Treatment of Patients with IgA Nephropathy: A call for a new paradigm

IgA nephropathy (IgAN), the world's most common primary glomerular disease, carries a significant lifetime risk for kidney failure as well as an enormous socioeconomic burden. In the past, studies in patients with IgAN largely focused on optimizing so-called supportive care, i.e. blockade of the renin-angiotensin system (RAS), blood pressure control and lifestyle modifications. The effectiveness of immunosuppressive measures, particularly high-dose corticosteroid therapy, has been reported variably, but there is considerable evidence for an increase in serious adverse effects with such therapies. This disappointing situation has changed dramatically with better understanding of the pathogenesis of IgAN, and with regulatory agencies accepting changes in proteinuria and the eGFR loss or slope over 2-3 years as surrogate outcome markers. A multitude of new therapies are now being evaluated in IgAN, and several drugs, such as sodium-glucose transporter-2 inhibitors, sparsentan (a dual endothelin-1 and angiotensin II receptor blocker), nefecon (a targeted release formulation of budesonide) and iptacopan (a complement factor B inhibitor) have been approved, with more to come in the next few years. In this review, we propose a new treatment paradigm that combines therapies with different mechanisms of action to target the immune components and the chronic kidney disease components of IgAN in parallel to preserve long-term kidney survival.