Genetic Predisposition in Kidney Stone Disease

Kidney stone disease affects approximately 10–15% of the global population and is now recognized as a chronic systemic condition with metabolic and cardiovascular implications. Its pathogenesis is multifactorial, involving genetic, metabolic, and environmental factors that drive urinary supersaturation and crystal formation. Heritability estimates of 45–55% underscore the substantial genetic contribution to individual susceptibility.

The genetic architecture includes rare monogenic disorders such as primary hyperoxaluria, cystinuria, Dent disease, and Bartter syndrome, as well as common polygenic susceptibility identified through genome-wide association studies (GWAS). Key loci, including CLDN14, SLC34A1, CASR, VDR, and CYP24A1, disrupt mechanisms such as hypercalciuria, hyperoxaluria, hyperuricosuria, reduced urinary citrate, and renal tubular dysfunction.

Advances in next-generation sequencing have improved diagnostic precision and enabled genotype-guided management. Emerging approaches involving pharmacogenomics, RNA interference therapies, and microbiome–genetics interactions offer promising avenues for precision medicine. This chapter reviews the genetic basis of kidney stone disease, encompassing monogenic causes, polygenic risk, implicated pathways, and clinical implications to inform personalized prevention and treatment strategies.