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 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.

1.07 (0.98-1.17)Notes: 1 Adjusted for age, sex, calendar year, kidney disease, hypertension, chronic obstructive pulmonary disease, chronic liver disease, rheumatoid arthritis or connective tissue disease, cancer, diabetes, markers of smoking, baseline eGFR, AKI stage, AKI location, AKI setting, and prescription drugs listed in Table 1.In addition, the adjusted analyses of cardiovascular disease subtypes included adjustments for other cardiovascular disease subtypes.Abbreviations: AKD, acute kidney disease; AKI, acute kidney injury; CI, confidence interval; HR, hazard rate.

Table S2 . Characteristics of all patients with acute kidney injury
Based on diagnoses and pCr tests. 2 Including diabetic nephropathy, hypertensive kidney disease, glomerular disease, tubulointerstitial disease, and congenital kidney disease.3Based on diagnosis and prescription drug use.

Table S3 . Information on follow-up time and plasma creatinine tests after acute kidney injury Abbreviations:
AKD, acute kidney disease; AKI, acute kidney injury; IQR, interquartile range, pCr, plasma creatinine.

Table S4 . Characteristics of patients at risk of chronic kidney disease All, n (%) Rapid reversal AKI, n (%)
Based on diagnoses and pCr tests. 2 Including diabetic nephropathy, hypertensive kidney disease, glomerular disease, tubulointerstitial disease, and congenital kidney disease.3Based on diagnosis and prescription drug use.

Table S5 . Characteristics of patients at risk of cardiovascular disease
Based on diagnoses and pCr tests.2Includingdiabeticnephropathy,hypertensive kidney disease, glomerular disease, tubulointerstitial disease, and congenital kidney disease.3Based on diagnosis and prescription drug use.Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; AKD, acute kidney disease; AKI, acute kidney injury; ARB, angiotensin II receptor blocker; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; ICU, intensive care unit; IQR, interquartile range; NSAID, non-steroidal anti-inflammatory drug; pCr, plasma creatinine.

Table S6 . Twenty-year risks and HRs of chronic kidney disease and kidney failure among patients with a baseline within 90 days before acute kidney injury
Adjusted for age, sex, calendar year, ischemic heart disease, heart failure, atrial fibrillation or flutter, peripheral artery disease, hypertension, chronic obstructive pulmonary disease, chronic liver disease, rheumatoid arthritis or connective tissue disease, cancer, diabetes, markers of smoking, baseline eGFR, AKI stage, AKI location, AKI setting, and prescription drugs listed in Table1.Abbreviations: AKD, acute kidney disease; AKI, acute kidney injury; CI, confidence interval; HR, hazard rate.

Table S8 . HRs of chronic kidney disease and kidney failure among patients with acute kidney injury after 1 April 2010
Adjusted for age, sex, calendar year, ischemic heart disease, heart failure, atrial fibrillation or flutter, peripheral artery disease, hypertension, chronic obstructive pulmonary disease, chronic liver disease, rheumatoid arthritis or connective tissue disease, cancer, diabetes, markers of smoking, baseline eGFR, AKI stage, AKI location, AKI setting, and prescription drugs listed in Table1.Abbreviations: AKD, acute kidney disease; AKI, acute kidney injury; CI, confidence interval; HR, hazard rate.Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting.The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/,Annals of Internal Medicine at http://www.annals.org/,and Epidemiology at http://www.epidem.com/).Information on the STROBE Initiative is available at www.strobe-statement.org. *Note: