Ergocalciferol in ESRD Efficacy Safety and Biology

描述（由申请人提供）：我们假设终末期肾病（ESRD）中营养性维生素D（25-羟基维生素D; 25 D）的严重缺乏导致免疫应答改变，易于早期发病和感染死亡，感染是ESRD的第二大死亡原因。除了激素维生素D（1，25-二羟基维生素D; 1，25 D）的肾脏合成受损外，ESRD还伴有几乎普遍的25 D不足。本研究组和其他人进行的体外、离体和观察性人体研究表明，25 D（而不是1，25 D）通过改变炎性细胞因子和关键抗菌肽（包括凯萨林菌素）的产生与免疫防御密切相关，我们已经证明，凯萨林菌素可识别ESRD受试者的感染相关死亡风险。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、安全性和生物学作用的数据有限，因此缺乏使用该化合物治疗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，我们将在150例25 D水平<30 ng/ml的血液透析患者（50例/组× 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给药方案（50，000 IU/周和50，000 IU/月）和外观相同的安慰剂。主要结局是在12周时纠正维生素D不足（25 D>30 ng/ml）。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，在用促炎性介质（例如，杀死了S。 aureus)具有良好的抗菌活性。这些实验将告知我们，根据ESRD患者的维生素D状况和接受的治疗，他们可能会对感染做出怎样的反应。实验室检查将持续12周，临床随访和感染相关事件监测（包括抗生素使用、菌血症发生率和败血症）将持续20周。这项旨在解决肾病学中显著未满足需求的初步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、转化和临床研究者。这些数据将为设计未来的临床试验提供基础，以严格评估营养性维生素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): 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.