#1795 Next-generation sequencing in chronic kidney disease of unknown etiology: a step toward precision medicine

Abstract Background and Aims Chronic kidney disease (CKD) affects over 850 million people globally and is a significant contributor to mortality and morbidity. Approximately 10% of adult CKD cases are hereditary, predominantly involving autosomal dominant polycystic kidney disease (ADPKD) and other ciliopathies, glomerular diseases, and tubulopathies. CKD of unknown etiology (CKD-U) poses diagnostic and management challenges, particularly in advanced stages where renal biopsy is uninformative. Method A cross-sectional observational study was conducted at Sir Ganga Ram Hospital, New Delhi. Patients with CKD-U were recruited and underwent clinical evaluation, laboratory investigations, and genetic testing via next-generation sequencing (NGS). The analysis included genetic variant classification and assessment of pathogenicity based on American College of Medical Genetics guidelines. Patients were categorized into subgroups based on disease phenotype, and diagnostic yield was analyzed for each subgroup. The study also evaluated the implications of genetic findings on patient management, including treatment changes, donor selection, and genetic counseling. Results Genetic testing was performed on 100 patients, revealing pathogenic or likely pathogenic variants in 26% of cases. Variants of uncertain significance (VUS) were identified in 35% of patients. The highest diagnostic yield was observed in tubulopathies (100%), cystic renal diseases (57.14%), and glomerular diseases (37.5%). Alport syndrome and ADPKD were the most common genetic diagnoses. Among patients with genetic diagnoses, 23.07% had revised clinical diagnoses, 30.07% had their diagnoses confirmed, and 61.5% experienced management changes. These management changes included treatment modification (19.23%), donor selection (23.07%), and family planning guidance (19.23%). Patients with pathogenic variants were younger at disease onset compared to those without genetic diagnoses. Notably, reverse phenotyping based on genetic findings led to better disease characterization and informed management in several cases. Conclusion NGS provided valuable insights into the genetic basis of CKD-U, enabling more precise diagnoses and personalized management strategies. These findings emphasize the utility of genetic testing in CKD-U, particularly in cases with complex phenotypes or late presentations. Broader adoption of genetic testing in CKD-U has the potential to improve diagnostic accuracy, guide therapeutic decisions, and support at-risk families through genetic counseling and informed donor selection.