Endothelin & Proteinuria in Glomerular Pathophysiology

Episode Summary

Dr. Donald Kohan is a Professor of Medicine, Division of Nephrology & Hypertension at the University of Utah.

Dr. Yelena Drexler is an Associate Professor of Clinical Medicine, Division of Nephrology & Hypertension at the University of Miami.

Dr. Chris Gisler is a Senior Medical Director at Travere Therapeutics and an adult nephrologist.

Host Dr. Chris Gisler brings together two leading voices in nephrology, Dr. Donald Kohan and Dr. Yelena Drexler, for an energetic conversation about why proteinuria matters so much in FSGS and IgA nephropathy.

What starts as a discussion of proteinuria as a lab value soon deepens: what is it, why does it mean more than just numbers, and how does it actually drive kidney injury?

Dr. Donald Kohan breaks down the biology of endothelin, showing its role at every stage of glomerulonephritis. Then, Dr. Yelena Drexler links research to real patient care and shares the practical impact of proteinuria on outcomes.

Whether you’re a clinician, researcher, or patient advocate, this episode delivers clear takeaways–from the latest studies shaping proteinuria targets to the call for multi-pathway, biology-informed treatment strategies.

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Key Takeaways

“Fundamentally, FSGS is a podocytopathy. And proteinuria is so important because it’s a signature of podocyte loss, it’s a signature of podocyte injury” (07:48)

“Persistent proteinuria to me is really a sign of ongoing podocyte injury and ongoing podocyte loss and the formation of sclerosis, focal and segmental glomerulosclerosis, that ultimately is irreversible. And we want to intervene to prevent that” (10:47)

“We’re not just thinking about proteinuria as a marker of disease. Proteinuria itself can actually worsen kidney injury… And you end up with a vicious cycle — the more injury you get, the more proteinuria you get and then the cycle continues” (11:23)

“As we’re thinking about targeting the endothelin system, we have to think this system is activated throughout the entire course of the disease. And if we’re going to target it, we’ve got to target it throughout the entire course of the disease” (17:50)

Proteinuria is both a marker and a driver of FSGS and IgA nephropathy, actively fueling inflammation, fibrosis, and a “vicious cycle” of ongoing injury, thereby making early and sustained reduction a critical treatment goal.
Podocyte injury is the central pathway in glomerular diseases like FSGS, with diverse causes converging on podocyte loss, leading to proteinuria and irreversible kidney damage.
Endothelin is a key mechanistic driver across the kidney, damaging podocytes and other cell types while working synergistically with the renin-angiotensin system to accelerate disease progression.

Disclaimer: Guest speakers of the Rare Kidney Disease Show may be paid consultants of Travere Therapeutics. This podcast episode was recorded on March 6, 2026. Please always consult updated sources for the latest information, as information discussed may have changed since the recording date.

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