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New developments in the genetics, pathogenesis, and therapy of IgA nephropathy

2015; Elsevier BV; Volume: 88; Issue: 5 Linguagem: Inglês

10.1038/ki.2015.252

1523-1755

Riccardo Magistroni, Vivette D. D’Agati, Gerald B. Appel, Krzysztof Kiryluk,

Immunodeficiency and Autoimmune Disorders

Recent years have brought notable progress in the field of IgA nephropathy. Here, we highlight important new directions and latest developments, including successful discovery of several genetic susceptibility loci, formulation of the multihit pathogenesis model, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines. We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geoethnic disparities in disease susceptibility. Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The concerted pattern of interpopulation allelic differentiation across all genetic loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multilocus adaptation might have shaped the present-day landscape of IgA nephropathy. Importantly, the ‘Intestinal Immune Network for IgA Production’ emerged as one of the new targets for potential therapeutic intervention. We place these findings in the context of the multihit pathogenesis model and existing knowledge of IgA immunobiology. Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies. Recent years have brought notable progress in the field of IgA nephropathy. Here, we highlight important new directions and latest developments, including successful discovery of several genetic susceptibility loci, formulation of the multihit pathogenesis model, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines. We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geoethnic disparities in disease susceptibility. Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The concerted pattern of interpopulation allelic differentiation across all genetic loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multilocus adaptation might have shaped the present-day landscape of IgA nephropathy. Importantly, the ‘Intestinal Immune Network for IgA Production’ emerged as one of the new targets for potential therapeutic intervention. We place these findings in the context of the multihit pathogenesis model and existing knowledge of IgA immunobiology. Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies. Since its description in 1968,1.Berger J. Hinglais N. Intercapillary deposits of IgA-IgG.J Urol Nephrol. 1968; 74: 694-695PubMed Google Scholar IgA nephropathy (IgAN) has been recognized as the most common form of primary glomerulonephritis and an important cause of chronic kidney disease and end-stage kidney failure. Recent years have brought remarkable progress in the field of IgAN, largely because of increased collaborative efforts that enabled execution of well-powered clinical and genetic studies. Landmark developments include the discovery of new genetic susceptibility loci, formulation of the multihit pathogenesis model based on the studies of IgA1 O-glycosylation and anti-glycan antibodies, introduction of the Oxford pathology scoring system, and formalization of IgAN treatment guidelines. In this review, we provide an update on these developments, give our perspective on the treatment guidelines, outline the remaining areas of uncertainty, and highlight important new directions in the field. IgAN typically affects young adults, and can also occur in children and the elderly. The disease has a wide spectrum of clinical symptoms, ranging from asymptomatic microscopic hematuria to a more severe course characterized by sustained proteinuria and rapid deterioration of renal function. Definitive diagnosis of IgAN requires a kidney biopsy; the disease is defined immunohistologically by dominant or codominant glomerular deposits of IgA.2.Roberts I.S. Pathology of IgA nephropathy.Nat Rev Nephrol. 2014; 10: 445-454Crossref PubMed Google Scholar According to recent consensus, the IgA should be at least 1+ in intensity3.Working Group of the International Ig ANN, the Renal Pathology S, Roberts IS, et al.The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF Scopus (273) Google Scholar and in most cases is 2+ or more,4.Jennette J.C. The immunohistology of IgA nephropathy.Am J Kidney Dis. 1988; 12: 348-352Abstract Full Text PDF PubMed Google Scholar and involves the glomeruli diffusely. Typically, there is an obvious dominant staining for IgA with weaker and more variable staining for IgG and/or IgM.4.Jennette J.C. The immunohistology of IgA nephropathy.Am J Kidney Dis. 1988; 12: 348-352Abstract Full Text PDF PubMed Google Scholar The deposits consist predominantly of polymeric IgA of the IgA1 subclass.5.Valentijn R.M. Radl J. Haaijman J.J. et al.Circulating and mesangial secretory component-binding IgA-1 in primary IgA nephropathy.Kidney Int. 1984; 26: 760-766Abstract Full Text PDF PubMed Google Scholar Among 2249 cases of IgAN compiled from 13 published biopsy series, 100% of cases had positivity for IgA, 43% had positivity for IgG, and 54% for IgM.6.Haas M. IgA nephropathy and Henoch-Schonlein Purpura Nephritis.in: Jennette J.C. D’Agati V.D. Olson J.L. Heptinstall’s Pathology of the Kidney. 7th edn. Lippincott Williams & Wilkins, Philadelphia, PA2015: 475-524Google Scholar The stronger staining for λ light chain compared with κ light chain observed in most cases reflects the predominance of IgA1-λ in the circulation.7.Chui S.H. Lam C.W. Lewis W.H. et al.Light-chain ratio of serum IgA1 in IgA nephropathy.J Clin Immunol. 1991; 11: 219-223Crossref PubMed Scopus (8) Google Scholar The histologic features of IgAN are diverse and span the gamut seen in most forms of immune complex-mediated proliferative glomerulonephritis (Figure 1). These include no or minimal abnormalities by light microscopy, mesangial hypercellularity (defined as 4 or more mesangial cells per mesangial area in a 3-pm-thick histologic section; Figure 1a), focal endocapillary proliferative (involving<50% glomeruli; Figure 1b), diffuse endocapillary proliferative (involving ⩾50% glomeruli), necrotizing and crescentic lesions, and, more rarely, membranoproliferative patterns of injury.3.Working Group of the International Ig ANN, the Renal Pathology S, Roberts IS, et al.The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF Scopus (273) Google Scholar, 8.Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases.Am J Kidney Dis. 1997; 29: 829-842Abstract Full Text PDF PubMed Google Scholar Red blood cell casts may be associated with acute tubular injury (Figure 1h). In the chronic stages, progression to focal or diffuse segmental and global glomerulosclerosis9.Hill G.S. Karoui K.E. Karras A. et al.Focal segmental glomerulosclerosis plays a major role in the progression of IgA nephropathy.Immunohistochemical studies. Kidney Int. 2011; 79: 635-642Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar with attendant tubular atrophy and interstitial fibrosis occurs (Figure 1d and e). By electron microscopy, the glomerular deposits in IgAN are primarily localized to the mesangium, with variable subendothelial and rare subepithelial deposits in the more severe forms. Mesangial deposits tend to cluster beneath the glomerular basement membrane reflection over the mesangium, a location referred to as paramesangial (Figure 1i). The glomerular basement membranes may manifest focal thinning, rupture, and remodeling, which present sources for hematuria. Henoch-Schönlein purpura nephritis is a systemic form of IgA vasculitis with renal manifestations that occurs predominantly in the pediatric age group.10.Jennette J.C. Falk R.J. Bacon P.A. et al.2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.Arthritis Rheumat. 2013; 65: 1-11Crossref PubMed Scopus (0) Google Scholar This disease typically manifests with a tetrad of palpable purpura, arthralgia, abdominal pain, and renal disease. Although Henoch-Schönlein purpura nephritis is frequently self-limiting in children, persistent proteinuria and chronic or progressive renal dysfunction are often observed in adult cases.11.Pillebout E. Thervet E. Hill G. et al.Henoch-Schonlein Purpura in adults: outcome and prognostic factors.J Am Soc Nephrol. 2002; 13: 1271-1278Crossref PubMed Scopus (212) Google Scholar The renal disease has a similar histologic spectrum as IgA nephropathy, but with greater frequency of severe lesions such as glomerular necrosis and crescents (Figure 1g).6.Haas M. IgA nephropathy and Henoch-Schonlein Purpura Nephritis.in: Jennette J.C. D’Agati V.D. Olson J.L. Heptinstall’s Pathology of the Kidney. 7th edn. Lippincott Williams & Wilkins, Philadelphia, PA2015: 475-524Google Scholar Correspondingly, Henoch-Schönlein purpura nephritis has a higher frequency of glomerular staining for fibrin compared with IgAN, but with an otherwise similar immunofluorescence profile. Heuristic classification systems applied to IgAN in the past, including those by Lee et al.12.Lee S.M. Rao V.M. Franklin W.A. et al.IgA nephropathy: morphologic predictors of progressive renal disease.Hum Pathol. 1982; 13: 314-322Abstract Full Text PDF PubMed Google Scholar and Haas et al.8.Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases.Am J Kidney Dis. 1997; 29: 829-842Abstract Full Text PDF PubMed Google Scholar, were based on the pattern and severity of the proliferative and sclerosing lesions, similar to the World Health Organization classification of lupus nephritis. The Oxford IgAN classification, devised by a working group of over 40 nephrologists and pathologists representing the International IgA Nephropathy Network and the Renal Pathology Society, is unique as the first evidence-based schema.3.Working Group of the International Ig ANN, the Renal Pathology S, Roberts IS, et al.The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF Scopus (273) Google Scholar, 13.Working Group of the International Ig ANN, the Renal Pathology S, Cattran DC, et al.The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF Scopus (327) Google Scholar It sought to identify reproducible histologic features that predict progression in a large disease cohort with known outcomes, and thus represents a scoring system, not a comprehensive classification. The discovery cohort included 265 cases of IgAN from Europe, North America, and Asia, of which 78% were adults. Because the study excluded cases with proteinuria of <0.5 g per day, initial estimated glomerular filtration rate (eGFR) of 25% of the cortical area (T).3.Working Group of the International Ig ANN, the Renal Pathology S, Roberts IS, et al.The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF Scopus (273) Google Scholar Tubular atrophy/interstitial fibrosis involving >50% (vs. 26–50%) of the cortex was associated with even worse outcomes. Endocapillary hypercellularity (E) was associated with response to immunosuppressive therapy. The MEST (M, mesangial hypercellularity; E, endocapillary hypercellularity; S, segmental glomerulosclerosis/adhesion; T, tubular atrophy/interstitial fibrosis) score applies the designations M0 or M1 for mesangial hypercellularity involving ⩽50% or>50% of glomeruli, respectively; E0 or E1 for endocapillary hypercellularity in 0 vs. at least 1 glomerulus, S0 or S1 for segmental sclerosis in 0 vs. at least 1 glomerulus, and T0, T1, and T2 for tubular atrophy/interstitial fibrosis involving ⩽25%, 26–50%, and >50% of the cortical area, respectively.3.Working Group of the International Ig ANN, the Renal Pathology S, Roberts IS, et al.The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF Scopus (273) Google Scholar The major limitation of the Oxford system is that the study design constrained its ability to fully address the impact of crescents and specific immunofluorescence features, such as the presence of peripheral capillary wall deposits of IgA and codeposits of IgG. A number of studies have attempted to validate the predictive value of the MEST lesions in independent cohorts from North America,14.Herzenberg A.M. Fogo A.B. Reich H.N. et al.Validation of the Oxford classification of IgA nephropathy.Kidney Int. 2011; 80: 310-317Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 15.Yau T. Korbet S.M. Schwartz M.M. et al.The Oxford classification of IgA nephropathy: a retrospective analysis.Am J Nephrot. 2011; 34: 435-444Crossref PubMed Scopus (0) Google Scholar Europe,16.Alamartine E. Sauron C. Laurent B. et al.The use of the Oxford classification of IgA nephropathy to predict renal survival.Ctin J Am Soc Nephrot. 2011; 6: 2384-2388Crossref PubMed Scopus (0) Google Scholar, 17.Edstrom Halling S. Soderberg M.P. Berg U.B. 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Liu Z. et al.Validation of the Oxford classification of IgA nephropathy for pediatric patients from China.BMC Nephrot. 2012; 13: 158Crossref PubMed Scopus (0) Google Scholar including pediatric cases.29.Working Group of the International Ig ANN, the Renal Pathology S, Coppo R, et al.The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults.Kidney Int. 2010; 77: 921-927Abstract Full Text Full Text PDF Scopus (59) Google Scholar, 30.Coppo R. Troyanov S. Bellur S. et al.Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments.Kidney Int. 2014; 86: 828-836Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar These studies have generally confirmed the predictive value of various components by univariate and multivariate analyses, but with some differences.31.Haas M. Rastaldi M.P. Fervenza F.C. Histologic classification of glomerular diseases: clinicopathologic correlations, limitations exposed by validation studies, and suggestions for modification.Kidney Int. 2014; 85: 779-793Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 32.Lv J. Shi S. Xu D. et al.Evaluation of the Oxford Classification of IgA nephropathy: a systematic review and meta-analysis.Am J Kidney Dis. 2013; 62: 891-899Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The largest meta-analysis based on 16 retrospective cohort studies and involving a total of 3893 IgAN cases validated the predictive utility of the M, S, and T lesions, but did not confirm the prognostic value of the E score.32.Lv J. Shi S. Xu D. et al.Evaluation of the Oxford Classification of IgA nephropathy: a systematic review and meta-analysis.Am J Kidney Dis. 2013; 62: 891-899Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Although the E score exhibited some of the weakest and most heterogeneous associations with disease progression, the T score was consistently the most significant predictor of poor renal outcomes across all cohorts. In addition, 5 of 16 studies (4 Asian and 1 European with a total of 1487 patients) examined the association of crescents with clinical outcomes; meta-analysis of these studies showed that the C score (defined as the presence of any crescents) was strongly associated with progression to kidney failure.32.Lv J. Shi S. Xu D. et al.Evaluation of the Oxford Classification of IgA nephropathy: a systematic review and meta-analysis.Am J Kidney Dis. 2013; 62: 891-899Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Lastly, the recently published VALIGA (European Validation of the Oxford Classification of IgAN) study of 1147 patients from 13 European countries (not included in the above meta-analysis) provided an independent validation of the predictive value of the M, S and T lesions across a broader spectrum of the disease.30.Coppo R. Troyanov S. Bellur S. et al.Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments.Kidney Int. 2014; 86: 828-836Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar The E score, again, was not associated with outcomes. However, the relationship between some variables, such as the E score, and clinical outcomes might have been confounded by immunosuppressive treatment exposure, as all of the published validation studies have been based on retrospective observational data. In summary, the Oxford scoring system represents an important step toward improved prognostication and standardization of diagnosis, but further refinements of the score may be needed to enhance its prognostic utility. A more definitive assessment of the scoring system would require a sizeable randomized controlled trial in which decisions regarding therapy are not made on the basis of pathology. The TESTING study (see below) may present a unique opportunity to validate and refine this scoring system while removing inherent therapeutic biases. Because the diagnosis of IgAN requires a kidney biopsy, the exact disease prevalence remains difficult to establish. The prevalence of mesangial IgA deposits assessed in necropsy studies is surprisingly high, ranging from 4 to 16% depending on the population studied.33.Sinniah R. Occurrence of mesangial IgA and IgM deposits in a control necropsy population.J Ctin Pathot. 1983; 36: 276-279Crossref Google Scholar, 34.Waldherr R. Rambausek M. Duncker W.D. et al.Frequency of mesangial IgA deposits in a non-selected autopsy series.Nephrot Diat Transptant. 1989; 4: 943-946PubMed Google Scholar, 35.Varis J. Rantala I. Pasternack A. Immunofluorescence of immunoglobulins and complement in kidneys taken at necropsy.J Ctin Pathot. 1989; 42: 1211-1214Crossref Scopus (8) Google Scholar Similarly, the frequency of IgA deposition in protocol biopsies of living or cadaveric donor kidneys is reported to be as high as 16% in Japan.36.Suzuki K. Honda K. Tanabe K. et al.Incidence of latent mesangial IgA deposition in renal allograft donors in Japan.Kidney Int. 2003; 63: 2286-2294Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar These studies suggest that subclinical IgA deposition is common and may be more prevalent in East Asian populations. Another commonly reported metric of IgAN occurrence is a relative frequency of IgAN among all cases of primary glomerulonephritis in a biopsy registry. Depending on the geographic region, this number tends to be highly variable, ranging from 5% in the Middle East,37.Demircin G. Delibas A. Bek K. et al.A one-center experience with pediatric percutaneous renal biopsy and histopathology in Ankara, Turkey.Int Urot Nephrot. 2009; 41: 933-939Crossref Scopus (10) Google Scholar, 38.Monfared A. Khosravi M. Lebadi M. et al.Distribution of renal histopathology in Guilan: a single-center report.Iran J Kidney Dis. 2012; 6: 173-177Google Scholar 10–35% across Europe,39.Berthoux F. 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Young B. et al.Centre variation in incidence, indication and diagnosis of adult native renal biopsy in Scotland.Nephrol Dial Transptant. 2009; 24: 1524-1528Crossref PubMed Scopus (0) Google Scholar and local incidence of other glomerular diseases. An alternate approach to estimate the incidence of IgAN is to use data from national ESRD registries. These data still do not reflect true incidence as only the patients with progressive disease are captured. A subset of patients with ‘hypertension’ as the cause of ESRD may also represent patients with IgAN who never underwent kidney biopsy. In the United States, depending on the state of residence, the incidence of ESRD because of IgAN ranges from 18 to 264 cases per million population (USRDS 2009).47.Kiryluk K. Li Y. Sanna-Cherchi S. et al.Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.PLoS Genet. 2012; 8e1002765Crossref PubMed Scopus (64) Google Scholar The high level of variability between states may be attributable to regional differences in racial/ethnic composition and accessibility to health care, but it may also reflect a general lack of consensus among clinicians on the utility of biopsy in specific clinical settings, resulting in a high degree of regional disparities in biopsy practices even within the United States. Despite these limitations, some important prevalence patterns have clearly emerged.48.Okpechi I. Swanepoel C. 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