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The genetics of kidney stone disease and nephrocalcinosis

Abstract

Kidney stones (also known as urinary stones or nephrolithiasis) are highly prevalent, affecting approximately 10% of adults worldwide, and the incidence of stone disease is increasing. Kidney stone formation results from an imbalance of inhibitors and promoters of crystallization, and calcium-containing calculi account for over 80% of stones. In most patients, the underlying aetiology is thought to be multifactorial, with environmental, dietary, hormonal and genetic components. The advent of high-throughput sequencing techniques has enabled a monogenic cause of kidney stones to be identified in up to 30% of children and 10% of adults who form stones, with ~35 different genes implicated. In addition, genome-wide association studies have implicated a series of genes involved in renal tubular handling of lithogenic substrates and of inhibitors of crystallization in stone disease in the general population. Such findings will likely lead to the identification of additional treatment targets involving underlying enzymatic or protein defects, including but not limited to those that alter urinary biochemistry.

Key points

  • Kidney stone disease is a complex phenotype that results from the interactions of multiple genes with dietary and environmental factors.

  • Advanced genetic testing modalities have enabled the identification of monogenic causes of kidney stones and nephrocalcinosis in select patients with severe phenotypes.

  • In the past decade, genome-wide association studies have implicated common gene variants in the pathogenesis of kidney stones; many of these variants are in genes that are mutated in monogenic stone disease.

  • In the future, genetic analyses could enable a personalized approach to the diagnosis and treatment of patients with rare and common varieties of kidney stones.

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Fig. 1: Potential mechanisms of kidney stone initiation.
Fig. 2: Kidney mechanisms of nephrocalcinosis and kidney stone disease.

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P.S. and J.C.L. researched the data for the article. P.S., J.C.L. and P.C.H. wrote the text and made substantial contributions to discussion of the content. All authors reviewed and/or edited the article before submission.

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Correspondence to John C. Lieske.

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J.C.L. receives consulting fees from the American Board of Internal Medicine, Alnylam, OxThera, Dicerna, Synlogic, Orfan and Novobiome, and grant support from Alnylam, Allena, Retrophin, OxThera, NIDDK and Dicerna. D.J.S. has received consulting fees from Advicenne, and lecture fees from Retrophin. P.C.H. receives consulting fees from Otsuka Pharmaceuticals, Mitobridge, Regulus, Vertex Pharmaceuticals and Caraway Therapeutics. He has received grant support from Otsuka Pharmaceuticals, Navitor, Acceleron and Jemincare. P.S. has no competing interests.

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Singh, P., Harris, P.C., Sas, D.J. et al. The genetics of kidney stone disease and nephrocalcinosis. Nat Rev Nephrol 18, 224–240 (2022). https://doi.org/10.1038/s41581-021-00513-4

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