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维生素D（25-羟基维生素D； 25D）不足。我们和其他人的研究表明，25D通过改变炎症细胞因子和抗菌肽的产生与免疫防御密切相关。其中包括cathelicidin，我们已经证明它可以识别终末期肾脏疾病（ESRD）患者因感染而死亡的风险，这是该人群的第二大死亡原因。我们推测，ESRD中25D的缺乏会导致免疫反应的改变，从而导致感染的早期发病和死亡。麦角钙化醇可迅速转化为25D，是美国最广泛使用的营养性维生素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，尚无其在ESRD中的使用指南。为了直接解决这个问题，我们对105例（新样本量）25D不足（<30ng/ml）的慢性血液透析患者（35/组× 3）进行了一项双盲、安慰剂对照的随机试验，比较了两种麦角钙化醇剂量方案（50,000 IU/周和50,000 IU/月）和一种相同的安慰剂。主要结果将是在12周时纠正维生素D不足。每两周检测一次血清钙和磷酸盐水平以评估安全性，每4周检测一次血液细胞因子和抗菌肽水平以评估生物学反应。为了更详细地研究生物效应，将进一步分析来自每组的一部分受试者，在体外刺激细菌抗原（如杀死的金黄色葡萄球菌）后，用一系列巨噬细胞基因表达谱和全血细胞因子谱进行分析。截至2010年8月15日，我们随机选择了32名受试者加入ARRA支持的试验。此外，我们对30名计划受试者中的18名进行了离体研究。我们额外聘请了研究助理和护士，以确保这项研究的成功。我们平均每月招募约3.8名受试者。我们现在正在寻求2年的额外支持，以扩大入组人数以提高我们的能力（考虑到退出），增加一个额外的临床站点，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。这项研究解决了肾脏病学中一个重要的未满足的需求，涉及重要的临床和转化目标，将推进ESRD患者的护理。这些数据也将为设计临床试验提供重要的基础，以严格评估营养维生素D对ESRD感染和其他并发症的影响。

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.