Evaluation of genotype-phenotype correlation in pediatrics patients diagnosed with nephrotic syndrome

Objective: This study aimed to identify genetic mutations associated with nephrotic syndrome in pediatric patients. In addition, it sought to compare genetic findings with the patients' clinical, laboratory, histopathological, and therapeutic characteristics and to investigate the impact of mutation type on disease progression and renal survival. Materials and Methods: A total of 67 children diagnosed with nephrotic syndrome and followed at the Akdeniz University Faculty of Medicine, Department of Pediatric Nephrology, who underwent genetic testing related to the pathogenesis of nephrotic syndrome, were included in this retrospective study. Demographic characteristics, clinical findings, laboratory parameters, biopsy results, treatment responses, and genetic analyses were evaluated. Steroid response, response to calcineurin inhibitors (CNI), and the need for renal replacement therapy (RRT) were analyzed as clinical outcome variables. Results: Among the patients, 16.7% were steroid-sensitive, 64.1% were primary steroid resistance, and 18.2% were secondary resistance. Focal segmental glomerülosclerosis (FSGS) was detected in 91% of the biopsi speciment. Pathogenic or likely pathogenic (P/LP) variants were identified in 17.9% of all patients, with NPHS2 being the most frequently affected gene. The incidence of nephrotic syndrome in siblings and consanguinity between parents was higher in patients with detected P/LP mutations than in those without detected mutations (p < 0.05). The overall response rate to CNI therapy was 58.5%. The requirement for RRT was 3.4% in CNI responders and 60.9% in non-responders (p < 0.001). In univariate analysis, a positive family history of nephrotic syndrome and nonresponse to CNI treatment were identified as risk factors for RRT requirement (OR: 9.792, p= 0.011; and OR: 43.556, p= 0.001, respectively), whereas the presence of a P/LP variant was not (OR: 2.56, p= 0.161). Conclusion: In children with steroid-resistant nephrotic syndrome, the frequency of P/LP variants was 16.6%, while it was 17.9% in the total study population. The most significant determinants of long-term renal survival were response to CNI therapy and the presence of a family history of nephrotic syndrome. Despite the prognostic significance of family history, no significant association was observed between genetic mutations and renal survival. Large-scale, multicenter studies are needed to provide further insight into this relationship. Keywords: Nephrotic syndrome, genetic mutation, focal segmental glomerülosclerosis, steroid resistance, calcineurin inhibitors.