IgAN Pathogenesis and the Rationale for Complement Inhibition

In "IgAN Pathogenesis and the Rationale for Complement Inhibition," our experts connect disease mechanism to drug targets.

Dr. Rovin walks through the multi-hit hypothesis, once called the four-hit model. Hit one is elevated circulating galactose-deficient IgA1, likely overproduced at mucosal surfaces like the gut and respiratory tract. Hit two is autoantibodies, IgG or IgA, forming immune complexes against that antigen in predisposed individuals. Hit three is deposition of those complexes in the mesangium. Once there, he explains, they initiate pro-inflammatory and pro-fibrotic pathways that cause damage, proteinuria, hematuria, and GFR decline. Dr. Parikh maps the approved therapies onto this cascade. B-cell drugs, anti-APRIL, and budesonide act early, endothelin antagonists and RAS/SGLT2 protect the kidney, and complement blockers hit another node. He notes six therapies are now on the market across these targets. He then asks Dr. Mehdi why complement matters in IgA nephropathy, admitting the rationale first puzzled him. Dr. Mehdi explains that over 90% of biopsies show intense C3 co-staining with IgA. He notes robust evidence for alternative-pathway activation, since mesangial immune complexes activate complement. He cites elevated factor B fragments, Ba and Bb, and C3 with little C1q, pointing to the alternative rather than classical pathway. He adds that factor H mutations worsen disease while a protective factor H-related variant reduces risk. Dr. Mehdi describes iptacopan, a factor B inhibitor targeting the core of the amplification loop. Dr. Rovin and Dr. Parikh emphasize a key qualification: complement is an amplifier, not the disease driver. They note elevated urinary C5b-9 terminal complement and that C5 inhibitors are also in advanced trials. Blocking factor B upstream, they explain, attenuates C3 and C5 convertases and downstream deposition.

Up next, in "Complement Inhibition in IgAN: Interpreting the APPLAUSE Trial," Dr. Fervenza and Dr. Rovin interpret the APPLAUSE trial and debate where complement inhibition fits.