Genetic susceptibility to kidney stone disease: unveiling pathogenesis and potential therapeutic targets
Shiwei Li, Xuemei Wang, Ming Liu
Shiwei Li, Xuemei Wang, Ming Liu
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Commentary

Genetic susceptibility to kidney stone disease: unveiling pathogenesis and potential therapeutic targets

Abstract

Kidney stone disease (KSD) arises from a complex interplay of genetic predisposition, diet, metabolic disorders, and other environmental factors. In this issue of the JCI, Lovegrove et al. report a large GWAS that identifies 71 loci associated with an increased risk of KSD. Through an integrative approach combining Mendelian randomization and functional validation, they emphasize the roles of DGKD, SLC34A1, and CYP24A1 in maintaining homeostasis of calcium and phosphate. These findings offer insights into the pathogenesis of KSD and suggest potential targets for intervention. Further studies are needed to validate these findings across diverse populations and clinical settings.

Authors

Shiwei Li, Xuemei Wang, Ming Liu

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Figure 1

Genetic variants in DGKD, SLC34A1, and CYP24A1 and environmental factors contribute to the pathogenesis of KSD.

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Genetic variants in DGKD, SLC34A1, and CYP24A1 and environmental factors...
(A) The healthy kidney maintains homeostasis of calcium and phosphate. (B) Several variants independently perturb the calcium-phosphate balance and are associated with increased susceptibility to KSD. The DGKD variant rs838717 impairs CaSR signaling via DGKδ activity, disrupting conversion of DAG to PA, a lipid mediator downstream of MAPK signaling that modulates calcium and phosphate homeostasis. This defective signaling increases calcium reabsorption in the TAL and augments phosphate excretion in the PT. Moreover, rs838717 may contribute to elevated circulating calcium and reduced phosphate levels by directly promoting PTH secretion. Cinacalcet can partially rescue the impaired CaSR signal transduction. The SLC34A1 variant rs10051765 impairs phosphate reabsorption by reducing the activity of sodium-phosphate cotransporter NPT2a in the PT, leading to increased renal phosphate excretion. The CYP24A1 variant rs6127099 decreases 24-hydroxylase activity, resulting in elevated circulating 1,25-dihydroxyvitamin D and increased renal calcium absorption. Environmental and acquired risk factors, including dietary oxalate, sodium, animal protein intake, urinary tract infection, medications, metabolic disorders, and unidentified contributors, interact with genetic susceptibility to promote lithogenesis. MAPK, mitogen-activated protein kinase; PA, phosphatidic acid; PIP2, phosphatidylinositol 4,5-bisphosphate.