Review of the Clinical, Humanistic, and Economic Burden of Focal Segmental Glomerulosclerosis

ABSTRACT

Focal segmental glomerulosclerosis (FSGS) is a progressive glomerular disease characterized by podocyte injury, proteinuria, and risk of kidney failure. Until recently, no medicines had been approved by the FDA or European Medicines Agency, with management focused on supportive care and proteinuria reduction. This supplement explores the burden of FSGS from a clinical, humanistic, and economic perspective, informed by the results of 3 systematic literature reviews. FSGS is associated with poorer quality of life and high health care costs, and these outcomes are correlated with disease severity. Kidney Disease: Improving Global Outcomes guidelines recommend monitoring estimated glomerular filtration rate (eGFR) for kidney function; however, it is acknowledged that given the variable decline in FSGS, eGFR is not an ideal trial end point. Consequently, proteinuria reduction has become the preferred surrogate efficacy end point, as supported by the International Society of Glomerular Disease’s global Proteinuria and Other Biomarkers as Endpoints for Clinical Trials in Kidney Disease initiative and subsequent FDA endorsement. Available treatments, such as glucocorticoids or calcineurin inhibitors, are limited in efficacy and safety. Among emerging medicines, sparsentan, a dual endothelin and angiotensin receptor antagonist (DEARA), has demonstrated consistent and significant reductions in proteinuria among patients with primary and genetic FSGS resulting in its approval by the FDA to reduce proteinuria in adult and pediatric patients aged 8 years and older with FSGS without nephrotic syndrome. In the phase 2 DUET clinical trial (NCT01613118), those treated with sparsentan showed a urine protein–creatinine ratio reduction of –35.6% (95% CI, –46.3% to –24.6%) vs baseline at 240 weeks. Sparsentan also showed greater reductions in proteinuria vs irbesartan, a standard renin-angiotensin system agent, along with a comparable safety profile in the phase 3 DUPLEX trial (NCT03493685). In model-based projections among real-world registry cohorts, sustained reductions in proteinuria are associated with lower long-term risk of kidney failure. These findings align with the PARASOL-FSGS initiative, supporting the role of proteinuria reduction as a key end point, facilitating pragmatic trial designs to address the persistent treatment gap in FSGS.

Am J Manag Care. 2026;32(suppl 7):S126-S137. https://doi.org/10.37765/ajmc.2026.89947

For author information and disclosures, see end of text.

Introduction

Focal segmental glomerulosclerosis (FSGS) is a progressive kidney condition defined by a histological pattern of glomerular and podocyte damage.¹ While FSGS can be classified as primary, secondary, genetic, or FSGS of undetermined cause (FSGS-UC) based on factors including clinical presentation, genetics, imaging, and other secondary causes (Figure),² the underlying etiology of all forms of FSGS result in glomerular lesions mediated by podocyte injury.³ This underlying podocyte injury, or podocytopathy, leads to a variety of symptoms, including proteinuria and worsening glomerular filtration rate, and, if unaddressed, progression to kidney failure.^1,2,4-7

With an estimated United States incidence of primary FSGS of 1.7 per 100,000 patient-years⁸ and global incidence estimates for FSGS ranging from 0.2 to 2.5 per 100,000 population,⁹ FSGS is associated with a profound impact on health-related quality of life across dimensions of physical, emotional, and social well-being.^10,11 Prior to the recent approval of sparsentan to reduce proteinuria in adult and pediatric patients aged 8 years and older with FSGS without nephrotic syndrome,¹² there had been no pharmacological treatments for FSGS approved by either the FDA or the European Medicines Agency (EMA). Instead, management has focused on the reduction of proteinuria to slow the progressive course of the disease.¹³

This article, informed by the results of 3 systematic literature reviews (see eAppendix at ajmc.com for details), explores the burden of FSGS from clinical, humanistic, and economic perspectives.

Burden of Disease

The diagnosis of primary FSGS is established by kidney biopsy demonstrating focal and segmental glomerulosclerosis on light microscopy, accompanied by diffuse podocyte foot process effacement on electron microscopy. Clinically, primary FSGS is typically associated with nephrotic syndrome, characterized by heavy proteinuria (> 3.5 g/day), or hypoalbuminemia, with or without edema, in the absence of identifiable secondary or genetic causes.³ While differentiating between primary and secondary forms of FSGS based on histopathologic features has been inconsistent, diagnosis of secondary FSGS is clearer with identification of possible secondary causes, such as loss of renal parenchyma, metabolic derangements, other antecedent diseases, use of certain drugs, or viral infections. Although not always available, genetic testing may be beneficial to support the identification of patients who have FSGS that is the result of mutations in genes that encode proteins required for the normal structure and/or function of podocytes.³ In the absence of any identifiable characteristics of primary, secondary, or genetic FSGS, a diagnosis of FSGS-UC is warranted.^3,13

The clinical symptoms of FSGS include severe proteinuria, arterial hypertension, edema, and nephrotic syndrome. Historical cohorts of primary FSGS report 10-year renal survival estimates in the approximately 40% to 70% range, with outcomes strongly dependent on achieving remission of proteinuria^13-18; patients who fail to remit are substantially more likely to progress to kidney failure requiring dialysis or transplant.^19-21 Patients presenting with nephrotic-range proteinuria have an even poorer prognosis and, without treatment, typically progress to kidney failure in 3 to 6 years.^22,23 Similarly, lack of response to currently available treatments, such as steroids, has been identified as a negative prognostic sign.²² For patients with genetic FSGS, kidney survival rates are comparably poor, with the rate of progression to kidney failure tending to vary depending on mutation type. Moreover, treatment options are limited, as patients with genetic FSGS are generally resistant to immunosuppressive therapy.

Additionally, recurrent FSGS is a significant complication affecting individuals with primary FSGS following kidney transplantation. Recurrence rates range widely from approximately 6% to 55% of recipients,²⁴ with recurrence linked to poor graft survival.^25,26 Taken together, clinical data show FSGS is a serious clinical condition associated with significant morbidity.²⁷

Humanistic Burden

FSGS is associated with significant negative impacts on quality of life (QOL) for both patients and caregivers. Among adults with FSGS, poorer QOL was observed in both the mental component score (MCS) and physical component score (PCS) of the 36-Item Short Form Health Survey (SF-36) when compared with healthy controls.¹¹ Additionally, patients with FSGS reported worse MCS vs patients with end-stage kidney disease (ESKD) but better PCS.¹¹ Similarly, adults with FSGS also had lower SF-12 MCS and PCS scores vs the average US population, indicating worse QOL.²⁸

As measured by the Patient-Reported Outcomes Measurement Information System, improved QOL across multiple dimensions was observed in children and adults with FSGS based on proteinuria remission status.²⁹ In children, remission status was associated with less pain interference and anxiety. In adults, remission was associated with lower fatigue and better mental health and social satisfaction scores. In contrast, higher disease burden—specifically edema, symptom burden, and more frequent emergency department visits—were predictors of worse QOL.

One study reported Kidney Disease QOL scores among adults with FSGS, reporting lowest mean scores (indicating worse QOL) for burden of kidney disease (45.9 [SD, 29.3]), followed by effects of kidney disease (65.3 [SD, 23.1]), and symptoms/problems (67.9 [SD, 16.0]).²⁸

In children, when QOL was assessed via the Pediatric Quality of Life Inventory, mean scores (range, 65.8 to 72.3) were lower compared with population norms (range, 81.3 to 82.7), indicating poorer QOL; emotional functioning and school functioning were reported to be the most impaired domains.^11,28

One qualitative interview-based study aimed at developing a new patient-reported outcomes (PRO) tool for use in children and adults with FSGS highlighted patient concerns regarding the physical, mental, and social health effects of FSGS.³⁰ Patients reported issues concerning their mental health, primarily anxiety and sadness or depression, and the impact of their disease on relationships, recreational activity, and the feeling of missing out.³⁰

FSGS has also been reported to impact the QOL of caregivers of individuals with FSGS, with lower mental health scores on the SF-12 observed among caregivers of adults and children or adolescents with FSGS compared with general population norms.²⁸ Caregivers, especially those of pediatric patients, reported experiencing ongoing fear or uncertainty about the future due to their caregiving role, with one-third describing the emotional impact of this fear as significant or severe.²⁸

Economic Impact and Managed Care Considerations

FSGS is also associated with a significant economic impact reported among both Medicare and Veterans Affairs (VA) beneficiaries and commercially insured individuals. Higher health care resource utilization (HRU) (including hospitalizations, emergency department visits, skilled nursing facility visits, home health care visits, surgical procedures, and prescriptions) is reported among patients with FSGS compared with matched controls.³¹ Outpatient clinic visits were the most frequently utilized health care service in 2 studies, observed in 97.6% to 99.8% of participants.^32,33

Patients with FSGS incur primarily outpatient costs, followed by inpatient costs.^31,32,34 Mean health care costs per patient per year (PPPY) ranged from $29,834 to $36,543 among VA beneficiaries^32,34 and were as high as $59,753 among commercially insured and Medicare beneficiaries.³¹ Increased HRU and costs are associated with worse disease severity, including higher proteinuria levels and chronic kidney disease (CKD) stage.^31,35 Up to 3-fold greater HRU was observed in patients with nephrotic-range proteinuria vs non–nephrotic-range proteinuria.³¹ In addition to direct cost impacts of FSGS, work productivity is significantly affected; adults with FSGS report higher absenteeism and impairment while working.²⁸

Pharmacy costs varied greatly by study, as low as $356 PPPY among Medicare beneficiaries,³³ and as high as $4440 to $5402 PPPY among VA beneficiaries.³² Total prescription costs PPPY were greater among those with FSGS compared with matched non-FSGS controls ($7294 and $2216, respectively).³¹ Moreover, patients with nephrotic-range proteinuria incur approximately 40% higher prescription costs vs those with non–nephrotic-range proteinuria.³¹

In addition, 2 studies reported an increase in the health care costs of FSGS over time. One study reported a significant increase in both FSGS prevalence and spending, with total health care costs increasing from $49,026 per patient in 2016 to $72,183 in 2020.³⁶ Among these increased costs was a significant increase in prescription costs.³⁶ One study reported a 7.6-fold increase in immunosuppressive medication costs from 2000 to 2013, driven by rising use of calcineurin inhibitors (CNIs), mycophenolate mofetil (MMF), and rituximab, while the use of prednisone and cyclophosphamide dropped during this period.³⁷

Current Treatments and Gaps

Treatment for FSGS focuses on reducing proteinuria to preserve kidney function.³⁸ The most recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines from 2021 recommend supportive treatment for all adult patients with FSGS, comprising use of renin-angiotensin system (RAS) blockade, optimal blood pressure control, and dietary salt restriction.³ With few alternatives, high-dose oral glucocorticoids are recommended as the first-line immunosuppressive treatment for those with primary FSGS. CNIs are recommended for adults with secondary, genetic, or FSGS-UC or for those with primary FSGS and a glucocorticoid resistance or contraindication. For children with FSGS, KDIGO guidelines focus on the treatment of nephrotic syndrome regardless of the underlying disorder and recommend the use of oral glucocorticoids or alternatives if glucocorticoids are contraindicated.

Our review focused on evidence relating to the impact of treatment on estimated glomerular filtration rate (eGFR) and proteinuria (measured as urine protein-creatinine ratio [UPCR] or urine albumin-creatinine ratio [UACR]), with which we identified recognized gaps in the evidence base.

eGFR

KDIGO guidelines recommend monitoring eGFR to assess kidney function in patients with FSGS. However, due to the heterogeneous nature of FSGS, GFR may be highly variable and slow to change, making assessment of therapeutic effects in clinical trials difficult. Immunosuppressants and immunomodulators showed mixed eGFR effects: Several studies suggested stabilization (particularly with MMF), whereas others reported significant declines with specific agents, including cyclosporine and rituximab in certain contexts.

Among immunosuppressant and immunomodulatory therapies, significant increases in eGFR or stable/nonsignificant decreases in eGFR at follow-up have been reported with rosiglitazone, adalimumab or galactose,^39-42 rituximab,^43-45 MMF alone^46-48 or MMF in combination with prednisolone,⁴⁹ other low-dose corticosteroids,⁵⁰ and methylprednisone plus angiotensin blockade,⁵¹ fresolimumab,^52,53 tacrolimus plus prednisolone,⁵⁴ and cyclophosphamide.⁵⁵ In contrast, significant decreases in eGFR have been reported with cyclosporin A,^46,48,56 sirolimus,⁵⁷ and pirfenidone.⁵⁸

Trials investigating the effects of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in FSGS were limited and derived from subgroup analyses within larger CKD trials. Among patients with CKD, including FSGS, the SGLT2i dapagliflozin slowed eGFR decline vs placebo (median annual decline, –1.9 mL/min/1.73 m2/year [95% CI, –3.0 to –0.9 mL/min/1.73 m2/year] vs –4.0 mL/min/1.73 m2/year [95% CI, –4.9 to –3.0 mL/min/1.73 m2/year], respectively),⁵⁹ while similar rates of decline were seen when comparing empagliflozin vs placebo.⁶⁰ Combination therapy protocols showed mixed eGFR outcomes depending on the specific agents used. A significant increase in measured GFR from baseline to follow-up (mean [SD] GFR, 51 [23] mL/min/1.73 m2 vs 76 [22] mL/min/1.73 m2, respectively) was also reported in a small, single-center study (N=18) with combination treatment of an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a calcium channel blocker, and antiplatelet therapy, given with or without heparin.⁶¹

Overall, the impact of therapies on renal function trajectories, reflected by eGFR slope, was variable across treatments and difficult to assess given the frequently short treatment and follow-up horizons in these trials (typically ≤ 2 years).

Proteinuria

With evidence consistently underscoring proteinuria as a central driver of renal progression, it is acknowledged that none of the currently recommended treatment options are uniformly successful in achieving proteinuria remission, and all are associated with serious adverse effects (AEs).^62,63 The International Society of Glomerular Disease’s global PARASOL-FSGS initiative⁶⁴ has led to FDA acceptance of proteinuria as a surrogate end point for FSGS clinical trials.⁶⁵

Among immunosuppressive and immunomodulatory regimens, 12 studies reported UPCR outcomes with heterogeneous results. Across different doses and patient populations, several agents demonstrated proteinuria reductions (UPCR) that were significant, while others showed nonsignificant changes or mixed results. UPCR was observed with rituximab,⁶⁶ fresolimumab,^52,53 cyclosporin A,^46-48 prednisolone,⁴⁹ MMF plus dexamethasone (in adults and children),^47,48 MMF plus low-dose corticosteroids,⁵⁰ MMF plus prednisolone,⁴⁹ and MMF plus methylprednisolone plus angiotensin blockade (in adults and children).⁵¹ Nonsignificant changes were reported with rosiglitazone,³⁹ adalimumab,⁴⁰ and among the C-C chemokine receptor type 2 (CCR2) antagonists DMX-200⁶⁷ and CCX140-B.^68,69

Five studies reported UPCR outcomes for non-RAS blockade, nonimmunosuppressive, or combination therapies. Reductions in UPCR ranged from –48% to –95% with other therapies including HP Acthar gel (6 months),⁷⁰ inaxaplin (13 weeks),⁷¹ and low-density lipoprotein (LDL) absorption (24 months; adults and children),⁷² while a small, single-center study of losmapimod (24 weeks) did not report significant changes in UPCR.⁷³ In a pediatric population, vitamin E supplementation demonstrated a significant (–58%) reduction in UPCR from baseline (P < .005).⁷⁴

Combination therapies, including methylprednisolone plus MMF plus angiotensin blockade, significantly decreased UPCR from baseline (P < .01),⁵¹ while LDL adsorption plus prednisone achieved clinical remission in 7 of 11 children.⁷⁵

Safety

Safety outcomes were reported in 18 studies across multiple intervention classes. The treatments for primary or genetic FSGS were generally well tolerated, resulting in relatively few serious AEs and a low number of deaths in the studies.

Across the evaluated interventions, the proportion of patients experiencing any AE varied widely, depending on the agent and study design. Serious AEs and serious treatment-emergent AEs (TEAEs) were reported in multiple trials, with rates on the higher end being observed with dapagliflozin (9/45 [20%]; median follow-up, 2.4 years),⁵⁹ fresolimumab (3/12 [25%], 252-day follow-up),⁵² rituximab (3/9 [33%], 12-month follow-up),⁷⁶ sparsentan (68/184 [37%], 108-week follow-up),⁷⁷ and irbesartan (82/187 [44%], 108-week follow-up).⁷⁷ Few studies reported rates of AEs or TEAEs leading to discontinuation; these ranged from 0/8 (0%) with DMX-200,⁶⁷ 0/16 (0%) with inaxaplin,⁷¹ 3/45 (6.7%) with dapagliflozin,⁵⁹ 0/14 (0%) to 2/12 (6.7%) with fresolimumab,⁵² 2/73 (2.7%) to 26/184 (14.1%) with sparsentan, 1/36 (2.8%) to 22/187 (11.8%) with irbesartan,^77,78 and 4/6 (66.7%) with sirolimus.⁵⁷

A small phase 2a study among patients with recurrent primary FSGS post-kidney transplantation compared bleselumab plus standard immunosuppression with standard of care.⁷⁹ TEAEs were common in both the bleselumab and standard of care groups (100% and 91.2%, respectively), which included serious TEAEs (55.2% and 47.1%, respectively), drug-related serious TEAEs (27.6% and 17.6%, respectively), and TEAEs leading to treatment withdrawal (24.1% and 8.8%, respectively).⁷⁹

Sparsentan

The DEARA sparsentan has consistently demonstrated reductions in proteinuria, as assessed by UPCR, in clinical trials,^77,78,80 resulting in its recent approval by the FDA to reduce proteinuria in adult and pediatric patients aged 8 years and older with FSGS without nephrotic syndrome.¹² In the randomized, double-blind DUET trial, sparsentan (all doses) achieved significantly greater UPCR reduction compared with irbesartan at 8 weeks (P = .006), with a mean decrease of –44.8% vs –18.5%, respectively.^78,80 The open-label extension demonstrated sustained reduction in UPCR through a median 3.9 years of follow-up, with 41 patients remaining on sparsentan showing a mean UPCR reduction of –35.6% from baseline at 240 weeks, regardless of initial treatment assignment or addition of immunosuppressive therapy.^81,82 The phase 3 DUPLEX trial (N=371) corroborated these findings, demonstrating greater UPCR reduction with sparsentan vs irbesartan after 108 weeks of double-blind treatment (–50.0% vs –32.3%).⁷⁷ Interim results from the ongoing phase 2 EPPIK trial (NCT05003986) extended these observations to an expanded pediatric population (ages 1 year to < 18 years), showing a mean UPCR reduction of –27.2% from baseline after 12 weeks of sparsentan treatment.⁸³

Consistent with the PARASOL-FSGS initiative analyses recommending UPCR as a potential new regulatory approvable end point for interventional trials in FSGS, changes in eGFR with sparsentan were modest despite the significant improvements in proteinuria.^77,78,82 In the phase 3 DUPLEX trial, no significant difference was observed in eGFR slope after 108 weeks of treatment between sparsentan and irbesartan (–4.8 mL/min/1.73 m² vs –5.7 mL/min/1.73 m², respectively).⁷⁷ In the double-blind phase 2 DUET trial, no significant changes in eGFR or QOL (SF-36) vs baseline were observed in those treated with either sparsentan or irbesartan at 8 weeks.^78,84 During the open-label extension phase, among the 45 patients remaining at 240 weeks, median eGFR in those treated with sparsentan declined modestly from 69.4 mL/min/1.73 m² to 57.8 mL/min/1.73 m².⁸²

Recent modeling studies have explored the potential benefits of proteinuria reduction with sparsentan on long-term kidney failure risk.^85,86 These studies examined a real-world cohort of patients from the UK RaDaR registry with biopsy-proven or genetic FSGS and characteristics aligned with the DUPLEX clinical trial criteria. In these models, those with a UPCR of less than 0.3 g/g or
less than 0.7 g/g were associated with a significantly lower risk for kidney failure between 24 and 84 months, with hazard ratios of 0.16 (95% CI, 0.05-0.51) and 0.14 (95% CI, 0.05-0.38), respectively. In addition, for each log unit reduction in UPCR (a decrease of 63%), the associated risk of kidney failure was reduced by 59% (95% CI, 42%-71%). In the context of the DUPLEX trial, which reported a 26% relative reduction in UPCR observed for sparsentan vs irbesartan, this model predicted an estimated 23% reduction for 5-year kidney failure risk for sparsentan vs irbesartan.⁸⁵

Overall, sparsentan, a nonimmunosuppressive DEARA, has demonstrated significant effects on proteinuria. In alignment with the PARASOL-FSGS initiative findings, these proteinuria reductions should translate to slower kidney function decline.^85,86 Sparsentan demonstrated a safety profile broadly consistent with irbesartan, with no clinically meaningful concerns for edema at the 3 doses tested (200 mg, 400 mg, and 800 mg) or for heart failure.^77,78,81,87 Although drug-induced liver injury has been reported with some endothelin receptor antagonists, it was not observed with sparsentan in clinical trials or in available real-world experience; however, ongoing liver function monitoring is required through a Risk Evaluation and Mitigation Strategy program with quarterly assessment of hepatic enzymes. Information on the clinical trials appears in the Table, which begins on page S130.^{39,40,42,44-48,50-53,55,66-75,77,78,80-83}

Conclusion

FSGS represents a significant burden from a clinical, humanistic, and economic perspective. While therapies are limited in FSGS, sparsentan shows promise by lowering UPCR (–50.0% vs baseline at 108 weeks in DUPLEX,⁷⁷ and –35.6% vs baseline at 240 weeks in the DUET open-label extension^81,82), resulting in its recent approval by the FDA to reduce proteinuria in adult and pediatric patients aged 8 years and older with FSGS without nephrotic syndrome.¹² With the observed increase in the prevalence and cost of FSGS, the use of these novel therapies holds promise from both patient and caregiver perspectives and may help lower the substantial HRU and costs associated with FSGS.

Despite extensive clinical investigation, most FSGS trials have not demonstrated significant benefits on eGFR slope, owing to the heterogeneity of disease, limited sample sizes, and short study durations. Across therapeutic classes, treatment effects have generally been partial, with incomplete control of proteinuria and modest preservation of renal function. The cumulative evidence, now reinforced by the longitudinal PARASOL-FSGS data, has established proteinuria reduction as a pragmatic surrogate end point for assessing therapeutic efficacy in FSGS. This paradigm shift enables more feasible trial designs and supports the development of targeted therapies that address the underlying podocytopathy, including dual endothelin angiotensin receptor antagonists.

Author Affiliations: Travere Therapeutics, Inc (MEB, CG), San Diego, CA; Genesis Research Group (CN), Hoboken, NJ.

Source of Funding: This study was funded by Travere Therapeutics, Inc.

Author Disclosures: Dr Bensink is an employee of BenofitConsulting, which receives consulting fees from Travere Therapeutics, Inc. Dr Gisler owns stock and is an employee of Travere Therapeutics, Inc. Mr Navickas was an employee of and paid consultant for Genesis Research Group, which received funding from Travere Therapeutics, Inc, to conduct this study.

Authorship Information: Concept and design (MEB, CG, CN); analysis and interpretation of data (MEB, CG, CN); drafting of the manuscript (MEB, CG); critical revision of the manuscript for important intellectual content (MEB, CG, CN); obtaining funding (MEB); administrative, technical or logistic support (CN); supervision (MAB, CG).

Acknowledgements: Medical writing support was provided by Henry Blanton of Genesis Research Group.

Address Correspondence to: Mark Bensink, PhD. HEOR Lead for Sparsentan, Travere Therapeutics, Inc, 3611 Valley Centre Dr Suite 300, San Diego, CA 92130.Mark.Bensink@travere.com

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