Vitamin D analogs in uremia: integrating medical and nutritional issues

A system of regulatory molecules interacts at the cellular level to control and coordinate the many metabolic pathways that constitute normal mineral metabolism. Alterations that occur in uremia profoundly disrupt this intricate system of regulation. A lack of control poses serious consequences for patients with chronic renal disease, and restoring some level of control represents a significant treatment goal. To achieve adequate treatment, it is necessary to correct aberrations in the metabolism of the major regulatory molecules, parathyroid hormone, vitamin D, calcium, and phosphorus. The use of vitamin D hormone replacement therapy is one important part of this strategy, and the availability of newer vitamin D compounds may prove to be especially beneficial. The effective use of these compounds, nevertheless, depends on the coordinated efforts of each member of the health care team to design and implement an integrated treatment protocol that recognizes all aspects of intervention.     

Vitamin D receptor polymorphism and prostate cancer prognosis

BackgroundProstatic epithelial cells synthesize the active form of vitamin D (1,25-dihydroxyvitamin D₃), which participates in regulating prostate growth. Calcitriol, a synthetic form of vitamin D₃, exhibits antiproliferative and prodifferentiation activities in prostate cancer. The function of 1,25-dihydroxyvitamin D₃ is mediated by its binding to vitamin D receptor (VDR). VDR forms a heterodimer, typically with retinoid X receptor, to regulate vitamin D target genes. We evaluated the relationship between VDR polymorphism and clinical characteristics associated with prostate cancer risk and prognosis among Egyptian men.Materials and methodsThis case-control study included 2 groups of patients: group A, a control group of 50 subjects with benign prostate hyperplasia, and group B, 50 subjects newly diagnosed with prostate cancer. All participants performed complete blood count, liver and kidney function tests, prostate specific antigen measurement, histopathological analysis and immunohistochemistry for Dickkopf Homolog 3. Restriction fragment length polymorphism-polymerase chain reaction as performed to detect VDR polymorphism.ResultsPatients with prostate cancer and controls showed a significantly different CA genotype frequency (p = 0.007). Furthermore, prostate-specific antigen levels were significantly different in different genotypes in patients with prostate cancer (p < 0.001). Finally, T stage and the VDR ApaI C/A polymorphism were significantly associated (p < 0.041).ConclusionThe VDR ApaI C/A polymorphism may be a diagnostic and prognostic marker for prostate cancer in Egyptian men.     

Vitamin D receptor polymorphism and posttransplantation bone loss

Abstract not available.     

VDR基因型分布及其与骨矿含量的关系

近年来，在骨质疏松研究领域，维生素Ｄ受体基因（ＶＤＲ）与骨量及骨代谢的研究受到许多国外学者的重视。我们利用国际合作的机会，对９６名沈阳妇女ＶＤＲ基因进行了分析。研究对象来自于一项正在进行的骨代谢影响因素研究课题。采用标准方法（Ｎｕｃｌｅｏｎｋｉｔ，ｓｃｏｔｌａｂ，ＵＫ）从白细胞中提取ＤＮＡ，以聚合酶链反应（ＰＣＲ）来扩增特定基因段。用ＢｓａＭＩ限制性内切酶消化ＰＣＲ产物，以２％琼脂糖电泳分离判定ＶＤＲ基因型。使用ＤＰＸ－Ｌ（ＬｕｎａｒＵＳＡ）骨矿测定仪测定研究对象的腰椎（Ｌ２～４）及髋部骨矿含量（ＢＭＣ）。结果：与其他国家人群相比，该人群ＶＤＲ基因的分布状态不同。ＶＤＲ基因的ｂｂ型占总数的９１．７％；Ｂｂ型仅占８．３％，而且ＢＢ基因型完全不存在。在青年妇女中发现ｂｂ基因型组股骨颈ＢＭＣ高于Ｂｂ型组股骨颈ＢＭＣ（Ｐ＝０．０２７）。老年妇女ｂｂ基因型组股骨颈ＢＭＣ也高于Ｂｂ型组，但差异无统计学意义，没有发现其他部位ＢＭＣ与ＶＤＲ基因型有关。     

Vitamin D receptor: a highly versatile nuclear receptor

Vitamin D receptor (VDR) modulators are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). The therapy is associated with reduced mortality in stage 5 CKD patients, who experience an extremely high cardiovascular disease (CVD)-related mortality rate. Chen et al. report that VDR is involved in regulating type A natriuretic peptide receptor (NPR-A) in inner medullary collecting duct cells. The regulation of NPR-A may be one of several mechanisms by which VDR activation reduces CVD risk in CKD.     

Vitamin D analogs: actions and role in the treatment of secondary hyperparathyroidism

Although calcitriol has been shown to have an important role in the pathogenesis of hyperparathyroidism, its use as a therapeutic agent often has been limited by calcemic and phosphatemic toxicity. Vitamin D analogs and the synthetic prohormones, with the potential to have lesser effects on calcium and phosphorus, have been introduced and shown to be effective therapeutic agents. Paricalcitol is used widely in the United States and may be associated with improved clinical outcomes. Further studies on the effects of these vitamin D sterols on the skeleton and further studies of potential differential effects on calcification processes will be forthcoming, and as the mechanisms of their lesser toxicity become understood, perhaps this will pave the way for a future generation of vitamin D analogs with even greater specificity for the suppression of hyperparathyroidism with lesser toxicity.     

Vitamin D receptor gene polymorphisms and prostate cancer risk

BACKGROUND: Vitamin D is a steroid hormone that is thought to play a role in the etiology and progression of prostate cancer. Hormone activity requires binding to the vitamin D receptor (VDR), which contains several genetic polymorphisms that have been associated with risk of prostate cancer. To further evaluate this relationship, we conducted a population-based case-control study of the VDR BsmI, FokI, and Poly-A polymorphisms, and prostate cancer. METHODS: Germline DNA samples and survey data from incident prostate cancer cases (n = 559) and controls (n = 523) of similar age (40-64 years) without a history of the disease who resided in King County, Washington were analyzed. RESULTS: The frequency of the BsmI, FokI, and Poly-A genotypes were similar in cases and controls, and no overall association between any variants and prostate cancer risk were noted. Stratification by clinical features of disease revealed that among men with localized stage disease, the BsmI bb genotype was associated with a modest increase in risk (OR, 1.49; 95% CI, 1.02-2.17; P = 0.04) compared to the BB genotype. CONCLUSIONS: These results suggest that polymorphisms in the VDR gene are not strong predictors of prostate cancer risk among Caucasian men in the U.S.     

Vitamin D receptor gene polymorphism and prostate cancer risk

BACKGROUND: 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts antiproliferative effect on prostatic cells, mediated through the vitamin D receptor. In a case-control study, we examined whether the vitamin D receptor (VDR) gene polymorphism in exon 9 could affect prostate cancer susceptibility. METHODS: One hundred ninety newly diagnosed prostate cancer patients and 190 age-matched men with benign prostatic hyperplasia (BPH), in whom the presence of prostate cancer was excluded clinically or histologically, were recruited for this study. The VDR TaqI polymorphism was investigated by polymerase chain reaction (PCR) following restriction fragment length polymorphism using DNA from lymphocytes. Depending on the presence or absence of the TaqI restriction site at the third position of codon 352, patients were classified as TT, Tt, or tt. RESULTS: The frequency of the tt genotype was not significantly different between prostate cancer patients (18%) and controls (12%; P = 0.07). The odds ratio (OR), calculated relative to individuals with the TT genotype was 1.76 (95% confidence limit (CL) = 0.90-3.45). After stratification for Gleason score and prostate specific antigen levels in a case-case comparison (n = 190), no significant associations with the VDR genotypes were detectable either. CONCLUSIONS: In this case-control study of Austrian Caucasians, no statistically significant association of the VDR TaqI polymorphism and prostate cancer risk was found.     

Vitamin D receptor gene polymorphism in hypercalciuric children

Idiopathic hypercalciuria is a complex disease resulting from an interaction between environmental and genetic factors. Recently, the relationship between vitamin D receptor (VDR) alleles and calcium homeostasis has been investigated. This study was conducted to explore the association of VDR gene polymorphism with the risk of absorptive hypercalciuria (AH). We investigated the VDR gene polymorphisms, ApaI, BsmI, and TaqI, in relation to intact parathormone (PTH), osteocalcin, and 25-hydroxyvitamin D in 80 children (42 males, 38 girls) with AH and in 86 healthy children without hypercalciuria. A significant difference in the ApaI genotype was observed between the AH group and the control group (²=7.21, P=0.027). The AA genotype was associated with a 3.5-fold increased risk for idiopathic hypercalciuria compared with the Aa/aa genotype (odds ratio 3.5, 95% confidence interval 1.1–11). The BsmI and TaqI polymorphisms did not show any significant association with AH. Serum osteocalcin levels were significantly higher in the group with the AA genotype compared with those with the Aa or aa genotype (P=0.02, P=0.05, respectively). The results indicate that the ApaI AA genotype of the VDR gene is not only associated with AH but is also related to differences in serum osteocalcin.     

Vitamin D receptor activation and survival in chronic kidney disease

Replacement of activated vitamin D has been the cornerstone of therapy for secondary hyperparathyroidism (SHPT). Recent findings from several large observational studies have suggested that the benefits of vitamin D receptor activators (VDRA) may extend beyond the traditional parathyroid hormone (PTH)-lowering effect, and could result in direct cardiovascular and metabolic benefits. The advent of several new analogs of the activated vitamin D molecule has widened our therapeutic armamentarium, but has also made therapeutic decisions more complicated. Treatment of SHPT has become even more complex with the arrival of the first calcium-sensing receptor (CSR) agonist (cinacalcet hydrochloride) and with the uncovering of novel mechanisms responsible for SHPT. We provide a brief overview of the physiology and pathophysiology of SHPT, with a focus on vitamin D metabolism, and discuss various practical aspects of VDRA therapy and its reported association with survival in recent observational studies. A detailed discussion of the available agents is aimed at providing the practicing physician with a clear understanding of the advantages or disadvantages of the individual medications. A number of open questions are also analyzed, including the present and future roles of CSR agonists and 25(OH) vitamin D replacement.     

Vitamin D receptor gene polymorphism,bone mass,body size,and vitamin D receptor density

We determined vitamin D receptor (VDR) gene alleles (based on the BsmI restriction site polymorphism), duodenal mucosal receptor density, bone mass at spine and total body, and body size in 32 healthy premenopausal females. While we found no relationship between allele and receptor density in duodenal mucosa, bone mineral content (BMC) at both spine and total body was significantly associated with VDR gene alleles. BMC was highest for the bb allele, lowest for BB, and intermediate for Bb. A similar association was noted between allele and body size variables, particularly weight. When BMC was adjusted for body weight, the association with VDR polymorphism disappeared. The VDR gene polymorphism may be affecting bone mass not through classical nutritional mechanisms (e.g., intestinal calcium absorption), but through an influence on body size.     

Vitamin D receptor activators can protect against vascular calcification

An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification.     

Vitamin D receptor ligand therapy in chronic kidney disease

Chronic kidney disease is a growing public health concern, and secondary hyperparathyroidism is one of the most serious associated comorbidities. In healthy individuals, precisely controlled feedback loops dynamically modulate parathyroid hormone (PTH) levels. As kidney function declines, phosphate retention, decreased 1a,25-dihydroxyvitamin D3, and a tendency to hypocalcemia leads to overstimulation of PTH production and parathyroid hyperplasia. Vitamin D receptor (VDR) ligands are essential tools for controlling parathyroid activity. This review highlights the current clinical and biochemical VDR ligand studies, focusing on the differences between selective and nonselective VDR ligands. It is apparent that VDR ligands have important roles in the management of secondary hyperparathyroidism. Selective VDR ligands, in particular, may offer additional benefits in the treatment of bone disease, and may potentially reduce adverse effects related to cardiovascular disease.     

Vitamin D receptor gene polymorphisms in patients with urolithiasis

Urolithiasis is a multifactorial disease, the onset and severity of which is influenced by both genetic and environmental factors. This study represents an investigation of the role of vitamin D receptor (VDR) gene polymorphisms (ApaI, BsmI, and TaqI) and combined genotypes in urolithiasis in a Turkish population. We studied 110 patients with urinary stones and 150 control subjects. The polymorphic regions were amplified using polymerase chain reaction, followed by digestion with restriction enzymes BsmI, ApaI, and TaqI, and analyzed electrophoretically. Genotype and allele frequencies were calculated, and the association with urolithiasis, family history, and recurrence of stone was investigated. Our data provide no evidence for an association between urolithiasis and VDR ApaI, BsmI, and TaqI genotypes. We also analyzed the effects of VDR ApaI, BsmI, and TaqI genotypes in combination; the “GTT” VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms was overrepresented among the urolithiasis patients. However, no significant differences between heterozygous carriers (OR 1.302; 95% CI 0.527–3.215) and homozygous carriers (OR 3.39; 95% CI 0.719–15.985) were observed in our study population. A significant association was found only between the ApaI polymorphism and family history (P=0.017; χ ²=5.657). Our data indicate that the VDR ApaI, BsmI, and TaqI polymorphisms do not confer a significant risk for urolithiasis.     

Vitamin D receptor expression in human brain tumors.

Vitamin D receptor (VDR) has important effects not only on physiological processes related to Ca2+ metabolism but also on cell growth and differentiation. VDR is a member of the Steroid-Thyroid Receptors Superfamily (STRS). Work in our and other laboratories has shown that several other members of the STRS (androgen, estrogen, glucocorticoid, and progesterone receptors) are present in astrocytomas and glioblastomas. We now report the finding of VDR-like mRNA in human anaplastic astrocytomas and glioblastomas. VDR mRNA levels, as determined by a method, developed in our laboratory, based on the polymerase chain reaction, are significantly higher in glioblastomas compared to both low and high grade astrocytomas. We discuss the biological and clinical implications of our results.