Dialysis Infection and Vitamin D in New England: The DIVINE Study

描述(由申请人提供)：ESRD伴随着几乎普遍的维生素D缺乏(25-羟基维生素D；25D)。我们小组和其他人的研究表明，25D通过改变炎性细胞因子和抗菌肽的产生与免疫防御密切相关。其中包括放线菌素，我们已经证明它可以识别有感染死亡风险的终末期肾病(ESRD)患者，感染是该人群的第二大死亡原因。我们假设ESRD中25D的缺失会导致免疫反应的改变，从而导致早期发病和感染死亡。麦角钙化醇可迅速转化为25D，是美国最广泛使用的营养维生素D形式，但由于支持其有效性、安全性和生物学效应的数据有限，目前还没有关于其在ESRD中使用的指南。为了直接解决这一问题，我们正在对105名(新样本量)发生慢性血液透析患者(35例/臂×3)、25D不足(30 ng/ml)的患者进行双盲、安慰剂对照随机试验，比较两种麦角钙化醇剂量方案(50IU/周和500IU/月)和相同外观的安慰剂。主要结果将是在12周时纠正维生素D不足。每两周测量一次血钙和磷酸盐水平以评估安全性，每4周测量一次血细胞因子和排泄素水平以评估生物学反应。为了更详细地检验生物学效应，在细菌抗原(例如，被杀死的金黄色葡萄球菌)体外刺激后，将进一步分析来自每一臂的受试者的一系列巨噬细胞基因表达谱和全血细胞因子谱。截至2010年8月15日，我们已经将32名受试者随机纳入这项由ARRA支持的试验。此外，我们已经在计划的30名受试者中的18名进行了体外研究。我们已经聘请了额外的研究助理和护士来确保这项研究的成功。我们的招聘平均每个月有3.8个科目。我们现在正在寻求两年的额外支持，以扩大我们的招生人数，以提高我们的能力(占辍学人数)，增加一个额外的临床地点，结束我们的体外和基因表达研究，完成我们的分析，并发布我们的结果。这项研究解决了肾脏病中一个重要的未得到满足的需求，涉及重要的临床和翻译目标，将促进终末期肾病患者的护理。这些数据还将为设计临床试验提供重要基础，严格评估营养维生素D对ESRD感染和其他并发症的影响。 公共卫生相关性：感染是因肾功能衰竭而需要透析治疗的个人的第二大死亡原因。新的研究表明，感染的高风险可能部分是由于维生素D水平较低，而维生素D在肾脏疾病中非常常见。我们的研究旨在确定安全有效的方法来提高维生素D水平，同时监测对免疫系统的影响。

DESCRIPTION (provided by applicant): ESRD is accompanied by near universal insufficiency of nutritional vitamin D (25-hydroxyvitamin D; 25D). Studies by our group and others suggest 25D is intimately linked to immune defense via alterations in the production of inflammatory cytokines and antimicrobial peptides. These include cathelicidin, which we have shown to identify end-stage renal disease (ESRD) patients at risk for death from infection, the second-leading cause of death in this population. We hypothesize that deficiency of 25D in ESRD leads to an altered immune response, predisposing to early morbidity and mortality from infection. Ergocalciferol, which is rapidly converted to 25D, is the most widely available form of nutritional vitamin D in the US, yet guidelines for its use in ESRD are absent because of limited data supporting its efficacy, safety, and biological effects. To directly address this, we are performing a double-blind, placebo-controlled randomized trial in 105 (new sample size) incident chronic hemodialysis patients (35/arm x 3) with 25D insufficiency (<30ng/ml), comparing two ergocalciferol dosing regimens (50,000 IU/week and 50,000 IU/month) and an identically appearing placebo. The primary outcome will be correction of vitamin D insufficiency at 12 weeks. Serum calcium and phosphate levels will be measured biweekly to assess safety, and blood cytokine and cathelicidin levels will be measured every 4 weeks to assess biological responses. To examine biological effects in greater detail, a subset of subjects from each arm will be further analyzed with serial macrophage gene expression profiles and whole blood cytokine profiles following ex-vivo stimulation with bacterial antigens (e.g., killed S. aureus). As of August 15, 2010, we have randomized 32 subjects into this ARRA supported trial. Furthermore, we have performed ex-vivo studies in 18 of the 30 planned subjects. We have hired additional research assistants and nurses to ensure the success of this study. Our recruitment has averaged ~3.8 subjects per month. We are now seeking 2 years of additional support to expand the enrollment to improve our power (account for dropouts), add an additional clinical site, conclude our ex-vivo and gene expression studies, finalize our analyses, and publish our results. This study, addressing a significant unmet need in nephrology, involves important clinical and translational aims that will advance the care of patients with ESRD. These data will also provide an important foundation for designing clinical trials rigorously assessing the effect of nutritional vitamin D on infectious and other complications in ESRD. PUBLIC HEALTH RELEVANCE: Infection is the second-leading cause of death in individuals requiring dialysis treatment for kidney failure. New research suggests the high risk of infection may be due in part to low levels of vitamin D, which are extremely common in kidney disease. Our study is designed to determine safe and effective ways to raise vitamin D levels while monitoring effects on the immune system.