IgAN Pathogenesis: How Each Drug Class Targets the Multi-Hit Pathway

Dr. Wadhwani asks Dr. Cheung how each available drug class targets a different point in the multi-hit pathogenesis of IgAN, and how that thinking guides where each therapy belongs. Dr. Cheung begins with drugs that reduce production of pathogenic IgA and immune complexes. Targeted-release budesonide was the first approved. It is designed to release its maximum dose in the terminal ileum, where Peyer's patches prime the B cells that make pathogenic IgA. Much of it is metabolized in the liver, limiting systemic exposure.

Next come APRIL and BAFF inhibitors, which act on B-cell maturation and class switching to IgA-producing cells, as well as the plasma cells and plasmablasts that secrete antibody. Dr. Cheung notes lots of data on this class at Kidney Week. Agents still in development include anti-CD38 therapies that target plasma cells, along with approaches that aim to degrade galactose-deficient IgA1 and IgA itself.

Complement inhibitors act mainly on glomerular inflammation, although some data suggest effects on tubulointerstitial inflammation and fibrosis. They work at different levels of the cascade. More proximal agents, including an antisense oligonucleotide in a clinical trial, contrast with terminal pathway blockers. On the other side of the algorithm are kidney-protective drugs that manage the general response to nephron loss. These include familiar agents used across chronic kidney disease and newer options that may add anti-inflammatory effects.

Dr. Wadhwani calls this a good problem to have compared with six to ten years ago, when clinicians had mainly RAS inhibitors and corticosteroids. She notes that some regions still rely on lower-dose corticosteroids, while the new armamentarium offers greater efficacy and a better safety profile.

In "2025 KDIGO Guidelines in IgAN: Treatment Selection and Overcoming Inertia," the panel will turn to the 2025 KDIGO framework and how Dr. Geara and Dr. Cheung choose among six targeted therapies.