IgA Nephropathy: Molecular Mechanisms of the Disease

Městecký, Jiří; Raška, Milan; Julian, Bruce A.; Gharavi, Ali G.; Renfrow, Matthew B.; Moldoveanu, Zina; Novak, Lea; Matoušovic, K; Novák, Jan

doi:10.1146/annurev-pathol-011110-130216

Cited by 115 publications

(144 citation statements)

References 130 publications

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“…27 In recent years, it has become more apparent that IgAN is an autoimmune disease, in which IgA1-containing immune complexes initiate glomerular injury. 28 As in other autoimmune diseases, complement activation has also been reported in IgAN. 19 However, our understanding is limited regarding the precise mechanisms of complement activation in IgAN pathogenesis.…”

Section: Discussionmentioning

confidence: 90%

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Zhu

Zhai

Wang

et al. 2015

Journal of the American Society of Nephrology

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105

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Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1Δ) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1Δ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.

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Section: Discussionmentioning

confidence: 90%

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Zhu

Zhai

Wang

et al. 2015

Journal of the American Society of Nephrology

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125

105

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“…18 As we know, the galactose-deficient IgA1 (GdIgA1), the attributer to IgAN, has a deficiency in the O-glycan located at the Hinge region of IgA1. 19 GdIgA1 combined with its antibodies form circulating immune complex (CIC), which eventually deposit in kidney and cause the renal deterioration.…”

Section: Discussionmentioning

confidence: 99%

The efficacy of tonsillectomy on clinical remission and relapse in patients with IgA nephropathy: a randomized controlled trial

Yang

Peng

et al. 2016

Renal Failure

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Background The efficacy of tonsillectomy in immunoglobulin A nephropathy (IgAN) remains controversial. The aim of the study was to conduct a randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgAN. Methods We randomly selected 98 patients with biopsy-proven IgA nephropathy and randomly allocated to receive tonsillectomy combined with drug therapy (Group A) or drug therapy alone (Group B). The participating patients were entered into a 4-year single-center study. Remission and relapse rate were calculated for hematuria and proteinuria using the Kaplan-Meier method. Results No differences were found between the two groups in their baseline clinical and histological characteristics. Patients with tonsillectomy exhibited considerable improvement in the following aspects compared to those patients who did not undergo tonsillectomy: time to reach first remission (3.1 vs. 24.9 months, p50.001) for hematuria and (2.5 vs. 26.1 months, p50.001) for proteinuria, cumulative remission rate (91.8% vs. 46.9%, p50.001 by log-rank test) for hematuria and (95.9% vs. 51.0%, p50.001) for proteinuria, the duration of first remission (26.5 vs. 11.8 months, p ¼ 0.0047) for hematuria and (23.5 vs. 10.5 months, p ¼ 0.0012) for proteinuria, as well as lower relapse rate for hematuria and proteinuria in Group A. Conclusion Our clinical data demonstrated that tonsillectomy could be beneficial for IgAN patients, particularly by contributing to faster and longer remission, as well as reducing the frequency of possible future relapses.

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“…The pathogenesis of IgAN has recently been reviewed in detail (9)(10)(11). The central mechanism is the generation of nephritogenic immune complexes, whose antigen is a poorly galactosylated form of IgA1.…”

Section: Pathogenesismentioning

confidence: 99%

“…Human IgA1 normally contains 3-6 glycan chains O-linked to a unique proline-rich hinge region between the first and second constant heavy-chain regions (10,11). These glycan chains begin with N-acetylgalactosamine (GalNAc), with the subsequent addition of galactose or sialic acid residues.…”

Section: Pathogenesismentioning

confidence: 99%

“…Molecular mimicry is one hypothesis; the evidence is circumstantial but includes the fact that certain viruses and bacteria express potentially antigenic GalNAc-containing epitopes on their surfaces and observations that exacerbations of hematuria and proteinuria often follow mucosal infections (9). Food-derived antigens have also been implicated (11). Another hypothesis follows from the observation that mesangially deposited IgA1 in IgAN shares several features with normal mucosal IgA1, including relative galactose deficiency.…”

Section: Pathogenesismentioning

confidence: 99%

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Glomerular Diseases

Canetta

Kiryluk

Appel

2014

Clinical Journal of the American Society of Nephrology

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SummaryThe last decade has seen major progress in understanding the pathogenesis as well as the prognosis and treatment of patients with IgA nephropathy (IgAN). Although the diagnostic criterion of a kidney biopsy demonstrating dominant or codominant IgA deposition remains unchanged, much more is known about the genetic and environmental factors predisposing to disease development and progression. These advances have led to the identification of novel diagnostic and prognostic markers. Among the most promising clinically are genetic profiling, quantification of galactose-deficient IgA1 levels, and measurement of anti-IgA1 immunoglobulins. While targeted treatment for IgAN remains elusive, there is mounting evidence for therapeutic interventions that alter the disease course. The appropriate validation and integration of these discoveries into clinical care represent a major challenge, but one that holds tremendous promise for refining prognostication, guiding therapy, and improving the lives of patients with IgAN.

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IgA Nephropathy: Molecular Mechanisms of the Disease

Cited by 115 publications

References 130 publications

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

The efficacy of tonsillectomy on clinical remission and relapse in patients with IgA nephropathy: a randomized controlled trial

Glomerular Diseases

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