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

描述（由申请人提供）：ESRD伴有几乎普遍的营养性维生素D（25-羟基维生素D; 25 D）不足。我们小组和其他人的研究表明，25 D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。其中包括凯萨林菌素，我们已经证明凯萨林菌素可以识别终末期肾病（ESRD）患者因感染而死亡的风险，感染是该人群的第二大死亡原因。我们假设ESRD患者25 D缺乏导致免疫应答改变，易患早期感染性疾病和死亡。麦角钙化醇可迅速转化为25 D，是美国最广泛使用的营养维生素D形式，但由于支持其疗效、安全性和生物学效应的数据有限，因此缺乏其在ESRD中的使用指南。为了直接解决这一问题，我们在105例（新样本量）25 D功能不全（<30 ng/ml）的慢性血液透析患者（35例/组x3）中进行了一项双盲、安慰剂对照随机试验，比较了两种麦角钙化醇给药方案（50，000 IU/周和50，000 IU/月）和一种外观相同的安慰剂。主要结局是在12周时纠正维生素D不足。每两周测量一次血清钙和磷酸盐水平以评估安全性，每4周测量一次血液细胞因子和凯萨林菌素水平以评估生物学应答。为了更详细地检查生物学效应，在用细菌抗原（例如，杀死了S。 aureus)具有良好的抗菌活性。截至2010年8月15日，我们已将32例受试者随机分配至这项ARRA支持的试验中。此外，我们在30例计划受试者中的18例中进行了离体研究。我们聘请了额外的研究助理和护士，以确保这项研究的成功。我们的招募平均每月约3.8例受试者。我们现在正在寻求2年的额外支持，以扩大入组，提高我们的把握度（考虑脱落），增加一个额外的临床研究中心，完成我们的离体和基因表达研究，完成我们的分析，并发表我们的结果。本研究旨在解决肾病学中一个显著未满足的需求，涉及重要的临床和转化目标，将促进ESRD患者的护理。这些数据也将为设计严格评估营养性维生素D对ESRD感染和其他并发症影响的临床试验提供重要基础。 公共卫生相关性：感染是因肾衰竭需要透析治疗的患者的第二大死亡原因。新的研究表明，感染的高风险可能部分是由于维生素D水平低，而维生素D在肾脏疾病中极其常见。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.