Dr. Parikh introduces atrasentan, an endothelin receptor antagonist approved in April 2025, and asks how it differs mechanistically. Dr. Rovin explains that immune complexes in the mesangium activate the renin-angiotensin pathway, which is pro-inflammatory, pro-fibrotic, and vasoactive. The endothelin pathway is activated simultaneously along nearly the same routes. Blocking both, he argues, makes sense for reducing kidney injury, the rationale behind sparsentan and atrasentan. Dr. Rovin reviews the ALIGN trial, which showed a profound proteinuria effect driving accelerated approval. The GFR slope improved numerically by about 2.5 milliliters but did not reach statistical significance overall. On top of an SGLT2 inhibitor, however, the effect on GFR decline appeared profound, with the caveat of small numbers. He frames the class as a long-term add-on with limited immunosuppressive burden, likely safe alongside immunologic therapy. Dr. Rovin notes the main side effect concern is fluid retention, though edema was 14% versus 12% in controls. He suggests pairing with an SGLT2 inhibitor may offset that. Dr. Parikh asks whether an ERA plus RAS should now be first-line. Dr. Rovin says two large trials show the combination beats RAS alone for proteinuria, but cost is the deciding factor. He acknowledges US clinicians are privileged with access and insurance coverage most of the time. Dr. Mehdi raises the practical burden of prior authorizations and the difficulty of simply sending patients to the pharmacy. On sparsentan versus atrasentan, Dr. Mehdi says he generally does not differentiate. Dr. Parikh notes dual blockade in one pill aids adherence, but separate agents allow dose adjustment when blood pressure will not tolerate both.

Our next episode, "B-Cell Therapy in IgAN: APRIL, BAFF, and the VISIONARY and ORIGIN Trials," turns to the B-cell therapies, with Dr. Rovin explaining why targeting APRIL and BAFF succeeded where anti-CD20 failed.