Abstract: Chronic Kidney Disease (CKD) is a globally prevalent, progressive condition marked by a sustained decline in glomerular filtration rate and progression to ESRD. While environmental and lifestyle factors contribute, genetic predisposition plays a fundamental role in renal injury. This review examines the mechanistic pathways through which key variants contribute to CKD, emphasizing how molecular dysfunction links genotype to phenotype. Specifically, it highlights the roles of UMOD, APOL1, SHROOM3, GATM, MYH9, and GCKR in glomerular integrity, tubular function, mitochondrial dynamics, cytoskeletal regulation, and metabolic control. Polymorphisms in these genes underlie diverse renal pathologies, including autosomal dominant tubulointerstitial kidney disease (ADTKD), focal segmental glomerulosclerosis (FSGS), and diabetic nephropathy, by disrupting protein trafficking, cytoskeletal stability, creatine biosynthesis, and glucose/lipid metabolism, driving oxidative stress, inflammation, fibrosis, and podocyte damage. While UMOD and MYH9 act directly in renal tissue, systemic regulators like GCKR exert metabolic effects that secondarily injure the kidneys. By integrating molecular genetics with renal pathophysiology, this review underscores the role of genetic determinants in CKD and their translational potential for precision nephrology, including risk prediction, personalized interventions, and novel therapeutic targets.
Zahid et al. (2026) studied this question.