IgA nephropathy is the most common primary glomerulonephritis in the world, with an estimated annual incidence of at least 2.5 per 100 000 persons. The pathogenesis of IgA nephropathy is thought to involve 4 factors (or “hits”). First, elevated levels of mucosal circulating galactose-deficient IgA1 (hit 1) are recognized by IgG or IgA autoantibodies (hit 2). Pathogenic galactose-deficient IgA1–auto-Ab immune complexes form (hit 3) that are deposited in the mesangium, causing glomerular injury (hit 4). During immune complex formation, T-cell cytokines, such as a proliferation-inducing ligand, promote B-cell class switching to IgA1-producing plasma cells, while lectin and alternative complement pathways contribute to tissue injury. Genes and susceptibility loci have been identified that are associated with IgA1 production, mesangial deposition, complement activation, and disease progression.
