The Vitamin D Metabolite Diagnostic Ratio Associates With Phenotypic Traits of Idiopathic Hypercalciuria

Abstract

IntroductionUnderlying mechanisms for hypercalciuria remain unknown in most cases, hence the designation “idiopathic”. We hypothesized that the Vitamin D-inactivating enzyme CYP24A1 contributes to the pathogenesis of hypercalciuria in kidney stone formers. MethodsWe conducted association analyses between CYP24A1 activity, estimated by the Vitamin D metabolite diagnostic ratio (25(OH) Vitamin D3/total 24,25 (OH)2 Vitamin D ratio; VMDR), and the phenotype of participants in two observational cohorts of kidney stone formers, the Swiss Kidney Stone Cohort and the Bern Kidney Stone Registry. Circulating 25(OH)- and 24,25 (OH)2 Vitamin D were quantified using a validated LC-MS/MS assay. Results974 participants were included in the analysis. We found a positive association of VMDR (and hence negative association of CYP24A1 activity) with total (β 0.009 mmol/L; 95% CI 0.002, 0.016; p = 0.02) and ionized plasma calcium (β 0.005 mmol/L; 95% CI 0.002, 0.008; p < 0.01), absolute and fractional excretion of urinary calcium (β 0.054 mmol/24h; 95% CI 0.010, 0.097; p = 0.02 and β 0.046 %; 95% CI 0.018, 0.074; p < 0.01, respectively). Further, VMDR was associated with an increased likelihood of forming calcium oxalate dihydrate stones (Odds ratio 1.64; 95% CI 1.22, 2.35; p < 0.01) and reduced bone mineral density at the femoral neck (β -0.005 g/cm2; 95% CI -0.010, -0.001; p = 0.04). The described associations became stronger when the analysis was confined to idiopathic calcium stone formers. ConclusionOur study reveals that CYP24A1 activity, estimated by VMDR, is associated with clinical traits previously linked to idiopathic hypercalciuria.