II diabetes. J Clin Invest 1997;99:342–348.
Asanuma K, Shirato I, Ishido K, et al: Selective modulation of the secretion of proteinases and
their inhibitors by growth factors in cultured differentiated podocytes. Kidney Int 2002;62:
822–831.
Hishiki T, Shirato I, Takahashi Y, et al: Podocyte injury predicts prognosis in patients with IgA
nephropathy using a small amount of renal biopsy tissue. Kidney Blood Press Res 2001:24:
99–104.
Irani AA, Schechter NM, Craig SS, et al: Two types of human mast cells that have distinct neutral
protease compositions. Proc Natl Acad Sci USA 1986;83:4464–4468.
Kurusu A, Suzuki Y, Horikoshi S, et al: Relationship between mast cells in the tubulointerstitium
and prognosis of patients with IgA nephropathy. Nephron 2001;89:391–397.
Chandrasekharan UM, Sanker S, Glynias MJ, et al: Angiotensin II-forming activity in a reconstructed ancestral chymase. Science 1996;271:502–505.
Caughey GH, Raymond WW, Wolters PJ, et al: Angiotensin II generation by mast cell alpha- and
beta-chymases. Biochim Biophys Acta 2000;1480:245–257.

Yasuhiko Tomino
Division of Nephrology, Department of Internal Medicine
Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku
113–8421 Tokyo (Japan)
Tel. ⫹81 3 5802 1065, Fax ⫹81 3 3813 1183, E-Mail yasu@med.juntendo.ac.jp

Pathogenesis of IgA Nephropathy

7

Tomino Y (ed): IgA Nephropathy Today.
Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 8–12

Treatment for IgA Nephropathy
Yasuhiko Tomino
Division of Nephrology, Department of Internal Medicine,
Juntendo University, Tokyo, Japan

Abstract
The Committee on IgA nephropathy in Japan has published new clinical guidelines
(2nd edition) for the diagnosis and treatment of patients with this disease. The nonspecific
therapeutic approach involves a reduction of dietary intake of protein in patients with IgA
nephropathy who have developed renal failure. At present, the most important therapeutic
goal in patients with IgA nephropathy is the control of hypertension. It has been assumed that
removal of tonsillar tissues might reduce the production of polymeric IgA and decrease the
frequency of renal parenchymal damage resulting from episodes of macroscopic hematuria
and proteinuria. Although there have been no randomized controlled trials (RCT) of tonsillectomy, these are necessary to determine the efficacy of tonsillectomy in patients with IgA
nephropathy.
Copyright © 2007 S. Karger AG, Basel

Current Strategy of Treatment in Patients with
IgA Nephropathy in Japan

Nonspecific therapeutic approach involves reduction of dietary intake of
protein in patients with IgA nephropathy who have developed renal failure.
Long-term dietary restriction is generally considered to reduce the levels of
urinary protein and ameliorate glomerular injuries in patients with IgA
nephropathy.
Previous approaches to drug therapy of IgA nephropathy in Japan have included anti-platelet drugs, anticoagulants, prednisolone (PSL), immunosuppressants,
fish oil, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor
blockers (ARB) and/or tonsillectomy. At present, the most important therapeutic
goal in patients with IgA nephropathy is the control of hypertension. Blood pressure of less than 130/80 mm Hg is the therapeutic target in patients with IgA

nephropathy. Patients with more or less normal renal function, with or without
proteinuria or hypertension, have been preferably treated with ACE inhibitors.
Several investigators reported that ACE inhibitors reduce the levels of urinary
protein excretion and preserve renal function on patients with IgA nephropathy.
Furthermore, ACE inhibitors are recommended on the basis of their beneficial
effects on the production of cytokines and extracellular matrix (ECM) components, even when hypertension is not present. ACE inhibitors are generally considered to have cardiac and renal protective actions, and they may improve glomerular
hypertension due to dilatation of efferent arterioles in the kidneys and suppress
glomerular sclerosis. Pulse therapy with high-dose corticosteroids has not been
accepted in patients with IgA nephropathy, except in cases presenting as rapidly
progressive glomerulonephritis characterized histologically by necrotizing and/or
crescent formation, because the majority of patients with IgA nephropathy have an
indolent course.
Tonsillectomy has been applied in patients with IgA nephropathy for two
reasons [1]. First, tonsillar lymphocytes from patients with IgA nephropathy
have been found to produce more polymeric IgA than healthy controls. Second,
tonsillitis is a frequent precipitating event leading to macroscopic hematuria
and, frequently, glomerular crescent formation, acute tubular injury, and/or a
reduction in glomerular filtration rate (GFR). As a result of these observations,
it has been assumed that removal of tonsillar tissues might reduce the production of polymeric IgA and decrease the frequency of renal parenchymal damage
resulting from episodes of macroscopic hematuria [1].
The macroscopic hematuria seen in IgA nephropathy is commonly precipitated by mucosal stimulation (e.g. pharyngitis) suggesting the possibility of
aberrant mucosal immunity in the pathogenesis of IgA nephropathy. The tonsils
are also a significant source of under-glycosylated IgA1, implicated in the
pathogenesis of IgA deposition. Tonsillectomy also decreases the levels of
serum IgA. However, there have been no randomized controlled trials (RCT).
No recommendations can be made regarding tonsillectomy for disease progression in patients with IgA nephropathy on the basis of currently available retrospective studies and case reports in Kidney Disease Outcomes Quality
Initiatives, UK Renal Association, European Best Practice Guidelines, International
Guidelines and CARI (Caring for Australasians with Renal Impairment)
Guidelines [2]. The Canadian Society of Nephrology guidelines state that tonsillectomy could reduce proteinuria and hematuria in IgA nephropathy patients
with recurrent tonsillitis. Tonsillectomy should be performed in patients with
appropriate ENT (ear, nose, and throat) indications. Controlled trials are needed
before tonsillectomy should be considered for any other group.
Kano et al. in my division investigated toll-like receptor (TLR) expression
in tonsils from IgA nephropathy and determined their cell types. It is suggested

Treatment for IgA Nephropathy

9

that tonsillectomy with steroid pulse therapy may provide rapid and good therapeutic outcomes in IgA nephropathy patients who show high expression of
TLR9 in tonsillar plasmacytoid dendric cells. It appears that TLR9 activation in
the mucosa may be involved in the pathogenesis of this disease (submitted).

Guidelines for the Treatment of IgA Nephropathy in
Japan, 2nd Version (Joint Committee of the Japanese
Ministry of Health, Labor and Welfare)

The committee on IgA nephropathy of the Special Study Group on
Progressive Glomerular Diseases of the Japanese Ministry of Health, Labor and
Welfare published new clinical guidelines (2nd version) for the diagnosis and
treatment of patients with IgA nephropathy in Japan [3]. Patients with IgA
nephropathy are divided into the following four groups at the time of renal
biopsy: (a) good prognosis group: almost no necessity of dialysis; (b) relatively
good prognosis group: probability of dialysis requirement is relatively low;
(c) relatively poor prognosis group: dialysis is likely to be required within 5–20
years, and (d) poor prognosis group: high probability of dialysis requirement
within 5 years. Selection of treatment should be based on renal biopsy and clinical findings (renal function) in each patient [3].
Procedures
Good Prognosis Group
Regimen. No particular regimen. There are no special restrictions related to
status except that extremely vigorous exercise should be avoided. Visits to an
outpatient clinic once or twice a year for urinalysis and blood pressure determination are recommended.
Diet Therapy. No particular therapy except for the avoidance of excessive
salt intake.
Drug Therapy. Drug therapy is not required in principle, but antiplatelet
drugs are administered as required.
Relatively Good Prognosis Group
Regimen. No particular regimen is required, but the same recommendations apply as for the good prognosis group mentioned above. Visits to an outpatient clinic should be made at least three or four times a year.
Diet Therapy. There is no particular diet therapy, but the same recommendations apply as for the good prognosis group mentioned above.
Drug Therapy. Drug therapy is not required in principle, but antiplatelet
drugs or adrenocorticosteroids are administered as required.

Tomino

10

Relatively Poor Prognosis Group
Regimen. Patients are instructed to avoid overworking. Regular office
work or school activities are allowed. Working (especially night work) and
sports are restricted based on urinalysis and renal function data. Care is necessary during childbearing and parturition. Visits to an outpatient clinic
should be made once a month in principle, and blood chemistry and urinary
protein should be tested, in addition to urinalysis and determination of blood
pressure.
Diet Therapy. Diet therapy includes a low-salt diet of 7–8 g/day, a low protein diet of 0.8–0.9 g/kg ideal body weight (IBW)/day and a calorie intake of
35 kcal/kg IBW/day. Water intake is not restricted unless edema is present. Diet
therapy in children is adjusted according to age.
Drug Therapy. The drug therapy regimen is summarized below:
(a) Antiplatelet agents: Prolonged administration of an antiplatelet agent is
common, but each drug must be checked for indications covered by health
insurance.
(b) Antihypertensive agents: Angiotensin converting enzyme (ACE) inhibitors,
angiotensin II receptor blockers (ARB) and/or diuretics should be used in
patients without renal failure. For those with insufficient hypotensive
effects or with renal failure, calcium antagonists (CCB) or ␣-blockers
should be administered. If the decrease in blood pressure is still insufficient, ␣-methyldopa may be used concomitantly.
(c) Adrenocorticosteroids: Adrenocorticosteroids should be administered to
patients who show slight increases in mesangial matrix and interstitial
fibrosis associated with acute inflammatory changes in renal biopsy
specimens. In addition to these histological changes, if the patients show
more than a moderate degree of proteinuria (⬎0.5 g/day) and their creatinine clearance (Ccr) exceeds 70 ml/min, adrenocorticosteroids should
be used.
(d) Anticoagulants: When crescent formation, glomerulosclerosis and adhesion
to Bowman’s capsule are evident in renal biopsy, warfarin should be used,
although heparin may be used for inpatients.
(e) Immunosuppressants: Immunosuppressants are not usually used.
Poor Prognosis Group
Regimen. The regimen is based on that for chronic renal failure (CRF).
Pregnancy and parturition should be avoided. Visits to an outpatient clinic must
be made at least once a month, and laboratory examinations are basically the
same as those for CRF.
Diet Therapy. Diet therapy includes a low-salt diet of 7 g/day, a low-protein
diet of 0.6 g/kg IBW/day and a calorie intake of 35 kcal/kg IBW/day. Water

Treatment for IgA Nephropathy

11

intake is not restricted unless edema is present. Diet therapy in children is
adjusted according to age.
Drug Therapy. Drug therapy is similar to that for the relatively poor prognosis group. CRF is treated according to the disease state.

References
1
2
3

Silva G, Hogg RJ: IgA nephropathy; in Tisher CC, Brenner BM (eds): Renal Pathology. Philadelphia.
Lippincott, 1989, pp 434–491.
Thomas M: Specific management of IgA nephropathy: role of tonsillectomy. The CARI
Guidelines. Nephrology 2006;11(suppl 1):S146–S148.
Tomino Y, Sakai H, Special Study Group (IgA nephropathy) on Progressive Glomerular Disease:
Clinical guidelines for immunoglobulin A (IgA) nephropathy in Japan, ed 2. Clin Exp Nephrol
2003;7:93–97.

Yasuhiko Tomino
Division of Nephrology, Department of Internal Medicine
Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku
113–8421, Tokyo (Japan)
Tel. ⫹81 3 5802 1065, Fax ⫹81 3 3813 1183, E-Mail yasu@med.juntendo.ac.jp

Tomino

12

Clinical Reviews of IgA Nephropathy
Tomino Y (ed): IgA Nephropathy Today.
Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 13–18

International IgA Nephropathy Network
Clinico-Pathological Classification of IgA
Nephropathy
John Feehallya, Jonathan Barratta, Rosanna Coppob, Terry Cookc,
Ian Robertsd, on behalf of the International IgA Nephropathy Network
a

The John Walls Renal Unit, Leicester General Hospital, Leicester, UK; bNephrology
and Dialysis Unit, ‘Regina Margherita’ Children’s Hospital, Turin, Italy; cDepartment
of Histopathology, Imperial College London, Hammersmith Hospital, London, and
d
Oxford Radcliffe Hospitals and University of Oxford, Oxford, UK

Abstract
There is no international consensus for the pathological or clinical classification of IgA
nephropathy (IgAN). This has limited international comparisons between outcome studies
which use different histological classifications, and made it more difficult to identify appropriate patients to enter into clinical intervention trials, as well as making it harder to choose
appropriate therapy in individual patients. The International IgA Nephropathy Network
[www.igan-world.org], working with members of the Renal Pathology Society, has established an international working group which is developing a consensus classification.
Agreement has been reached on definitions of pathological features, and the consistency of
scoring these features has been tested by pathologists around the world. Pathological features
are now being scored in biopsies from large cohorts of patients from many parts of the world
in whom sequential clinical information is available. From the integrated analysis of these
clinical and pathological features, a clinico-pathological classification will be proposed
which will be further refined and tested in additional cohorts of patients. The goal is to establish a reproducible and clinically effective classification which will gain worldwide acceptance for use in clinical practice and research.
Copyright © 2007 S. Karger AG, Basel

Introduction

There is no international consensus for the pathological or clinical classification of IgA nephropathy (IgAN). Nephrologists use clinical information to
identify the risk of developing progressive chronic kidney disease (CKD) in

individual patients with IgAN. Pathologists have developed a number of classifications over the last 25 years, some semiquantitative [1–3], some single-grade
[4, 5]; each has strengths and limitations in predicting prognosis, and none has
gained pre-eminence. This lack of consensus has a number of disadvantages. It
has contributed to the slow progress in developing prognostic systems with the
sensitivity and specificity to predict outcome for individual patients. It limits
opportunities to make international comparisons between different outcome
studies which use different histological classifications. It has also limited
opportunities to refine the stratification of risk for the design of clinical intervention trials.
In 2004, a proposal to develop a consensus classification was developed by
the International IgA Nephropathy Network – an informal network of nephrologists and scientists with representation from the majority of nephrology research
groups around the world active in the field of IgAN [www.igan-world.org] –
working with members of the Renal Pathology Society interested in IgAN. A
questionnaire among renal pathologists showed support for the development of a
consensus classification of IgAN provided it could be demonstrated to have real
clinical benefit. Therefore, representatives of IIgANN and RPS together developed a programme of work leading to a consensus classification.
From the beginning this was designed as an international consensus aiming to involve nephrologists and pathologists from as many parts of the world as
possible, including all areas where IgAN is known to be of high prevalence.

Goals and Strategy

Our goal is to develop a new clinico-pathological classification for IgAN.
The purpose of this new consensus classification would be to identify the risk
of progression of renal disease in IgAN, thus enabling clinicians and researchers
to improve individual patient prognostication, identify potential for response to
immunosuppression or other specific treatments, and refine recruitment to clinical trials. It is necessary to approach this work without preconceptions, in order
to test the predictive power of a wide range of pathological and clinical features.
The consensus work has also required unity of purpose and a collaborative
approach. Organisational challenges have included the need to develop tools
allowing consistent data collection, and the need to meet the varying requirements of institutional review boards and ethics committees so that anonymised
pathological material and clinical data can be circulated within and beyond its
country of origin.
In more detail the goals are: (1) to agree a consensus classification of
histopathology of IgA nephropathy; (2) to test reproducibility of this classification

Feehally/Barratt/Coppo/Cook/Roberts

14

Agree pathological definitions

Data collection

Agree pathological scoring process

Data analysis to identify
elements with
prognostic predictive power

Agree clinical dataset
Select patient cohorts
Agree data collection process
and data verification

Refine and agree a
clinico-pathological classification

Publish
Achieve international usage

Test on further
patient cohorts

Fig. 1. Overall strategy for development of the IgA nephropathy consensus classification.

among pathologists; (3) to agree a clinical dataset useful for outcome studies in
IgA nephropathy; (4) to evaluate the value of pathology parameters combined
with clinical parameters in outcome studies in large cohorts of patients with IgA
nephropathy, including cohorts varying in age, and in geographical and racial
origin; (5) to develop from this work a validated clinico-pathological classification that discriminates patients with IgA nephropathy into groups identifiable
from their presenting clinical and laboratory data; and which predicts different
outcome out to at least 5 years as estimated by renal survival or by rate of deterioration in renal function, and (6) to promote the use of the new classification
once published as the convention to be used in future clinico-pathological outcome reports of IgA nephropathy, as well as in routine clinical practice.
The overall strategy for the project is shown in figure 1.

Summary of Achievements up to October 2006

A group of nephrologists and pathologists have committed themselves to
achieving these goals, and have met on several occasions: A first meeting of
interested nephrologists and pathologists was held in St Louis USA in October
2004; a draft plan was published for web-based consultation in July 2005; a
consensus meeting was held in Oxford, UK in September 2005, and pathologists involved in the project met in San Antonio, USA in February 2006.
These meetings were attended by 15 nephrologists and 18 pathologists,
from 10 countries on 4 continents.

Clinico-Pathological Classification of IgAN

15

Progress so far includes the following areas listed below.
Pathological Definitions and Scoring
The consensus group agreed on the pathological features on light
microscopy which need to be evaluated, and definitions for each of those features. The inter-observer reproducibility in identifying those features was then
tested by circulating biopsies of 40 patients with IgAN among a worldwide
group of 16 pathologists. Inconsistencies were debated at a further meeting,
leading to agreement on a scoring system to be applied in subsequent analyses.
Clinical Dataset
The consensus group agreed on a clinical dataset sufficient to make useful
correlations with pathological parameters. This included demographic data, and
clinical and laboratory features at the time of diagnostic renal biopsy and annually thereafter. It was recognised that an ideal dataset was not always available
from clinical records (e.g., smoking history is inconsistently recorded), but a
minimum dataset was defined, including measurements of blood pressure, proteinuria and excretory renal function.
Selection of Patient Cohorts for Testing
300 patients with available clinical datasets, available biopsies for review
and a minimum of 5 years follow-up from time of biopsy are being selected for
the next analysis which will lead to an initial proposal for a classification. The
300 cases comprise 250 adults and 50 children, and are being identified from
centres across the world whose staff are involved in the consensus group and
from others who have indicated their support. Centres are asked to contribute
between 10 and 50 cases. It is necessary to ensure that selected cases include
some in whom there is significant deterioration in GFR over 5 years to maximise the opportunity to identify discriminatory clinical or pathological features. Patients who have received a range of treatments are included. So far 15
centres (3 paediatric centres and 12 adult centres) from 9 countries in 4 continents have contributed cases (table 1).
Biopsies from these cases are being circulated among pathologists for
scoring, after ensuring that the various requirements of institutional review
boards and ethics committees have been met, to allow circulation of pathological material and clinical data within and beyond the country of origin.
Data Analysis, Definition and Testing of a Proposed Classification
The anonymised clinical and laboratory data are being collected centrally
with the biopsy scores. From the analysis of these data will emerge a proposed

Feehally/Barratt/Coppo/Cook/Roberts

16

Table 1. Centres providing cases for the first phase of
IgAN consensus classification 2006/07
Asia
PR China

Japan
Europe
France
Italy

United Kingdom
North America
Canada
United States

South America
Chile

Beijing
Hong Kong
Nanjing
Tokyo
St Etienne
Bari
Milano
Roma
Torino
Glasgow
Toronto
Birmingham
Mayo Clinic
South West Study Group
Santiago

classification of IgAN which will then be tested and re-tested in further cohorts
of patients until its consistency and clinical utility have been determined as far
as is possible with retrospective analysis. If necessary, additional centres will be
involved in the study, and it is hoped that the truly international dimension and
careful design of this project will encourage other centres to be involved. It
will be important to avoid premature publication of the proposed new classification, which will be tested and validated thoroughly before dissemination of
the proposal.

Conclusion

The eventual success of this project will depend on the validity and clinical
utility of the classification, and also the confidence with which it is received
within the worldwide IgAN community. By our inclusive approach and systematic
planning, we hope that we have given it the best chance of success.

Clinico-Pathological Classification of IgAN

17

References
1

2
3
4
5

Alamartine E, Sabatier JC, Berthoux FC, et al: Comparison of pathological lesions on repeated
renal biopsies in 73 patients with primary IgA glomerulonephritis: value of quantitative scoring
and approach to final prognosis. Clin Nephrol 1990;34:45–51.
Radford MG, Donadio JV, Bergstralh EJ, Grande JP: Predicting renal outcome in IgA nephropathy.
J Am Soc Nephrol 1997;8:199–207.
Katafuchi R, Kiyposhi Y, Oh Y, et al: Glomerular score as a prognosticator in IgA nephropathy: its
usefulness and limitation. Clin Nephrol 1998;49:1–8.
Lee SM, Rao VM, Franklin WA, et al: IgA nephropathy: morphologic predictors of progressive
renal disease. Hum Pathol 1982;13:314–332.
Haas M: Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases.
Am J Kidney Dis 1997;29:829–842.

Prof. John Feehally
The John Walls Renal Unit, Leicester General Hospital
Gwendolen Road
Leicester LE5 4PW (UK)
Tel. ⫹44 1162 58 4132, Fax ⫹44 1162 58 4764, E-Mail jf27@le.ac.uk

Feehally/Barratt/Coppo/Cook/Roberts

18

Tomino Y (ed): IgA Nephropathy Today.
Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 19–26

IgA Nephropathy: A Clinical Overview
Bruce A. Juliana, Robert J. Wyattb, Karel Matousovicc,
Zina Moldoveanua, Jiri Mesteckya, Jan Novaka
a
University of Alabama at Birmingham, Birmingham, Ala., bUniversity of Tennessee
Health Sciences Center, Memphis, Tenn., USA; cCharles University School of
Medicine and Faculty Hospital, Prague and Pilsen, Czech Republic

Abstract
Our understanding of the clinical aspects of IgA nephropathy (IgAN) has advanced
since the 10th International Symposium on IgA Nephropathy in 2004. In this review we discuss new developments in areas of familial IgAN, the emerging field of biomarkers, and
prognostic features. Familial disease continues to account for a significant number of newly
diagnosed patients with IgAN. These patients have clinical manifestations and long-term outcomes similar to those of patients with sporadic disease. Characterization of the IgAN1 gene
linked to IgAN in some Italian and American multiplex families has remained elusive. Other
multiplex IgAN pedigrees have shown no linkage to any locus. With advances in technology
to better measure and characterize polypeptides in small concentrations, the area of biomarkers has generated substantial interest since 2004. New potential disease-specific biomarkers of
IgAN include the IgA1 neoepitope at the threonine228 and/or serine230 IgA1 hinge-region
residues, serum levels of galactose-deficient IgA, and urinary IgA-IgG immune complexes.
Other investigators have used proteomic approaches to find panels of urinary polypeptides
(many of which have not been sequenced) that discriminate patients with IgAN from normal
healthy controls as well as patients with various other proteinuric renal diseases. These or
other related findings may provide the necessary tools to better classify phenotypes in multiplex pedigrees and to improve monitoring of disease progression or response to therapy.
Copyright © 2007 S. Karger AG, Basel

Since the 10th International Symposium on IgA Nephropathy in March
2004 in St. Etienne, France, investigators continue to unravel the clinical complexities of IgAN. Here, we review recent advances in the areas of genetics and
familial IgAN, the emerging field of proteomic biomarkers, and prognostic
markers. Papers elsewhere in this volume address treatment of patients with
IgAN.

The proportion of native-kidney biopsies with IgAN in the USA has
recently been shown to be higher than that published 10–20 years ago. In an
Arkansas referral center, IgAN was diagnosed in 6.9% of the 4,504 biopsy specimens processed from March 2001 to February 2005 from patients older than
20 years [1]. In young adults aged 20–39 years, IgAN was the most common
glomerulonephritis, accounting for 14.2% of the 1,082 biopsy specimens.

Genetics and Familial IgAN

As many as 10–15% of newly diagnosed patients with IgAN have a family
history of renal disease. Families with multiple members with IgAN have been
discovered worldwide, but the precise location and function of a gene linked to
IgAN remain elusive. The IgAN1 gene at chromosome 6q22–23 linked to IgAN
in Italian and American pedigrees has not been characterized. Other multiplex
families have failed to show linkage to any locus. Individuals in some multiplex
families have non-IgAN renal disease, including immune-complex glomerulonephritis [2] or thin glomerular basement membrane glomerulopathy [3],
whereas renal disease in other families is restricted to IgAN and HenochSchoenlein purpura nephritis [4]. A recent study from Italy found that the longterm outcome is similar in patients with familial and sporadic IgAN [5]. Pursuit
of a gene that accounts for familial IgAN has been hampered by the lack of a
non-invasive diagnostic marker of disease. Thus, individuals with subclinical
renal disease may be misclassified as unaffected, confounding the analysis of
the segregation of renal disease with genetic markers.

Biomarkers for IgAN

Advances in the last few years in the methodology for precise analysis of
the composition of polypeptides have renewed interest in the field of biomarkers. Biomarkers may be any of several biological characteristics that can be
objectively measured and evaluated as indicators of normal biological
processes, pathogenic processes or pharmacologic response to therapy [6].
Candidates for biomarkers include metabolites, mRNA profiles, lipids, proteins, and polypeptide fragments. The best candidates would be measured with
accurate and easy-to-perform assays that can be performed quickly and serially.
Biomarkers should be in an easily sampled medium; urine would likely provide
the best source for patients with renal disease. For patients with IgAN, ideal
biomarkers would obviate the need for a requisite invasive kidney biopsy for

Julian/Wyatt/Matousovic/Moldoveanu/Mestecky/Novak

20

diagnosis, elucidate pathogenetic mechanisms, forecast clinical course, and
monitor response to treatment.
A fundamental biochemical abnormality with immunological consequences in patients with IgAN is the increased amount of circulating IgA1 with
galactose-deficient hinge-region O-linked glycans [7]. The serum level of this
aberrantly glycosylated IgA1 can be measured by its selective binding to Helix
aspersa (HAA) lectin that is specific for N-acetylgalactosamine. In a group
of 153 Caucasian patients with IgAN, we found that 76% had a serum HAAbinding IgA level above the 90th percentile value for the 150 Caucasian
controls (Moldoveanu Z et al., Kidney Int, in press). High levels were detected
in patients with familial and sporadic IgAN. About 30% of 133 firstdegree relatives had high levels, possibly indicating a genetically determined
predisposition.
Another potential serum biomarker for IgAN derives from the galactosedeficient IgA1 hinge-region glycans. Using mass spectrometry and Western
blots, we have narrowed the span in the hinge-region that apparently serves as
the antigenic epitope in the nephritogenic circulating immune complexes. After
digestion of the IgA1 heavy chain from an IgAN patient by site-specific IgA
proteases, a Western blot developed with HAA showed that the threonine228
and/or the serine230 were the amino acid residues with attached galactosedeficient glycans [8; also Novak J et al., this volume].
Urine also contains biomarkers for IgAN. Much of the growing interest in
this field has centered on proteomics. Proteomics is the assessment of proteins
and peptides within a particular compartment, a proteome, using a wide range
of analytical methods. The technology has evolved to include two-dimensional
gel electrophoresis and other electrophoretic methods, protein arrays, chromatography, and mass spectrometry (fig. 1). Urine is a better fluid than serum
for proteomic analysis because it is less complex. In serum, concentrations of
various proteins span 10 orders of magnitude, the predominance of a few proteins obscures less abundant peptides, and some potential biomarkers escape
detection due to their binding to albumin. Furthermore, the urinary proteome is
more stable. Polypeptides do not degrade in urinary samples stored up to six
hours at room temperature or for several months at –20⬚C.
Proteomics has uncovered urinary biomarkers for several renal diseases,
including IgAN. Using a cross-capture ELISA and factoring for creatinine concentration, we found that patients with IgAN excreted more IgA-IgG-containing
immune complexes than did disease controls with non-IgA nephropathies with
comparable or greater proteinuria [9]. Using capture ELISA and immune complex-specific ELISA, the amounts of urinary IgA and IgA-containing immune
complexes were significantly higher in patients with IgAN than in patients with
primary non-IgAN glomerulonephritis or healthy controls (Novak J. et al.,

IgA Nephropathy: A Clinical Overview

21

Sample collection
and preparation

Sample separation
(electrophoresis, liquid chromatography,
chips and microfluidics)

Verification in an independent
cohort of patients and controls

Sample analysis
(mass spectrometry,
image analysis)

Identification of biomarkers
for diagnosis of IgAN

Data processing
and database searches

Fig. 1. Scheme of proteomic approaches to identification of polypeptide biomarkers
for diagnosis of IgAN. Samples (blood, urine, or tissue) from patients with IgAN, healthy
controls, and disease controls are collected and processed. Separation by electrophoretic
methods (1- or 2-dimensional gel electrophoresis, capillary electrophoresis), liquid chromatography, or chip-based techniques is followed by analytical techniques (image analysis or
mass spectrometry) to characterize and quantify differentially present polypeptides.
Additional characterization of these polypeptides may include peptide mass fingerprinting
and/or sequencing by tandem mass spectrometry and characterization of post-translational
modifications. Data analysis by bioinformatic approaches and database searches will assist
in the identification of potential biomarkers. Candidate biomarkers must be validated in an
independent cohort of patients.

poster at this conference). Furthermore, these urine samples were analyzed by
SDS-PAGE and Western blot with IgA- and IgG-specific antibodies. Sample
loading was normalized to urinary creatinine concentration. Protein profiles of
IgAN samples showed high concentrations of the IgA heavy chain and its proteolytic fragments. In contrast, samples from controls without nephritis had
profiles similar to those of healthy controls showing modest IgA and no proteolytic fragments.

Julian/Wyatt/Matousovic/Moldoveanu/Mestecky/Novak

22

In a study using the classic method of two-dimensional electrophoresis
with subsequent isolation of proteins from the gel for analysis by mass spectrometry, Park et al. [10] found 84 protein spots that were differentially expressed
in the pooled urine sample from 13 patients with IgAN compared to that from
12 normal controls. Of these protein spots, 42 were over-expressed in the IgAN
patients and 42 were under-expressed. By mass spectrometry sequencing, the
over-expressed protein spots were found to be derivatives of 27 different proteins. The over-expressed proteins included intracellular or cytoplasmic proteins, nuclear-associated proteins, membrane-associated proteins, and secreted
or plasma proteins. Unfortunately, this technology is time-consuming and small
proteins (below 10 kDa) may escape detection. Another method, surface-enhanced
laser desorption and ionization (SELDI) mass spectrometry, is fast but has low
resolution, and many proteins are lost in the process due to the matrices selecting particular polypeptides.
Some investigators have turned to capillary electrophoresis coupled on-line
to mass spectrometry because it is faster, has high resolution, and can identify up
to 600 polypeptides in a urine sample. Haubitz et al. [11] evaluated 45 patients
with IgAN, 13 patients with membranous glomerulopathy, and 57 healthy controls. They described 22 urinary polypeptides that discriminated patients with
IgAN from normal controls, 12 of which were over-expressed in the patients.
Frequencies of the discriminating polypeptides did not differ by magnitude of
proteinuria, gender, age, or serum creatinine concentration. Even patients with
IgAN in clinical remission without pathological proteinuria were distinguished
from healthy controls. After grouping patients by the number of antihypertensive
medications, the polypeptide pattern trended toward normal with more intensive
therapy, independent of age or magnitude of proteinuria. Comparison of the
marker peptides of patients with IgAN to those of patients with membranous
glomerulopathy showed a sensitivity of 77% and specificity of 100%. The
authors also compared their biomarkers to previously identified markers for
other renal diseases compiled in a database. Patients with IgAN were discriminated from patients with focal segmental glomerulosclerosis, minimal-change
disease or diabetic nephropathy with a sensitivity of 100% and a specificity of
100%. Sequencing of three of the polypeptides that discriminated between
patients IgAN from healthy controls by mass spectrometry identified three different fragments of serum albumin. The basis by which these fragments were
restricted to IgAN remains unknown. Perhaps the polypeptides were generated
by unique protease activity in inflamed glomeruli. In view of these preliminary
studies, disease-specific biomarkers are more likely to be comprised of a panel
of several distinct and well-defined peptides than a single molecule. In any
event, with proteomics the search for disease-specific biomarkers is not hindered
by antecedent bias arising from hypothesized mechanisms of disease.

IgA Nephropathy: A Clinical Overview

23

Table 1. Recently reported genetic polymorphisms
that have been associated with development or progression
of IgA nephropathy
Polymorphism

Ethnicity

Development of IgAN
Megsin A23167G
Interleukin-10 promoter

Chinese (14)
Korean (15)

Progression of IgAN
Megsin A23167G
MUC20, a novel mucin protein
CC-chemokine receptor 5
Monocyte chemoattractant protein-1
Fc␥RIIa
Fc␥RIIIa

Chinese (14)
Chinese (16)
French (17)
Japanese (18)
Japanese (19)
Japanese (19)

Loss of renal allograft
HLA-B8DR3 haplotype

European (20)

Prognosis and Monitoring Progressive Disease in IgAN

In the absence of a validated biomarker to predict prognosis and monitor
response to treatment, investigators continue to use the well-known clinical
measures to assess the activity of IgAN. There has been a general consensus
that hypertension and increasing magnitude of proteinuria, and the pathological
findings of glomerular crescents or sclerosis, tubular atrophy and interstitial
fibrosis portend a less favorable long-term outcome. Proteinuria is the focus of
great attention because it is amenable to therapy. Whether the benefits of twodrug suppression of the effects of angiotensin (with angiotensin-convertingenzyme inhibitors and angiotensin-receptor-type-1 blockers) for preservation of
renal function can be monitored by serially measuring proteinuria has not yet
been clarified.
In the last few years, other features have been proposed as prognostic
markers. An increased serum uric acid level appears to be an independent risk
factor for progressive disease [12]. Other investigators have found that patients
with IgAN and thin glomerular basement membranes have a better outcome
than patients with membranes of normal thickness [13]. In addition, the prognosis of IgAN is undoubtedly impacted by genetically determined variations of
factors that likely influence the inflammatory and scarring consequences of an
immune-complex-mediated glomerular injury. Since 2004, polymorphisms of

Julian/Wyatt/Matousovic/Moldoveanu/Mestecky/Novak

24

several such factors have been associated with development of IgAN or progressive renal injury (table 1; [14–20]).

Acknowledgments
Supported in part by a grant from the National Institutes of Health, PO1 DK61525, by
the General Clinical Research Centers of the University of Alabama at Birmingham M01
RR00032 and the University of Tennessee Health Sciences Center, M01 RR00211 (USA),
and by a grant from the Research Project MSM 0021620819 (Czech Republic).

References
1
2
3
4
5
6
7
8

9
10
11
12
13

14

15

16

Nair R, Walker PD: Is IgA nephropathy the commonest primary glomerulopathy among young
adults in the USA? Kidney Int 2006;69:1455–1458.
Izzi C, Sanna-Cherchi S, Prati E, et al: Familial aggregation of primary glomerulonephritis in an
Italian population isolate: Valtrompia study. Kidney Int 2006;69:1033–1040.
Frasca GM, Soverini L, Gharavi AG, et al: Thin basement membrane disease in patients with
familial IgA nephropathy. J Nephrol 2004;17:778–785.
Julian BA, Quiggins PA, Thompson JS, et al: Familial IgA nephropathy: evidence for an inherited
mechanism of disease. N Engl J Med 1985;312:202–208.
Izzi C, Ravani P, Torres D, et al: IgA nephropathy: the presence of familial disease does not confer
an increased risk for progression. Am J Kidney Dis 2006;47:761–769.
Hewitt SM, Dear J, Star RA: Discovery of protein biomarkers for renal diseases. J Am Soc
Nephrol 2004;15:1677–1689.
Tomana M, Matousovic K, Julian BA, et al: Galactose-deficient IgAl in sera of IgA nephropathy
patients is present in complexes with IgG. Kidney Int 1997;52:509–516.
Novak J, Moldoveanu Z, Renfrow MB, et al: Analysis of aberrant O-glycosylation of IgA1 in
patients with IgA nephropathy (IgAN). American Society of Nephrology, 39th Renal Week
Annual Meeting, San Diego, CA, November 14–19, 2006.
Matousovic K, Novak J, Yanagihara T, et al: IgA1-containing immune complexes in the urine of
IgA nephropathy patients. Nephrol Dial Transplant 2006;21:2478–2484.
Park M-R, Wang E-H, Jin D-C, et al: Establishment of a 2-D human urinary proteomic map in IgA
nephropathy. Proteomics 2006;6:1066–1076.
Haubitz M, Wittke S, Weissinger EM, et al: Urine protein patterns can serve as diagnostic tools in
patients with IgA nephropathy. Kidney Int 2005;67:2313–2320.
Myllymaki J, Honkanen T, Syrjanen J, et al: Uric acid correlates with the severity of histopathological parameters in IgA nephropathy. Nephrol Dial Transplant 2005;20:89–95.
Linossier M-T, Palle S, Berthoux F: Different glycosylation profile of serum IgA1 in IgA
nephropathy according to the glomerular basement membrane thickness: normal versus thin. Am
J Kidney Dis 2003;41:558.
Xia YF, Huang S, Li X, et al: A family-based association study of megsin A23167G polymorphism
with susceptibility and progression of IgA nephropathy in a Chinese population. Clin Nephrol
2006;65:153–159.
Chin HJ, Na KY, Kim SJ, et al: Interleukin-10 promoter polymorphism is associated with the predisposition to the development of IgA nephropathy and focal segmental glomerulosclerosis in
Korea. J Korean Med Sci 2005;20:989–993.
Li G, Zhang H, Lv J, et al: Tandem repeats polymorphism of MUC20 is an independent factor for
the progression of immunoglobulin A nephropathy. Am J Nephrol 2006;26:43–49.

IgA Nephropathy: A Clinical Overview

25

17

18

19
20

Berthoux FC, Berthoux P, Mariat C, et al: CC-chemokine receptor five gene polymorphism in primary IgA nephropathy: the 32 bp deletion allele is associated with late progression to end-stage
renal failure with dialysis. Kidney Int 2006;69:565–572.
Mori H, Kaneko Y, Narita I, et al: Monocyte chemoattractant protein-1 A-2518G gene polymorphism and renal survival of Japanese patients with immunoglobulin A nephropathy. Clin Exp
Nephrol 2005;9:297–303.
Tanaka Y, Suzuki Y, Tsuge T, et al: Fc␥RIIa-131R allele and Fc␥RIIIa-176V/V genotype are risk
factors for progression of IgA nephropathy. Nephrol Dial Transplant 2005;20:2439–2445.
Andresdottir MB, Haasnoot G, Persijn GG, et al: HLA-B8DR3: a novel risk factor for graft failure
after renal transplantation in patients with underlying IgA nephropathy. Transplantation 2006;
82(suppl 2):646–647.

Bruce A. Julian, MD
University of Alabama at Birmingham, Division of Nephrology
Department of Medicine, 1530 Third Avenue South, THT 643
Birmingham, AL 35294 (USA)
Tel. ⫹1 205 934 9045, Fax ⫹1 205 934 7742, E-Mail bjulian@uab.edu

Julian/Wyatt/Matousovic/Moldoveanu/Mestecky/Novak

26

Tomino Y (ed): IgA Nephropathy Today.
Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 27–36

Angiotensin Antagonists and Fish Oil
for Treating IgA Nephropathy
R. Coppo, A. Amore, L. Peruzzi, D. Mancuso, R. Camilla
Pediatric Nephrology School, Nephrology, Dialysis and Transplantation Department,
Regina Margherita University Hospital, Turin, Italy

Abstract
In IgA nephropathy (IgAN), ACE inhibitors (ACE-I) and angiotensin receptor blockers (ARB) are beneficial against hypertension, and their anti-proteinuric effect has been
clearly demonstrated. However, sub-analyses of IgAN patients enrolled in large studies
failed to prove a benefit against progression to renal failure. The European Community
Biomed Concerted Action – a placebo-controlled randomized controlled trial begun in 1995 –
in children and adults (9–35 years old) with proteinuria ⬎ 1 ⬍ 3.5 g/day/1.73 m2 and normal or moderately reduced renal function proved the significant benefit of ACE-I on progression of kidney disease. The combination of ACE-I and ARB in proteinuric
normotensive IgAN patients showed greater antiproteinuric effect and the COOPERATE
trial also reported a superior effect of combination therapy in protecting against renal function deterioration. Treating IgAN with fish oil has a good rationale for renal inflammation
as well as for prevention of cardiovascular morbidity. However, the published reports gave
conflicting conclusions and also very recent data did not show significant benefits. In conclusion, ACE-I and ARB have a definite role in treating IgAN, particularly the hypertensive
and proteinuric forms. These patients should be treated to target BP to ⬍130/70 mm Hg and
proteinuria ⬍0.5 g/day.
Copyright © 2007 S. Karger AG, Basel

It is well known that the effects of angiotensin II go beyond the regulation
of renal hemodynamics and glomerular permselectivity [1]. Angiotensin II can
modulate the immune system, triggering pro-fibrogenic cytokines (TGF-␤),
stimulating fibroblast proliferation, acting as a growth factor and leading to cell
hypertrophy and proliferation, inducing cytokines (IL-6, IL-8, RANTES,
MCP-1), generating ROS, activating the transcription factor NF-␬B, upregulating
TLR-4 on mesangial cells, and downregulating nephrin and podocin on
podocytes [1]. All these activities, summarized in figure 1, lead to inflammation,

MCP1
RANTES
IL-8

Angiotensin
II
Proteinuria

LM infiltration
and activation

↑ Cytokine
production

↑ TGF-β and
ECM
↑ Glomerular
hyperfiltration

Endothelial and
mesangial cell
exposure to shear
stress/stretch

↑ PAI-1

↑ Aldosterone

ROS
↓ ECM
degradation

ECM accumulation
Inflammation

Injury to glomerular cells

Glomerular and
tubulointerstitial fibrosis

Fig. 1. Activities of angiotensin II.

injury of glomerular cells and matrix accumulation. To sum up, the reninangiotensin system (RAS) plays a pivotal role in the progression of renal diseases, promoting both intraglomerular and systemic hypertension, and acting
on angiotensin receptors of mesangial and tubular cells triggering progression
of interstitial fibrosis. On the other hand, IgA deposits may activate mesangial
cells, leading to production of biological effects which contribute to amplification of the angiotensin II-induced damage, suggesting a unique role for RAS in
IgA nephropathy (IgAN). Among the intracellular signaling activated by both
angiotensin II and deposited IgA, NF-␬B has been supposed to play a major
role in IgAN, as it was detected in renal biopsies from these patients, particularly in those with active lesions [2]. NF-␬B was demonstrated to be activated
and translocated into the nucleus of mesangial cells upon incubation with
aggregated IgA or IgA immune complexes. We previously demonstrated that
aberrantly glycosylated IgA, which are thought to play a pathogenetic role in
IgAN, when incubated with cultured mesangial cells, trigger the nuclear
translocation of the two NF-␬B active subunits p65 and p50 [3] and the coincubation of angiotensin-converting-enzyme inhibitors (ACE-I) or angiotensinreceptor-1 blockers (ARB) significantly blunts the activation of this transcription
factor in a dose-dependent manner.

Coppo/Amore/Peruzzi/Mancuso/Camilla

28

Hence there is a theoretical disease-specific benefit in IgAN for angiotensin II antagonism, since it is aimed to normalize altered mesangial cell
responses enhanced by aberrantly glycosylated IgA. We previously demonstrated that in IgAN, particularly in proteinuric cases, there is a local RAS
hyperreactivity [4], and precocious activation of the RAS was also reported.
There is a general consensus that high urinary protein excretion is one of
the most relevant risk factors for progression of IgAN [5]. Proteinuria mostly
precedes the development of other clinical risk factors such as hypertension and
reduced renal function, which tend to be more related to irreversible sclerotic
changes. Persistent nephrotic-range proteinuria in IgAN – as well as in other
nephropathies – has been found to be associated with very poor outcome [6],
but also moderate proteinuria has been recognized as a risk factor for progression of IgAN [7]. Proteinuria may activate tubular cells and trigger a local
activation of the RAS system and the NF-␬B nuclear translocation with consequent release of a large series of mediators inducing lymphomonocyte interstitial infiltration, and release of mediators which lead to interstitial fibrosis
[reviewed in 1].
Finally, hypertension is one of the major risk factors for progression of
IgAN [5], as recognized by several investigators, who recently stressed that
even border-line high values of BP may be harmful, particularly when proteinuria is associated.
For all the above reviewed mechanisms of renal damage related to angiotensin activation and concomitant IgA mesangial deposition, angiotensin II
antagonists have a specific strong theoretical indication for IgAN, particularly
the hypertensive and proteinuric forms.
Table 1 reports a synopsis of the most relevant clinical studies which used
angiotensin antagonism (mostly ACE-I) in hypertensive IgAN and the different
blood pressure (BP) targets.
Most of the retrospective study reported ACE-I superior effects in comparison to other antihypertensive drugs in limiting the glomerular filtration rate
(GFR) loss and the amount of proteinuria [8]. Most recent prospective studies
detected a stabilization of GFR only in intensive treatment groups, when BP
was reduced to ⬍130/70 mm Hg often with a multidrug combination, while
patients who had BP ⬎135/75 mm Hg failed to be protected against functional
decline [9].
The antiproteinuric effect was reported in early short-term investigations
and confirmed in long-term studies (table 2); however, the effect was not reproduced in each patient and did not lead to complete remission of proteinuria, as
only 40% of the cases showed a reduction of urinary protein excretion by more
than 50%. It was therefore logical to wonder whether this partial effect was
enough for a relevant reno-protection. Ruggenenti [10] made a sub-analysis of

Angiotensin Antagonists and Fish Oil for Treating IgAN

29

Table 1. Angiotensin antagonism in patients with hypertensive IgAN
Author (year)

Target BP

Regimen-FU

Efficacy of ACE-I

Cattran (1994)
retrospective

⬍140/90

ACE-I vs. other
treatments 30
months FU

Significant
reduction of GFR
loss and proteinuria

Rekola (1991)
retrospective

⬍140/90

ACE-I or ␤-blockers
3 years FU

Significant
reduction of GFR loss

ACE-I or CCB
1 year FU

No effect on GFR
loss, some
reduction in
proteinuria

ACE-I plus CCB
3 years FU

Stabilization of
GFR only in
intensive
treatment group
(BP ⬍ 130/70),
while BP
⬎ 135/75 had
GFR decline

Bannister (1995)
prospective

Kanno (2000)
Non randomized

Different BP
targets

ACE-I ⫽ Angiotensin converting enzyme inhibitors; CCB ⫽ calcium channel blockers;
BP ⫽ blood pressure; FU ⫽ follow-up.

Table 2. Angiotensin antagonism in patients with proteinuric IgAN
Author (year)

uP

Regimen-FU

Efficacy of ACE-I

Maschio (1994)

1–2.5 g

Fosinopril vs. Placebo
12 months FU

Mild significant reduction
in proteinuria

Perico (1998)

0.5–4 g

ACE-I or ARB
1 month FU

Significant reduction of
proteinuria in both arms

Russo (1994)

1–3 g

ACE-I 1 or x2
ARB 1 or x2
or ACE-I plus ARB

Significant reduction in
proteinuria, even more in
combination group

Song (2003)

⬎1 g/day

ACE-I plus ARB
33 weeks FU

Significant mild reduction
in proteinuria no BP effect

Park (2003)

2–2.3 g

ARB or CCB 12 weeks

ARB reduced proteinuria

ACE-I ⫽ Angiotensin converting enzyme inhibitors; ARB ⫽ angiotensin I receptor
blockers; uP ⫽ urinary protein (g/day); FU ⫽ follow-up.

Coppo/Amore/Peruzzi/Mancuso/Camilla

30

the response to ACE-I in 352 proteinuric nephropathies enrolled in the REIN
prospective, double-blind, placebo-controlled trial. In a subgroup of 75 IgAN
patients with 3 ⫾ 2 g/day proteinuria (always ⬎1 g/day), ACE-I had some protective effect, as it saved a loss of 2.3 ml/min/year in comparison to the untreated
patients. The effect was not statistically significant, possibly due to the small
sample size.
In 2001, Dillon [11] performed a meta-analysis of 237 IgAN patients
enrolled in 3 short-term crossover trials (3 months), 1 randomized and controlled trial (1 year) and 3 retrospective controlled trials (2 years), and reported
that the effect on proteinuria was clearly seen, while, due to defects in the original design, no definitive conclusion could be drawn about the nephro-protective effect. His conclusions were that ‘we do not know which treatment is the
most effective’.
In 2003, the first randomized controlled trial (RCT) of ACE-I in IgAN was
published by Praga et al. [12], but it was not placebo-controlled, and enrolled a
limited number of patients (44 subjects) from only one center with a wide range
of proteinuria (from 0.5 to 5 g/day) and various degrees of renal function
impairment, hence with likely variable prognosis. After a mean follow-up of
75 months, the proportion of patients developing the primary endpoint (50%
increase of baseline plasma creatinine) was significantly lower in the treated
group than in the control group (12 vs. 57%, respectively).
In 1995 we designed a double-blind placebo RCT, supported by the European
Community Concerted Action of Biomedicine and Health (Biomed) [13]. At that
time there was a definite expectation for a trial on ACE-I in IgAN, since the effect
of ACE-I on progression of chronic nephropathies had just been proved, but not yet
for IgAN. This was the first multicenter, double-blind, placebo-controlled RCT,
investigating, in a selected cohort of IgAN, the effects of ACE-I on renal function
decline and proteinuria. The trial strictly selected young patients (3–35 years old)
of a very constant level of moderate proteinuria (between 1 and 3.5 g/day/1.73 m2
over the 3 months before enrolment) and normal or moderately reduced renal function (creatinine clearance (CrCl) ⬎ 50 ml/min/1.73 m2).
Fifty-seven patients, average age 19.9 years (range 9–35 years), randomized to receive Benazepril 0.2 mg/kg/day (ACE-I) or placebo (PL), completed
the trial (median follow-up 42 months). The primary outcome was progression
of kidney disease, defined as ⬎30% decrease of baseline CrCl and/or worsening of proteinuria until ⱖ3.5 g/day/1.73 m2. Secondary outcome was proteinuria
partial (⬍0.5 g/day/1.73 m2) or total remission (⬍160 mg/day/1.73 m2) for
⬎6 months. The survival to the events was evaluated by univariate (KaplanMeier, log-rank test) and Cox multivariate analysis.
Of the 57 subjects who had a follow-up, one single patient (4.3%) in the ACE-I
group and 5 (14.7%) in the PL group showed a worsening of CrCl ⬎30%.

Angiotensin Antagonists and Fish Oil for Treating IgAN

31

No patient on ACE-I developed nephrotic syndrome, versus 7 (20.6%) on PL.
The primary outcome of renal disease progression resulted significantly different between the two groups (log-rank P ⫽ 0.035). Mean levels of proteinuria
were significantly reduced, as expected, and a stable partial remission of proteinuria was observed in 13/23 (56.5%) ACE-I patients versus 3/34 (8.8%) PL
patients (log-rank P ⫽ 0.033), with total remission in 17.4% of ACE-I treated
patients and in none of PL (log-rank P ⫽ 0.029). The multivariate Cox analysis
showed that treatment with ACE-I was the independent predictor of prognosis,
while no influence on the progression of renal damage was found for gender,
age, baseline CrCl, systolic or diastolic blood pressure, mean arterial pressure,
or proteinuria [13].
In conclusion, angiotensin antagonism is successful in limiting progression of renal damage in young IgAN patients with proteinuria between 1 and
3.5 g/day. A new trial is ongoing in collaboration with Pozzi et al. [14], to test
whether the angiotensin inhibition by both ACE-I and ARB may decrease the
risk of progression in patients with IgAN so far considered benign (proteinuria
⬍ 0.5 g/day). Such inhibition will be at first achieved with a unique pharmacological class (ACEI or ARB), then shifting to the association of the two classes
as soon as the inhibition with one drug becomes ineffective.
Is it possible to increase the angiotensin antagonist effect? We could consider using higher doses, or switching from ACE-I to ARB, or combining ACE-I
and ARB. High doses of ACE-I or ARB (up to four-fold increase) have been
proved to be of benefit by experimental evidence in a model of remnant kidneys
[15] limiting the development of renal sclerosis. The superior effect of higher
doses versus conventional ones was, however, not confirmed in other models.
In some clinical investigations, doubling ACE-I or ARB doses in 12 adults with
IgAN did not improve the anti-proteinuric effect, while the side effects were
increased [16].
Inhibition of the RAS can be achieved by means of ACE-I or ARB. Both
drugs have positive effects and drawbacks. ACE-I drugs depress aldosterone
synthesis, which has independent deleterious effects, and limit the degradation
of bradykinin, with some additional favourable effects on reduction of proteinuria and of glomerular hypertension. On the other hand, ACE-I also reduces the
effects related to AT2-R stimulation, which are thought to lead to vasodilation
and inhibition of fibrosis. This treatment leaves uncontrolled non-ACE produced angiotensin II by chymase and CAGE. ARB have the advantage of being
placebo-like, without any relevant side effect, but their main supposed advantage, the lack of inhibition and even stimulation of AT2-R, seems indeed more
harmful than benign, after the last reports indicating that AT2-R may trigger
NF-␬B. No reduction of aldosterone is induced by ARB, while angiotensin II
and angiotensin IV are left active with consequent increase in PAI-1 and

Coppo/Amore/Peruzzi/Mancuso/Camilla

32

proteolysis. The combination of these two drugs has the advantage of overcoming the limitations of either individual drug, and an effective blocking of TGF␤ has been observed. The combination of ACE-I and ARB in proteinuric
normotensive IgAN patients has obtained much greater effect than each individual drug. The effect of the combination therapy was not further increased by
doubling the doses [15].
Information on the effects of combination treatment of ARB and ACE-I
in IgAN can be derived by the COOPERATE trial [17], which involved
263 patients of whom 131 (50%) were IgAN. Patients were randomized to maximal antiproteinuric effect ACE-I Trandolapril 3 mg/day or Losartan 100 mg/day,
or a combination of both. BP was targeted at 130/80 mm Hg. The end points
were doubling of serum creatinine or ESRF. Nakao [17] reported a superior
effect of combination therapy over individual drug use in reducing proteinuria
as well as in protecting against renal function deterioration. The 3-year renal
survival in the combination group was mainly due to reduction of proteinuria
and irrespective of patients’ baseline proteinuria levels. The effect was not
increased by doses of ARB increased up to threefold.
Angiotensin antagonism therapy has still debated points. The relative contribution of BP reduction and other additional in vivo effects has been questioned [18]. It is not clear whether ACE-I remains effective over time or whether
there is an escape mechanism [19]. An additional effect has been envisaged for
anti-aldosterone drugs. Aldosterone increases after long-term ACE-I, showing
an ‘aldosterone escape’ [20]; in is still unclear whether this is relevant to longterm prognosis.
Cardiovascular complications are major causes of morbidity and mortality
in patients with chronic kidney diseases (CKD). IgAN patients with CKD are
more likely to die of cardiovascular events than reach the need of dialysis. We
must prevent not only end stage renal failure but, perhaps even more, the risk
factors for cardiovascular events: hypertension, proteinuria, smoking, and dyslipemia. Considering these points, treating IgAN with fish oil has a good rationale, since eicosapentanoic (EPA) and docosahexaenoic (DHA) acids shift the
cyclooxygenase effects from the synthesis of pro-inflammatory mediators, like
thromboxane TxA2 and prostaglandin PGI2, towards the less harmful products
TxA3 and PGI3; similarly, the lipoxygenase activity is shifted from the synthesis of TB4 to the less phlogogenic leucotriene LTB5.
Fish-oil and omega-3 polyunsaturated fatty acids (PUFA) have been shown
to be useful in prevention of cardiovascular events and reduction of proteinuria
in several experimental glomerular diseases. In anti-Thy1–1 experimental glomerulonephritis, omega-3 PUFA had suppressive effects on mesangial cell proliferation, effect on reduction of proteinuria, and inhibition of renal inflammation.
Preliminary pilot studies gave conflicting results: stabilization of GFR for some

Angiotensin Antagonists and Fish Oil for Treating IgAN

33

patients, but no benefit for others. In a controlled trial of fish oil in IgAN [21],
106 IgAN patients with proteinuria ⬎1 g/day, hypertension (60%), and impaired
GFR were treated with EPA 1.8 g/day and DHA 1.2 g/day for 2 years and followed
up for 5 years. A significant benefit was observed on renal function decline,
even though proteinuria levels remained unchanged. The outcome of studies
treating IgAN with fish oil evaluated in a meta-analysis by Dillon [22] failed to
prove an overall benefit of this therapy.
A controlled trial of fish oil and prednisone in IgAN (Hogg R et al., personal communication), on 100 IgAN patients, aged under than 40 years, with a
urinary protein/creatinine ratio ⬎0.5 and GFR ⬎50 ml/min, randomized the
patients to 4 g/day omega-3 PUFA or alternate day prednisone or placebo for
2 years. No significant difference was found between treatment groups and
placebo, as the end-points were reached in 2 patients on prednisone, 8 on fish
oil and 4 on placebo. Ron Hogg has recently reported that the effect of Omacor
(omega-3 PUFA) in patients with IgAN is dependent upon the serum levels of
EPA and DHA, and the antiproteinuric effect is significantly correlated to the
dose (mg per kg body weight).
However, fish oil in IgAN remains of controversial benefit; it is expensive
and carries some side effects; however, it can be of benefit for patients with
IgAN since it is of benefit against the cardiovascular deterioration. Hence, it is
mostly left to individual choice.
In conclusion, ACE-I and ARB have a definite role in treating IgAN, particularly the hypertensive and proteinuric forms. The best strategy for proteinuric and hypertensive IgAN patients includes the following therapies [23]:
control BP aggressively by means of ACE-I and/or ARB; give the maximum
tolerated doses or target BP to proteinuria ⬍0.5 g/day; control blood lipids with
statins; reduce salt intake; reduce excessive body weight, and increase physical
activity.
BP should be targeted according to concomitant proteinuria levels: in
cases with proteinuria ⬍1 g/day, BP should not exceed 135/85 mm Hg (MAP
99 mm Hg); when proteinuria is ⬎1 g/day, BP should not exceed ⬎125/75 mm
Hg (MAP 92 mm Hg); target BP is ⬍130/70 mm Hg (MAP 92 mm Hg) when
proteinuria is ⬎1 g/day. The target for proteinuria is ⬍0.5 g/day and it should be
attained by combination therapy ACE-I and ARB, wait for the effect 12 months.
Consider other therapeutic options (steroids) in case of failure.

References
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Wolf G, Ritz E: Combination therapy with ACE inhibitors and angiotensin II receptor blockers to
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1544–1547.
Coppo R, Amore A, Gianoglio B, Cacace G, Picciotto G, Roccatello D, Peruzzi L, Piccoli G,
De Filippi PG: Angiotensin II local hyperreactivity in the progression of IgA nephropathy. Am J
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control. Nephrol Dial Transplant 2005;20:1533–1539.

Prof. Rosanna Coppo
Nephrology Dialysis Transplantation
Regina Margherita University Hospital
Piazza Polonia 94
IT–10126 Torino (Italy)
Tel. ⫹39 011 3135362, Fax ⫹39 011 6635543
E-Mail nefrologia@oirmsantanna.piemonte.it

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Tomino Y (ed): IgA Nephropathy Today.
Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 37–43

Treatment of IgA Nephropathy:
Corticosteroids, Tonsillectomy, and
Mycophenolate Mofetil
Tetsuya Kawamura
Department of Medicine, Division of Kidney and Hypertension,
Jikei University School of Medicine, Tokyo, Japan

Abstract
Previous studies exploring the potential of glucocorticoid therapy on proteinuria and
renal survival of patients with IgA nephropathy (IgAN) indicate that corticosteroid therapy
is recommended if the patients show a moderate degree of proteinuria and their creatinine
clearance exceeds 70 ml/min, although these studies, most of which are not prospective or
randomized, have not provided conclusive results. Recently, Pozzi et al. demonstrated that
treatment with glucocorticoids for 6 months significantly improved renal survival and proteinuria for 10 years of follow-up. A recent meta-analysis by Samuels et al. supports the
use of corticosteroids in reducing proteinuria and preventing progression to end-stage
renal disease. Increasing attention has been drawn to the role of tonsillectomy in the longterm prognosis of IgAN. The notion that tonsillectomy not only helps to prevent episodic
macroscopic hematuria in the short-term but also gives long-term renal protection in IgAN
is supported by two large retrospective studies from Japan. A study of 329 patients with
IgAN by Hotta et al. found that tonsillectomy plus high-dose methylprednisolone was
identified as one of the independent variables in predicting remission of clinical findings
and lack of renal progression. Moreover, Xie et al. have reported that, for 20 years of
follow-up, renal survival was significantly better in IgAN patients who underwent tonsillectomy than those who did not undergo the procedure. However, the role of tonsillectomy
in the long-term prognosis of IgAN remains unclear, since it has not yet been tested in a
controlled randomized trial. The role of mycophenolate mofetil (MMF) in IgAN has been
examined in four major trials. Two prospective randomized studies report no benefit from
MMF. The remaining two studies showed a greater reduction of proteinuria in patients
treated with MMF compared to prednisone or placebo. In both studies, however, MMF did
not effectively modify the progressive course of the disease. Thus, despite promising
results in large randomized controlled trials in lupus nephritis, the evidence for the use of
MMF in IgAN is inconclusive.
Copyright © 2007 S. Karger AG, Basel

Corticosteroids

Many previous studies have examined the renoprotective effects of corticosteroids in patients with IgA nephropathy (IgAN). An early retrospective study by
Kobayashi et al. demonstrated the potential of glucocorticoid therapy on proteinuria and renal survival of IgAN patients, especially of those with initial creatinine
clearance (Ccr) values of 70 ml/min or more, but not of those with values below
than 70 ml/min [1]. The same authors also reported that steroid therapy for an
average period of 18 months in IgAN patients with a Ccr of 70 ml/min or more
and proteinuria between 1 and 2 g/day resulted in a better renal survival rate 10 years
after therapy compared with an untreated group (80 vs. 34%) [2].
On the other hand, most randomized prospective studies clearly demonstrated that corticosteroids have an antiproteinuric effect, but do not preserve the
glomerular filtration rate (GFR). This is probably because of small sample sizes
and short duration of follow-up. Among those previous prospective studies, an
exception to the mixed results comes from the well-designed, randomized, controlled trial by Pozzi et al. [3, 4]. In this study, 86 IgAN patients with serum creatinine of 1.5 mg/dl or less and proteinuria of 1.0–3.5 g/day were randomized to
receive ‘pulse’ methylprednisolone (1 g/day for 3 days at the beginning of months
1, 3, and 5) followed by alternate day oral prednisolone (0.5 mg/kg) or placebo for
6 months. After 12 months, proteinuria in 31 patients (72%) of steroid group had
dropped below 1 g/day, whereas only 13 patients (30%) of the placebo group
experienced a similar improvement in proteinuria. After 10 years of follow-up,
the renal survival was significantly better in the steroid group than in the placebo
group (97 vs. 53%) [4] (fig. 1). Thus, this well-designed trial strongly suggests a
role for a 6-month trial of corticosteroids in IgAN patients with urinary protein
excretion more than 1.0 g/day yet with preserved renal function. A recent metaanalysis by Samuels et al. supports the use of corticosteroids in reducing proteinuria and preventing progression to end-stage renal disease [5].
A prospective multicenter trial of corticosteroids in Japanese patients with
IgAN was performed in 1996–2001 by the Special Study Group on Progressive
Glomerular Disease of the Japanese Ministry of Health, Labor and Welfare [6].
Sixty-nine IgAN patients with proteinuria of 0.5–3.4 g/day and Ccr of
70 ml/min or more were divided into two groups: an anti-platelet drug (Dilazep)
group and a corticosteroid (PSL) group. The PSL group received prednisolone
for 2 years as well as the anti-platelet drug dilazep hydrochloride. There were
no differences between the two groups in terms of blood pressure, proteinuria,
Ccr, total protein or albumin at baseline. Proteinuria in the PSL group was significantly attenuated at one year and three years compared to baseline, whereas
it was not significantly changed in the Dilazep group. Of note, Ccr significantly
decreased in the Dilazep group at four years compared to baseline, while it was

Kawamura

38

1.0
Log rank p = 0.0003
0.8
0.6
0.4
0.2

Treatment

Events

Yes
No

1/43
13/43

0
0

2

4
6
Follow-up (years)

Treatment
Yes
No

43
43

42
40

39
33

33
23

20
14

8

10
12
7

Fig. 1. Renal survival estimated on the basis of an increase in plasma creatinine concentrations to ⬎100% above baseline values.

well preserved throughout the course in the PSL group, suggesting that corticosteroids can confer antiproteinuric and GFR-preserving effects in IgAN
patients with normal renal function.
In contrast to the efficacy of corticosteroids in IgAN patients with normal
renal function, it is not well elucidated whether corticosteroids might be effective for patients with advanced IgAN and impaired re