Genetic Link to Adult Kidney Disease May Reshape Diagnosis

LONDON, UK – April 29, 2026 – A landmark study has uncovered a substantial, previously under-recognized genetic driver of a serious adult kidney disease, potentially reshaping diagnostic protocols and paving the way for a new generation of precision therapies. The research, published in Kidney International Reports, suggests that specific genetic variants are a major cause of adult-onset Focal Segmental Glomerulosclerosis (FSGS), a condition that scars the kidney's filters and can lead to end-stage renal disease.

The findings, announced by precision nephrology company Purespring Therapeutics, challenge the long-held view that the genetic basis for adult FSGS is rare. By analyzing over 1.2 million genomes, the collaborative study predicts a large population of patients whose disease is driven by inherited mutations, many of whom may have been misdiagnosed or received ineffective treatments.

A Shifting Paradigm in FSGS Diagnosis

FSGS is a debilitating disease characterized by scarring (sclerosis) in the glomeruli, the tiny filtering units of the kidneys. For decades, diagnosis has relied on kidney biopsy, and in many adult cases, the underlying cause remains unknown, leading to a diagnosis of "idiopathic" FSGS. This has resulted in a one-size-fits-all treatment approach, often involving powerful immunosuppressants like steroids, which come with significant side effects and are frequently ineffective.

The new study pinpoints pathogenic variants in the NPHS2 gene, which provides instructions for making a protein called podocin, a crucial component of the kidney's filtration barrier. While NPHS2 mutations have been a known cause of FSGS in children, their role in adults was considered minor. This research dramatically alters that understanding.

The analysis revealed that a significant number of adult cases are likely caused by "compound heterozygosity," where an individual inherits two different pathogenic variants of the NPHS2 gene, one from each parent. The study highlights a common combination in US and UK populations: the R229Q variant paired with another, more damaging variant. While R229Q is relatively common and often harmless on its own, it can lead to adult-onset FSGS when combined with a second faulty gene.

"The results reinforce the importance of integrating genetic screening across paediatric and adult renal care, not only for diagnosis but also for guiding treatment decisions," said Moin Saleem, Professor of Paediatric Renal Medicine at the University of Bristol and a founder of Purespring, in a statement. He expressed hope that the findings "lead to increased uptake in clinical practice."

The Case for Broader Genetic Screening

The implications for clinical practice are profound. The study strongly suggests that genetic screening should be a more routine part of the diagnostic workup for adults with FSGS, especially those who do not respond to standard immunosuppressive therapy. An accurate genetic diagnosis can spare patients from ineffective treatments and provide clarity on the nature of their disease.

"Our findings highlight a substantial, previously undiagnosed population of adults with NPHS2-mediated FSGS," commented Fredrik Erlandsson, Chief Medical Officer at Purespring Therapeutics. "This underscores a clear need to expand genetic testing, improve diagnosis and enable more targeted treatment strategies for patients."

This shift is supported by real-world data from clinical cohorts, including Natera’s RenaSight™ genetic testing platform and Travere’s DUPLEX study. In these cohorts, a majority of adult patients identified with NPHS2-associated disease were found to carry the R229Q variant, validating the population modeling's predictions. Expanding genetic testing would not only improve diagnostic accuracy but also provide critical prognostic information, as the course of genetic FSGS can differ significantly from other forms of the disease.

Paving the Way for Precision Therapies

For Purespring Therapeutics, the study does more than advance scientific understanding; it illuminates the path forward for its lead therapeutic candidate. The company is developing PS-001, a gene therapy designed specifically to treat FSGS caused by faulty NPHS2 genes.

PS-001 is an adeno-associated virus (AAV) based therapy that delivers a correct copy of the NPHS2 gene directly to the podocytes, the cells affected by the disease. The goal is to restore normal podocin protein function, repair the kidney's filtration barrier, and halt disease progression.

Preclinical data has been highly encouraging. In mouse models of the disease, a single administration of an analogue to PS-001 rescued renal function, resolved severe protein leakage in the urine, and reduced kidney scarring. Studies in larger animal models also demonstrated that the therapy could effectively and specifically target the correct cells in the kidney without affecting other organs.

By identifying and quantifying a large adult patient population with NPHS2-driven FSGS, the new study provides a clear clinical development and regulatory pathway for PS-001. It defines the target audience for the therapy, which is crucial for designing clinical trials and demonstrating efficacy to regulators. This strategic research de-risks the development program and solidifies Purespring's position as a leader in the emerging field of precision nephrology.

Implications for Health Equity

Crucially, the research also carries significant implications for health equity. The study found that one of the key pathogenic variants, A284V, is particularly prevalent in individuals with mixed-ancestry, including those of Latin American heritage. When paired with the more common R229Q variant, it is predicted to be a major driver of the disease in these populations.

This finding underscores the critical need for inclusive genetic screening programs. Without equitable access to advanced diagnostics, certain demographic groups could be left behind, continuing to receive non-specific diagnoses and suboptimal care while others benefit from precision medicine. The study highlights that a comprehensive understanding of genetic architecture across diverse populations is essential for ensuring that the benefits of genomic medicine are distributed fairly.

By shedding light on these population-specific genetic factors, the research advocates for a more nuanced and inclusive approach to both diagnosis and future clinical trial recruitment. This ensures that new, targeted therapies are tested in and developed for the diverse communities that need them most, marking a vital step toward closing disparity gaps in kidney disease outcomes.