24-25-dihydroxyvitamin-d-3 and Renal-Insufficiency--Chronic

Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23.. Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks.. ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events.. Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Calcifediol; Calcium; Creatinine; Delayed-Action Preparations; Double-Blind Method; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Humans; Hyperparathyroidism; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency; Vitamins

The formation of 24,25-dihydroxyvitamin D (24,25(OH)

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Biomarkers; Calcifediol; Female; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Vitamin D; Vitamins

While vitamin D deficiency is common in patients with end stage renal disease on dialysis and treatment with Vitamin D. The subjects given Vitamin D. We conclude that the enzymatic activity of CYP24A1 is abnormal in end stage renal patients on dialysis. These trials were registered on clinicaltrials.govNCT00511225 on 8/1/2007; NCT01325610 on 1/17/2011; and NCT01675557 on 8/28/2012.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Cholecalciferol; Dietary Supplements; Ergocalciferols; Female; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Vitamin D Deficiency; Vitamins

Vitamin D insufficiency is prevalent in chronic kidney disease (CKD) and associated with secondary hyperparathyroidism (SHPT) and increased risk of bone and vascular disease. Unfortunately, supplementation of stage 3 or 4 CKD patients with currently recommended vitamin D2 or D3 regimens does not reliably restore serum total 25-hydroxyvitamin D to adequacy (≥30ng/mL) or effectively control SHPT. Preclinical and clinical studies were conducted to evaluate whether the effectiveness of vitamin D repletion depends, at least in part, on the rate of repletion. A modified-release (MR) oral formulation of calcifediol (25-hydroxyvitamin D3) was developed which raised serum 25-hydroxyvitamin D3 and calcitriol levels gradually. Single doses of either bolus intravenous (IV) or oral MR calcifediol were administered to vitamin D deficient rats. Bolus IV calcifediol produced rapid increases in serum 25-hydroxyvitamin D3, calcitriol and FGF23, along with significant induction of CYP24A1 in both kidney and parathyroid gland. In contrast, oral MR calcifediol produced gradual increases in serum 25-hydroxyvitamin D3 and calcitriol and achieved similar hormonal exposure, yet neither CYP24A1 nor FGF23 were induced. A 10-fold greater exposure to bolus IV than oral MR calcifediol was required to similarly lower intact parathyroid hormone (iPTH). Single doses of oral MR (450 or 900μg) or bolus IV (450μg) calcifediol were administered to patients with stage 3 or 4 CKD, SHPT and vitamin D insufficiency. Changes in serum 25-hydroxyvitamin D3 and calcitriol and in plasma iPTH were determined at multiple time-points over the following 42 days. IV calcifediol produced abrupt and pronounced increases in serum 25-hydroxyvitamin D3 and calcitriol, but little change in plasma iPTH. As in animals, these surges triggered increased vitamin D catabolism, as evidenced by elevated production of 24,25-dihydroxyvitamin D3. In contrast, MR calcifediol raised serum 25-hydroxyvitamin D3 and calcitriol gradually, and meaningfully lowered plasma iPTH levels. Taken together, these studies indicate that rapid increases in 25-hydroxyvitamin D3 trigger CYP24A1 and FGF23 induction, limiting effective exposure to calcitriol and iPTH reduction in SHPT. They also support further investigation of gradual vitamin D repletion for improved clinical effectiveness. This article is part of a Special Issue entitled "17th Vitamin D Workshop".

Topics: 24,25-Dihydroxyvitamin D 3; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Administration, Oral; Animals; Calcifediol; Calcium; Dietary Supplements; Drug Liberation; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression Regulation; Humans; Male; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; RNA, Messenger; Vitamin D Deficiency; Vitamin D3 24-Hydroxylase; Vitamins

The optimal circulating concentration of 25(OH) vitamin D is controversial.. The aim was to investigate if FGF-23 and 24,25(OH)2D can guide cholecalciferol replacement.. Oral cholecalciferol (10,000 IU weekly) administered to subjects with 25(OH)D levels < 20 ηg/mL and eGFR > 60 mL/min/1.73 m(2) (n = 25), chronic kidney disease (CKD) (n = 27), or end stage renal disease (ESRD) (n = 14).. The study was conducted at the Veterans Affairs clinics.. Serum FGF-23, PTH, 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, calcium, and phosphorous concentrations, and urinary excretion of calcium and phosphorus at baseline and after 8 weeks of treatment.. Cholecalciferol treatment increased concentrations of serum 25(OH)D by (19.3 ± 8 ηg/mL, P = .001; 12.2 ± 9 ηg/mL, P = .0001) and 24,25(OH)2D (1.14 ± 0.89 ηg/mL, P = .0024; 1.0 ± 0.72 ηg/mL P = .0002), and reduced serum PTH (-11 ± 21 pg/mL, P = .0292; -42 ± 68 pg/mL, P = .0494) in normal and CKD subjects, respectively. Cholecalciferol increased serum FGF-23 levels only in normal subjects (44 ± 57 ηg/mL, P = .01). Increments in serum 25(OH)D positively correlated with serum FGF-23 and 24,25(OH)2D and negatively correlated with PTH. In ESRD, cholecalciferol administration increased 25(OH)D by (16.6 ± 6.6 ηg/mL P ≤ .05) without changing 24,25(OH)2D, FGF-23 or PTH levels.. Modest elevations of serum 25(OH)D levels after cholecalciferol treatment are sufficient to induce compensatory degradative pathways in patients with sufficient renal reserves, suggesting that optimal circulating 25(OH)D levels are approximately 20 ηg/mL. In addition, catabolism of 25(OH)D may also contribute to the low circulating vitamin D levels in CKD, since elevations of FGF-23 in CKD are associated with increased 24,25(OH)2D after cholecalciferol administration.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Cholecalciferol; Drug Monitoring; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney; Male; Middle Aged; Multivariate Analysis; Parathyroid Hormone; Prospective Studies; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency; Vitamins