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Genetics of kidney stone disease

Abstract

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.

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 prevention management and identification of associated phenotypes.

  • Advances in our understanding of the polygenic factors contributing to risk of kidney stone disease might enable a precision medicine approach.

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Fig. 1: Radiographic appearance of kidney stone disease in three patients.
Fig. 2: Monogenic disorders of nephrolithiasis resulting in renal tubular dysfunction.
Fig. 3: Vitamin D metabolism.
Fig. 4: Schematic representation of purine metabolism.

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Acknowledgements

The authors are supported by National Institute for Health Research (NIHR) Academic Clinical Lectureship (S.A.H.); Kidney Research UK project grant (RP_030_20180306; S.A.H.); Wellcome Trust Investigator Award (R.V.T.); NIHR Oxford Biomedical Research Centre Programme (R.V.T.); and NIHR Senior Investigator Award (R.V.T.).

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Howles, S.A., Thakker, R.V. Genetics of kidney stone disease. Nat Rev Urol 17, 407–421 (2020). https://doi.org/10.1038/s41585-020-0332-x

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