Ergocalciferol in ESRD Efficacy Safety and Biology

描述(申请人提供)：我们假设在终末期肾病(ESRD)中严重缺乏营养维生素D(25-羟基维生素D；25D)会导致免疫反应改变，容易导致早期发病率和死亡率，感染是ESRD的第二大死亡原因。除了肾脏激素维生素D(1，25-二羟基维生素D；1，25D)的合成受损外，ESRD还伴有几乎普遍的25D不足。我们团队和其他人进行的体外、体外和观察性人体研究表明，25D(而不是125D)与免疫防御密切相关，这是通过炎性细胞因子和关键抗菌肽(包括长春新碱)的产生的变化来实现的，我们已经证明，这些变化可以识别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，目前还没有使用这种化合物治疗ESRD患者的指南。为了确定麦角钙化醇治疗终末期肾病的有效和安全剂量，我们将对150名25D水平和30 ng/ml的偶发血液透析患者(50例/臂×3)进行双盲安慰剂对照试验，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(25D和30 ng/ml)。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，在用促炎介质(例如，杀死的金黄色葡萄球菌)体外刺激后，将进一步分析每组受试者的一系列巨噬细胞基因表达谱和全血细胞因子谱。这些实验将告诉我们，根据ESRD患者的维生素D状况和他们接受的治疗，ESRD患者可能会对感染做出什么反应。实验室措施将持续12周，对感染相关事件(包括抗生素使用、菌血症和败血症)的临床跟踪和监测将持续20周。这项针对肾脏病领域尚未得到满足的重大需求的试点试验将涉及在维生素D研究、感染和炎症以及涉及终末期肾病受试者的试验方面经验丰富的基础、翻译和临床研究人员。这些数据将为设计未来的临床试验提供基础，严格评估营养维生素D对ESRD感染和其他结果的影响。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): 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.