Abstract: TH-PO0609
Adult-Onset NPHS1 Nephrotic Syndrome: Two Cases Highlighting Diagnostic and Therapeutic Gaps
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
- Stein, Quinn, Natera, Inc., Austin, Texas, United States
- Narasimha Krishna, Vinay, MultiCare Nephrology Specialists, Kent, Washington, United States
- Ky, Trung Q., Natera, Inc., Austin, Texas, United States
- Baddar, Nour, Natera, Inc., Austin, Texas, United States
- Punj, Sumit, Natera, Inc., Austin, Texas, United States
Introduction
Adult-onset nephrotic syndrome due to biallelic NPHS1 variants is exceptionally rare, with only one prior reported case. Here, we present 2 new adult cases illustrating diagnostic challenges, phenotypic variability, therapeutic uncertainties, and potential genetic underdiagnosis.
Case Description
Case 1: A 27-year-old female had proteinuria (0.5 g/day) and a kidney biopsy indicating unspecified kidney disease. Irbesartan maintained proteinuria at 0.4–0.7 g/day, but was discontinued during pregnancy in 2021, causing a surge to 10 g/day with hypertension, prompting preterm delivery. Postpartum, proteinuria fell to 2 g/day, persisting for 2 years. Genetic testing identified biallelic (likely) pathogenic NPHS1 variants. Sparsentan, a potentially effective treatment for FSGS, was denied for off-label use by insurance. In 2025, the patient's proteinuria was 1.8 g/day. The patient calls her journey ‘frightening and overwhelming', fearing ESKD.
Case 2: A 22-year-old patient had a fatigue workup in 2023 revealing proteinuria (3.5 g/day) and hypoalbuminemia (1.8 g/dL). Symptoms including fatigue, foamy urine, hypercholesterolemia traced to proteinuria identified at age 7. Genetic testing identified biallelic (likely) pathogenic NPHS1 variants, and kidney biopsy confirmed FSGS. Treatment with lisinopril (5 mg/day), tacrolimus (2.5 mg BID), rosuvastatin (10 mg daily), and a low-sodium diet raised albumin to 2.7 g/dL and reduced proteinuria to 1.5 g/day by 2025. The patient continues to experience fatigue and anxiety.
Discussion
Here, we present 2 adult-onset NPHS1-related nephrotic syndrome cases, highlighting its rarity, possibly driven by hypomorphic variants with residual nephrin function. Their distinct phenotypes, one exacerbated by pregnancy and the other, long-smoldering, reflect the broader clinical spectrum of this condition. Genetic testing in individuals with unexplained nephrotic syndrome is critical as identifying monogenic forms can help avoid prolonged or ineffective immunosuppression. The lack of clear treatment strategies for NPHS1-related disease adds to patient burden, underscoring the need for evidence-based care. These cases show the importance of expanding access to genetic testing, developing targeted therapies, and establishing treatment guidelines to bridge the gap between genetic diagnosis and therapeutic uncertainty.