calcitriol and Metabolic-Diseases

Vitamin D3 is made in the skin from 7-dehydrocholesterol under the influence of UV light. Vitamin D2 (ergocalciferol) is derived from the plant sterol ergosterol. Vitamin D is metabolized first to 25 hydroxyvitamin D (25OHD), then to the hormonal form 1,25-dihydroxyvitamin D (1,25(OH)2D). CYP2R1 is the most important 25-hydroxylase; CYP27B1 is the key 1-hydroxylase. Both 25OHD and 1,25(OH)2D are catabolized by CYP24A1. 1,25(OH)2D is the ligand for the vitamin D receptor (VDR), a transcription factor, binding to sites in the DNA called vitamin D response elements (VDREs). There are thousands of these binding sites regulating hundreds of genes in a cell-specific fashion. VDR-regulated transcription is dependent on comodulators, the profile of which is also cell specific. Analogs of 1,25(OH)2D are being developed to target specific diseases with minimal side effects. This review will examine these different aspects of vitamin D metabolism, mechanism of action, and clinical application.

Topics: Cytochrome P-450 Enzyme System; DNA; Humans; Immune System; Metabolic Diseases; Neoplasms; Receptors, Calcitriol; Response Elements; Vitamin D

Phosphate retention and, later, hyperphosphatemia are key contributors to chronic kidney disease (CKD)-mineral and bone disorder (MBD). Phosphate homeostatic mechanisms maintain normal phosphorus levels until late-stage CKD, because of early increases in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Increased serum phosphorus, and these other mineral abnormalities, individually and collectively contribute to bone disease, vascular calcification, and cardiovascular disease. Earlier phosphate control may, therefore, help reduce the early clinical consequences of CKD-MBD, and help control hyperphosphatemia and secondary hyperparathyroidism in late-stage CKD. Indeed, it is now widely accepted that achieving normal phosphorus levels is associated with distinct clinical benefits. This therapeutic goal is achievable in CKD stages 3 to 5 but more difficult in dialysis patients. Currently, phosphate control is only initiated when hyperphosphatemia occurs, but a potentially beneficial and simple approach may be to intervene earlier, for example, when tubular phosphate reabsorption is substantially diminished. Early CKD-MBD management includes dietary phosphate restriction, phosphate binder therapy, and vitamin D supplementation. Directly treating phosphorus may be the most beneficial approach because this can reduce serum phosphorus, PTH, and FGF-23. This involves dietary measures, but these are not always sufficient, and it can be more effective to also consider phosphate binder use. Vitamin D sterols can improve vitamin D deficiency and PTH levels but may worsen phosphate retention and increase FGF-23 levels, and thus, may also require concomitant phosphate binder therapy. This article discusses when and how to optimize phosphate control to provide the best clinical outcomes in CKD-MBD patients.

Topics: Chelating Agents; Chronic Disease; Dietary Supplements; Fibroblast Growth Factor-23; Homeostasis; Humans; Hyperphosphatemia; Kidney Diseases; Metabolic Diseases; Phosphorus, Dietary; Practice Guidelines as Topic; Time Factors; Treatment Outcome; Vitamin D

A compromised vitamin D status, characterized by low 25-hydroxyvitamin D (25-(OH)D) serum levels, and a nutritional calcium deficit are widely encountered in European and North American countries, independent of age or gender. Both conditions are linked to the pathogenesis of many degenerative, malignant, inflammatory and metabolic diseases. Studies on tissue-specific expression and activity of vitamin D metabolizing enzymes, 25-(OH)D-1 alpha-hydroxylase and 25-(OH)D-24-hydroxylase, and of the extracellular calcium-sensing receptor (CaR) have led to the understanding of how, in non-renal tissues and cellular systems, locally produced 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) and extracellular Ca(2+) act jointly as key regulators of cellular proliferation, differentiation and function. Impairment of cooperative signalling from the 1,25-(OH)(2)D(3)-activated vitamin D receptor (VDR) and from the CaR in vitamin D and calcium insufficiency causes cellular dysfunction in many organs and biological systems, and, therefore, increases the risk of diseases, particularly of osteoporosis, colorectal and breast cancer, inflammatory bowel disease, insulin-dependent diabetes mellitus type I, metabolic syndrome, diabetes mellitus type II, hypertension and cardiovascular disease. Understanding the underlying molecular and cellular processes provides a rationale for advocating adequate intake of vitamin D and calcium in all populations, thereby preventing many chronic diseases worldwide.

Topics: Autoimmune Diseases; Calcium; Calcium, Dietary; Cardiovascular Diseases; Chronic Disease; Gene Expression Regulation; Humans; Metabolic Diseases; Neoplasms; S100 Calcium Binding Protein G; Vitamin D; Vitamin D Deficiency

This study examined differences in the concentration of markers of mineral metabolism across race in patients with advanced CKD not requiring dialysis and ESRD.. Concentrations of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF-23) were measured in stored plasma samples of 1497 patients with advanced CKD not yet on dialysis and ESRD who participated in the Homocysteine in Kidney and End Stage Renal Disease study. Linear regression models were used to examine the relationship between race and 25(OH)D, 1,25(OH)(2)D, iPTH, and FGF-23 concentrations.. Non-Hispanic white patients comprised 58% of the cohort, whereas non-Hispanic blacks comprised 42%. Median (interquartile range) FGF-23 concentrations were lower in blacks compared with whites with CKD (323 [181-655] versus 431 [232-1026] RU/ml; P<0.001) but not in ESRD. In adjusted linear regression models, blacks with CKD not requiring dialysis had significantly lower plasma FGF-23 concentrations (difference, -159; 95% confidence interval, -205 to -106; P<0.001) compared with whites, independent of plasma 25(OH)D, 1,25(OH)(2)D, and iPTH concentrations. This difference was not observed in the ESRD group. The magnitude of correlation for the relationships between 1,25(OH)(2)D with iPTH, FGF-23 with 1,25(OH)(2)D, and FGF-23 with iPTH were stronger among blacks than whites with CKD not requiring dialysis.. In advanced CKD not requiring dialysis, blacks have lower FGF-23 concentrations than whites. Blacks with CKD and ESRD have lower 25(OH)D and higher iPTH compared with whites, independent of FGF-23 concentrations.

Topics: Aged; Biomarkers; Black or African American; Bone and Bones; Chi-Square Distribution; Chronic Disease; Cross-Sectional Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Diseases; Kidney Failure, Chronic; Linear Models; Male; Metabolic Diseases; Middle Aged; Multivariate Analysis; Parathyroid Hormone; Prospective Studies; United States; Vitamin D; White People

We investigated to which extent disturbances in mineral metabolism predict 90-day clinical outcome in end-stage heart failure patients.. Among numerous biochemical parameters, we measured serum levels of sodium and magnesium, the calciotropic hormones parathyroid hormone and 1,25-dihydroxyvitamin D as well as fibroblast growth factor-23 (a phosphaturic hormone) in 305 cardiac transplant candidates. Primary endpoint was a composite of the need of mechanical circulatory support (MCS), transplantation, or death.. Of the study cohort, 33.4% reached the primary endpoint. In detail, 19% were transplanted (the vast majority was listed "high urgent"), 8.8% died and 5.6% received MCS implants. As determined by logistic regression analysis, all aforementioned biochemical parameters were independently related to the primary endpoint. Results did not change substantially when transplanted patients were censored. A risk score (0-5 points) was developed. Of the patients who scored 5 points 89.5% reached the primary endpoint whereas of the patients with a zero score only 3.8% reached the primary endpoint.. Our data demonstrate that in addition to the well-known predictive value of disturbed sodium metabolism, derangements in calcium, phosphate, and magnesium metabolism also predict midterm clinical outcome in end-stage heart failure patients.

Topics: Biomarkers; Disease-Free Survival; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Germany; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Kaplan-Meier Estimate; Logistic Models; Magnesium; Male; Metabolic Diseases; Middle Aged; Parathyroid Hormone; Pilot Projects; Prognosis; Risk Assessment; Risk Factors; Sodium; Time Factors; Vitamin D