How should we measure and interpret glomerular inflammation and what is the best anti-inflammatory approach in IgA nephropathy?

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. The pathogenesis of IgAN is complex, characterized by gut mucosa-kidney interactions that lead to the production of galactose-deficient IgA1 and formation of immune complexes with antiglycan antibodies. Both arms of the adaptive and innate immune system are implicated in modifying or amplifying inflammatory cascades that lead to disease progression. Thus, altering the disease trajectory in IgAN requires therapies that target these underlying inflammatory processes. Broad immunosuppression, including systemic or locally gut mucosa-delivered corticosteroids and mycophenolate mofetil, have demonstrated efficacy in reducing proteinuria, although these are tempered by the risk of adverse effects. More recently, targeted treatment approaches at specific pathways, including complement inhibition and BAFF and/or APRIL inhibitors, have demonstrated promise and are under evaluation. Our ability to measure the degree of glomerular inflammation and predict response to treatment remains limited. To date, the IgA International Risk Prediction Tool remains the gold standard for the prediction of up to 5-year kidney outcomes guided by clinical criteria including proteinuria, estimated glomerular filtration rate and histologic criteria through the MEST-C score. With multiple potential emerging treatments, there is a need for validated biomarkers that reflect the degree of inflammation or IgAN disease activity that may facilitate personalized treatment strategies and improve long-term outcomes.