Breaking tolerance in the glomerulus: complement as a driver and therapeutic target in IgA nephropathy

IgA nephropathy is an autoimmune kidney disease caused by failure of mucosal tolerance, abnormal IgA1 glycosylation, and formation of anti-glycan autoantibodies. The main pathogenic process is the deposition of galactose-deficient IgA1 complexes in the glomerular mesangium, with IgA2 also contributing to the disease. The complement system in IgA nephropathy is activated through classical, lectin, and alternative pathways, with the alternative pathway capable of independent activation. Complement activation in the glomerular mesangium leads to damage of endothelial cells, leukocytes, and podocytes, ultimately causing proteinuria, sclerosis, and fibrosis. Complement biomarkers correlate with specific histological changes. New therapies targeting individual components of the complement system (MASP-2, factor B, C5aR, and C5) should complement optimized supportive care and modulation of the IgA axis.