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Pathogenesis of IgA nephropathy

Nature Reviews Nephrology volume 8, pages 275–283 (2012)Cite this article

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Abstract

Since its first description in 1968, IgA nephropathy has remained the most common form of idiopathic glomerulonephritis leading to chronic kidney disease in developed countries. The exact pathogenesis of IgA nephropathy is still not well defined. Current data implicate an important genetic factor, especially in promoting the overproduction of an aberrant form of IgA1. The immunochemical aberrancy of IgA nephropathy is characterized by the undergalactosylation of O-glycans in the hinge region of IgA1. However, such aberrant glycosylation alone does not cause renal injury. The next stage of disease development requires the formation of glycan-specific IgG and IgA antibodies that recognize the undergalactosylated IgA1 molecule. These antibodies often have reactivity against antigens from extrinsic microorganisms and might arise from recurrent mucosal infection. B cells that respond to mucosal infections, particularly tonsillitis, might produce the nephritogenic IgA1 molecule. With increased immune-complex formation and decreased clearance owing to reduced uptake by the liver, IgA1 binds to the glomerular mesangium via an as yet unidentified receptor. Glomerular IgA1 deposits trigger the local production of cytokines and growth factors, leading to the activation of mesangial cells and the complement system. Emerging data suggest that mesangial-derived mediators following glomerular deposition of IgA1 lead to podocyte and tubulointerstitial injury via mesangio–podocytic–tubular crosstalk. This Review summarizes the latest findings in the pathogenesis of IgA nephropathy.

Key Points

  • IgA nephropathy is mediated by the deposition of IgA1 immune complexes

  • Increased synthesis of aberrantly galactosylated IgA1 is the first step in disease pathogenesis and remains fundamental to the formation of immune complexes

  • The formation of glycan-specific IgG and IgA antibodies that recognize the undergalactosylated IgA1 is required for the development of disease

  • Genetic factors heavily influence the production of undergalactosylated IgA1 and familial clustering of IgA nephropathy is well recognized

  • The initial event of mesangial deposition of IgA1 immune complexes induces injury to podocytes and renal tubular epithelial cells via a mesangio–podocytic–tubular crosstalk involving various mediators

  • The tubulointerstitial injury that follows chronic inflammation subsequently leads to end-stage renal disease

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Figure 1: Proposed pathways involved in the mesangial deposition of IgA1 in IgA nephropathy—a multihit mechanism.
Figure 2: Microheterogeneity of the O-glycans in the hinge region of IgA1.
Figure 3: Proposed pathways leading to glomerular damage, podocyte dysfunction and tubulointerstitial injury in IgA nephropathy.

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Lai, K. Pathogenesis of IgA nephropathy. Nat Rev Nephrol 8, 275–283 (2012). https://doi.org/10.1038/nrneph.2012.58

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