Abstract
BackgroundThe ability of extrarenal tissues to convert 25(OH)D (calcidiol) into 1,25(OH)2D (calcitriol) and dependence of the conversion on substrate levels provide the rationale for supplementing vitamin D in dialysis patients who usually have severe depletion of both: 25(OH)D and 1,25(OH)2D. The primary aim of the study was to compare effects of small doses of cholecalciferol (12,000 IU/week) with frequently used in Europe, small doses of alfacalcidol (1.5 μg/week) or placebo, given for 12 weeks, on serum 1,25(OH)2D in hemodialysis patients with 25(OH)D deficiency. Secondary outcomes were changes in serum calcium, phosphate, 25(OH)D, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and sclerostin during the treatment.MethodsThis was a prospective, randomized, partly double-blind (cholecalciferol vs. placebo) study. Out of 522 patients dialyzed in 5 centers in the Mazovian Province, 93 gave informed consent and met the inclusion criteria: any vitamin D metabolites and calcimimetics naïve; no history of liver or intestinal disease; serum 25(OH)D <20 ng/ml, iPTH <1,000 –>110 pg/ml, calcium <10.2, and phosphate <6.8 mg/dl. The subjects were stratified by serum iPTH, then randomized into 3 groups according to the treatment.ResultsTo our knowledge, this is the first study comparing head-to-head these drugs in the hemodialysis population. There were no significant differences between the groups at baseline. 81 patients completed the study. Cholecalciferol normalized serum 25(OH)D, with a mean rise from 12.9 ± 6.7 to 31.3 ± 10.1 ng/ml (p < 0.0001). This was accompanied by a marked increase of 1,25(OH)2D from 13.8 ± 9.3 to 25.1 ± 14.2 pmol/l (p < 0.0001). A rise in serum 1,25(OH)2D was also observed in alfacalcidol treated patients, however much smaller (from 13.5 ± 10.1 to 18.5 ± 11.0 pmol/l; p = 0.02). Neither cholecalciferol nor alfacalcidol treatment resulted in significant changes in serum PTH and the remaining parameters.ConclusionsIn most patients, treatment with cholecalciferol in a 12,000 IU/week dose permits safe correction of 25(OH)D deficiency and is more effective than 1.5 μg/week dose of alfacalcidol in rising serum 1,25(OH)2D. This, together with a lack of influence on circulating iPTH the usefulness of such small alfacalcidol doses in hemodialysis patients is debatable.
Highlights
According to current knowledge, vitamin D regulates the function of many organs and systems, mineral and bone metabolism
Enrolled subjects were stratified by serum parathyroid hormone (PTH) and randomly assigned in 1:1:1 ratio to oral cholecalciferol, alfacalcidol, or placebo, taken three times a week, during hemodialysis for 3 months
Serum 25(OH)D correlated with a duration of dialysis treatment (r = −0.272, p = 0.014), residual diuresis (r = 0.289, p < 0.01), serum phosphate (r = −0.393, p < 0.001), fibroblast growth factor 23 (FGF23) (r = −0.295, p = 0.008), and sclerostin (r = −0.260, p = 0.019)
Summary
Vitamin D regulates the function of many organs and systems, mineral and bone metabolism. We know that both 1-alphahydroxylase (CYP27B1) and vitamin D receptor (VDR) are present in almost every human tissue and that vitamin D may exert its actions via two general ways These are: [1] the endocrine way with 1,25(OH)2D (calcitriol) as a hormone produced in kidneys, and [2] paracrine, autocrine and intracrine ways, in which its precursor −25(OH)D (calcidiol) is converted locally by CYP27B1 to 1,25(OH)2D in the target cell, which activates the VDR and downstream gene expression in the same or a neighboring, VDR-expressing cell [1]. The recognition of the ability of extrarenal tissues to produce calcitriol and the suggestions that many of the significant biological consequences of dysregulated vitamin D balance may be associated with changes in the extracellular concentration of substrate 25(OH)D together with the fact of severe deficiency of both, 1,25(OH)2D and 25(OH)D, in patients on long-term dialysis therapy provided a rationale to the study. Secondary outcomes were changes in serum calcium, phosphate, 25(OH)D, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and sclerostin during the treatment
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