Hereditary podocitopathies with nephrotic syndrome in pediatric patients: features of the clincal phenotype, mutations genes and pathogenesis

BACKGROUND. The relevance of the pediatric problem of hereditary podocytopathy in children is due to the peculiarities of the age at which the clinical phenotype of NS manifests with typical histology of focal segmental glomerulosclerosis (FSGS) or diffuse mesangial sclerosis (DMS), less often minimal changes (MC) due to variants of gene mutations and pathogenesis, with a high frequency of steroid resistance and the risk of progression to the end-stage chronic kidney disease (CKD) already in childhood. THE AIM: to identify the characteristics of the clinical phenotype, genotype, and pathogenesis of nephrotic syndrome (NS) in podocytopathies caused by mutations in genes encoding structural and functional proteins of epithelial podocyte cells of the glomerular filtration barrier.

PATIENTS AND METHODS: The study included 24 pediatric patients (aged 6 months to 17 years) with hereditary podocytopathies accompanied by NS, including 15 boys (62.5 %) and 9 girls (37.5 %). Clinical, biochemical, imaging, and molecular genetic diagnostic methods were used. The severity of chronic kidney disease (CKD) was stratified according to the K/DOQI classification (2002). RESULTS: Among 24 patients with NS, monogenic mutations were identified in 19 (79.2 %), digenic mutations in 3 (12.5 %), and trigenic mutations in 2 (8.3 %). In 24 children with identified pathogenic variants in the genes NPHS2 (4), PLCE1 (3), WT (3), PTPRO (1), COQ6 (1), NUP93 (2), NUP205 (1), NUP85 (1), KANK2 (1), MYO1E (1), TRPC6 (3), PAX2 (1), SGPL1 (1), and DAAM2 (1), the features of pathogenesis, clinical phenotype, and renal function in hereditary podocytopathy-associated NS were characterized.

CONCLUSION: Distinct features of the clinical phenotype, gene mutation variants, pathogenesis, and renal prognosis of NS were identified in 24 children with podocytopathies. Among 21 patients older than 2 years with hereditary podocytopathy with NS (20) and without NS (1), CKD stage C1 with normal glomerular filtration rate was observed in 16 (76.2 %), while progression to CKD stage C5 occurred in 5 (23.8 %). Of these 5 patients, two are receiving maintenance hemodialysis, and three patients with mutations in NPHS2, PLCE1, and WT have a functioning renal transplant. Among three infants with congenital NS, preserved renal function was observed in one case, while acute kidney injury, multiple organ failure, and fatal outcome were reported in two cases.

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