Randomized Controlled Trial for the Effect of Vitamin D Supplementation on Vascular Stiffness in CKD

Abstract

Background and objectives: Vitamin D is implicated in vascular health in CKD. This study compared placebo, calcifediol, and calcitriol treatment with changes in vascular stiffness, BP, proteinuria, mineral metabolism parameters, C-reactive protein, and fibroblast growth factor 23 in patients with stable CKD.

Design, setting, participants, & measurements: We conducted a double-blind, randomized controlled trial in out-patient CKD clinics in Vancouver, Canada, from February of 2011 to August of 2014, enrolling 119 patients with an eGFR of 15-45 ml/min per 1.73 m2. Change in pulse wave velocity (PWV) was measured after 6 months of treatment with a fixed dose of oral calcifediol (5000 IU 25-hydroxyvitamin D3), calcitriol (0.5 µg 1,25-dihydroxyvitamin D3), or placebo, thrice weekly.

Results: Eighty-seven participants were evaluated. Mean age was 66 years, 71% were men, 40% were diabetic, and mean baseline PWV was 11.5 m/s (SD=3.9 m/s). After 6 months, the PWV decreased in the calcifediol group (mean change, -1.1; 95% confidence interval [95% CI], -2.2 to 0.1 m/s), remained unchanged in the calcitriol group (mean change, 0.2; 95% CI, -0.9 to 1.4 m/s), and increased in the placebo group (mean change, 1.1; 95% CI, -0.1 to 2.2 m/s). The overall P value for between-arm changes was 0.03. Absolute PWV change was significantly different between groups (P=0.04): the combined vitamin D treatment group saw decreased PWV (mean change, -0.4; 95% CI, -1.2 to 0.4 m/s) whereas the placebo group saw increased PWV (mean change, +1.1; 95% CI, -0.1 to 2.2 m/s). The treatment group demonstrated significantly decreased serum parathyroid hormone (mean difference, -0.5; 95% CI, -0.7 to -0.3 ln[pg/ml]; P<0.001) and increased calcium (mean difference, 0.4; 95% CI, -0.1 to 0.7 mg/dl; P=0.02). In observational analysis, participants in the highest 25-hydroxyvitamin D tertile at trial end had significant decreases in PWV (mean change, -1.0; 95% CI, -2.0 to 0.0 m/s) compared with the middle and lowest tertiles (P<0.01). Side effects were minor and rare.

Conclusions: Six months of supplemental vitamin D analogs at fixed doses may achieve a reduction of PWV in patients with advanced CKD. Because the treatment effect was attenuated when baseline PWV was included as a covariate, these findings should be replicated in larger populations and further studied.

Keywords: Aged; Arm; C-Reactive Protein; Calcifediol; Calcitriol; Canada; Fibroblast Growth Factors; Humans; Male; Minerals; Outpatients; Pulse Wave Analysis; Renal Insufficiency, Chronic; Vascular Stiffness; Vitamin D; Vitamins; blood pressure; calcium; diabetes mellitus; fibroblast growth factor 23; mineral metabolism; parathyroid hormone; proteinuria; vascular calcification; vascular disease.

Copyright © 2017 by the American Society of Nephrology.

Figures

Figure 1.

Participant flow diagram/CONSORT study diagram (). Fifteen patients (five in the placebo group, six in the calcitriol group, and four in the calcifediol group) who completed the study but do not have the primary end point measure because of technical difficulties in measurement (difficulties obtaining good tracing because of body habitus, arrhythmias, or pacemakers that produced recordings that the SphygmoCor machine was unable to analyze). CONSORT, CONsolidated Standards Of Reporting Trials; PWV, pulse wave velocity.

Figure 2.

25(OH)D and 1,25(OH)2D levels by treatment group at baseline and 6 months. Serum 25(OH)D and 1,25(OH)2D levels were summarized using mean (SD) and compared across treatment arms by analysis of covariance with baseline levels as covariate. P values are adjusted for multiple comparisons using the Tukey–Kramer method. The 25(OH)D and 1,25(OH)2D levels were balanced at the baseline. The 6-month change in the 25(OH)D levels in the calcifediol group was statistically significantly higher than both calcitriol (P<0.001) and placebo (P<0.001) group changes. The between-arm differences in the 6-month changes in the 1,25(OH)2D levels were not statistically significant. SI conversion factors: to convert 25(OH)D to nmol/L, multiply by 2.496; to convert 1,25(OH)2D to pmol/L, multiply by 2.6. 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D.

Figure 3.

PWV levels by study arm at baseline and after 6 months of treatment. PWV levels were summarized using box-plots (mean, median, lower and upper quartile, 1.5 of interquartile range, and outliers) and compared between treatment arms using the t test. By chance, the vitamin D treatment arm had a higher baseline PWV. The 6-month change in PWV levels in the vitamin D treatment arm was statistically significantly different than the placebo group change (P=0.04). PWV, pulse wave velocity.