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- Low-dose cholecalciferol supplementation and dual vitamin D therapy in haemodialysis patients. [JOURNAL ARTICLE]
- Int Urol Nephrol 2014 Sep 28.
Traditionally, secondary hyperparathyroidism (SHPT) due to low calcitriol synthesis in failing kidneys has been treated with synthetic vitamin D receptor (VDR) activators. Recently, also the importance of low native vitamin D status beyond the issue of SHPT has been recognized in these patients. The aim of this work was to evaluate the effect of cholecalciferol supplementation in haemodialysis patients with low vitamin D serum levels. Another aim was to evaluate dual vitamin D therapy (cholecalciferol supplementation plus paricalcitol) in haemodialysis patients with vitamin D deficiency and concomitant SHPT.Ninety clinically stable maintenance haemodialysis patients were included. Supervised cholecalciferol supplementation was administered due to low vitamin D status. Patients with SHPT were also treated with synthetic VDR activator. Two pre hoc subgroups for statistical analysis were formed: patients treated solely with cholecalciferol (N = 34; 5,000 IU once weekly) and patients treated with a combination of cholecalciferol (identical dose, i.e. 5,000 IU/week) plus paricalcitol (N = 34, median dose 10 μg/week). Follow-up visit was scheduled 15 weeks later. Serum concentrations of calcidiol (25-D), parathyroid hormone (PTH) and beta-cross laps (CTX) were assessed at baseline and at follow-up. Serum calcium, phosphate and alkaline phosphatase (ALP) were monitored monthly. Only non-calcium gastrointestinal phosphate binders were administered. Dialysate calcium was 1.5 mmol/L in all patients, and no oral calcium-containing preparations were prescribed. Depending on data distribution, parametric or nonparametric statistical methods were used for comparison within each group (i.e. baseline vs. follow-up data) as well as between groups.In the whole group of 90 patients, mean baseline 25-D serum level was 20.3 (standard deviation 8.7) nmol/L, and it increased to 66.8 (19) nmol/L (p < 0.0001) after supplementation. In both preformed subgroups, the effect of vitamin D supplementation was almost identical. In cholecalciferol monotherapy, 25-D levels increased from 18.4 (8.2) to 68.6 (21.2) and in dual vitamin D therapy from 18.4 (5.0) to 67.6 (17.7) nmol/L (both p < 0.0001). In addition, both treatment modalities decreased serum PTH levels importantly: from 21.7 (interquartile range 17.3; 35.4) to 18.1 pmol/L (15.3; 24.7) in monotherapy (p = 0.05) and from 38.6 (31.8; 53.3) to 33.9 pmol/L (26.1; 47.5) in dual vitamin D therapy (p = 0.01). Serum calcium, phosphate, ALP and CTX did not change. We have not observed any episode of hypercalcemia in any subject during the whole period of follow-up. At baseline, slightly lower 25-D levels were observed in diabetic than in non-diabetic patients. This difference disappeared after substitution. Vitamin D status and its changes were not related to the patient's age.Low 25-D levels were very common in haemodialysis patients. They were safely and effectively corrected with supervised low-dose cholecalciferol supplementation. In patients with higher baseline PTH levels, dual vitamin D therapy (cholecalciferol plus paricalcitol) was safely and effectively used.
- Serum calcium and bone: effect of PTH, phosphate, vitamin D and uremia. [JOURNAL ARTICLE]
- Nefrologia 2014 Sep 26; 34(5):658-669.
Hyperparathyroidism develops in chronic kidney disease (CKD). A decreased calcemic response to parathyroid hormone (PTH) contributes to the development of hyperparathyroidism and is presumed due to reduced calcium efflux from bone. Contributing factors to the decreased calcemic response to PTH in CKD include: 1) hyperphosphatemia; 2) decreased serum calcitriol; 3) downregulation of the PTH1 receptor; 4) large, truncated amino-terminal PTH fragments acting at the carboxy-PTH receptor; and 5) uremic toxins. Also, prolonged high dose calcitriol administration may decrease the exchangeable pool of bone calcium independent of PTH. The goal of the review is to provide a better understanding of how the above cited factors affect calcium efflux from bone in CKD. In conclusion, much remains to be learned about the role of bone in the regulation of serum calcium.
- Health outcomes of vitamin D. Part I. Characteristics and classic role. [JOURNAL ARTICLE]
- Rocz Panstw Zakl Hig 2014; 68(3):179-184.
Vitamin D is a compound responsible for maintaining mineral homeostasis. It protects against calcium and phosphate deficiency through the effects on the intestine, kidney, parathyroid gland and bone. All mechanisms that help maintain mineral homeostasis of the body are regulated by the vitamin D hormonal form - calcitriol. Synthesis of vitamin D starts in the skin as a non-enzymatic process, which begins during exposure to sunlight, when the absorption of ultraviolet B (UVB) radiation results in convertion of 7-dehydrocholesterol, a metabolite of cholesterol that is stored in the skin, to precholecalciferol (previtamin-D3) that is immediately converted into cholecalciferol (vitamin D3). After the skin synthesis cholecalciferol is transported to the liver where it undergoes hydroxylation, what results in formation of calcidiol (25(OH)D3). The second metabolic process takes place in the kidney, where calcidiol undergoes hydroxylation at the C-1 position to the hormonal, the most active metabolite - 1,25-dihydroxyvitamin D (calcitriol). Vitamin D deficiency may result in bone diseases, such as rickets in children and osteomalacia and osteoporosis in adults. Symptoms of osteomalacia affect mainly the skeletal system and are similar to that observed in rickets. It concerns thoracic kyphosis, pelvis deformities and also the varus knee. Osteoporosis is another condition that is related to abnormalities of mineral homeostasis. It is characterized by the progressive loss of bone mass, impaired bone microarchitecture, and consequently increased fragility and susceptibility to fracture. For the last several years other, non-classic actions of vitamin D3 have been discussed. It was engendered by the discovery of vitamin D3 receptor (VDR) in the most of body tissues and cells. Hence, there are many hypotheses which suggest the inverse relationship between vitamin D status and various diseases, such as cancer, autoimmune diseases, diabetes mellitus and others.vitamin D, vitamin D3, cholecalciferol, mineral homeostasis, vitamin D deficiency, vitamin D3 receptor, VDR, pleiotropic actions.
- Improved Clinical Outcomes Associated With Vitamin D Supplementation During Adjuvant Chemotherapy in Patients With HER2(+) Nonmetastatic Breast Cancer. [JOURNAL ARTICLE]
- Clin Breast Cancer 2014 Aug 15.
Vitamin D (VD) supplementation has pleiotropic effects that extend beyond their impact on bone health, including the disruption of downstream VD receptor signaling and human epidermal growth factor receptor 2 (HER2) signaling through the ErbB2/AKT/ERK pathway. In the present study, we examined our institutional experience with patients having nonmetastatic HER2-positive (HER(+)) breast cancer and hypothesized that those patients who received VD supplementation during neoadjuvant chemotherapy would have improved long-term outcomes.We performed a retrospective review of all patients (n = 308) given trastuzumab-based chemotherapy between 2006 and 2012 at the University of Miami/Sylvester Comprehensive Cancer Center (UM/SCCC). We identified 2 groups of patients for comparison-those who received VD supplementation during neoadjuvant chemotherapy (n = 134) and those who did not (n = 112). Univariate and multivariate Cox proportional hazard regression models were fitted to overall survival (OS) and disease-free survival (DFS).More than half of the patients received VD during neoadjuvant chemotherapy (54.5%), with 60% receiving a dose < 10,000 units/wk and 33.3% having a VD deficiency at the start of therapy. In our final multivariate model, VD use was associated with improved DFS (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.15-0.88; P = .026], whereas larger tumor size was associated with worse DFS (HR, 3.52; 95% CI, 1.06-11.66; P = .04). There were no differences in OS based on any of the categories, including VD use, tumor size, number of metastatic lymph nodes, age at diagnosis, or lymphovascular invasion (LVI).VD supplementation in patients with nonmetastatic HER2(+) breast cancer is associated with improved DFS.
- Vitamin D3 metabolite calcidiol primes human dendritic cells to promote the development of immunomodulatory IL-10-producing T cells. [JOURNAL ARTICLE]
- Vaccine 2014 Sep 15.
Vitamin D is recognized as a potent immunosuppressive drug. The suppressive effects of vitamin D are attributed to its physiologically active metabolite 1,25 dihydroxy vitamin D3 (calcitriol), which was shown, to prime dendritic cells (DCs) to promote the development of regulatory T (Treg) cells. Despite the potential benefit in treating autoimmune diseases, clinical application of calcitriol is hindered by deleterious side effects manifested by hypercalcemia and hypercalciuria. Conversely, the physiological precursors of calcitriol, vitamin D3 (cholecalciferol) and its first metabolite 25-hydroxy vitamin D3 (calcidiol) are widely applied in the clinic due to their low calcimic burden. However, the mechanisms by which cholecalciferol and calcidiol may modulate adaptive immunity remain elusive. This prompted us to unravel the immunosuppressive capacity of these precursors by assessing their influence on DC functions and the subsequent polarization of naïve CD4(+) T cells. In this study we show that, whereas cholecalciferol has insignificant effects on DC maturation and cytokine production, it only weakly primed DCs to induce suppressive T cells. However, like calcitriol, calcidiol not only exerted an inhibitory effect on DC maturation and cytokine production, and primed DCs to promote the development of suppressive IL-10-producing Treg cells. Strikingly, in contrast to the population of IL-10-producing Treg cells induced by calcitriol-primed DCs, the IL-10-producing Treg cells induced by calcidiol-primed DCs exhibited sustained IFN-γ production in face of their suppressive capacity. Experiments with the steroid synthesis inhibitor ketoconazole indicated that the immunomodulatory features of the precursors are dependent on their conversion into calcitriol. Collectively, calcidiol is a potent immune modulator, which may be more adequate than calcitriol for the treatment of chronic inflammatory diseases, since it is less hypercalcimic. This may be of particular interest for the treatment of allergic disease, where concurrent suppression and sustained IFN-γ production by Treg cells effectively counterbalance the Th2-dominated immune responses.
- Vitamin D and experimental invasive aspergillosis. [JOURNAL ARTICLE]
- Med Mycol 2014 Sep 17.
Immune cells express the vitamin D receptor and vitamin D metabolizing enzymes. Favorable vitamin D effects have been indicated in tuberculosis. Vitamin D deficiency increases T helper (Th) 2 responses to Aspergillus, and it suppresses Th2 responses in cystic fibrosis-allergic bronchopulmonary aspergillosis. Can vitamin D modulate the proinflammatory effects of amphotericin B (AmB) therapy in aspergillosis? Groups of mice were infected intravenously (IV) with 3-8 × 10(6) Aspergillus fumigatus conidia. In six experiments, doses of 0.08, 2, or 4 μg/kg calcitriol (active form of vitamin D) were given intraperitoneally +/- AmB-deoxycholate (AmBd) at 0.4, 0.8, 1.2, 1.8, 3.3, or 4.5 mg/kg or 0.8 or 1.2 mg/kg IV. Calcitriol doses were selected to range from doses used in humans to those just below doses shown to decalcify murine bones. In most experiments, doses of calcitriol and AmBd (or control diluents) were given five times, on alternate days, to minimize drug-drug interactions. Calcitriol treatment began on the day of challenge, and survival assessed for 10 days. In no experiments did calcitriol alone significantly worsen or enhance survival or affect residual infection in survivors. Calcitriol also did not affect the efficacy of AmBd. In a representative experiment, AmBd at 0.8 or 1.2 mg/kg IV alone +/- calcitriol at 2 μg/kg enhanced survival (P ≤ 0.01). However, the AmBd regimens with calcitriol were not different than those without, and calcitriol alone was identical to controls. In disseminated invasive aspergillosis, calcitriol did not affect outcome nor influence antifungal efficacy.
- Vitamin D for Prevention and Treatment of Colorectal Cancer: What is the Evidence? [JOURNAL ARTICLE]
- Curr Colorectal Cancer Rep 2014 Sep 1; 10(3):339-345.
Vitamin D insufficiency is highly prevalent in the U.S., particularly among colorectal cancer (CRC) patients. These low levels of vitamin D are concerning in light of increasing evidence that vitamin D may have health benefits beyond skeletal outcomes. Prospective observational studies suggest that higher vitamin D levels are associated with lower risk of incident CRC as well as improved survival in patients with established CRC, and randomized clinical trials are desperately needed to establish causality. Moreover, there remains a great need to improve prognosis for patients with CRC, and investigating vitamin D as a potential therapeutic modality is an attractive option in regards to safety and cost, particularly in this era of expensive and often toxic anti-neoplastic agents. In this review, the available published evidence on vitamin D's activity in CRC will be summarized, spanning preclinical, epidemiological, and clinical studies, and future research directions will be discussed.
- Vitamin D deficiency promotes nonalcoholic steatohepatitis through impaired enterohepatic circulation in Animal Model. [JOURNAL ARTICLE]
- Am J Physiol Gastrointest Liver Physiol 2014 Sep 11.
Vitamin D deficiency (VDD) or insufficiency is recognized for its association with nonalcoholic steatohepatitis (NASH), while the underlying mechanism remains unknown. Using animal models we found that vitamin D deficiency promoted the high fat diet (HFD) initiated simple steatosis into typical NASH, characterized by elevated hepatic inflammation and fat degeneration. The NASH derived from VDD+HFD was related to poor retention of bile acids in the liver and biliary tree, in line with down-regulation of the ileal apical sodium-dependent bile acid cotransporter (iASBT). The impediment of hepatic bile acids by the VDD+HFD mice was related to increased expression of hepatic SREBP1c and fatty acid synthase (FAS), suggesting that VDD may up regulate endogenous fatty acid synthesis into NASH through impaired enterohepatic circulation. Administration of 1,25(OH)2VD3 (calcitriol) corrected the NASH phenotypes in line with restoration of iASBT, promotion of bile filling in the biliary tree, suppression of hepatic lipogenesis and inflammation. Moreover, administration of a bile acid sequestering agent suppressed ileal FGF15 expression, leading increased iASBT expression to restore bile filling in the liver and biliary tree, which ameliorates steatosis and inflammation in the liver. These results suggest a novel mechanism for NASH development, by which VDD down regulates iASBT expression, resulting in poor bile acid pool and elevation of hepatic lipogenesis and inflammation. In conclusion, vitamin D and bile acid sequestration may be explored as new strategies to treat or prevent NASH.
- Preventing Postoperative Hypocalcemia in Patients with Graves Disease: A Prospective Study. [JOURNAL ARTICLE]
- Ann Surg Oncol 2014 Sep 12.
Hypocalcemia occurs after total thyroidectomy (TT) for Graves disease via parathyroid injury and/or from increased bone turnover. Current management is to supplement calcium after surgery. This study evaluates the impact of preoperative calcium supplementation on hypocalcemia after Graves TT.A prospective study of patients with Graves disease undergoing TT was performed. Patients with Graves disease managed over a 9-month period took 1 g of calcium carbonate (CC) three times a day for 2 weeks before TT. Those managed the previous year without supplementation served as historic controls. Age-, gender-, and thyroid weight-matched, non-Graves TT patients were procedure controls. Patient demographics, postoperative laboratory values, complaints, and medications were reviewed. Parathyroid hormone (PTH)-based postoperative protocols dictated postoperative CC and calcitriol use.Forty-five patients with Graves disease were treated with CC before TT, and 38 patients with Graves disease were not. Forty control subjects without Graves disease were identified. Age, gender, and thyroid weight were comparable. Preoperative calcium and PTH levels were equivalent. PTH values immediately after surgery, at postoperative day 1, and at 2-week follow-up were equivalent. Postoperative use of scheduled CC (p = 0.10) and calcitriol (p = 0.60) was similar. Postoperatively, patients with untreated Graves disease had lower serum calcium levels than pretreated patients with Graves disease or control subjects without Graves disease (8.3 mg/dL vs. 8.6 vs. 8.6, p = 0.05). Complaints of numbness and tingling were more common in nontreated Graves disease (26 %) than in pretreated Graves disease (9 %) or in control subjects without Graves disease (10 %, p < 0.05).Calcium supplementation before TT for Graves disease significantly reduced biochemical and symptomatic postoperative hypocalcemia. Preoperative calcium supplementation is a simple treatment that can reduce symptoms of hypocalcemia after Graves TT.
- Interaction of hedgehog and vitamin D signaling pathways in basal cell carcinomas. [Journal Article]
- Adv Exp Med Biol 2014.:329-41.
Basal Cell Carcinomas (BCCs) are the most commonly diagnosed tumors among people in the western world. Most BCCs are caused by mutational inactivation of the tumor suppressor Patched (PTCH), which results in activation of Smoothened (SMO) and of the Hedgehog (HH) signaling pathway. Recent studies indicate that BCC progression involves a crosstalk between Hh signaling, vitamin D derivatives and the vitamin D receptor (Vdr) signaling pathway. This has been demonstrated in BCC-bearing Ptch mutant mice and BCC cell lines, in which both vitamin D3 and its active metabolite calcitriol (1alpha-25(OH)2D3) exert antitumor effects. Interestingly, the antitumor effects are mainly ascribed to an inhibition of Hh signaling. Furthermore, as evident from studies in Vdr deficient mice, calcitriol may also repress the activity of Hh signaling in a Vdr-dependent fashion thereby establishing an additional inhibitory feedback on Hh signaling activity. In this chapter, we discuss the current understanding and controversial findings of the inhibition of Hh signaling by vitamin D derivatives and the implication of these findings for BCC carcinogenesis.