FSGS Subtypes and Genetics: Why Classification Still Falls Short

In "FSGS Subtypes and Genetics: Why Classification Still Falls Short," the panel breaks down how FSGS is classified and traces the regulatory history behind its first approved therapy.

Dr. Campbell opens by explaining that the current KDIGO classification divides FSGS into four categories, acknowledging the framework is overdue for revision. Primary FSGS, he explains, is thought to stem from a circulating permeability factor that increases glomerular permeability to albumin; researchers have studied candidates including antinephrin antibodies, anti-CD40, suPAR, and apolipoprotein A1B, and this form tends to present with a more fulminant nephrotic syndrome. Secondary FSGS arises from drugs, infections, or hemodynamic adaptive changes that strain the filtration barrier. Genetic FSGS involves more than 60 identified genes encoding podocyte or basement membrane proteins, such as nephrin and podocin; Dr. Campbell notes that APOL1 variants function as a genetic modifier rather than a monogenic cause but carry outsized impact in patients of African ancestry. A fourth category captures FSGS of undetermined cause.

Dr. Trachtman reflects on the classification's origins, noting FSGS was first described by pathologists in the 1950s, when clinicians did not initially recognize the lesion's poor prognosis. He credits astute clinical observation for identifying that patients with this partial glomerular scarring counterintuitively fared worse, and calls the current framework a rational, if incomplete, attempt to incorporate what's now understood about kidney biology. Dr. Campbell then reviews the treatment landscape: until recently, no FDA-approved therapies existed for FSGS, leaving clinicians to extrapolate immunosuppressive regimens and RAS inhibitors from other kidney diseases. He introduces sparsentan, a dual endothelin type A and angiotensin II type 1 receptor antagonist, explaining the mechanistic rationale for blocking both pathways simultaneously, since each is independently linked to podocyte injury and fibrosis. He traces its regulatory path: initial IgA nephropathy approval in February 2023, full approval in September 2024, and full FSGS approval in April 2026, making it the first pharmacotherapy approved specifically for FSGS.

Our next episode, "Corticosteroids, RAS Inhibitors, or Sparsentan First for FSGS?," turns to how corticosteroids and RAS inhibitors fit alongside sparsentan in everyday practice.