Kidney Week 2025 Annual Meeting-Proteinuria and eGFR as Clinical Trial End Points in FSGS

Video Transcription

Video Summary

This symposium focused on whether proteinuria and eGFR can serve as clinical trial endpoints in focal segmental glomerulosclerosis (FSGS), a heterogeneous condition that reflects podocyte injury from primary (diffuse foot process effacement), secondary (maladaptive hyperfiltration/intraglomerular hypertension), or genetic causes.<br /><br />Dr. Linus Butt presented mechanistic and imaging work showing how podocyte foot process effacement drives albuminuria and promotes progression to podocyte loss and sclerosis. Using a podocin-mutant mouse model and super-resolution microscopy, his group quantified slit diaphragm loss over time and demonstrated a strong correlation between reduced slit diaphragm length and rising albuminuria, replicated across models and in patients. They proposed a biomechanical model in which effacement weakens podocyte “buttress force,” decompressing the glomerular basement membrane and increasing permeability to albumin. In vivo imaging showed capillary dilation—exaggerated by angiotensin II—supporting reduced podocyte mechanical support. Modeling suggested increased shear stress across fewer remaining filtration slits, triggering a vicious cycle of podocyte detachment, sclerosis, and transition from selective albuminuria to nephrotic, nonselective proteinuria.<br /><br />Dr. Kirk Campbell reviewed regulatory pathways and the Parasol Project, an international observational effort to identify feasible endpoints for FSGS drug approval. Because eGFR slope is highly variable (especially early CKD and pediatrics), it would require impractically large trials. In contrast, achieving a urine protein/creatinine ratio ≤0.7 g/g (for patients starting >1.5 g/g) strongly predicted kidney survival, similar to complete remission, and was validated in an external cohort—supporting proteinuria reduction as a practical endpoint, while acknowledging remaining questions and FSGS heterogeneity.

Asset Subtitle

Moderator(s): David Salant

Presentation(s):

Introduction - David Salant
Impact of Filtration Barrier Defects in FSGS - Linus Butt
Leveraging Proteinuria and eGFR for Approval of New Treatments for FSGS - Kirk Campbell

Support is provided by an educational grant from Travere Therapeutics, Inc.

Meta Tag

Date 11/8/2025

Pathway 1 Glomerular Diseases

Pathway 2 CKD Non-Dialysis

Session ID 519171

Keywords

focal segmental glomerulosclerosis

FSGS clinical trial endpoints

proteinuria reduction

eGFR slope variability

podocyte foot process effacement

slit diaphragm loss

albuminuria mechanism

podocyte detachment and sclerosis

Parasol Project

urine protein-to-creatinine ratio 0.7 g/g