Treating IgA Nephropathy: Looking at the Future Without Forgetting the Past

IgA nephropathy (IgAN) is an inflammatory glomerular disease due to production of galactose-deficient IgA1 (Gd-IgA1) which induces formation of autoantibodies and IgA immune complexes (IgAIC) finally deposited in the mesangium. This event triggers mesangial cell proliferation, cytokine release and complement activation, glomerular and interstitial damage leading to kidney function decline. Persisting proteinuria is the most relevant marker of disease progression. The powerful anti-inflammatory approach with systemic corticosteroids (CS) in patients with IgAN at risk of progression with persistent proteinuria provided kidney function protection in early trials. However, subsequent studies raised alarm on severe adverse events associated with high doses of methylprednisolone doses or reported limited long-term benefits. This led to KDIGO 2021 guidelines conclusion to limit CS to selected patients who accepted the high risk of adverse events. The scenario changed when reduced doses of methylprednisolone associated with Pneumocystis prophylaxis reported benefits on kidney function like methylprednisolone full doses and limited adverse events. Finally, an innovative approach to steroid therapy in IgAN was offered by a budesonide formulation targeting the Peyer’s patches, major site of production of Gd-IgA1. The benefits were like those obtained with systemic CS administration, with valuable limitations of adverse events. A series of new drugs targeting the pathogenetic events of IgAN are under investigation and exciting reports have been published over the last months. The new targets include B cell activation with production of Gd-IgA1, the complement cascade triggered by deposited IgAIC and the endothelin system, a multipotential kidney damage amplifier system perpetuating chronicity of IgAN.