Bridging pathogenesis and therapy in focal segmental glomerulosclerosis: the rise of dual receptor blockade with sparsentan.

Focal segmental glomerulosclerosis (FSGS) represents a heterogeneous clinicopathological entity characterized by podocyte injury, progressive glomerular scarring, and a high risk of progression to end-stage renal disease. Despite advances in understanding its pathophysiology, therapeutic options have remained limited, largely centered on supportive care and immunosuppression, with inconsistent efficacy and significant adverse effects. The recent approval of sparsentan, a dual endothelin type A and angiotensin II type 1 receptor antagonist, marks a significant advancement in the management of FSGS by targeting key hemodynamic and molecular pathways implicated in disease progression. This article provides a comprehensive overview of the pathogenesis of FSGS, emphasizing the central role of podocyte injury and maladaptive responses to mechanical stress. It further reviews current treatment strategies and examines the clinical evidence underpinning the approval of sparsentan, particularly findings from the DUPLEX trial. Although sparsentan did not demonstrate a statistically significant benefit in preserving estimated glomerular filtration rate, it achieved a clinically meaningful reduction in proteinuria compared with irbesartan. The safety profile was generally acceptable, with manageable adverse effects, including hyperkalemia and hypotension. While sparsentan introduces a novel, non-immunosuppressive therapeutic option, its long-term impact on renal outcomes remains to be fully established. Ongoing research will be critical to defining its role within combination regimens and optimizing patient selection in this complex disease spectrum.