Genetics of kidney stone disease

• Published in: Nature reviews. Urology 2020-07, Vol.17 (7), p.407-421
• Main Authors: Howles, Sarah A., Thakker, Rajesh V.
• Format: Article
• Language: English
• Subjects: 631/208/2489/144; 692/420/2489; 692/499; 692/699/1585/273; Care and treatment; Carrier proteins; Development and progression; Genetic aspects; Genetic regulation; Genome-Wide Association Study; Genotype; Health aspects; Humans; Kidney Calculi - etiology; Kidney Calculi - genetics; Kidney stones; Medicine; Medicine & Public Health; Review Article; Twin studies; Urology
• ISSN: 1759-4812; 1759-4820
• DOI: 10.1038/s41585-020-0332-x

Kidney stone disease (nephrolithiasis) is a common problem that can be associated with alterations in urinary solute composition including hypercalciuria. Studies suggest that the prevalence of monogenic kidney stone disorders, including renal tubular acidosis with deafness, Bartter syndrome, primary hyperoxaluria and cystinuria, in patients attending kidney stone clinics is ∼15%. However, for the majority of individuals, nephrolithiasis has a multifactorial aetiology involving genetic and environmental factors. Nonetheless, the genetic influence on stone formation in these idiopathic stone formers remains considerable and twin studies estimate a heritability of >45% for nephrolithiasis and >50% for hypercalciuria. The contribution of polygenic influences from multiple loci have been investigated by genome-wide association and candidate gene studies, which indicate that a number of genes and molecular pathways contribute to the risk of stone formation. Genetic approaches, studying both monogenic and polygenic factors in nephrolithiasis, have revealed that the following have important roles in the aetiology of kidney stones: transporters and channels; ions, protons and amino acids; the calcium-sensing receptor (a G protein-coupled receptor) signalling pathway; and the metabolic pathways for vitamin D, oxalate, cysteine, purines and uric acid. These advances, which have increased our understanding of the pathogenesis of nephrolithiasis, will hopefully facilitate the future development of targeted therapies for precision medicine approaches in patients with nephrolithiasis. Kidney stone disease is common and can be associated with alterations in urinary solute composition. Here, the authors outline general approaches for stone prevention, describe current understanding of the genetic influences underlying kidney stone formation and discuss the implications of a correct diagnosis for the clinical management of recurrent stone formers. Key points Studies suggest that the prevalence of monogenic kidney stone disease in patients attending kidney stone clinics is ∼15%. For patients without a monogenic cause of nephrolithiasis, the heritability of kidney stone disease and hypercalciuria is >45% and >50%, respectively. Increased understanding of the genetic factors contributing to kidney stone disease helps to improve our understanding of the pathogenesis of this condition. Identification of a monogenic cause of kidney stone disease facilitates optimal stone prevent