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

Introduction: Underlying mechanisms for hypercalciuria remain unknown in most cases; thus, the designation "idiopathic." We hypothesized that the vitamin D-inactivating enzyme, CYP24A1 contributes to the pathogenesis of hypercalciuria in kidney stone formers.

Methods: We conducted association analyses between CYP24A1 activity, estimated by the vitamin D metabolite diagnostic ratio (25(OH) vitamin D/total 24,25 (OH) vitamin D ratio; VMDR), and the phenotype of participants in 2 observational cohorts of kidney stone formers, the Swiss Kidney Stone Cohort (SKSC) and the Bern Kidney Stone Registry (BKSR). Circulating 25(OH)- and 24,25 (OH) vitamin D were quantified using a validated liquid chromatography tandem mass spectrometry assay.

Results: A total of 974 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% confidence interval [CI]: 0.002, 0.016;  = 0.02) and ionized plasma calcium (β 0.005 mmol/l; 95% CI: 0.002, 0.008;  < 0.01), absolute and fractional excretion of urinary calcium (β 0.054 mmol/24h; 95% CI: 0.010, 0.097;  = 0.02 and β 0.046%; 95% CI: 0.018, 0.074;  < 0.01, respectively). Further, VMDR was associated with an increased likelihood of forming calcium oxalate dihydrate stones (Odds ratio [OR] 1.64; 95% CI: 1.22, 2.35;  < 0.01) and reduced bone mineral density (BMD) at the femoral neck (β -0.005 g/cm; 95% CI: -0.010, -0.001;  = 0.04). The described associations became stronger when the analysis was confined to idiopathic calcium stone formers.

Conclusion: Our study reveals that CYP24A1 activity, estimated by VMDR, is associated with clinical traits previously linked to idiopathic hypercalciuria.