Abstract: TH-PO0611
Phenotypic and Biopsy Characteristics of Adult-Onset NPHS2-Associated FSGS
Session Information
- Monogenic Kidney Diseases: Glomerular
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Nyabera, Akwe, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States
- Guaman, Karina P., Columbia University, New York, New York, United States
- Martínez-Belotto, Miguel, Hospital Universitario Marques de Valdecilla Servicio de Medicina Interna, Santander, Cantabria, Spain
- Navarro Torres, Mariela, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States
- Bomback, Andrew S., Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States
Background
The NPHS2 gene encodes podocin, a protein expressed in podocytes. Mutations are typically associated with childhood nephrotic syndrome. Milder disease phenotypes in adults have been reported, either due to hypomorphic mutations or the R229Q variant inherited in association with a pathogenic mutation. Literature on adult-onset focal segmental glomerulosclerosis (FSGS) due to NPHS2 mutations is limited. We report on 10 adult patients with biopsy-proven FSGS and pathogenic NPHS2 variants.
Methods
In a retrospective study we reviewed the genetic database at Columbia University Medical Center for patients >18 years of age at FSGS diagnosis with NPHS2 mutations and biopsy-confirmed FSGS. 10 met inclusion criteria. Charts were reviewed for: Patient demographics, labs, treatment, and biopsy data.
Results
Follow-up duration was 3.72 ± 2.94 years. Age at symptom onset was 31.7 ± 11.2 years. 30% were female, 60% White, 10% Black, and 30% Hispanic. 44.4% had preserved eGFR. Mean creatinine was 1.4 ± 1.01 mg/dL, with proteinuria of 5.89 ± 6.24 g/g and serum albumin of 3.06 ± 0.85 g/dL. 80% were compound heterozygotes for the R229Q variant and another pathogenic mutation, 20% were homozygous for p.Val180Met or p.Arg138Gln. Prior to genetic testing, 40% received immunosuppressive therapy. 4 patients progressed to ESKD, and 2 underwent transplantation. All patients had a kidney biopsy prior to genetic testing. Biopsy findings included global and segmental sclerosis in 90%, with an average interstitial fibrosis and tubular atrophy of 23% ± 15.8. Arteriolosclerosis was seen in 60%. Immunofluorescence revealed C3 deposits in 50%, IgM in 30%, and IgA in 10%. Foot process effacement ≥ 80% was seen in 70% of patients.
Conclusion
This study reports on 10 adults with biopsy confirmed FSGS and pathogenic NPHS2 variants. The R229Q variant in NPHS2 is benign alone but can cause disease when paired in trans with specific C-terminal pathogenic mutations, disrupting podocin function. In this study, 40% of patients progressed to ESKD. Histologically, segmental sclerosis and varying degrees of foot process effacement were seen. One case misdiagnosed as IgA nephropathy was reclassified after genetic confirmation. Findings support the role of genetic testing in diagnosis and management, favoring supportive care over immunosuppression in genetically confirmed FSGS.