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Kidney disease and vitamin D levels: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and VDR activation.

ABSTRACT: A normal vitamin D status is essential for human health. Vitamin D deficiency is a recognized risk factor for all-cause mortality in normal individuals and in chronic kidney disease (CKD) patients. The link between vitamin D deficiency and death is a defective activation of the vitamin D receptor (VDR) by 1,25-dihydroxyvitamin D (calcitriol, the vitamin D hormone) to induce/repress genes that maintain mineral homeostasis and skeletal integrity, and prevent secondary hyperparathyroidism, hypertension, immune disorders, and renal and cardiovascular (CV) damage. The kidney is the main site for the conversion of 25-hydroxyvitamin D (25D) to circulating calcitriol, and therefore essential for the health benefits of endocrine VDR activation. The kidney is also essential for the uptake of 25D from the glomerular ultrafiltrate for its recycling to the circulation to maintain serum 25D levels, extrarenal calcitriol synthesis, and the prosurvival benefits of autocrine/paracrine VDR activation. Indeed, both calcitriol and vitamin D deficiency increase progressively in the course of CKD, and associate directly with accelerated disease progression and death. Therefore, the safe correction of calcitriol and vitamin D deficiency/insufficiency is becoming a high priority among nephrologists. This review updates the pathophysiology behind 25D and calcitriol deficiency and impaired VDR activation in CKD, the adequacy of current recommendations for vitamin D supplementation, and potential markers of the efficacy of therapy to prevent or slow the development of renal and CV lesions unrelated to parathyroid hormone suppression, a knowledge required for the design of trials to obtain evidence-based recommendations for vitamin D and calcitriol replacement at all stages of CKD.

SUBMITTER: Dusso AS

PROVIDER: S-EPMC4089671 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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Project description:Low vitamin D concentrations are prevalent in patients with chronic kidney disease (CKD). We investigated the relationship between plasma 25-hydroxyvitamin D (25[OH]D) or 1,25-dihydroxyvitamin D (1,25[OH](2)D) concentrations with death, cardiovascular events, and dialysis therapy initiation in patients with advanced CKD.The HOST (Homocysteinemia in Kidney and End Stage Renal Disease) Study was a randomized double-blind trial evaluating the effects of high doses of folic acid on death and long-term dialysis therapy initiation in patients with advanced CKD (stages 4 and 5 not yet on dialysis therapy). 25(OH)D and 1,25(OH)(2)D were measured in stored plasma samples obtained 3 months after trial initiation and evaluated at clinically defined cutoffs (<10, 10-30, and >30 ng/mL) and tertiles (<15, 15-22, and >22 pg/mL), respectively. Cox proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes.1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers.25(OH)D and 1,25(OH)(2)D concentrations.Death, cardiovascular events, and time to initiation of long-term dialysis therapy.After a median follow-up of 2.9 years, 41% (n = 453) died, whereas 56% (n = 615) initiated dialysis therapy. Mean 25(OH)D and 1,25(OH)(2)D concentrations were 21 ± 10 ng/mL and 20 ± 11 pg/mL, respectively. After adjustment for potential confounders, the lowest tertile of 1,25(OH)(2)D was associated with death (HR, 1.33; 95% CI, 1.01-1.74) and initiation of long-term dialysis therapy (HR, 1.78; 95% CI, 1.40-2.26) compared with the highest tertile. The association with death and initiation of dialysis therapy was moderately attenuated after adjustment for plasma fibroblast growth factor 23 (FGF-23) concentrations (HRs of lower tertiles of 1.20 [95% CI, 0.91-1.58] and 1.56 [95% CI, 1.23-1.99], respectively, compared with highest tertile). There was no association between 25(OH)D concentrations and outcomes.Participants were mostly men.Low plasma 1,25(OH)(2)D concentrations are associated with death and initiation of long-term dialysis therapy in patients with advanced CKD. FGF-23 level may attentuate this relationship.

Project description:Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3), but not inactive 25-hydroxyvitamin D3 (25OHD3), correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02), velocity (Vmax, rho = 0.40, p = 0.02) and jump height (rho = 0.36, p = 0.04). Lean mass correlated positively with 1α,25(OH)2D3 (rho = 0.47, p = 0.02), in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively). Serum 25OHD3 and 24,25(OH)2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR) mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH)2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH)2D3 has limited effects on muscle gene expression, but is associated with increased muscle strength and lean mass in women. These pleiotropic effects of the vitamin D 'metabolome' on muscle function indicate that future supplementation studies should not be restricted to conventional analysis of the major circulating form of vitamin D, 25OHD3.

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Kidney disease and vitamin D levels: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and VDR activation.

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