How should we target and reduce the production of pathogenic IgA in IgAN?

IgA nephropathy represents the most common primary glomerulonephritis worldwide and is characterized by a progressive decline in kidney function, with a large proportion of patients developing kidney failure within their lifetime. Significant progress in the understanding of its pathogenesis has led to a multi-hit model being established, where elevated levels of galactose-deficient-IgA1 (Gd-IgA1), probably from a mucosal source, are found in the circulation and recognized by autoantibodies, leading to the formation of pathogenic immune complexes that deposit within the glomerular mesangium, and subsequent inflammation and damage. Several therapies are currently being developed in IgAN that target the production of pathogenic IgA, including those directed at mucosal B cell priming, inhibitors of the B cell survival mediators APRIL and B cell activation factor, and drugs that target IgA-producing plasma cells. In this review, we describe the production of IgA and summarize the emerging clinical data arising from these strategies.