In this episode of Clinical Countdown, Professors Jonathan Barratt and Sydney Tang discuss the evolving treatment strategies for IgA nephropathy, focusing on lowering proteinuria through combination therapy. They examine differences in disease presentation across global populations and emphasize updated KDIGO guidance on aggressive proteinuria reduction targets. The discussion includes evidence from the PROTECT trial supporting sparsentan’s efficacy as a dual endothelin–angiotensin receptor antagonist and considers the role of SGLT2 inhibitors based on outcomes from the DAPA-CKD and EMPA-KIDNEY trials. Our experts also review recent real-world data showing that when added to SGLT2 inhibitors and RAS blockade, sparsentan can significantly reduce proteinuria without notable safety concerns.