Ergocalciferol in ESRD Efficacy Safety and Biology

描述（由申请人提供）：我们假设终末期肾脏疾病（ESRD）中营养维生素D（25-羟基维生素D； 25D）的严重缺乏导致免疫反应改变，易导致早期发病和感染死亡，感染是ESRD死亡的第二大原因。除了激素维生素D（1,25-二羟基维生素D； 1,25D）的肾脏合成受损外，ESRD还伴有几乎普遍的25D不足。我们小组和其他人进行的体外、离体和观察性人体研究表明，25D（而不是1,25d）通过改变炎症细胞因子和包括抗菌肽在内的关键抗菌肽的产生，与免疫防御密切相关，我们已经证明，这些肽可以识别ESRD患者感染相关死亡的风险。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，尚无使用该化合物治疗ESRD患者的指南。为了确定麦角钙化醇在ESRD中的有效和安全剂量，我们将在150例25D水平< 30ng/ml的血透患者（50例/组x 3例）中进行双盲安慰剂对照随机试验，比较两种麦角钙化醇给药方案（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（25D /ml ~ 30ng /ml）。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，在促炎介质（如杀死的金黄色葡萄球菌）体外刺激后，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。这些实验将告诉我们ESRD患者如何根据他们的维生素D状态和他们接受的治疗对感染做出反应。实验室检测将持续12周，临床随访和感染相关事件（包括抗生素使用、菌血症和败血症发生率）监测将持续20周。该试点试验将涉及在维生素D研究、感染和炎症以及涉及ESRD受试者的试验方面经验丰富的基础、转化和临床研究人员，以解决肾脏病学中未满足的重大需求。这些数据将为设计未来的临床试验提供基础，以严格评估营养维生素D对ESRD感染和其他结局的影响。公共卫生相关性：感染是肾衰竭患者需要透析治疗的第二大死亡原因。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，同时监测其对免疫系统的影响。

DESCRIPTION (provided by applicant): We hypothesize that a profound deficiency of nutritional vitamin D (25-hydroxyvitamin D; 25D) in end-stage renal disease (ESRD) leads to an altered immune response, predisposing to early morbidity and mortality from infection, the second-leading cause of death in ESRD. In addition to impaired renal synthesis of hormonal vitamin D (1,25-dihydroxyvitamin D; 1,25D), ESRD is accompanied by near universal insufficiency of 25D. In-vitro, ex-vivo, and observational human studies by our group and others suggest 25D (and not 1,25D) is intimately linked to immune defense via alterations in the production of inflammatory cytokines and critical antimicrobial peptides including cathelicidin, which we have shown to identify ESRD subjects at risk for infection-related mortality. Ergocalciferol, which is rapidly converted to 25D, is the most widely available form of nutritional vitamin D in the US, yet guidelines to treat ESRD patients with this compound are absent because of limited data supporting its efficacy, safety, and biological effects. To determine effective and safe doses of ergocalciferol in ESRD, we will perform a double blind placebo controlled randomized trial in 150 incident hemodialysis patients (50/arm x 3) with 25D levels < 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 (25D >30 ng/ml) 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 pro-inflammatory mediators (e.g., killed S. aureus). These experiments will inform us on how individuals with ESRD, based on their vitamin D status and the treatment they receive, may respond to infection. Laboratory measures will continue for 12 weeks, and clinical follow-up and monitoring for infection-associated events (including antibiotic use, rates of bacteremia, and sepsis) will continue for 20 weeks. This pilot trial addressing a significant unmet need in nephrology will involve basic, translational, and clinical investigators experienced in vitamin D research, infection and inflammation, and in trials involving ESRD subjects. These data will provide a foundation for designing future clinical trials rigorously assessing the effect of nutritional vitamin D on infectious and other outcomes 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.