title: Decreased conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with CKD.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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)2D3 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 D3 and 25(OH)D3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D3 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)D3 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 1α,25(OH)2D3 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)2D3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)2D3 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<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)2D3 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)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; jstubbs@kumc.edu.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Stubbs
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Shiqin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Friedman
authors.affiliation: Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, and Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh Schools of Pharmacy and Medicine, Pittsburgh, Pennsylvania.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Nolin
mesh_terms: D015650:24,25-Dihydroxyvitamin D 3 / Q000096:biosynthesis / Q000097:blood; D000328:Adult; D000368:Aged; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D002112:Calcifediol / Q000097:blood; D002117:Calcitriol / Q000097:blood; D016022:Case-Control Studies; D002762:Cholecalciferol / Q000097:blood* / Q000627:therapeutic use*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D005919:Glomerular Filtration Rate; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014808:Vitamin D Deficiency / Q000097:blood* / Q000209:etiology
chemical_list: D050071:Bone Density Conservation Agents; C000717427:FGF23 protein, human; D002762:Cholecalciferol; D015650:24,25-Dihydroxyvitamin D 3; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002117:Calcitriol; D002112:Calcifediol
keywords: 24-hydroxylase; FGF23; calcidiol; cholecalciferol; vitamin D