The US Food and Drug Administration approval of sparsentan to reduce proteinuria in adults and children aged 8 years or older with focal segmental glomerulosclerosis (FSGS) without nephrotic syndrome represents a regulatory and therapeutic milestone, but also creates a new clinical challenge: how to translate a US proteinuria-based indication into phenotype-driven practice without treating FSGS as a single disease. DUPLEX established a robust antiproteinuric effect compared with irbesartan, but did not demonstrate a statistically significant between-group difference in eGFR slope at 108 weeks, underscoring the need for careful patient selection. This Perspective argues that the main post-approval task is to define a treatment boundary. Accordingly, sparsentan is best positioned not as a broad FSGS therapy, but as a nonimmunosuppressive antiproteinuric strategy for a delimited phenotype: biopsy-confirmed FSGS, persistent clinically relevant proteinuria, absence of overt nephrotic syndrome, and no clear indication for intensive immunosuppression. Primary nephrotic, secondary/adaptive, genetic, and advanced chronicity-dominant phenotypes require different therapeutic reasoning. We propose a practical framework integrating syndrome definition, exclusion of secondary drivers, genetic assessment, histologic chronicity, early proteinuria response, and safety monitoring. The clinical value of sparsentan in FSGS will depend less on broad adoption than on careful identification of patients in whom proteinuria reduction is likely to reflect a meaningful therapeutic target rather than a nonspecific pharmacodynamic effect.
Corrêa et al. (Mon,) studied this question.