New Insights into the Pathogenesis of IgA Nephropathy

Abstract

Background: IgA nephropathy, a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli and induce renal injury. Multiple genetic loci associated with disease risk have been identified. The prevalence of risk alleles varies geographically: it is the highest in eastern Asia and northern Europe, lower in other parts of Europe and North America, and the lowest in Africa. IgA nephropathy is diagnosed by the pathological assessment of a renal biopsy specimen. Currently, therapy is not disease targeted but rather focused on maintaining control of blood pressure and proteinuria, ideally with suppression of angiotensin II. Possible additional approaches differ between countries. Disease-specific therapy as well as new tools for the diagnosis, prognosis, and assessment of responses to therapy are needed. Summary: Glycosylation pathways associated with aberrant O-glycosylation of IgA1 and, thus, production of autoantigen, have been identified. Furthermore, unique characteristics of the autoantibodies in IgA nephropathy have been uncovered. Many of these biochemical features are shared by patients with IgA nephropathy and Henoch-Schönlein purpura nephritis, suggesting that the two diseases may represent opposite ends of a spectrum of a disease process. Understanding the molecular mechanisms involved in the formation of pathogenic IgA1-containing immune complexes will enable the development of disease-specific therapies as well as diagnostic and prognostic biomarkers. Key Messages: IgA nephropathy is an autoimmune disease caused by the glomerular deposition of nephritogenic circulating immune complexes consisting of galactose-deficient IgA1 (autoantigen) bound by anti-glycan autoantibodies. A better understanding of the multi-step process of the pathogenesis of IgA nephropathy and the genetic and environmental contributing factors will lead to the development of biomarkers to identify patients with progressive disease who would benefit from a future disease-specific therapy.

Rapamycin Enhances Repressed Autophagy and Attenuates Aggressive Progression in a Rat Model of IgA Nephropathy

“…There is growing evidence to show that IgAN is an immune-complex-mediated renal disease [3,4]. In addition to the well-known multihit pathogenesis [2], a variety of factors, such as complement activation and autophagy, are involved in its occurrence and development [5,6,7,8]. …”

IgA1 Glycosylation Is Heritable in Healthy Twins

“…In IgAN patients an increased proportion of IgA1 glycans terminate in N-acetylgalactosamine or sialylated Nacetylgalactosamine. 5,18 This type of IgA1 is termed galactose-deficient IgA1 (gd-IgA1). gd-IgA1 has an established role in the development of IgAN.…”

Variation in complement factor H affects complement activation in immunoglobulin A vasculitis with nephritis

“…Similar to the four hits hypothesis for IgAN proposed by Novak et al , Heineke et al proposed a multi‐hit hypothesis to illustrate the mechanism of IgAVN and IgAV, suggesting that IgAVN is caused by multiple factors. In the four hits hypothesis for IgA nephropathy, galactose‐deficient IgA1 (Gd‐IgA1) is the initiating factor in the development of the disease.…”