Nephrotic syndrome / focal segmental glomerulosclerosis (FSGS)

Nephrotic syndrome is defined by a urine protein/creatinine ratio ≥ 200 mg/mmol or a 24-h sample ≥ 1,000 mg/m2/day, hypoalbuminemia (serum albumin < 30 g/L), and oedema. Approximately 85% of cases are steroid-sensitive, and approximately 15% are steroid-resistant. FSGS is the predominant histopathological pattern of podocyte injury in SRNS. Genetic SRNS may be non-syndromic, confined to an isolated kidney phenotype, or syndromic, with extrarenal manifestations such as sensorineural hearing loss, ocular abnormalities, disorders of testicular development, or neurodevelopmental features. Age of onset spans the full clinical spectrum, from congenital presentation within the first three months of life through childhood and adolescence to adult-onset disease.

The estimated incidence of FSGS is approximately 10 cases per million population per year (Regalia et al. 2024). Approximately 30% of individuals with childhood-onset SRNS and 10-15% of individuals with adult-onset SRNS carry pathogenic variants in one of approximately 60 SRNS-associated genes.

More than 60 genes are associated with genetic SRNS. The genetic forms can be grouped into non-syndromic SRNS/FSGS and syndromic SRNS. Pathogenic variants in NPHS2 are the most frequently identified cause in childhood-onset disease (~20-30%). Other genes associated with non-syndromic forms include NPHS1 and INF2. Syndromic forms include (caused by variants in COL4A3, COL4A4, and COL4A5) and WT1-associated disorders (Denys-Drash and Frasier syndromes).

The genetic conditions associated with nephrotic syndrome and FSGS follow heterogeneous inheritance patterns. Reported modes include autosomal recessive (most congenital and many childhood-onset forms), autosomal dominant (notably WT1-related SRNS and adult-onset INF2-related FSGS), and, rarely, X-linked, digenic, and mitochondrial inheritance. Where a familial pathogenic variant has been identified, predictive testing of at-risk relatives is technically possible.

• Where nephrotic syndrome or FSGS is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Lipska-Ziętkiewicz BS, Trautmann A, Schaefer F. Genetic Steroid-Resistant Nephrotic Syndrome Overview. 2021 Aug 19. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: . Available from:
• Bassanese G, Wlodkowski T, Servais A, Heidet L, Roccatello D, Emma F, et al. The European Rare Kidney Disease Registry (ERKReg): objectives, design and initial results. Orphanet Journal of Rare Diseases. 2021;16(1):251. doi: 10.1186/s13023-021-01872-8. PMID: . PMCID: PMC8173879.
• Regalia A, Abinti M, Alfieri CM, Campise M, Verdesca S, Zanoni F, et al. Post-transplant glomerular diseases: update on pathophysiology, risk factors and management strategies. Clinical Kidney Journal. 2024;17(12):sfae320. doi: 10.1093/ckj/sfae320. PMID: . PMCID: PMC11630810.
• Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatric Nephrology (Berlin, Germany). 2020;35(8):1529-1561. doi: 10.1007/s00467-020-04519-1. PMID: . PMCID: PMC7316686.
• KDIGO Conference Participants. Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney International. 2022;101(6):1126-1141. doi: 10.1016/j.kint.2022.03.019. PMID: . PMCID: PMC9922534.