Genetics of kidney stone disease-Polygenic meets monogenic

Kidney stone disease comprising nephrolithiasis and nephrocalcinosis is a clinical syndrome of increasing prevalence with remarkable heterogeneity. Stone composition, age of manifestation, rate of recurrence, and impairment of kidney function varies with underlying etiologies. While calcium-based kidney stones account for the vast majority their etiology is still poorly understood. Recent studies underline the notion that genetic susceptibility together with dietary habits constitutes the major driver of kidney stone formation. In addition to single gene (Mendelian) disorders, which are most likely underestimated in the adult population, common risk alleles explain part of the observed heritability. Interestingly, identified GWAS loci often match those of Mendelian disease genes and vice versa (CASR, SLC34A1, CYP24A1). These findings provide mechanistic links related to renal calcium homeostasis, vitamin D metabolism, and CaSR-signaling regulated by the CaSR-CLDN14-CLDN16/19 axis (paracellular Ca²⁺ reabsorption) and TRPV5 (transcellular Ca²⁺ reabsorption). Recent identification of new single gene disorders of calcium-oxalate-nephrolithiasis (SLC26A1, CLDN2) and distal renal tubular acidosis with nephrocalcinosis (FOXI1, WDR72, ATP6V1C2) enabled additional insights into the kidney-gut axis and molecular prerequisites of proper urinary acidification. Implementation of centralized patient registries on hereditary kidney stone diseases are necessary to build up well characterized cohorts for urgently needed clinical studies.