Decreased conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with CKD

Background and objectives Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking. Design, setting, participants, & measurements An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH) 2 D 3 in vitamin D–insufficient patients with CKD ( n =15) and controls with normal kidney function ( n =15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters. Results Vitamin D 3 and 25(OH)D 3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D 3 change, 8.6 ng/ml [interquartile range, 3.9–25.6 ng/ml] for controls versus 12.6 ng/ml [6.9–41.2 ng/ml] for CKD [ P =0.15]; 25(OH)D 3 change, 39.2 ng/ml [30.9–47.2 ng/ml] for controls versus 39.9 ng/ml [31.5–44.1 ng/ml] for CKD [ P =0.58]). Likewise, the absolute increase in 1 α ,25(OH) 2 D 3 was similar between CKD participants and controls (change, 111.2 pg/ml [64.3–141.6 pg/ml] for controls versus 101.1 pg/ml [74.2–123.1 pg/ml] for CKD; P =0.38). Baseline and post-treatment 24,25(OH) 2 D 3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH) 2 D 3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3–3.5 ng/ml] for controls versus 1.2 ng/ml [0.6–1.9 ng/ml] for patients with CKD; P 2 D 3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis. Conclusions Patients with CKD exhibit an altered ability to increase serum 24,25(OH) 2 D 3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH) 2 D 3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.