In April 2026, the US Food and Drug Administration (FDA) approved sparsentan to reduce proteinuria in adults and children aged 8 years or older with focal segmental glomerulosclerosis (FSGS) without nephrotic syndrome, closing a historic US regulatory gap but not simplifying the clinical problem.1,2 The indication – to reduce proteinuria in patients aged 8 years or older with FSGS without nephrotic syndrome – was supported by DUPLEX, in which sparsentan achieved higher rates of partial proteinuria remission than maximally dosed irbesartan, although no statistically significant difference in the estimated glomerular filtration rate (eGFR) slope was observed at 108 weeks.1–3 This dissociation makes a simplified interpretation of the trial untenable.3–5 A drug that reduces proteinuria more effectively than an active comparator, without demonstrating a corresponding benefit on kidney function decline, should not be framed as a universal standard for FSGS; its clinical value depends on how carefully the eligible phenotype is defined.3–5 Approval therefore ended the era in which no therapy was approved for FSGS, but inaugurated the era of phenotypic selection.1,2 The central post-approval question is not whether sparsentan reduces proteinuria, but where its use should define a new treatment boundary between nonimmunosuppressive antiproteinuric therapy, conventional immunosuppression, and optimized supportive care.1–5

The need for selection does not arise from approval itself, but from the biological heterogeneity concealed beneath the diagnostic umbrella of FSGS.6–8 FSGS is not a single disease, but rather a histologic pattern in which biologically distinct processes converge on podocyte injury and segmental sclerosis.6–8 Primary, genetic, secondary/adaptive, and undetermined forms may overlap morphologically, yet differ in pathogenesis, clinical trajectory, and plausibility of response to a dual endothelin and angiotensin receptor antagonist.6–8 The post-approval clinical problem, therefore, is not simply to choose a drug; it is to avoid treating patients with fundamentally different disease mechanisms as though they shared the same therapeutic substrate.6–8 A regulatory indication identifies a population in which the benefit–risk profile was judged acceptable; it does not eliminate the need to define the biological substrate of FSGS at the bedside.1,2,6–8 Any prescribing algorithm that incorporates sparsentan without first clarifying phenotype, mechanism, and chronicity risks converting a specific proteinuria-based approval into a nonselective therapeutic standard.6–8

Following sparsentan approval, the distinction between nephrotic-range proteinuria and overt nephrotic syndrome has gained renewed practical importance in the evaluation of FSGS.9 Pathophysiologically, primary FSGS is associated with the abrupt presentation of the full syndrome – characterized by hypoalbuminemia, edema, and diffuse podocyte foot process effacement – reflecting extensive cellular injury.6,9 By contrast, maladaptive and secondary forms arise from hemodynamic overload, manifesting with high-grade proteinuria but only rarely with the complete nephrotic syndrome.6,7,9 This distinction prevents management from being reduced to a numerical UPCR threshold.6,7,9 In FSGS, the syndrome-level phenotype – proteinuria, serum albumin, edema, tempo of presentation, and extent of foot process effacement – determines whether the lesion is more consistent with acute primary podocytopathy, maladaptive stress, genetic disease, or an undetermined-cause phenotype.6,7,9

The absence of nephrotic syndrome should not be interpreted as synonymous with low risk or a benign course.10,11 Although this presentation has historically been regarded as less aggressive, contemporary data indicate that these patients may experience kidney outcomes as severe as those observed in syndromic disease, with progression to renal replacement therapy (RRT) occurring in approximately 26.8% of cases.10,11 This adverse outcome is concentrated among cases with substantial chronicity and tubulointerstitial fibrosis on biopsy, encompassing secondary and genetic forms with insidious progression.6,10 Because organ failure is driven by the sustained burden of proteinuria, persistent levels above 1.5–3.5g/day predict kidney deterioration.12 Thus, non-nephrotic FSGS is clinically dangerous for two opposing reasons: it may be undertreated when interpreted as benign proteinuria, but overtreated when histologic FSGS is equated with primary immune-mediated disease.6,10,12 This dual risk is precisely what makes the non-nephrotic phenotype the key post-approval treatment boundary.6,10,12

The evidence base for sparsentan in FSGS is strong enough to change the therapeutic conversation, but not strong enough to remove the need for phenotype-based selection.3–5 In DUET, sparsentan produced greater short-term proteinuria reduction than irbesartan and increased the proportion of patients reaching the FSGS partial remission endpoint.13 DUPLEX confirmed a sustained antiproteinuric advantage, with higher partial remission at 36 weeks and greater UPCR reduction through 108 weeks, but did not demonstrate a statistically significant between-group difference in total eGFR slope at 108 weeks.3,14 This pattern supports sparsentan as a potent antiproteinuric therapy, while leaving unresolved the central post-approval question: in this setting, proteinuria reduction should be interpreted as a necessary pharmacodynamic signal, but not as sufficient proof that dual endothelin–angiotensin receptor antagonism will produce durable kidney protection across biologically heterogeneous FSGS phenotypes.4,5

In post-approval practice, sparsentan should be framed as a boundary-defining therapy rather than a category-wide FSGS therapy.3–5 The most defensible candidate is the patient in whom four conditions converge: biopsy-confirmed FSGS; persistent clinically relevant proteinuria, typically aligned with the DUPLEX threshold of UPCR ≥1.5g/g; absence of overt nephrotic syndrome; and no clear clinical indication for intensive immunosuppression after exclusion of primary nephrotic, maladaptive, viral, drug-induced, and other secondary drivers.3,6,7,14 Patient selection should also be understood as dynamic rather than static.4,15,16 DUET extension and remission analyses suggest that early achievement of partial or complete proteinuria remission may identify patients with a more favorable subsequent kidney trajectory; however, no threshold has been validated as a mandatory stop-or-continue rule in post-approval practice.4,13,15,16 A pragmatic, explicitly nonvalidated reassessment point is to evaluate treatment response after approximately 8–12 weeks, asking whether UPCR has fallen by roughly ≥40% and/or is moving toward the FSGS partial remission endpoint, defined as UPCR ≤1.5g/g with >40% reduction from baseline.4,13,15,16 Failure to meet this threshold should not automatically mandate discontinuation, but it should trigger reassessment of adherence, blood pressure and sodium control, competing mechanisms of proteinuria, safety, and whether continued therapy remains biologically plausible and clinically worthwhile.4,15,16 Thus, sparsentan use after approval should be framed not only as phenotype-conditioned initiation, but also as response-conditioned continuation.4,15,16 It is a pragmatic post-approval framework designed to prevent two errors: reflexive immunosuppression in non-nephrotic disease and reflexive sparsentan use in biologically discordant FSGS phenotypes.6–8 In light of contemporary data, the most consistent clinical niche for sparsentan appears to lie in an intermediate population: patients with FSGS and persistent proteinuria, but without nephrotic syndrome, in whom immunosuppression is not clearly indicated and whose long-term risk may remain clinically consequential despite optimized supportive care.7,12

The post-approval era makes untenable the simplistic view that genetic FSGS is equivalent to therapeutic futility.8,17 A recent exploratory analysis of DUPLEX in patients with pathogenic or likely pathogenic genetic variants demonstrated a consistent antiproteinuric signal with sparsentan: at 36 weeks, the median reduction in UPCR was 56% in the sparsentan group versus 26% in the irbesartan group, with a treatment difference of −47% (95% CI, −72% to −5%; P=0.03).17 At 108 weeks, the median reduction was 64% versus 38%, respectively, with a treatment difference of −40% (95% CI, −68% to 2%; P=0.06), a nominally non-significant result that should be interpreted as exploratory rather than guideline-directive.17 However, this was a post hoc, exploratory analysis of the DUPLEX subset with genetic-associated FSGS, in which next-generation sequencing identified 31 patients with podocyte gene variants, 25 with COL4A3–COL4A5 variants, and 14 with apolipoprotein L1 (APOL1) high-risk genotypes. Because baseline characteristics varied across genetic subgroups and the analysis was exploratory, these findings should not be overinterpreted as definitive evidence of uniform benefit across all type IV collagen, podocyte-gene, and APOL1-risk contexts.8,17 The post-approval question is no longer whether genetics excludes treatment by definition, but which genotypes and clinical contexts remain plausible for antiproteinuric benefit.7,8,17 This does not authorize gene-agnostic extrapolation: patients with genetic FSGS should avoid unnecessary immunosuppression, but may be reasonable candidates for sparsentan when they have persistent proteinuria and preserved kidney function.7,8,17 The value of these preliminary data is not to justify genotype-agnostic prescribing, but to move the field beyond the false binary in which genetic FSGS is either automatically untreatable or treated as biologically equivalent to primary disease.7,8,17 Genotypic precision should determine whether sparsentan is a plausible antiproteinuric strategy, whether immunosuppression should be avoided, and which outcomes should be considered realistic.7,8,17

The traditional FSGS algorithm remains strongly anchored in KDIGO guidelines, which recommend high-dose glucocorticoids as first-line therapy for primary disease, reserving calcineurin inhibitors (CNIs) as an alternative or rescue strategy in specific settings of resistance or intolerance.7 However, this deeply entrenched clinical tradition coexists with an evidence base that is considerably less robust than many nephrologists assume.18,19 A Cochrane Database systematic review demonstrated the scarcity of randomized clinical trials directly comparing corticosteroids with placebo or strictly conservative supportive care in adults with FSGS.18 In addition, recent meta-analyses highlight profound uncertainty regarding the true efficacy of immunosuppressive therapy in preserving long-term hard kidney outcomes in nonspecific settings, in stark contrast to the well-documented cumulative toxicity of these regimens.19 Systemic adverse effects, ranging from incident diabetes to osteoporosis and infectious morbidity, are highly prevalent and substantially compromise overall patient health in proteinuric kidney diseases, thereby driving the current nephrology-wide effort toward global glucocorticoid minimization.20,21 It is within this landscape of evidentiary fragility and toxicity that dual endothelin and angiotensin receptor antagonism is positioned.3,18–21 Sparsentan does not enter an empty therapeutic field; it enters a field in which the boundary between immune-mediated podocytopathy and nonimmune proteinuric progression is often clinically blurred.3,7,18,19 Its most important post-approval contribution may therefore be not the replacement of immunosuppression, but the requirement that nephrologists define more explicitly when immunosuppression is biologically justified, when it is avoidable, and when supportive antiproteinuric therapy is the more coherent strategy.3,7,18,19

In this sense, recalibrating the therapeutic armamentarium requires refined pathophysiologic reasoning in daily clinical practice.6,7,22 The residual role of immunosuppression remains well established in adult patients with a clinical presentation highly suggestive of acute primary podocytopathy, provided that secondary causes have been excluded through coherent clinicopathologic assessment.22 Historically, it is in this restricted population that immunosuppressive intensity has shown the greatest capacity to induce complete remission, with consequent effects on functional preservation.23 Conversely, within the clinical spectrum of non-nephrotic FSGS, particularly when phenotypic features point toward a maladaptive, genetic, or undetermined etiology, the rationale for early exposure to prolonged courses of corticosteroids or CNIs becomes less automatic and fundamentally less defensible, supporting the growing incorporation of systematic genetic testing to avoid futile therapies.6,24 In these more insidiously progressive patients, in whom subnephrotic proteinuria reflects secondary glomerular scarring and mechanical stress more than acute immune-mediated inflammation, sustained reduction of proteinuric and hemodynamic stress becomes a central priority of nephroprotective management.25 In this context, targeting pathways that modulate intrarenal hemodynamics may help reduce proteinuric stress without the heavy burden of immunosuppression.3,25 Thus, sparsentan approval should not be interpreted as an argument against immunosuppression in primary nephrotic FSGS.7,22,23 Rather, it sharpens the question of where immunosuppression remains justified.7,22,23 In non-nephrotic FSGS with maladaptive, genetic, chronicity-dominant, or undetermined features, prolonged corticosteroid or CNI exposure should require a higher evidentiary threshold, whereas nonimmunosuppressive antiproteinuric therapy becomes a more coherent initial strategy when safety conditions are met.6,7,22–25

The first post-approval step should not be prescription, but classification.6,7 Clinicians should confirm that the biopsy shows true FSGS rather than focal global glomerulosclerosis, define whether the patient has overt nephrotic syndrome, and integrate electron microscopy, serum albumin, edema, tempo of presentation, and tubulointerstitial chronicity before assigning a therapeutic path.6,7,26 Secondary and adaptive drivers – including obesity, reduced nephron mass, long-standing hypertension, reflux nephropathy, viral infection, drug exposure, hyperfiltration injury, and early type IV collagen disease – should be systematically assessed because they change both the rationale for immunosuppression and the expected meaning of proteinuria reduction.6–8,24,25 Only after this classification step should clinicians choose among three paths: immunosuppression for convincing primary nephrotic disease; sparsentan or other optimized antiproteinuric therapy for persistent non-nephrotic proteinuria without a clear immune target; or driver-directed supportive care when a secondary mechanism dominates.3–7,24,25 This sequence converts sparsentan approval from a drug-centered event into a phenotype-centered decision framework.3–5,7 Because the regulatory indication includes children aged 8 years or older, this framework should be applied across age groups with age-specific and developmental caution.1,2,7,14,24 In pediatric patients, treatment selection should additionally account for weight-based dosing and titration, growth and pubertal development, school-age medication routines, caregiver capacity, reproductive counseling when applicable, adherence during adolescence, and transition to adult care.1,2,7,14,24 Pediatric use should therefore not be treated as simple extrapolation of adult FSGS practice; it requires family-centered monitoring of blood pressure, edema and volume status, kidney function, potassium, liver enzymes, and early proteinuria response.1,2,7,14,24Fig. 1 summarizes this post-approval treatment-boundary framework by separating FSGS heterogeneity, the most plausible sparsentan niche, and the corresponding therapeutic implications.3–7Table 1 translates this framework into common post-approval clinical scenarios and decision safeguards.3–8,14,24,25

Fig. 1.

Where sparsentan fits in focal segmental glomerulosclerosis without nephrotic syndrome. Sparsentan approval creates a need for phenotype-driven treatment selection rather than category-wide prescribing. The framework emphasizes that focal segmental glomerulosclerosis (FSGS) is biologically heterogeneous and that phenotype should precede treatment selection. Sparsentan is best positioned as a nonimmunosuppressive antiproteinuric strategy when biopsy-confirmed FSGS, persistent proteinuria, absence of overt nephrotic syndrome, and no clear indication for intensive immunosuppression coexist. Patients with convincing primary nephrotic FSGS remain candidates for immunosuppression, whereas patients with secondary/adaptive dominant disease require driver-directed supportive care. Proteinuria reduction supports therapeutic relevance but should not be interpreted as proof of durable kidney benefit across all FSGS phenotypes.

In the post-approval setting, the introduction of sparsentan shifts the focus from isolated efficacy to a more decisive question: which patients with FSGS without nephrotic syndrome should receive it, at what point, and in place of which potentially avoidable immunosuppressive exposure.3,18–21,28 In this context, the evidence agenda should prioritize comparisons across subphenotypes to avoid inappropriate extrapolation.3,28,29 It also requires validation of clinicopathologic selection criteria and integration of genetic data and biomarkers to refine risk stratification.30,31 Therefore, endpoints must move beyond proteinuria, incorporating kidney disease progression, toxicity, and quality of life.4,32

A further post-approval gap is the absence of validated response-enrichment tools.4,32 Genetic testing can prevent inappropriate immunosuppression and refine expectations, but genotype alone is unlikely to capture the full biological substrate of sparsentan responsiveness.6,8,17,24,31 Experimental and translational studies suggest that dual endothelin–angiotensin receptor antagonism may influence glomerular hemodynamics, podocyte and endothelial cell function, inflammatory signaling, and tissue-repair pathways; however, these observations remain hypothesis-generating for clinical selection.33,34 Future studies should therefore test whether clinical phenotype, genotype, histologic chronicity, and noninvasive biomarkers can be integrated into a response-enrichment model rather than applied as isolated variables.4,5,30–32

Real-world observational data will therefore be essential to determine whether – and in which scenarios – specific immunosuppressive exposures can be safely avoided.28,32 If the pre-approval era was defined by the absence of an approved therapy, the post-approval era should be judged by the precision of its use.3–5,28,32 The success of sparsentan in FSGS will depend less on how broadly it is prescribed than on whether nephrologists can identify the phenotype in whom proteinuria reduction is a meaningful surrogate for durable kidney benefit – and avoid exposing biologically discordant patients to either unnecessary immunosuppression or poorly targeted drug adoption.4,5,28,32

Finally, translation of the FDA approval into European practice should be explicitly jurisdiction-specific. At the time of revision, the European Medicines Agency (EMA) public product information listed Filspari as authorised in the European Union for adults with primary IgA nephropathy, whereas an EMA-authorised FSGS indication was not publicly listed.35 Thus, for Spanish and European nephrologists, the FDA label is clinically informative but should not be treated as a European prescribing authorisation. Until an EMA decision, national availability, reimbursement, and any FSGS-specific risk-minimisation measures are clarified, use in Europe should be limited to locally authorised pathways, clinical trials, compassionate or managed-access mechanisms where available, and institutionally approved off-label frameworks.35 Potential European implementation may also differ from the US label in age range, indication wording, pharmacovigilance requirements, additional monitoring, and reimbursement criteria.35 This regulatory gap reinforces, rather than weakens, the central argument of this review: sparsentan should be implemented through phenotype-driven selection, response reassessment, safety monitoring, and equitable access pathways rather than diagnosis-wide adoption.1,2,35

This evidence agenda is also consistent with the fact that KDIGO has initiated renewed FSGS-focused discussion after the 2021 Glomerular Diseases guideline, including a dedicated FSGS summit in May 2026, although no formal FSGS guideline update has yet replaced the 2021 KDIGO recommendations.7,36

Research idea and study design: LMAC and SLPA; literature acquisition: LKVB, YRDS, CCSF, IMP, EVBS, GWF, MCNM; data analysis/interpretation: LMAC, LKVB, YRDS, CCSF, IMP, EVBS, GWF, MCNM; statistical analysis: not applicable; supervision or mentorship: LMAC and SLPA. Each author contributed important intellectual content, approved the final manuscript for submission, and agrees to be accountable for their own contributions.

Not applicable.

Not applicable.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

None declared.

No new data were generated or analysed for this article.