The Search for Answers in FSGS Recurrence, With Priya Verghase, MBBS (MD), MPH

Focal segmental glomerulosclerosis (FSGS) remains one of the most challenging glomerular diseases in nephrology, particularly in the transplant setting. It represents a common cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children.

While kidney transplantation offers patients with end-stage kidney disease a path forward, the risk of disease recurrence continues to undermine long-term graft survival and patient outcomes.

Despite decades of research, clinicians are still left navigating significant uncertainty when it comes to predicting, preventing, and treating recurrence. In an interview with HCPLive at at the World Congress of Nephrology (WCN) Conference in Yokohama, Japan, Priya Verghese, MBBS (MD), MPH, Division Head of Pediatric Nephrology, and Professor of Pediatrics at Northwestern University, Ann & Robert H. Lurie Children’s Hospital, stressed that the key issue begins with how FSGS itself is defined, emphasizing that FSGS is not a single disease, but rather a histopathologic pattern of injury that can arise from multiple underlying causes.

“Focal segmental glomerular sclerosis actually is a misnomer in my mind. FSGS is a description of the pathology in the kidney. It is the end result of any kidney that is damaged,” she said.

Verghese describes this distinction as critical, noting that secondary forms of FSGS driven by factors such as genetic mutations, metabolic disease, or chronic injury generally do not recur after transplant if the underlying cause is addressed. In contrast, primary FSGS, which is thought to involve a circulating permeability factor, carries a high risk of recurrence, yet remains poorly understood.

Verghese highlights that despite decades of investigation dating back to the 1970s, the field has yet to definitively identify the causative circulating factor. This gap has profound clinical implications, as clinicians cannot reliably predict which patients will progress to kidney failure, which will experience recurrence after transplant, or which therapies will be effective once recurrence occurs. As a result, management strategies are often empirical and variable.

Recent research has renewed interest in potential immune-mediated mechanisms, particularly the role of nephrin-targeting antibodies. While early findings suggested a possible association between these antibodies and recurrence, Verghese notes that subsequent data have been inconsistent. Questions remain regarding assay sensitivity, specificity, and whether these antibodies represent a causative factor or simply a biomarker in a subset of patients.

Sparsentan, a non-immunosuppressive, oral medication designed to directly target podocyte injury by optimally blocking the endothelin A receptor and the angiotensin II subtype 1 receptor, is currently being reviewed by the US Food and Drug Administration as a potential first treatment for FSGS. Its previously assigned Prescription Drug User Fee Act (PDUFA) target action date of January 13, 2026, was extended to April 13, 2026, following a request from the Agency for further characterization of sparsentan’s clinical benefit. Upon submission of responses, the FDA determined they constituted a Major Amendment to the sNDA, and extended the PDUFA action date accordingly.

Beyond biology, she underscores a critical barrier to progress: the difficulty of conducting rigorous clinical trials in rare diseases like FSGS. Efforts to evaluate preventive strategies, such as plasmapheresis with or without rituximab, have been hindered by poor enrollment. Verghese explains that both patients and clinicians often favor more aggressive treatment approaches over randomization, limiting the ability to generate high-quality evidence.

“I think with this type of a relatively rare glomerular disease, we need to galvanize the community to be very clear on what we know and what we don't know,” she said.

Looking ahead, Verghese stresses the need for greater collaboration across the nephrology community, including clinicians, researchers, and patients. Advancing the field will require not only scientific breakthroughs, but also more inclusive and pragmatic trial designs that align with real-world preferences and priorities.

Editors’ note: Verghese reports relevant disclosures with Boehringer Ingelheim, Memo Therapeutics, and Viracor.

References

1. Rout P, Hashmi MF, Baradhi KM. Focal Segmental Glomerulosclerosis. December 11, 2024. Accessed March 30, 2026. https://www.ncbi.nlm.nih.gov/books/NBK532272/

2. Hillenbrand A. FDA Extends Sparsentan (Filspari) sNDA Review for Focal Segmental Glomerulosclerosis. January 13, 2026. Accessed March 30, 2026. https://www.hcplive.com/view/fda-extends-sparsentan-filspari-focal-segmental-glomerulosclerosis-snda-review