Clinical impact of genetic testing in inherited kidney diseases

Inherited kidney diseases (IKDs) and congenital anomalies of the kidney and urinary tract (CAKUT) are a clinically heterogeneous subset of chronic kidney disease and rank among the leading causes of kidney failure (KF), especially in younger patients. Although next-generation sequencing has expanded diagnostic opportunities, data linking genetic findings to clinical outcomes across both adults and children remain limited.

We enrolled 256 patients with suspected IKD (175 adults, 81 children) at a single tertiary center between 2020 and 2023. Genetic testing was performed using targeted panels or exome sequencing, including copy number variant (CNV) and MUC1 analyses. Clinical data, including family history, proteinuria, hematuria, extrarenal manifestations, and kidney survival, were systematically assessed.

Pathogenic variants were identified in 38.7% of patients. Five genes (PKD1, PKD2, COL4A5, COL4A4, and HNF1B) accounted for 62.6% of solved cases. Diagnostic yield was highest in cystic kidney diseases (72.0%), followed by tubulopathies (34.3%), glomerulopathies (25.8%), and CAKUT (19.2%). Multivariable regression identified positive family history, extrarenal manifestations, and arterial hypertension as predictors of a genetic diagnosis, with tubular proteinuria serving as an additional predictor in children. Kidney survival varied substantially across genetic subgroups: patients with PKD2 variants and tubulopathies showed more favorable outcomes, whereas individuals with COL4A5-associated Alport syndrome and glomerulopathies progressed rapidly. In the overall cohort, females reached 50% KF significantly later than males. Genetically solved men had the poorest outcomes, with a significant difference compared with solved women; however, this difference was reduced to a nonsignificant trend after excluding X-linked disorders.

Genetic testing provided clinically relevant diagnoses in nearly 40% of patients with suspected IKD, enabling more accurate prognostication and patient stratification. High yield in cystic disease and pediatric tubular proteinuria, sex-specific survival differences, and CNV analysis highlight the value of integrating genetics into routine nephrology care to guide diagnosis, management, and family counselling.