The current classification of FSGS, or focal segmental glomerulosclerosis, divides the disease into four categories, according to Dr. Campbell. Primary FSGS is thought to stem from a circulating permeability factor, while secondary FSGS arises from drugs, infections, or hemodynamic adaptive changes. Genetic FSGS involves more than 60 identified genes, and a fourth category captures FSGS of undetermined cause.
Dr. Campbell explains that primary FSGS tends to present with a more severe nephrotic syndrome, and researchers have studied candidates including antinephrin antibodies, anti-CD40, suPAR, and apolipoprotein A1B. The framework is overdue for revision, he acknowledges.
Dr. Trachtman reflects on the classification’s origins, noting FSGS was first described by pathologists in the 1950s. Clinicians did not initially recognize the lesion’s poor prognosis, but astute clinical observation identified that patients with this partial glomerular scarring counterintuitively fared worse.
The current framework is a rational, if incomplete, attempt to incorporate what’s now understood about kidney biology, Dr. Trachtman says. Dr. Campbell then reviews the treatment options, noting that until recently, no FDA-approved therapies existed for FSGS.
Clinicians had to extrapolate immunosuppressive regimens and RAS inhibitors from other kidney diseases. Dr. Campbell introduces sparsentan, a dual endothelin type A and angiotensin II type 1 receptor antagonist, explaining the mechanistic rationale for blocking both pathways simultaneously.
Each pathway is independently linked to podocyte injury and fibrosis, Dr. Campbell explains. He traces sparsentan’s 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.
Sparsentan’s approval marks a significant development in the treatment of FSGS, particularly for patients who have limited treatment options.
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Dr. Campbell notes that APOL1 variants function as a genetic modifier rather than a monogenic cause, but carry significant impact in patients of African ancestry.
The treatment setting is complex, and the approval of sparsentan is a significant step forward. As clinicians continue to consider the various treatment options available, they must determine the best course of treatment for each patient.
Sparsentan is a dual endothelin type A and angiotensin II type 1 receptor antagonist. It has been approved by the FDA for FSGS.
Clinicians will continue to study the effects of sparsentan on patients with FSGS. They will also explore other treatment options to improve patient outcomes.
Research is ongoing to develop new treatments for FSGS.
It is a new era for FSGS treatment.
