Rare Kidney Disease Show

Endothelin & Proteinuria in Glomerular Pathophysiology

Welcome to Travere Therapeutics’ Rare Kidney Disease podcast, where rare kidney disease gets a spotlight. Host 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. Speakers: * Dr. Chris Gisler is a medical director at Travere Therapeutics and an adult Nephrologist * 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  Key Takeaways: * Proteinuria is both a marker and a driver of FSGS and IgAN, 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, directly damaging podocytes and other cell types while working synergistically with the renin-angiotensin system to accelerate disease progression Key Quotes: * “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 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.

Insights from the SPARTAN Study with Drs. Jonathan Barratt and Shikha Wadhwani

In this episode, Drs. Jonathan Barratt and Shikha Wadhwani discuss findings from the SPARTAN study, a Phase 2 open-label, single-arm trial evaluating sparsentan in 12 treatment-naïve patients with IgA nephropathy. The conversation explores the trial’s design, including assessments of proteinuria reduction and urinary biomarkers to better understand sparsentan’s mechanism of action.   Results from SPARTAN demonstrate a 69% mean reduction in proteinuria at 24 weeks, alongside biomarker trends consistent with decreased glomerular inflammation.    Dr. Barratt notes that no new safety signals emerged, with hypotension observed at a rate consistent with prior studies and no adverse hepatic events reported.   Together, the experts reflect on how these data support the biological plausibility of sparsentan’s anti-inflammatory properties and may inform the development of biomarker-guided strategies in IgA nephropathy, including ongoing evaluation of sparsentan in the PROTECT trial.    Key Takeaways: * SPARTAN demonstrated a robust mean reduction in proteinuria (~69%) in treatment-naïve patients with IgA nephropathy after 24 weeks of sparsentan therapy. * Biomarker analysis revealed reductions in markers of macrophage activation, complement activity, and inflammatory cytokines, supporting the hypothesis of a potential anti-inflammatory effect. * No new safety signals were observed; hypotension rates were consistent with earlier trials, and no clinically significant changes in hepatic function were reported. * These findings contribute to our mechanistic understanding of sparsentan and provide a framework for future investigation of biomarkers from samples from larger studies such as PROTECT.   Speakers:   * Dr. Jonathan Barratt, PhD, FRCP. Professor of Renal Medicine at the University of Leicester, where he leads the IgA Nephropathy Research Programme. He is internationally recognized for his leadership in translational and clinical research in glomerular diseases, particularly IgA nephropathy. Dr. Barratt directs the UK’s Rare Disease Group for the UK National Registry of Rare Kidney Diseases (RaDaR). * Dr. Shikha Wadhwani, MD, MS, FASN. Associate Professor of Medicine in the Division of Nephrology and Vice Chair of Clinical Research in the Department of Medicine at University of Texas Medical Branch. She is also the inaugural Associate Research Officer for clinical research, overseeing clinical trials across all 5 schools at UTMB. She is the founding member of the International Society of Glomerular Disease (ISGD) and is steering a global effort aimed at supporting the growth and success of physician-trialists. In her spare time, Dr. Wadhwani co-hosts a podcast called Kidney Compass: Navigating Clinical Trials.   Disclaimer:  Guest speakers of the Rare Kidney Disease Show may be paid consultants of Travere Therapeutics. This podcast episode was recorded on July 25, 2025. Please always consult updated sources for the latest information, as information discussed may have changed since the recording date.

From Podocyte to Patient: The Pathophysiology of FSGS

In this episode, Drs. Tobias Huber and Chris Gisler take a deep dive into the critical role of podocytes in kidney health and their involvement in the development and progression of FSGS. They explore how podocyte injury leads to the breakdown of the glomerular filtration barrier and the emergence of proteinuria. They highlight the intertwined roles of endothelin 1 and angiotensin II in worsening podocyte dysfunction and driving disease progression. They discuss current and emerging data, treatment options, and biomarkers, including findings from Dr. Huber’s latest research. Lastly, they emphasize the value of proteinuria as both a marker and mediator of podocyte damage, reinforcing its role as a key therapeutic target in FSGS.   Key Takeaways: * Podocytes are essential for maintaining the integrity and health of the kidney. * Podocyte damage directly contributes to proteinuria and disease progression. * Proteinuria is both a symptom and a driver of FSGS disease progression. * Endothelin 1 and angiotensin II promote podocyte dysfunction.   Speakers:  * Tobias Huber is the Chair of the Center of Internal Medicine at University Medical Center Hamburg-Eppendorf, Germany and president of the International Society of Glomerular Disease. * Chris Gisler is a medical director at Travere Therapeutics and a community nephrologist practicing in Pittsburgh.

Intro to FSGS - Dr. Howard Trachtman

Title:  Intro to FSGS Episode Description: In this episode of the Rare Kidney Disease Show, Howard Trachtman, Adjunct Professor of Pediatrics at the University of Michigan, and Chris Gisler, medical director at Travere Therapeutics, explore the complexities of FSGS, covering its pathophysiology, classifications, and clinical presentation. They discuss key drivers of kidney failure, challenges in diagnosis and management, and the unmet need for safe and effective treatments. Listeners will gain insights into the patient journey, role of precision medicine, disease heterogeneity, and the future of clinical trial design. The episode concludes with how PARASOL is shaping advancements in FSGS research and clinical trials.   Key Takeaways: * Evolving Classification of FSGS – Once defined primarily by histopathology, FSGS is now recognized as a heterogeneous disorder with distinct genetic, immune, and metabolic etiologies. This shift has critical implications for diagnosis and treatment. * FSGS and the Role of Podocyte Injury – Podocyte loss is a key driver of FSGS progression, with genetic, immune, and metabolic insults leading to irreversible damage. Understanding this mechanism is crucial for developing targeted therapies. * Challenges in Treatment and Therapeutic Gaps – Current treatment strategies rely on empiric use of steroids and calcineurin inhibitors, with variable efficacy and significant side effects. A more targeted approach is needed to improve patient outcomes. Speakers:  * Howard Trachtman is the Adjunct Professor of Pediatrics at the University of Michigan. * Chris Gisler is a medical director at Travere Therapeutics and a former community nephrologist practicing in Pittsburgh.

ASN Update - Sparsentan Redefining IgAN Treatment

In this episode of the Rare Kidney Disease Show, a panel of nephrology experts explore the latest data on sparsentan, as presented at ASN Kidney Week 2024. Dr. Hiddo Heerspink presents a post hoc analysis of the PROTECT trial comprised of patients who achieved complete proteinuria remission. Dr. Chee Kay Cheung shares interim data from the SPARTAN study on sparsentan therapy in treatment-naïve patients with IgA nephropathy. Lastly, Dr. Bruce Hendry discusses combination treatment of sparsentan with SGLT2i in the SPARTACUS study.  These discussions are introduced by Dr. Edgar Lerma, who offers his insights into the possible clinical implications of these data.