维生素D对心血管系统保护作用的研究进展(英文)

维生素D是机体内维持钙磷代谢稳定的重要物质,临床用于治疗骨质疏松以及甲状旁腺功能亢进。有证据显示日晒减少以及摄入不足导致的维生素D缺乏症与心血管疾病以及慢性肾脏疾病紧密相关。维生素D激活其受体,在辅助因子的作用下形成转录复合物,从而直接或间接调节机体内约3%的基因转录。肾素、肿瘤坏死因子、基质金属蛋白酶等都受其调控。基础及临床实验都已证明维生素D对心血管系统有保护作用。它可保护心脏功能、降低血压、改善血管内皮功能、抑制氧化应激、降低肾素-血管紧张素活性等。本文将就维生素D及其受体激动剂对心血管系统的保护作用以及分子机制的最新研究进展作一简单综述。     

成纤维细胞生长因子23（FGF23)在终末期肾病患者继发性甲状旁腺功能 亢进中的作用

目的:探究成纤维细胞生长因子23(FGF23)在终末期肾病患者继发性甲状旁腺功能亢进中的作用机制。方法:选取我院2013年2月-2015年5月期间收治的58例终末期肾病进入血液透析的患者,所有患者均经甲状旁腺CT增强扫描,无增生及结节。按照i PTH值将其分为两组,i PTH300 pg/m L为观察组,150 pg/m L≤i PHT≤300 pg/m L为对照组,每组29例。患者均予碳酸钙以及活性维生素D3进行治疗。对患者钙、磷、白蛋白、血脂以及FGF23、i PTH、1,25(OH)_2D_3进行检验。结果:治疗后观察组患者FGF23及i PTH均高于对照组,差异具有统计学意义(P0.05)。观察组血尿素氮、血肌酐与透析前相比明显下降,对照组血尿素氮、血肌酐与透析前相比明显下降,差异有统计学意义(P0.01);1,25(OH)_2D_3以及血白蛋白水平是影响Log FGF23的独立影响因素。结论:FGF23在终末期肾病患者继发性甲状旁腺功能亢进发病中发生作用,可作用临床诊断依据。     

西那卡塞治疗血液透析患者继发性甲状旁腺功能亢进症的临床研究

通过研究两个相同随机、双盲、安慰剂对照试验,本研究评估了拟钙剂盐酸西那卡塞治疗血液透析患者继发性甲状旁腺功能亢进症的临床效果。将接受血液透析及进行标准治疗仍控制不佳的继发性甲状旁腺功能亢进患者随机分配接受西那卡塞(80名患者)或安慰剂(80名患者)治疗26周。每日一次的剂量从30 mg增加到180 mg,以达到患者体内每毫升250 mg或更少的完整甲状旁腺激素水平。主要终点是进行为期14周的疗效评估阶段的患者在该范围内的值的百分比。西那卡塞组有43%的患者达到主要终点,而安慰剂组仅为5%(p<0.001)。总体而言,接受西那卡塞治疗的患者平均甲状旁腺激素水平下降43%,而安慰剂组平均甲状旁腺激素水平下降9%(p<0.001)。西那卡塞组患者体内血清钙磷乘积下降15%,安慰剂组则维持不变(p<0.001)。西那卡塞可有效降低甲状旁腺激素水平,而不依赖于疾病严重程度或维生素D甾醇剂量的变化。西那卡塞可降低接受血液透析的不受控制继发性甲状旁腺功能亢进症患者体内的甲状旁腺激素水平,提高钙磷稳态。     

慢性肾脏病高磷血症研究进展

磷是生命组成的必需元素,参与了能量代谢、信号转导和蛋白合成等一系列重要的生命过程。肾脏在人体磷稳态的维持中具有重要的功能。慢性肾脏病(CKD)患者普遍伴随着磷代谢紊乱,长期的高磷血症引起继发性甲状旁腺功能亢进症(SHPT)、肾性骨营养不良(ROD)、心血管系统病变(CVD)以及促进肾病的进展,增加了患者的死亡率。近年来,高磷血症作为上述疾病发生的独立危险因素得到了越来越多的关注和研究,进一步提升了慢性肾脏病的治疗效果。     

甲状旁腺切除术对维持性血液透析继发性甲状旁腺功能亢进患者微炎症、营养状况的影响

继发性甲状旁腺功能亢进(SHPT)是维持性血液透析患者常见的严重并发症之一,主要表现为钙磷代谢紊乱、异位钙化、骨折等,严重影响患者的生活质量及生存时间。药物保守治疗效果通常不佳,研究表明[1],甲状旁腺切除术(parathyroidectomy,PTX)是解决SHPT的有效手段,能明显缓解临床症状。     

阿法骨化醇的药理与临床评价

阿法骨化醇是目前研制出的较理想的活性维生素D的衍生物制剂,与维生素D结合蛋白的亲和力强,在肝脏经肝微粒体羟基化酶作用后形成具有活性的1α,25-（OH）z,分布于肠道及骨等靶组织内与受体结合而表现出促进肠道吸收钙、促进骨形成、抑制甲状旁腺激素（PTH）过剩分泌等代谢调节作用。现临床常用于治疗骨质疏松症,改善慢性肾功能不全,甲状旁腺机能减退,抗维生素D的佝偻病和骨软化病等。本文就阿法骨化醇的药理与临床评价作简要综述。     

维生素D及其受体在帕金森病中的作用

帕金森病(Parkinson's disease,PD)是一种常见的中枢神经系统退行性疾病,引起帕金森病的发病机制至今尚未明确。帕金森病患者及老年人普遍存在维生素D缺乏,这可能是帕金森病的重要发病机制之一。由于维生素D具有免疫调节,抗氧化,调节神经营养因子,降低神经毒性的功能,能同时针对几种导致神经退行性病变因素发挥作用,特别是老年人纠正维生素D缺乏可能会阻止神经元的损失和PD相关的认知功能下降。因此补充维生素D可能成为治疗PD的方法。近年来研究发现,维生素D受体基因多态性与帕金森病的发病有相关性。该文就维生素D及其受体在帕金森病中可能发生的保护作用及其机制作一综述。     

终末期肾病患者行甲状旁腺切除对颈动脉钙化的影响

目的:探讨对终末期肾病患者行甲状旁腺切除对颈动脉钙化的影响.方法:选择我院2009年10月至2010年12月收治的20例继发性甲状旁腺功能亢进的终末期肾病患者,行甲状旁腺切除术,对患者术前、术后进行颈动脉彩超检查颈动脉钙化情况,并将患者术前、术后的血钙、血磷、钙磷乘积、PTH、C反应蛋白、血红蛋白、白蛋白等指标进行比较.结果:与术前比较,术后患者颈动脉钙化斑块有明显减少,血钙、血磷、钙磷乘积、PTH、C反应蛋白均明显降低,差异性有显著(P＜0.05);血红蛋白较术前明显升高(P＜0.05).结论:切除甲状旁腺(PTX)能安全有效的降低甲状旁腺素水平、改善钙磷代谢紊乱,并控制颈动脉钙化的进展.     

维生素D与PTH相关性研究进展

维生素D是人体必需的一种脂溶性营养素,随着科学技术不断进步,维生素D对人类健康的作用逐渐被发现。已有研究表明,维生素D不仅与多种骨代谢相关疾病有关,并与心血管疾病、代谢综合征、感染、肿瘤、自身免疫疾病等关系密切。在骨代谢方面,维生素D的缺乏可能会导致软骨病、佝偻病、骨质疏松症,甚至会导致急性跌倒事件的发生和骨折的形成,而甲状旁腺激素(PTH)是骨代谢过程中的关键分子。本文综述了维生素D代谢过程及维生素D受体多样性及维生素D与甲状旁腺激素(PTH)相关性,以便有助于探究维生素D与骨代谢之间的关系。     

维生素D缺乏导致良性前列腺增生症发生的研究进展

良性前列腺增生症(BPH)是全球范围内中老年男性的常见病和多发病,发病机制尚未完全明确,其可致腺体增大而引起排尿受阻,严重影响老年男性的生活质量。维生素D是人类必需的一种脂溶性维生素,其缺乏可以导致良性前列腺增生的发生,近年来也引起广大学者广泛关注。我们简要综述维生素D缺乏导致BPH的临床前研究、临床研究及其维生素D受体激动剂对BPH的治疗机制研究,为相关研究提供证据。     

Protective and toxic effects of vitamin D on vascular calcification: clinical implications

The presence of vascular calcification (VC) is a predictor of poor survival in the general population. The development of VC is an active process that requires a pre-existing injury as an inducer and promoting factors such as hyperphosphatemia and hypercalcemia, as well as a deficiency in calcification repressor factors. Vascular smooth muscle cells possess an endogenous enzyme system for the biosynthesis of the vitamin D hormone calcitriol from its precursor 25-hydroxyvitamin D and also a cytosolic calcitriol receptor, indicating that the vasculature is an important target tissue for vitamin D. The toxic effects of supra-physiological vitamin D dosages on the vasculature have been known for several decades. Recent experimental data also demonstrate important physiological effects of vitamin D on factors that are protective for vascular health. This review article summarises the molecular basis of protective and toxic vitamin D actions on the vasculature. Chronic kidney disease can be considered as a human model of severe VC and poor survival. The disease is associated with calcitriol deficiency, hyperparathyroidism, and hyperphosphatemia. Evidence is increasing that phosphate overload plays a key role in the process of VC in chronic kidney disease. The first clinical studies indicate that vitamin D receptor activation can improve survival in these patients. Although less severe than in chronic kidney disease, vitamin D deficiency and secondary hyperparathyroidism are also frequent in the general population, especially in elderly and obese subjects. Future studies should focus on the impact of vitamin D deficiency on VC and clinical outcome in these groups.     

Enriched uranium affects the expression of vitamin D receptor and retinoid X receptor in rat kidney

An increasing awareness of the radiological impact of the nuclear power industry and other nuclear technologies is observed nowadays on general population. This led to renew interest to assess the health impact of the use of enriched uranium (EU). The aim of this work was to investigate in vivo the effects of a chronic exposure to EU on vitamin D(3) metabolism, a hormone essential in mineral and bone homeostasis. Rats were exposed to EU in their drinking water for 9 months at a concentration of 40 mg l(-1) (1mg/rat day). The contamination did not change vitamin D plasma level. Vitamin D receptor (vdr) and retinoid X receptor alpha (rxralpha), encoding nuclear receptors involved in the biological activities of vitamin D, showed a lower expression in kidney, while their protein levels were paradoxically increased. Gene expression of vitamin D target genes, epithelial Ca(2+) channel 1 (ecac1) and Calbindin-D28k (cabp-d28k), involved in renal calcium transport were decreased. Among the vitamin D target organs examined, these molecular modifications occurred exclusively in the kidney, which confirms that this organ is highly sensitive to uranium exposure. In conclusion, this study showed that a chronic exposure to EU affects both mRNA and protein expressions of renal nuclear receptors involved in vitamin D metabolism, without any modification of the circulating vitamin D.     

Insulin resistance and vitamin D deficiency in patients with chronic kidney disease stage 2-3

Vitamin D status and the relationship between serum 25(OH) vitamin D concentrations and the components of insulin resistance were examined in 120 patients with chronic kidney disease stage 2 and 3. Insulin sensitivity/resistance was calculated by the quantitative insulin sensitivity check index (QUICKI). In this analysis, the prevalence of insulin resistance was 42 %. Only 17 % of patients had serum 25(OH) vitamin D concentration in the recommended range (>/=30 ng/ml), 42 % suffered from vitamin D insufficiency and 41 % had moderate vitamin D deficiency. Insulin resistance significantly correlated with serum 25(OH)D and 1,25(OH)(2)D concentrations, renal function and protein excretion rate. Our results support the increasing evidence that vitamin D deficiency may be one of the factors participating in the development of insulin resistance already in the early stages of chronic kidney disease.     

Vitamin D and vascular calcification

PURPOSE OF REVIEW: Vascular calcification is frequently found in patients with osteoporosis, atherosclerosis and chronic kidney disease, leading to high morbidity and mortality rates. The effects of vitamin D excess and deficiency on vascular calcification are reviewed in this article. RECENT FINDINGS: There is evidence from experimental studies that mediacalcinosis induced by vitamin D excess is an active and reversible process. Vitamin D excess, however, is rarely seen in the general human population. Experimental data also demonstrate that physiologic vitamin D actions include the inhibition of processes that are important for intimal and medial artery calcification such as pro-inflammatory cytokine release, adhesion molecule release, and proliferation and migration of vascular smooth muscle cells. In uremic rats, low levels of the vitamin D hormone calcitriol are associated with massive vascular and soft tissue calcifications. Whereas retrospective studies already indicate a beneficial effect of active vitamin D on mortality rates in chronic kidney disease, little is yet known about the effect of vitamin D deficiency on cardiovascular morbidity and mortality in the general population. SUMMARY: Available data indicate that vitamin D exerts a biphasic 'dose response' curve on vascular calcification with deleterious consequences not only of vitamin D excess but also of vitamin D deficiency.     

Vitamin D,Calcium, and Cardiovascular Mortality: A Perspective from A Plenary Lecture Given at the Annual Meeting of the American Association of Clinical Endocrinologists

ObjectiveTo examine data showing associations between serum 25-hydroxyvitamin D levels and calcium intake and cardiovascular mortality.MethodsThe articles reviewed include those published from 1992-2011 derived from search engines (PubMed, Scopus, Medscape) using the following search terms: vitamin D, calcium, cardiovascular events, cardiovascular mortality, all-cause mortality, vascular calcification, chronic kidney disease, renal stones, and hypercalci- uria. Because these articles were not weighted (graded) on the level of evidence, this review reflects my own perspective on the data and how they should be applied to clinical management.ResultsFor skeletal health, vitamin D and calcium are both needed to ensure proper skeletal growth (modeling) and repair (remodeling). Nutritional deficiencies of either vitamin D or calcium may lead to a spectrum of metabolic bone disorders. Excessive consumption of either nutrient has been linked to a variety of medical disorders, such as hypercalcemia or renal stones. There have also been associations between vitamin D or calcium intake and cardiovascular disease. However, neither of these associations have established evidence nor known causality for increasing cardiovascular risk or all-cause mortality in patients with creatinine clearances greater than 60 mL/ min. In patients with more severe chronic kidney disease, stronger data link excess calcium (or phosphorus) intake and increase in vascular calcification, but not mortality. The safe upper limit for vitamin D intake is at least 4000 IU daily and probably 10 000 IU daily; for calcium, the safe upper limit is between 2000 and 3000 mg daily.ConclusionsWhile no solid scientific evidence validates that serum vitamin D levels between 15 and 70 ng/ mL are associated with increased cardiovascular disease risk, stronger but inconsistent evidence shows an association between calcium supplementation greater than 500 mg daily and an increase in cardiovascular disease risk. Most professional societies suggest that replacement levels of these nutrients be personalized with the goal of reaching a 25-hydroxyvitamin D concentration between 30 and 50 ng/ mL and a calcium intake of 1200 mg daily. (Endocr Pract. 2011;17:798-806)     

维生素D与阿尔茨海默病的关系

阿尔茨海默病(Alzheimer disease,AD)是神经科学领域研究最热点的问题之一,同时也是老年痴呆的最常见类型之一。流行病学研究发现老年人血清中维生素D普遍缺乏,而阿尔茨海默病患者血清中维生素D也普遍缺乏,这可能是老年人患阿尔茨海默病的重要原因之一。老年人皮肤合成维生素D前体的能力下降,活动能力下降导致接受日光照射减少,进而影响血清中维生素D含量。近年的研究表明,维生素D具有保护神经元的潜在功能和调节多种大脑靶组织,如提高神经生长因子水平、神经保护作用、提高其抗氧化酶活性、增加抗氧化及水平、降低自由基含量、减少炎症因子的产生及影响APOE基因多态性等,这些功能与AD的病理生理改变相关。这些研究为AD的发病机制及其早期预防和治疗奠定了基础。     

In vivo effects of chronic contamination with depleted uranium on vitamin D3 metabolism in rat

The extensive use of depleted uranium (DU) in today's society results in the increase of the number of human population exposed to this radionuclide. The aim of this work was to investigate in vivo the effects of a chronic exposure to DU on vitamin D₃ metabolism, a hormone essential in mineral and bone homeostasis. The experiments were carried out in rats after a chronic contamination for 9 months by DU through drinking water at 40 mg/L (1 mg/rat/day). This dose corresponds to the double of highest concentration found naturally in Finland. In DU-exposed rats, the active vitamin D (1,25(OH)₂D₃) plasma level was significantly decreased. In kidney, a decreased gene expression was observed for cyp24a1, as well as for vdr and rxrα, the principal regulators of CYP24A1. Similarly, mRNA levels of vitamin D target genes ecac1, cabp-d28k and ncx-1, involved in renal calcium transport were decreased in kidney. In the brain lower levels of messengers were observed for cyp27a1 as well as for lxrβ, involved in its regulation. In conclusion, this study showed for the first time that DU affects both the vitamin D active form (1,25(OH)₂D₃) level and the vitamin D receptor expression, and consequently could modulate the expression of cyp24a1 and vitamin D target genes involved in calcium homeostasis.     

In vivo effects of chronic contamination with depleted uranium on vitamin D3 metabolism in rat

The extensive use of depleted uranium (DU) in today's society results in the increase of the number of human population exposed to this radionuclide. The aim of this work was to investigate in vivo the effects of a chronic exposure to DU on vitamin D(3) metabolism, a hormone essential in mineral and bone homeostasis. The experiments were carried out in rats after a chronic contamination for 9 months by DU through drinking water at 40 mg/L (1 mg/rat/day). This dose corresponds to the double of highest concentration found naturally in Finland. In DU-exposed rats, the active vitamin D (1,25(OH)(2)D(3)) plasma level was significantly decreased. In kidney, a decreased gene expression was observed for cyp24a1, as well as for vdr and rxralpha, the principal regulators of CYP24A1. Similarly, mRNA levels of vitamin D target genes ecac1, cabp-d28k and ncx-1, involved in renal calcium transport were decreased in kidney. In the brain lower levels of messengers were observed for cyp27a1 as well as for lxrbeta, involved in its regulation. In conclusion, this study showed for the first time that DU affects both the vitamin D active form (1,25(OH)(2)D(3)) level and the vitamin D receptor expression, and consequently could modulate the expression of cyp24a1 and vitamin D target genes involved in calcium homeostasis.     

Vitamin D compounds and diabetic nephropathy

Vitamin D therapies for renal disease have been used for over a half century and are likely to be utilized for many more years. Past roles have been to alter calcium and phosphorus metabolism to prevent or lessen bone disease and reduce PTH levels in dialysis patients and more recently, pre-dialysis patients. However, emerging evidence indicates new applications for vitamin D compounds are likely to exist for this patient population. In addition to the possible new targets in this therapeutic area, a popularly debated topic is the ideal form of vitamin D for use in renal disease. Because the vitamin D metabolism system is severely altered in kidney disease, a thorough understanding of the disease progression relative to the vitamin D signaling pathway is necessary. The current state of knowledge in this area with the primary focus on patients with diabetic nephropathy will be the scope of this review.