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

Nasser A Dhayat; Cédric Mattmann; Harald Seeger; Alexander Ritter; Thomas Ernandez; Catherine Stoermann-Chopard; Florian Buchkremer; Stephan Segerer; Beat Roth; Gregoire Wuerzner; Carsten A Wagner; Olivier Bonny; Albrecht W Popp; Bruno Vogt; Matteo Bargagli; Daniel G Fuster

doi:10.1016/j.ekir.2024.01.004

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

Kidney Int Rep. 2024 Jan 10;9(4):1072-1082. doi: 10.1016/j.ekir.2024.01.004. eCollection 2024 Apr.

Authors

Nasser A Dhayat^{1

2}, Cédric Mattmann³, Harald Seeger⁴, Alexander Ritter⁴, Thomas Ernandez⁵, Catherine Stoermann-Chopard⁵, Florian Buchkremer⁶, Stephan Segerer⁶, Beat Roth^{7

8}, Gregoire Wuerzner⁹, Carsten A Wagner^{2

10}, Olivier Bonny^{2

9

11

12}, Albrecht W Popp¹³, Bruno Vogt³, Matteo Bargagli^{2

3}, Daniel G Fuster^{2

3}

Affiliations

¹ B. Braun Medical Care AG, Nephrology and Dialysis Care Center, Hochfelden, Zürich, Switzerland.
² Swiss National Centre of Competence in Research Kidney.CH, Zürich, Switzerland.
³ Department of Nephrology and Hypertension, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
⁴ Division of Nephrology, University Hospital Zürich, Zürich, Switzerland.
⁵ Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland.
⁶ Division of Nephrology, Kantonsspital Aarau, Aarau, Switzerland.
⁷ Department of Urology, Lausanne University Hospital, CHUV, University of Lausanne, Switzerland.
⁸ Department of Urology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
⁹ Service of Nephrology and Hypertension, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁰ Institute of Physiology, University of Zürich, Zürich, Switzerland.
¹¹ Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
¹² Service of Nephrology, Fribourg State Hospital and University of Fribourg, Fribourg, Switzerland.
¹³ Department of Osteoporosis, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

Abstract

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 D₃/total 24,25 (OH)₂ 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)₂ 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; 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 [OR] 1.64; 95% CI: 1.22, 2.35; P < 0.01) and reduced bone mineral density (BMD) 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.

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

Keywords: CYP24A1; calcium; kidney stones; nephrolithiasis; vitamin D.