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Kidney-shaped aquarium with protein streaming through cracked viewing glassKidney-shaped aquarium with protein streaming through cracked viewing glass

In Focal Segmental Glomerulosclerosis (FSGS)

Elevated Proteinuria Increases Risk of Disease Progression

Endothelin-1 and angiotensin II are key mechanisms of disease progression in FSGS1:

  • Working in tandem via their receptors to amplify podocyte injury
  • Causing injury resulting in glomerular filtration breakdown
  • Increasing proteinuria

Epidemiology of FSGS

  • FSGS is a leading glomerular cause of kidney failure2
  • Affects those of all ages and represents a significant proportion of glomerulopathy diagnoses3,a
  • Is prevalent in patients with recent African ancestry, with up to 80% of biopsies identifying FSGS as the cause of idiopathic nephrotic syndrome4,b
  • In adults, identifying FSGS requires biopsy. Further evaluation may be required to differentiate the classification of primary, genetic, or secondary FSGS, or FSGS of undetermined cause (FSGS-UC)5

aAnalyses conducted from the NEPTUNE cohort; n=441 proteinuric patients (≥0.5 g/24 hrs) undergoing kidney biopsy; NEPTUNE=Nephrotic Syndrome Study Network.

bBased on US data.

Elevated proteinuria correlates with accelerated decline in kidney function and reduced survival probability in FSGS6-8

FSGS is characterized by glomerular injury resulting from podocyte damage.9

Reduction of proteinuria to remission and partial remission thresholds can significantly improve outcomes.5,6,10,11

TARGET PROTEINURIA GOAL10,11,c

<1.5 g/g

Achieving this goal correlates with extended kidney survival

cFSGS partial remission threshold defined as <1.5 g/g with a 40% reduction from baseline.

Significantly extended survival in patients with FSGS who achieved <1.5 g/g and 40% decrease in PCR11,d

Graph depicts survival data from Saleem 2021 study showing that achievement of complete or partial remission of proteinuria resulted in a 13-year improvement in survival probabilityGraph depicts survival data from Saleem 2021 study showing that achievement of complete or partial remission of proteinuria resulted in a 13-year improvement in survival probability

Endpoints based on PCR follow-up 6 to 12 months from first nephrotic-range PCR valuee:

CR/FPRE-R, PCR <1.5 g/g and 40% decrease in PCR

FPRE-NR, not achieving CR/FPRE

Reducing proteinuria from nephrotic-range baseline to <1.5 g/g correlated with a 13-year extension in median survival probability vs patients who did not reach this thresholde

CR=complete remission; eGFR=estimated glomerular filtration rate; ESKD=end-stage kidney disease; FPRE=FSGS partial remission endpoint; FPRE-NR=FPRE-non-responder; FPRE-R=FPRE-responder; FSGS=focal segmental glomerulosclerosis; PCR=protein-creatinine ratio; UP/C=urinary protein-to-creatinine ratio.

dTime to ESKD or death was analyzed using accelerated failure time modelling of the Weibull distribution and Kaplan-Meier estimates of cumulative incidence.

eBaseline pertains to first nephrotic-range proteinuria value (≥3.0 g/g) at or after disease onset.

Based on data from the National Registry of Rare Kidney Diseases (RaDaR), a UK Kidney Association initiative, in 270 patients with FSGS (150 adults age 18 and older and 120 pediatrics) with long-term data collection and comprehensive follow-up, representing a nationwide database and involving a large proportion of UK renal centers. ESKD was defined as chronic kidney disease stage 5 (confirmed eGFR <15 mL/min/1.73m2 or CKD stage 5 recorded in RaDaR) or receiving chronic dialysis or kidney transplant. Time to ESKD or death was analyzed using accelerated failure time modeling.

Treatment options are limited

There are no FDA-approved drugs indicated for the treatment of FSGS.12

Treatment strategies are based on limited evidence and include5,12:

  • Immunosuppressive treatment
  • ACEi/ARB

Research is ongoing to help address the needs in patients with FSGS who are at high risk for rapid progression13

ET-1 and Ang II work in tandem via their receptors to exacerbate kidney injury

ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; FDA=Food and Drug Administration; IgA=immunoglobulin A.

References:

1. Komers R, et al. Am J Physiol Regul Integr Comp Physiol. 2016:R877-R884. 2. Rosenberg AZ, et al. Clin J Am Soc Nephrol. 2017;12:502-517. 3. Gipson DS, et al. Clin J Am Soc Nephrol. 2016;11:81-89. 4. Korbet SM. J Am Soc Nephrol. 2012;23:1769-1776. 5. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. Kidney Int. 2021;100(4S):S1-S276. 6. Troyanov S, et al. J Am Soc Nephrol. 2005;16:1061-1068. 7. Le WB, et al. Nephrol Dial Transplant. 2012;27:1479-1485. 8. Reich HN, et al. J Am Soc Nephrol. 2007;18:3177-3183. 9. D’Agati VD, et al. New Engl J Med. 2011;365:2398-2411. 10. Troost JP, et al. Clin J Am Soc Nephrol. 2018;13:414-421. 11. Saleem MA, et al. American Society of Nephrology (ASN) Kidney Week virtual, November 4-7, 2021. PO1529. 12. Raina R, et al. Kidney Dis. 2020;6:22-34. 13. Nephcure Kidney International. Accessed November 2022. https://kidneyhealthgateway.com/trials-research/. 

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