KHI Current Project

Surrogate Endpoints in FSGS


The goals of this project are to identify surrogate endpoint(s) for use in clinical trials in FSGS patients. Despite being associated with a relatively rapid decline in kidney function, there are no approved drugs and no accepted endpoints for registration of investigational products for FSGS. We propose the following goals: review published literature and analyze data from cohorts/completed trials to identify candidate surrogates for endpoints, identify risk factors for progression, critically assess the candidate measures, and identify gaps in the data. The completion of this project should guide future trials and ultimately result in new drugs approved for FSGS.


Publications addressing surrogate endpoints and clinical trial design


Summer 2019

Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disorder which may result in extreme proteinuria and rapid progression to end-stage renal-disease. FSGS can present in a variety of ways varying from proteinuria to arterial hypertension, edema and nephrotic syndrome and can progress to ESRD over the course of 5-10 years1. FSGS is a leading and growing cause of nephrotic syndrome worldwide 2 and accounts for 3-4% of prevalent ESRD in the United States 3.

At present, there are no FDA-approved treatments for FSGS. Potential predictors of more rapidly progressive disease have included demographics, genetics, higher baseline proteinuria, histopathologic type, and response to treatment (remission status). Reduction in proteinuria is regarded as beneficial and is the primary goal of treatment to slow the progressive course of FSGS. Current treatment is inhibition of the renin-angiotensin-aldosterone system followed by steroids and potentially immunosuppressives.

Despite the relatively rapid decline in renal function among patients with FSGS, few randomized, controlled trials have been conducted, and guidelines for the treatment of FSGS remain based on generally low-level evidence 4. This is in part due to fact that the disease is rare and requirement of demonstrating a treatment effect on the "hard endpoints" of ESRD or a halving of eGFR or death would require too large and too long of a trial to be feasible. Thus, there is a recognized need to identify an earlier surrogate endpoint that could be used in clinical trials to establish the efficacy of therapies for patients with FSGS who are at high risk of progressing to ESRD 5.

The working group will seek to identify potential short-term and intermediate candidate surrogate outcome measures by: 1) performing a critical review of the literature in FSGS, focused on prospective cohort studies and prospective interventional clinical trials; and 2) analyzing data from available FSGS databases.

Role Name Organization/Location
Co-ChairKeisha Gibson, MD, MPH, FASNUniversity of North Carolina Kidney Center
Co-ChairLaura Mariani, MD, MSUniversity of Michigan
MemberMichelle Denburg, MDThe Children's Hospital of Philadelphia
MemberLisa CiminoBoston, MA
MemberUlysses Diva, PhDRetrophin, Inc.
MemberJürgen Floege, MDUniversity of Aachen, Germany
MemberDuvuru Geetha, MD, FASNJohn Hopkins Bayview Medical Center
MemberDebbie Gipson, MD, MSUniversity of Michigan Children's Hospital
MemberPeter Greasley, PhDAstrazeneca
MemberMichelle Hladunewich, MD, MS, FASNUniversity of Toronto
MemberRobert Huizinga, RN, PhD, CNeph(C)Aurinia Pharmaceuticals
MemberJula Inrig, MD, MS, FASNIQVIA
MemberMona Khurana, MDUS Food and Drug Administration
MemberRadko Komers, MD, PhDRetrophin, Inc.
MemberLouis-Philippe Laurin, MDHospital Maisonneuve-Rosemont
MemberDustin Little, MDAstraZeneca
MemberPatrick Nachman, MD, FASNUniversity of Minnesota
MemberKimberly Smith, MD, MSUS Food and Drug Administration
MemberAliza Thompson, MD, MSUS Food and Drug Administration
MemberLiron WalshGoldfinch Bio
MemberDine WatsonWashington, DC
NephCure Kidney International LiaisonRick WinnekerNephCure Kidney International
Additional Support Judith SchimpfUniversity of Aachen, Germany
Board of Directors LiaisonBarbara Gillespie, MD, FASNCovance CRO
Staff LiaisonMeaghan AllainKidney Health Initiative
Staff LiaisonMelissa WestKidney Health Initiative

Selected References:

  1. Korbet, S. M. (2002) Treatment of primary focal segmental glomerulosclerosis. Kidney Int, 62, 2301-10., 2002
  2. D'Agati VD et al. Focal segmental glomerulosclerosis. N Eng J Med 2011 Dec 22;365(25):2398-411.; Rosenberg et al. Glomerular Disease: Focal Segmental Glomerulosclerosis. cJASN 12:502-517, 2017.
  3. 2014 USRDS ESRD Database (accessed 12/13/2015)
  4. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney inter., Suppl. 2012; 2: 139–274.
  5. Spino C et al. Changing the paradigm for the treatment and development of new therapies for FSGS. Front Pediatr 4: 25, 2016.