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FSGS in Focus: Drivers of Progression and the Patient Burden

Published on March 25, 2026

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Nephrology FSGS
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Welcome by Dr George Vasquez-Rios

In FSGS, podocyte injury activates a self-perpetuating cycle that drives disease progression and kidney damage1-6

FSGS is a rare, progressive, kidney condition characterized by a histological pattern of podocyte and glomerular injury that results in a variable degree of proteinuria and often concomitant nephrotic syndrome at presentation.7,8 Although FSGS represents a heterogeneous group of conditions with diverse etiologies, it is unified by a shared feature: podocyte injury.9,10 Podocyte injury in FSGS may arise from immune-mediated, genetic, hemodynamic, or circulating permeability factors, ultimately disrupting the integrity of the glomerular filtration barrier.2,7

FSGS

Introduction to FSGS

Hear Dr. Howard Trachtman discuss FSGS classification, the role of podocyte injury, and treatment challenges that patients face

Listen now

In FSGS, early podocyte stress can promote enhanced endothelin-1 (ET-1) and angiotensin (Ang II) signaling, activating inflammatory pathways that perpetuate glomerular damage and disease progression.1-4 Within this cycle, Ang II activates ET-1 production in a positive feedback loop, promoting perpetual upregulation and continuous pathway activation.1,3,11 Signaling through the endothelin type A (ETA) and angiotensin type 1 (AT1) receptors then propagates further podocyte injury, leading to podocyte detachment and apoptosis.1,6,12 As podocyte loss accumulates, integrity of the filtration barrier declines, resulting in worsening proteinuria.1,6,12 Collectively, these mechanisms sustain a self-perpetuating cycle of ongoing podocyte injury, persistent proteinuria, and progressive kidney damage.2-5

Figure. FSGS mechanism of disease

FSGS

From Podocyte to Patient: The Pathophysiology of FSGS

Listen to Dr. Tobias Huber discuss the role of ET-1 and Ang II signaling in FSGS disease progression

Listen now

Real-world evidence supports that ongoing podocyte injury and proteinuria drive long-term disease progression and poor clinical outcomes in patients living with FSGS13-17

Long-term real-world evidence from registries and cohort studies demonstrate that the pathophysiologic processes underlying FSGS, particularly elevated proteinuria, are closely linked to progressive kidney function decline, frequently culminating in end-stage kidney disease (ESKD), kidney failure, and the need for dialysis or kidney transplantation.13-17

FSGS is associated with significant long-term clinical burden13-17

Figure. Long-term clinical outcomes in FSGS

MCD, minimal change disease
†Major adverse kidney event defined as ≥40% eGFR decline, kidney failure, dialysis/transplant, or death13
††Retrospective data from the Providence and University of California (UCLA) Health Systems’ records within the CURE-CKD registry (2016-2022; N=629)13
§Retrospective data from a Veteran Affairs cohort of patients with FSGS (N=2,515)16
||Retrospective, observational data from from Optum Market Clarity on a real-world US cohort of patients with FSGS15
*Retrospective data from the UK National Registry of Kidney Diseases (RaDaR; N=4,066)14

Evaluation of the FSGS cohort from the Center for Kidney Disease Research, Education, and Hope (CURE-CKD) registry (N=629) showed that 42% experienced a major adverse kidney event (MAKE), defined as ≥40% estimated glomerular filtration rate (eGFR) decline, kidney failure, dialysis/transplant, or death, over a median follow-up period of 2.9 years.13 Over 50% of patients experienced ≥40% eGFR decline as the first MAKE.13 In addition, cohort data from US veterans with FSGS (N=2,515) showed that 43.3% underwent dialysis over a mean 8.9-year follow-up.16

A real-world US cohort of patients with FSGS (N=7,974) also showed that higher baseline proteinuria levels (urine protein-creatinine ratio [UPCR] >1.5 g/g and ≥3.5 g/g) were associated with increased risks of death and major cardiovascular events compared with lower baseline levels.15

Additionally, the FSGS cohort from the UK National Registry of Rare Kidney Diseases (RaDaR) (N=4,066) experienced a significantly lower 10-year kidney survival rate compared with minimal change disease (58% vs. 87%).14 Survival from kidney failure correlated with greater proteinuria remission with those achieving complete remission (<0.3 g/g) having a survival rate of 88% (95% CI: 70-96).14

FSGS

Long-Term Outcomes in Nephrotic Syndrome by Kidney Biopsy Diagnosis and Proteinuria

Review insights from RaDaR on long-term kidney survival outcomes and risk of disease progression in FSGS

Read publication summary

Collectively, real-world data from registries such as RaDaR, CURE-CKD, and cohort studies underscore the substantial and sustained long-term clinical burden of FSGS.13-17

FSGS is associated with a humanistic burden that extends beyond clinical manifestations and kidney function measures16,18

The burden of disease impacts not only patients but also their care-partners, with effects that extend beyond clinical measures to daily functioning, emotional well-being, and quality of life.18 In the cross-sectional, observational HONUS survey study, adults with FSGS (n=78) or their care-partners (n=77) reported significantly impaired health-related quality of life (HRQOL) compared with the general US population, reflecting a meaningful physical and mental health impact.18

The most burdensome symptoms reported by adults with FSGS were bone or joint pain (67.9% reported being “somewhat bothered” to “extremely bothered”), headache (60.3%), and facial swelling (56.4%).18

These physical limitations were accompanied by high levels of emotional distress, with 28.2% of adults reporting moderate-to-severe anxiety and 37.3% reporting moderate-to-severe depression, alongside feelings of uncertainty related to disease progression and long-term prognosis.18

Patients and caregivers experience humanistic burdens from FSGS18

Figure. Humanistic burden of FSGS

*Observational survey data from the HONUS study (adults with FSGS, n=78; caregivers, n=77)18

Group of people
FSGS

The Humanistic Burden of Focal Segmental Glomerulosclerosis on Patients and Care-Partners in the United States

Learn more about the physical, emotional, and productivity burdens experienced by patients with FSGS and their care-partners in the HONUS study

Read publication summary

In FSGS, underlying podocyte injury and sustained proteinuria drive progressive kidney decline that may culminate in kidney failure and the need for dialysis or transplantation.3,8,13,14 At the same time, the impact of FSGS extends beyond kidney function decline, with physical limitations and emotional distress contributing to the humanistic burden faced by patients and their care-partners.13-16,18 Together, these findings showcase gaps in care for the FSGS community.15,16,18

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Exploring Clinical Trial Endpoints in FSGS: Spotlight on Proteinuria

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  14. Pitcher D et al. Journal of the American Society of Nephrology. 2025;36(7):1398-1413.
  15. Velez JCQ et al. Kidney360. 2024;5(8).
  16. Goldschmidt D et al. PLOS ONE. 2024;19(12):e0315302.
  17. Kiffel J et al. Adv Chronic Kidney Dis. 2011;18(5):332-338.
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MA-DS-26-0013 | March 2026