B-cell modulators in immunoglobulin A nephropathy

Immunoglobulin A nephropathy (IgAN), defined by mesangial immune-complex deposition enriched for galactose-deficient IgA1 (Gd-IgA1), is the most prevalent biopsy-confirmed primary glomerulonephritis worldwide. Advances in mucosal immunobiology and genetics have underscored the role of dysregulated B-cell activity, increased Gd-IgA1 production, and corresponding Gd-IgA1-specific autoantibodies in the pathogenesis of IgAN. Therapeutic strategies targeting the mucosal immune system, particularly pathways involved in B-cell survival and differentiation, offer a specific approach to disease modification based on our understanding of its pathogenesis. Emerging therapies, including agents targeting gut-associated lymphoid tissue, antagonists of B-cell activating factor (BAFF) and/or a proliferation-inducing ligand (APRIL), and B-cell depletion therapies like anti-CD38 monoclonal antibodies, have demonstrated promising positive results across multiple clinical trials at various stages of development. In this review, we highlight targeting the underlying immunology of IgAN pathogenesis and shed light on newly emerging B-cell modulators for the treatment of the disease.