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

新英格兰的透析感染和维生素 D：神圣研究

• 批准号: 8143959
• 负责人: RAVI THADHANI
• 金额: $ 45.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143959
• 关键词: 25-hydroxyvitamin D; Accounting; Address; Bacterial Antigens; Biological; Blood; Cause of Death; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Data; Dialysis procedure; Dose; Double-Blind Method; Dropout; Drops; End stage renal failure; Enrollment; Ensure; Ergocalciferols; Foundations; Funding; Gene Expression; Gene Expression Profile; Guidelines; Harvest; Hemodialysis; Hormonal; Hypercalcemia; Immune; Immune response; Immune system; Individual; Infection; Inflammation Mediators; Inflammatory; Kidney Diseases; Kidney Failure; Lead; Link; Measures; Molecular Profiling; Monitor; Morbidity - disease rate; Nephrology; New England; Nurses; Nutritional; Oral; Outcome; Patient Care; Patients; Placebo Control; Placebos; Plasma; Population; Predisposition; Production; Publishing; Randomized; Randomized Clinical Trials; Recommendation; Regimen; Reporting; Research; Risk; Role; Safety; Sample Size; Serum; Staging; Staphylococcus aureus; Supplementation; Testing; Vitamin D; Whole Blood; Work; antimicrobial peptide; arm; base; calcium phosphate; cathelicidin; clinical research site; cytokine; design; functional restoration; high risk; improved; killings; macrophage; microbial; mortality; primary outcome; randomized placebo controlled trial; response; success

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.

描述（由申请人提供）：ESRD 几乎普遍伴有营养维生素 D（25-羟基维生素 D；25D）不足。我们小组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。其中包括导管素，我们已证明它可以识别因感染而死亡的终末期肾病 (ESRD) 患者，感染是该人群的第二大死因。我们假设 ESRD 中 25D 的缺乏会导致免疫反应改变，从而导致感染导致的早期发病和死亡。麦角钙化醇可迅速转化为 25D，是美国最广泛使用的营养维生素 D 形式，但由于支持其功效、安全性和生物效应的数据有限，因此缺乏其用于 ESRD 的指南。为了直接解决这个问题，我们正在 105 名（新样本量）患有 25 天血透不足（<30ng/ml）的慢性血液透析患者（35 名/臂 x 3）中进行一项双盲、安慰剂对照随机试验，比较两种麦角钙化醇剂量治疗方案（50,000 IU/周和 50,000 IU/月）和外观相同的安慰剂。主要结果是在 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抗菌肽水平以评估生物反应。为了更详细地检查生物效应，在用细菌抗原（例如杀死的金黄色葡萄球菌）进行离体刺激后，将使用连续巨噬细胞基因表达谱和全血细胞因子谱对来自每组的一部分受试者进行进一步分析。截至 2010 年 8 月 15 日，我们已将 32 名受试者随机纳入这项 ARRA 支持的试验中。此外，我们已经对 30 名计划受试者中的 18 名进行了离体研究。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。我们的招聘平均每月约 3.8 名受试者。我们现在正在寻求 2 年的额外支持，以扩大招募范围，以提高我们的能力（考虑到退出），增加额外的临床中心，完成我们的离体和基因表达研究，完成我们的分析，并发布我们的结果。这项研究解决了肾脏病学中未满足的重大需求，涉及重要的临床和转化目标，将促进 ESRD 患者的护理。这些数据还将为设计严格评估营养维生素 D 对 ESRD 感染和其他并发症的影响的临床试验提供重要基础。 公共卫生相关性：感染是因肾衰竭而需要透析治疗的个体的第二大死亡原因。新研究表明，感染风险高的部分原因可能是维生素 D 水平较低，而维生素 D 在肾脏疾病中极为常见。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。