IgA Nephropathy: Progress Before and Since Berger
2011; Elsevier BV; Volume: 58; Issue: 2 Linguagem: Inglês
10.1053/j.ajkd.2011.03.024
ISSN1523-6838
Autores Tópico(s)Blood groups and transfusion
ResumoImmunoglobulin A nephropathy (IgAN) is linked inextricably to the name Jean Berger, the Parisian pathologist who published the first description of IgAN in 1968. We reflect on the significance of Berger's first report and consider 40 years of progress in our understanding of IgAN since it was published. We also look back to the days before Berger, when IgAN could not have been identified (because there were no techniques for detecting IgA deposits), classification of glomerulonephritis was even more contentious and confusing than it is today, and it is likely that the literature describing focal glomerulonephritis contained many of the cases we would now identify as IgAN. Immunoglobulin A nephropathy (IgAN) is linked inextricably to the name Jean Berger, the Parisian pathologist who published the first description of IgAN in 1968. We reflect on the significance of Berger's first report and consider 40 years of progress in our understanding of IgAN since it was published. We also look back to the days before Berger, when IgAN could not have been identified (because there were no techniques for detecting IgA deposits), classification of glomerulonephritis was even more contentious and confusing than it is today, and it is likely that the literature describing focal glomerulonephritis contained many of the cases we would now identify as IgAN. Identifying IgANThis section is adapted and reproduced from an earlier exploration of Jean Berger's work by Feehally,1Feehally J. Jean Berger, the man who identified IgA nephropathy The International IgA Nephropathy Network website.http://www.igan-world.org/berger.htmGoogle Scholar with permission of The International IgA Nephropathy Network.Berger and the First Description of IgANThe first public appearance of Berger's seminal observations was modest: an oral report to the Société de Néphrologie in Paris in winter 1968, followed by publication in French of a summary less than 1 page long.2Berger J. Hinglais N. Les dépôts intercapillaires d'IgA-IgG.J Urol Nephrol. 1968; 74: 694-695PubMed Google Scholar This report, now cited time and again all over the world, was entitled "Les dépôts intercapillaires d'IgA-IgG,"2Berger J. Hinglais N. Les dépôts intercapillaires d'IgA-IgG.J Urol Nephrol. 1968; 74: 694-695PubMed Google Scholar and the coauthor was Nicole Hinglais, an expert electron microscopist.At the time Berger reported his seminal observations, he was working as a pathologist in Paris at Hôpital Necker and also was Professor at the Université René Descartes. In the late 1960s, kidney biopsy was an increasingly used technique for investigating kidney disease, and the nephrologists with whom Berger worked at Hôpital Necker and Hôpital Tenon in Paris were among the leaders in this new wave of work. A classification of glomerulonephritis (GN) had been developed based on the various pathologic appearances on specimens obtained using kidney biopsy, but in the mid-1960s, it was based largely on morphologic characteristics seen on light microscopy. The new technique of immunofluorescence microscopy, undertaken with fresh kidney biopsy material to identify the presence of immunoglobulins and complement components, was still regarded as experimental. Berger applied the technique to kidney biopsy specimens and recognized that there was a group of patients, not previously well defined, in whom the dominant finding was IgA deposition in the glomerular mesangium. Electron microscopy showed mesangial electron-dense deposits corresponding to the mesangial IgA. Light microscopic findings were variable, but typically included mesangial hypercellularity, which usually was focal and segmental, but sometimes diffuse. Interpreting his findings in the light of clinical information, he realized that these typically were young adults with low-grade proteinuria and microscopic hematuria and most often with recurrent episodes of macroscopic hematuria coinciding with upper respiratory tract infection.Within a short time, Berger made further key observations. First, he identified that similar mesangial IgA deposits also typified the GN associated with Henoch-Schönlein purpura,3Berger J. IgA glomerular deposits in renal disease.Transplant Proc. 1969; 1: 939-944PubMed Google Scholar which morphologically often was indistinguishable from IgAN. Second, he showed that mesangial IgA deposits recurred frequently in kidneys transplanted into patients who had developed end-stage renal disease due to IgAN.4Berger J. Yaneva H. Nabarra B. Barbanel C. Recurrence of mesangial deposition of IgA after renal transplantation.Kidney Int. 1975; 7: 232-241Crossref PubMed Scopus (209) Google Scholar Third, Berger also published a major description of the secondary form of IgAN associated with alcoholic liver disease.5Berger J. Yaneva H. Nabarra B. Glomerular changes in patients with cirrhosis of the liver.Adv Nephrol Necker Hosp. 1977; 7: 3-14PubMed Google ScholarIt might be tempting to belittle Berger's observations with the apparent wisdom of hindsight. After all, he merely applied a new technique and got an interesting answer, the sort of thing in modern scientific vernacular we might term a "fishing expedition." But what he picked out of his net was enduring and remarkably important.Berger (Fig 1) was a charming and modest man. Liliane Striker (née Morel-Maroger) has published an affectionate memoir from her experience as a young research fellow in Berger's laboratory in Hôpital Necker in the 1960s in which she describes the excitement of those early days when Berger identified IgAN. She also vividly tells of Berger's great skills not only as a researcher, but as a teacher and diagnostician.6Berger J. Hinglais L. Striker L. Intercapillary deposits of IgA-IgC.J Am Soc Nephrol. 2000; 11: 1957-1959PubMed Google ScholarWhat's in a Name: IgAN or Berger disease?Many titles have been used for IgAN during the last 40 years. Berger followed his original descriptive phrase, "dépôts intercapillaires d'IgA-IgG,"2Berger J. Hinglais N. Les dépôts intercapillaires d'IgA-IgG.J Urol Nephrol. 1968; 74: 694-695PubMed Google Scholar by using the term "nephropathy with mesangial IgA-IgG deposits."3Berger J. IgA glomerular deposits in renal disease.Transplant Proc. 1969; 1: 939-944PubMed Google Scholar However, this soon was replaced by a number of other terms, including IgAN, mesangial IgA disease, mesangial IgA GN, and IgA-IgG nephropathy; of these, IgAN has proved the most enduring. In 1973, the term Berger disease was proposed first by Levy et al7Levy M. Beaufils H. Gubler M.C. Habib R. Idiopathic recurrent macroscopic haematuria and mesangial IgA-IgG deposits in children (Berger's disease).Clin Nephrol. 1973; 1: 63-69Google Scholar in Paris, although this term subsequently sometimes was restricted to patients who had recurrent episodes of visible hematuria.Because Berger's observations were so innovative and influential, why has the term Berger disease gradually fallen out of use? Perhaps this simply is because eponymous titles for diseases are becoming less fashionable. However, much more importantly, it seems that Berger himself preferred not to see his name attached to the disease he first described, an object lesson in due modesty that adds to Berger's justified reputation as a great figure in the history of glomerular disease.Early History of IgANThis section is adapted and reproduced from an earlier exploration of Berger's work by Cameron,8Cameron J.S. Berger's disease before Berger The International IgA Nephropathy Network website.http://www.igan-world.org/bergercameron.htmGoogle Scholar with permission of The International IgA Nephropathy Network.Progress Before BergerClassifications of Nephritis, 1820-1970The 1968 report of Berger and Hinglais2Berger J. Hinglais N. Les dépôts intercapillaires d'IgA-IgG.J Urol Nephrol. 1968; 74: 694-695PubMed Google Scholar was more than just a novel observation, it introduced a new level of descriptive classification into the study of GN and highlighted the confusions of the time about the classification of glomerular disease, which even now await full resolution. To understand fully this report's importance requires a long look back.From the time of Richard Bright's9Bright R. Reports of Medical Cases. Vol I. Longman, Orme Rees, London1827Google Scholar remarkable book in 1827, ideas about nephritis were dominated by the combination of clinical observation and macroscopic and microscopic observation of kidney tissue obtained at autopsy. There was an uneasy tension between this level of description and clinical observation from the start: very early, it was noted that in one clinical setting (say dropsy and proteinuria), a number of different appearances could be seen in the kidney. These appearances initially were described in the 1840s as either a fatty kidney with normal or nearly normal glomeruli or, in contrast, a form in which the presence of cells and tubular destruction predominated. Debate about the relationship between these 2 forms and their relationship to scarred granular kidneys dominated renal pathology up to and beyond the First World War.Pathologists naturally believed that their level of description was more fundamental than clinical classifications and that the underlying "diseases" were expressed primarily in morphologic terms. A further, apparently more fundamental, layer of description was introduced as the cause of some of the appearances was teased out: "poststreptococcal nephritis" was the first, in the 1880s. Then the idea of time came to influence classification: "acute" and "chronic" forms, for example, the "Dauerstadium" (dormancy) of nephritis, coined by Volhard and Fahr,10Volhard F. Fahr T. Die Brightsche Nierenkrankheit. Springer, Berlin1914Crossref Google Scholar and the "chronic latent nephritis" of Addis.11Addis T.A. Glomerular Nephritis. McMillan, New York, NY1948Google Scholar As ideas of immunology developed, immunologic terms came into use. Thus, in the 1960s, "(chronic) hypocomplementemic nephritis" made its appearance and by analogy from studies of experimental nephritis in animals, different patterns of deposition of immune reactants, such as complement and immunoglobulin, were seen: the "lumpy bumpy" and "linear" deposits that Germuth and Rodriguez12Germuth F.J. Rodriguez E. The Immunopathology of the Renal Glomerulus. Little Brown, Boston, MA1973Google Scholar and Dixon13Dixon F.J. The pathogenesis of glomerulonephritis.Am J Med. 1968; 44: 493-498Abstract Full Text PDF PubMed Scopus (190) Google Scholar correlated to different routes of immunopathogenesis. Finally, from the 1950s onward, terms based on results of the new effective treatments, such as corticosteroid-sensitive and corticosteroid-resistant nephrotic syndrome, appeared.How then should GN be classified: by morphologic characteristics, by clinical presentation, by cause, by tempo, or by treatment response? The result of all this was great confusion for pathologists, physicians, and, not least, patients. A further major breakthrough in the 1950s was the advent of kidney biopsy, which allowed the study of early disease and began to show the plasticity of renal histologic appearances.Such was the context of Berger's 1968 seminal observations on IgA deposition.Background of IgAN: An Intersection of PathsTo place IgAN in context, we must trace the evolution of 3 layers of description in GN: the clinical syndrome of recurrent hematuria, the histologic appearance of focal or mesangial nephritis, and the immunohistochemical identification of IgA deposition (Fig 2).Figure 2Relationship of the 3 cardinal features of immunoglobulin A (IgA) nephropathy. Abbreviation: GN, glomerulonephritis.Adapted and reproduced from Cameron8Cameron J.S. Berger's disease before Berger The International IgA Nephropathy Network website.http://www.igan-world.org/bergercameron.htmGoogle Scholar with permission of The International IgA Nephropathy Network.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Recurrent and persistent hematuriaDuring the latter half of the 19th century, urine microscopy produced data as good as any today, including observations of acanthocytes in renal bleeding. About the same time, patients with recurrent attacks of macroscopic hematuria were described who had microscopic hematuria between attacks. However, the study of GN at that time was dominated by the focus on the presence and quantity of proteinuria. Although hematuria and proteinuria had been known to coexist in urine since Wells14Wells W.C. Observations on the dropsy which succeeds scarlet fever.Trans Soc Improve Med Chir Knowl. 1812; 3: 167-186Google Scholar in 1808, the presence or absence of hematuria in GN was not widely discussed until the 1920s, when Thomas Addis15Addis T. The number of formed elements in the urinary sediment of normal individuals.J Clin Invest. 1926; 2: 409-415Crossref PubMed Google Scholar described the quantitative excretion of formed elements in urine, including red blood cells, as a measure of the activity and/or progression of kidney diseases. The "Addis count" was performed widely as a surrogate until kidney biopsy became available 30 years later.Focal nephritisThe first reports to draw wide attention to focal segmental nephritis were in the early 1920s. At first, focal nephritis was noted in patients with endocarditis and thus described as "embolic," a term that erroneously persisted for decades. Then, in 1926, Baehr16Baehr G. A benign and curable form of acute hemorrhagic nephritis.JAMA. 1926; 86: 1001-1004Crossref Scopus (29) Google Scholar described 14 young adults without endocarditis, but with recurrent macroscopic hematuria, many of whom did well and some of whom had focal segmental nephritis. In the report by Arthur Ellis17Ellis A. Natural history of Bright's disease Clinical, histological and experimental observations.Lancet. 1942; 1: 1-7Abstract Scopus (59) Google Scholar discussing the work of the team led by his clinical associate, Clifford Wilson, at the London Hospital in the 1940s, patients also were described who today would be given the diagnosis clinically of IgAN, despite which Wilson opposed the idea of focal nephritis when it resurfaced in kidney biopsy specimens a decade later.It was not until the advent of kidney biopsy in the 1950s that focal nephritis really came to attention. In 1957, Bates, Jennings, and Earle,18Bates R.C. Jennings R.B. Earle D.P. Acute nephritis unrelated to group A hemolytic streptococcus infection.Am J Med. 1957; 23: 510-528Abstract Full Text PDF PubMed Scopus (9) Google Scholar as part of a study of acute nephritis, noted immediate postpharyngitic macroscopic hematuria with proteinuria in 10 young soldiers with normal serum complement concentrations and normal antistreptolysin O titers. Biopsy specimens showed red blood cells in tubules and generally mild and often focal segmental nephritis. However, it was the report of Heptinstall and Joekes19Heptinstall R.H. Joekes A.M. Focal glomerulonephritis A study based on renal biopsies.Q J Med. 1959; 28: 329-346PubMed Google Scholar in London published 2 years later that showed the range of clinical features associated with focal segmental nephritis; only 3 of their 31 patients in 1960 showed recurrent hematuria as a presentation, many having Henoch-Schönlein purpura or lupus nephritis. Ross20Ross J.H. Recurrent focal nephritis.Q J Med. 1960; 29: 391-406Google Scholar at the London Hospital in 1960 identified a group of patients with long-term relapsing hematuria. Two articles in 1965 also described similar cases in childhood.21Bodian M. Black J.A. Kobayashi N. Lake B.D. Shuler S.E. Recurrent haematuria in childhood.Q J Med. 1965; 34: 359-382PubMed Google Scholar, 22Ayoub E.M. Vernier R.L. Benign recurrent hematuria.Am J Dis Child. 1965; 109: 217-223PubMed Google Scholar Thus, by the 1960s, focal segmental GN was a recognized subgroup of proliferative GN.Finally, during the late 1950s, electron microscopy first was applied to kidney biopsy material, and in 1962, Galle and Berger23Galle P. Berger J. Dépôts fibrinoïdes intercapillaires.J Urol Néphrol. 1962; 68: 123-127PubMed Google Scholar noted "intercapillary" electron-dense material, presumed by analogy from animal work, to be deposits of circulating immune complexes in biopsy specimens showing predominantly mesangial nephritis.IgA deposition within glomeruliFluorescent-labeled specific antibodies first were used to detect and trace proteins in the early 1950s, but until the mid-1960s, very few laboratories offered this technique, and the antisera used often were of poor specificity. By 1963, antibodies were available commercially against IgG, IgA, and IgM, but the few laboratories studying immunofluorescence in kidney biopsy specimens at that time mostly used only anti-IgG reagents because this was thought to be the predominant immunoglobulin class involved in the immunopathogenesis of nephritis. For example, Bodian et al21Bodian M. Black J.A. Kobayashi N. Lake B.D. Shuler S.E. Recurrent haematuria in childhood.Q J Med. 1965; 34: 359-382PubMed Google Scholar from Great Ormond Street Hospital, London, in 1965 reported biopsies from children with recurrent hematuria using immunofluorescent techniques for the first time, but only antisera against whole immunoglobulin and IgG were used and thus an opportunity to identify IgAN surely was missed.Then in 1968 came the report by Berger and Hinglais2Berger J. Hinglais N. Les dépôts intercapillaires d'IgA-IgG.J Urol Nephrol. 1968; 74: 694-695PubMed Google Scholar of predominant IgA mesangial deposition in kidney biopsy specimens, although they emphasized that it usually was associated with some IgG. Comparative quantification was unsatisfactory, but in these patients, the IgA reagent "outshone" the IgG reagent strongly. Berger had trained with the pathologist Deborah Doniach in London, where he got the idea of applying fluorescent techniques to kidney disease as she had to liver problems. Berger and his colleagues also had the advantage of a pure anti-IgA antibody prepared by immunologist Maxime Seligmann, who had described anti-DNA antibodies for the first time a decade previously.Emergence of IgAN as a Recognized EntityThe world of nephrology remained a little skeptical about IgAN as a discrete entity. Other reports from Paris emerged from Druet et al24Druet Ph Bariéty J. Bernard D. Lagrue G. Les glomerulonéphrites primitives à dépôts mésangiaux d'IgA et d'IgG Étude clinique et morphologique.Presse Méd. 1970; 78: 583-587PubMed Google Scholar and Morel-Maroger et al,25Morel-Maroger L. Mery J.P. Robert C.L. Richet G. Mesangial IgA deposits.Perspect Nephrol Hypertens. 1973; 1: 301-304PubMed Google Scholar so that for a short time the disease seemed to be confined to France. Then in 1972 and 1973, reports from outside France appeared, including series from the groups of Maintz (the Netherlands), McEnery (United States), Davies (United Kingdom), Ueda (Japan), and Woodroffe (Australia).26Maintz J. Elema J.D. Henningsen B. et al.Ein Sonderform der chronischen Glomerulonephritis IgA-IgG nephropathie.Dtsch Med Wochenschr. 1972; 97: 1527-1533Crossref PubMed Scopus (15) Google Scholar, 27McEnery P.T. McAdams J. West C.D. Glomerular morphology, natural history and treatment of children with IgA-IgG mesangial nephropathy.in: Mathew T. Kincaid-Smith P. Glomerulonephritis Morphology, Natural History and Treatment. John Wiley, New York, NY1973: 305-320Google Scholar, 28Davies D.R. Tighe J.R. Recurrent haematuria and glomerular IgA deposition.J Clin Pathol. 1973; 26: 672-677Crossref PubMed Scopus (47) Google Scholar, 29Ueda Y. Sakai O. Yamagata M. Kitajima T. Kawamara K. IgA glomerulonephritis in Japan.Contrib Nephrol. 1973; 4: 37-47Google Scholar, 30Woodroffe A.J. Thomson N.M. Meadows R. Lawrence J.R. IgA-associated glomerulonephritis.Aust N Z J Med. 1975; 5: 97-100Crossref PubMed Scopus (16) Google Scholar Quickly, the finding of predominant mesangial IgA in hematuric patients with mesangial or focal nephritis was realized to be common worldwide. Nevertheless, only a dozen reports were published on the subject up to 1975, when a UK opinion leader wrote that "it seems debatable whether the use of terms such as 'mesangial IgA disease' and 'IgA nephropathy' is warranted."31Sissons J.G.P. Woodrow D.F. Curtis J.R. et al.Isolated glomerulonephritis with mesangial IgA deposits.Br Med J. 1975; 3: 611-614Crossref PubMed Scopus (108) Google Scholar(p614) There still were only a few dozen reports during the late 1970s; this slow progress occurred in part because immunofluorescence techniques were far from universally available in renal pathology laboratories even during the early 1970s, when workers still needed to fluorosceinate their own antibodies before use. However, after this, interest expanded rapidly and more than 600 reports appeared from 1981 to 1988.Nevertheless, by 1975, the salient features of IgAN were established: a condition with moderate mesangial proliferative glomerular changes, often focal and segmental; associated with hematuria, often macroscopic; and associated with increased serum IgA concentration. Clinical evolution often was stable or slow, but renal failure, increasing proteinuria, and hypertension occurred eventually in some patients. When such patients underwent transplant, Berger showed in 1975 that IgA rapidly recurred in the transplanted kidney in about half the recipients, but that not all transplants failed as a result.4Berger J. Yaneva H. Nabarra B. Barbanel C. Recurrence of mesangial deposition of IgA after renal transplantation.Kidney Int. 1975; 7: 232-241Crossref PubMed Scopus (209) Google ScholarWith the advent of these methods to identify and classify glomerular disease, the focus could move to the study of pathogenesis, clinical course, and treatment.The International IgA Nephropathy NetworkA key element in the more rapid progress of our understanding of IgAN from the 1980s onward was a series of international symposia devoted exclusively to IgAN. At the second of these symposia, organized in Bari, Italy, an informal "IgA Club" was established, which started as little more than a diffuse alliance of colleagues and friends with a shared interest in the field. The main initial output of the club was the series of international symposia held every 2 or 3 years (Table 1). These small meetings, typically no more than 100-150 registrants, served as an effective forum for the exchange of ideas and new findings, increasingly expanding to involve not only nephrologists, but also renal pathologists, immunologists, biochemists, cell biologists, and geneticists. Restyling itself the International IgA Nephropathy Network in 2000 (www.igan-world.org), it increasingly has formed the basis for substantial collaborative research efforts. Most notable to date has been the development, working with the Renal Pathology Society (and supported by the International Society of Nephrology), of a novel evidence-based approach to clinicopathologic classification resulting in the Oxford classification of IgAN published in 2009.38Cattran D.C. Coppo R. Cook H.T. et al.Working Group of the International IgA Nephropathy Network and the Renal Pathology SocietyThe Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Crossref PubMed Scopus (865) Google Scholar The network remains without formality, but now is serving as a basis for emerging validation studies for the Oxford classification. It is hoped that the network also will facilitate the collaborative efforts that are needed to maximize progress in understanding the complex genetics of IgAN and will provide a focus for mounting treatment trials of sufficient power to give credible answers to continuing uncertainties in the treatment of IgAN.Table 1International Symposia on IgAN 1983-2013Adapted and reproduced from http://www.igan-world.org/meetings.htm with permission of The International IgA Nephropathy Network.YearSiteOrganizersPublished Proceedings1983Milano, ItalyGiuseppe D'Amico, Luigi Minetti, Claudio PonticelliRef. 32D'Amico G. Minetti L. Ponticelli C. IgA Mesangial Nephropathy 1st International Milano Meeting of Nephrology, Milano, October 1983.Contrib Nephrol. 1984; 40: 1-308Google Scholar1987Bari, ItalyF. Paolo Schena, Steven N. EmancipatorRef. 33Emancipator S.N. Schena F.P. Immunoglobulin A nephropathy.Semin Nephrol. 1987; 7: 275-398PubMed Google Scholar1988Washington, DC, United StatesIra Greifer, Bruce A. JulianNovember 1988 issue of AJKDaThis issue of AJKD was devoted to IgAN articles, a subset of which constitute the proceedings of this meeting.1990Tokyo, JapanHideto Sakai, Osamu Sakai, Yasuo NomotoNA1992Nancy, FranceMarie-Christine Bene, Gilbert C. Faure, Michèlle KesslerRef. 34Béné M.C. Faure G.C. Kessler M. IgA nephropathy: the 25th year.Contrib Nephrol. 1993; 104: 1-202Google Scholar1994Adelaide, AustraliaAnthony R. Clarkson, Andrew J. WoodroffeRef. 35Clarkson A.R. Woodroffe A.J. IgA nephropathy: pathogenesis and treatment.Contrib Nephrol. 1995; 111: 1-200Google Scholar1996SingaporeKeng-Thye Woo, Grace S.L. LeeRef. 36Woo K.T. Lee G.S.L. Proceedings from 7th International Symposium on IgA Nephropathy 1-2 October 1996 Singapore.Nephrology. 1997; 3: 1-135Crossref Google Scholar1998Leiden, HollandLeendart A. van Es, Mohammed E. DahaNA2001Kyongju, KoreaMyung-Jae KimRef. 37Kim M.J. The 9th International Symposium on IgA Nephropathy.Nephrology. 2002; 7: S73-S172Google Scholar2004Saint Etienne, FranceFrancois BerthouxNA2006Tokyo, JapanYasuhiko TominoNA2009Stresa, ItalyRosanna CoppoNA2013Nanjing, ChinaZhi-Hong LiuAbbreviations: IgAN, immunoglobulin A nephropathy; NA, not applicable (no proceedings published).a This issue of AJKD was devoted to IgAN articles, a subset of which constitute the proceedings of this meeting. Open table in a new tab Progress and Challenges in Our Understanding of IgANA review of the programs and proceedings for those 12 international symposia since 1983 (Table 1) confirms that the preoccupations of those who study IgAN and the research challenges have been consistent, and that progress in our knowledge and understanding unsurprisingly has been incremental rather than spectacular. Progress to date and the major unresolved issues are briefly summarized here, but continue to be reviewed in greater detail elsewhere.39Glassock R.J. The pathogenesis of IgA nephropathy.Curr Opin Nephrol Hypertens. 2011; 20: 153-160Crossref PubMed Scopus (53) Google ScholarEpidemiology and GeneticsA picture has steadily emerged of global variations in the prevalence of IgAN, apparently based on ancestry. Differences in attitude about the use of kidney biopsy in patients with minor urine abnormalities are no more than a partial explanation for these differences. There is no doubt now that there is a higher prevalence in East Asians compared with Europeans and an even lower prevalence in those of African origin. Perhaps more remarkable and still unexplained is the difference in sex distribution: IgAN is markedly male predominant in Europeans and equal in males and females in Asia.Genetic explanations for these differences have been slow to emerge. Case-control association studies of candidate genes have continued to disappoint, rarely producing replicable results. The 3 large kindreds of IgAN that have been studied in some detail have each been associated with different regions of the genome and to date have not yielded plausible candidates. However, the first genome-wide analysis of IgAN performed in Europeans40Feehally J. Farrall M. Boland A. et al.HLA has strongest association with IgA nephropathy in genome-wide analysis.J Am Soc Nephrol. 2010; 21: 1791-1797Crossref PubMed Scopus (165) Google Scholar has opened a new era in genetic analysis of IgAN, and with other large cohorts of differing ancestry under analysis and partnership opportunities for meta-analysis, there soon may be significant progress in this field.Clinical and Pathologic CharacteristicsOur clinical and pathologic view of IgAN has in many ways improved little since the lucid original descriptions of Berger and his contemporaries. It is notable that one archetypal feature, the onset of visible hematuria within 24 hours of mucosal infection, still defies a convincing pathogenic explanation.Although there has been steady progress in understanding the natural history of IgAN, especially from registry studies, our ability to prognosticate with great accuracy for an individual patient is still somewhat limited, and this has inhibited therapeutic progress by preventing the efficient design of clinical trials that focus on the highest risk patients.None of the various attempts to classify the pathologic features has gained widespread approval, but the recent evidence-based Oxford classification of IgAN now has identified pathologic features that still add to the prediction of outcome even when clinical features at presentation and during follow-up are known.38Cattran D.C. Coppo R. Cook H.T. et al.Working Group of the International IgA Nephropathy Network and the Renal Pathology SocietyThe Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Crossref PubMed Scopus (865) Google Scholar This needs further validation in a broader range of patients, including those of different ancestry, but this may prove to be an important step forward.Relationship With Henoch-Schönlein Purpura NephritisThe precise pathogenic relationship between IgAN and Henoch-Schönlein purpura nephritis is poorly defi
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