Vitamin D and Arterial Function in Patients with Chronic Kidney Disease

描述（由申请人提供）：Kendrick博士目前是丹佛健康科学中心科罗拉多大学的首席肾脏病学研究员，其主要研究领域是维生素D失调及其与慢性肾脏病（CKD）患者全因死亡率和心血管疾病（CVD）的关系。她在流行病学研究方面有着坚实的基础，已经完成并在同行评审的期刊上发表了几项矿物质代谢领域的观察性研究，从而获得了研究设计，数据分析和手稿撰写方面的经验和技能。她在全国会议上发表了许多关于她的研究的摘要和口头报告，并与她的导师Michel Chonchol博士一起参加了NIH赞助的随机对照临床试验。她获得了为期2年的AMGEN奖学金，用于她对1133例晚期CKD患者进行的观察性研究的研究项目，在该研究中，她彻底检查了25-羟基维生素D（25（OH）D）和1，25-二羟基维生素D（1，25（OH）2D）水平与全因死亡率和心血管疾病事件之间的关系，为本提案提供了良好的初步数据。她的直接职业目标是成为矿物质代谢领域的独立研究者。她的长期职业目标是成为一名成功的临床研究者和院士，并建立和指导CKD患者矿物质代谢和血管疾病的壁外资助临床研究。为了成为一名成功的独立研究者，Kendrick博士将通过她的主要导师Chonchol博士接受临床技术培训，包括研究设计，患者招募和数据分析，Chonchol博士是丹佛科罗拉多大学医学副教授，肾脏疾病和高血压部临床研究主任，CKD患者矿物质代谢和CVD领域经验丰富的临床研究者。她还将通过她的共同导师道格拉斯西尔斯博士接受肱动脉血流介导的扩张、内皮细胞收集和免疫荧光测量方面的培训。西尔斯博士是位于博尔德的科罗拉多大学的中西医结合教授，是一位经验丰富、全国知名的血管病理生理学研究者。她将通过咨询导师Kim McFann博士接受实验设计和统计分析方面的额外培训，Kim McFann博士是科罗拉多大学公共卫生学院的教员。她还将通过她的咨询导师，科罗拉多大学健康科学中心医学教授Tomas Berl博士接受进行临床试验的进一步培训。Berl博士拥有丰富的临床试验经验，20多年来一直是协作研究小组的成员，现在担任执行委员会成员。她已经完成了公共卫生科学证书，她参加了生物统计学，流行病学，研究设计和伦理学课程。她正在攻读公共卫生硕士课程，并将在奖励期的前两年完成该学位。她已经获得了硕士学位所需的42个学分中的21个。她还将参与其他活动，这将提高她的学术生涯，包括教学和出版物的机会。她已经通过科罗拉多IRB完成了负责任的研究行为培训以及公共卫生课程，并将在整个奖励期间继续接受培训。Kendrick博士将有75-85%的时间用于K23奖的研究活动。肾脏科还将为她提供一名研究协调员，该协调员将帮助患者招募和随访，并将协助本提案中计划的测量。CVD是CKD患者死亡的主要原因，大动脉损伤是导致这些患者死亡的主要因素。我们假设，与补充胆钙化醇相比，在IIIB期和IV期维生素D不足或缺乏的慢性肾脏病（CKD）患者中使用骨化三醇补充剂将改善血管内皮功能。我们将在128例患者中进行一项前瞻性、随机、双盲试验，比较骨化三醇与胆钙化醇对IIIB期和IV期CKD患者维生素D不足或缺乏对通过肱动脉血流介导的扩张（FMD）测量的管道动脉内皮依赖性扩张（EDD）的影响。主要结局是骨化三醇组和胆钙化醇组之间在6个月FMD中对治疗反应的差异。次要目的是通过测定骨化三醇与胆钙化醇对CRP、IL-6血浆浓度和NF-κB内皮细胞表达的影响，探讨维生素D是否通过减少炎症来改善血管内皮功能。受试者将在基线和6个月时进行这些测量，并将每月抽取钙和磷以评估安全性。这项研究将回答重要的临床问题，即营养（即，胆钙化醇）或活性物质（即，骨化三醇）维生素D补充剂改善中度至重度CKD患者的血管内皮功能的直接头对头比较。此外，临床和体外方法将用于确定维生素D影响血管内皮功能的机制，这将增强我们对维生素D非钙调作用的理解。

DESCRIPTION (provided by applicant): Dr. Kendrick is currently the chief Nephrology fellow at the University of Colorado at Denver Health Sciences Center whose main area of interest is in vitamin D dysregulation and its relationship with all-cause mortality and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). She has a strong foundation in epidemiologic research having completed and published in peer-reviewed journals several observational studies in the field of mineral metabolism thereby gaining experience and skills in study design, data analysis, and manuscript writing. She has presented numerous abstracts and oral presentations on her research at national meetings and has participated in a NIH sponsored randomized controlled clinical trial with her mentor, Dr. Michel Chonchol. She received a 2 year AMGEN fellowship grant for her research project on an observational study of 1133 patients with advanced CKD in which she thoroughly examined the relationship between 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels with all-cause mortality and cardiovascular disease events, providing good preliminary data for the present proposal. Her immediate career goal is to establish herself as an independent investigator in the field of mineral metabolism. Her long-term career goal is to become a successful clinical investigator and academician and to establish and direct extramurally funded clinical studies in mineral metabolism and vascular disease in CKD patients. In order to become a successful independent investigator, Dr. Kendrick will receive training in clinical techniques including study design, patient recruitment and data analysis through her primary mentor, Dr. Chonchol, Associate Professor of Medicine at the University of Colorado at Denver and Director of Clinical Research in the Division of Renal Diseases and Hypertension, a highly experienced clinical investigator in the field of mineral metabolism and CVD in patients with CKD. She will also receive training in brachial artery flow- mediated dilation, endothelial cell collections and immunofluorescence measurements through her co-mentor Dr. Douglas Seals, Professor of Integrative Medicine at the University of Colorado at Boulder, a highly experienced and nationally renowned investigator in vascular pathophysiology. She will receive additional training in experimental design and statistical analyses through a consulting mentor, Dr. Kim McFann, Faculty member at the University of Colorado School of Public Health. She will also receive further training in conducting clinical trials through her consulting mentor, Dr. Tomas Berl, Professor of Medicine at the University of Colorado Health Sciences Center. Dr. Berl has vast experience conducting clinical trials and has been a member of the Collaborative Study Group for over 20 years and now serves on the executive committee. She has already completed a Certificate in Public Health Sciences in which she took classes in biostatistics, epidemiology, research design, and ethics. She is enrolling in the Master of Public Health Program and will complete this degree in the first two years of the award period. She already has 21 of the 42 credits required for the Master's degree. She will also be involved in other activities that will enhance her academic career including opportunities for teaching and for publications. She has completed training in the responsible conduct of research through the Colorado IRB as well as public health classes and will continue to receive training throughout the award period. Dr. Kendrick will have 75-85% protected time to devote to the proposed research activities of the K23 award. She will also be provided with a research coordinator by the Nephrology Division who will help with patient recruitment and follow-up and will assist with measurements planned in this proposal. CVD is the leading cause of mortality in CKD patients and large artery damage is a major factor that contributes to death in these patients. We hypothesize that the use of calcitriol supplementation in stage IIIB and IV chronic kidney disease patients (CKD) with vitamin D insufficiency or deficiency will result in improved vascular endothelial function as compared to cholecalciferol supplementation. We will perform a prospective, randomized, double-blind trial of 128 patients comparing the effects of calcitriol versus cholecalciferol in stage IIIB and stage IV CKD patients with vitamin D insufficiency or deficiency on conduit artery endothelium- dependent dilation (EDD) measured by brachial artery flow-mediated dilation (FMD). The primary outcome is the difference between the calcitriol and cholecalciferol groups in 6 month FMD in response to treatment. Secondary aims are focused to explore whether vitamin D improves vascular endothelial function through decreases in inflammation by determining the effects of calcitriol versus cholecalciferol on plasma concentrations of CRP, IL-6 and endothelial cell expression of NF-κB. Subjects will have these measurements performed at baseline and at 6 months and will have calcium and phosphorus drawn monthly to assess safety. This study will answer the important clinical question of whether nutritional (i.e., cholecalciferol) or active (i.e., calcitriol) vitamin D supplementation improves vascular endothelial function in moderate to severe CKD in a direct head to head comparison. Furthermore, clinical and in vitro methods will be used to identify the mechanisms by which vitamin D affects vascular endothelial function, which will enhance our understanding of the non-calcemic effects of vitamin D.