Vitamin D and Arterial Function in Patients with Chronic Kidney Disease

慢性肾病患者的维生素 D 和动脉功能

• 批准号: 8274826
• 负责人: Jessica B Kendrick
• 金额: $ 15.62万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274826
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; 7-dehydrocholesterol; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arteries; Award; Biometry; Blood Vessels; Bone Diseases; C-reactive protein; Calcitriol; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Cholecalciferol; Chronic; Chronic Kidney Failure; Clinical; Clinical Investigator; Clinical Research; Collection; Colorado; Conduct Clinical Trials; Consult; Data; Data Analyses; Diabetes Mellitus; Dialysis procedure; Disease; Double-Blind Method; Educational process of instructing; End stage renal failure; Endothelial Cells; Endothelium; Enrollment; Epidemic; Epidemiologic Studies; Ergocalciferols; Ethics; Event; Experimental Designs; Faculty; Fellowship; Foundations; Functional disorder; Funding; Future; General Population; Goals; Health; Health Sciences; Heart failure; Hormones; Hypertension; Hypertrophy; Immunofluorescence Immunologic; In Vitro; Incidence; Inflammation; Inflammatory; Institutional Review Boards; Integrative Medicine; Interleukin-6; Journals; Kidney; Kidney Diseases; Knowledge; Light; Link; Liver; Manuscripts; Master of Public Health; Master' s Degree; Measurement; Measures; Mediating; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolism; Methods; Minerals; Mixed Function Oxygenases; Myocardial Infarction; NF-kappa B; Nephrology; Nutritional; Observational Study; Oral; Outcome; Pathogenesis; Patient Recruitments; Patients; Peer Review; Phosphorus; Plasma; Population; Prevalence; Prospective Studies; Public Health; Public Health Schools; Publications; Publishing; Randomized; Randomized Controlled Clinical Trials; Renal Hypertension; Research; Research Activity; Research Design; Research Personnel; Research Project Grants; Research Proposals; Risk; Risk Factors; Safety; Skin; Staging; Supplementation; Techniques; Testing; The Sun; Time; Tissues; Training; United States National Institutes of Health; Universities; Vascular Diseases; Vascular Endothelial Cell; Vitamin D; Vitamin D Analog; Vitamin D Deficiency; Vitamin D2; Vitamin D3 Receptor; Writing; abstracting; arterial stiffness; autocrine; brachial artery; career; comparative efficacy; cytokine; experience; follow-up; head-to-head comparison; high risk; improved; interest; meetings; member; mortality; paracrine; prevent; primary outcome; professor; programs; prospective; response; responsible research conduct; seal; skills; trial comparing; vascular inflammation

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-?B. 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.

描述（由申请人提供）：Kendrick博士目前是科罗拉多大学丹佛健康科学中心的首席肾病学研究员，他的主要研究领域是维生素D失调及其与慢性肾脏疾病（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很强的基础，在矿物质代谢领域完成了几项观察性研究，并在同行评议的期刊上发表，从而获得了研究设计、数据分析和手稿写作方面的经验和技能。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。她的研究项目是1133例晚期CKD患者的观察性研究，她获得了为期2年的AMGEN奖学金，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，为目前的建议提供了良好的初步数据。她近期的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外部资助临床研究。为了成为一名成功的独立研究者，Kendrick博士将接受临床技术方面的培训，包括研究设计，患者招募和数据分析，她的主要导师，科罗拉多大学丹佛分校医学副教授，肾脏疾病和高血压临床研究主任，CKD患者矿物质代谢和心血管疾病领域经验丰富的临床研究者。她还将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，她的共同导师Douglas Seals博士是科罗拉多大学博尔德分校的中西医结合教授，是一位经验丰富的全国知名的血管病理生理学研究者。她将通过咨询导师、科罗拉多大学公共卫生学院教员Kim McFann博士接受实验设计和统计分析方面的额外培训。她还将通过她的顾问导师，科罗拉多大学健康科学中心医学教授Tomas Berl博士接受进一步的临床试验培训。Berl博士拥有丰富的临床试验经验，并担任the Collaborative Study Group的成员超过20年，目前任职于执行委员会。她已经获得了公共卫生科学证书，在此期间她学习了生物统计学、流行病学、研究设计和伦理学。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。她已经修完了硕士学位所需的42个学分中的21个。她还将参与其他活动，以提高她的学术生涯，包括教学和出版的机会。她已经完成了科罗拉多州IRB以及公共卫生课程的负责任研究行为培训，并将在整个奖励期间继续接受培训。Kendrick博士将有75-85%的受保护时间用于K23奖的拟议研究活动。她还将由肾脏病科提供一名研究协调员，该协调员将帮助患者招募和随访，并协助本提案中计划的测量。心血管疾病是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，与补充胆骨化醇相比，在维生素D不足或缺乏的IIIB期和IV期慢性肾脏疾病（CKD）患者中补充骨化三醇会改善血管内皮功能。我们将对128例患者进行一项前瞻性、随机、双盲试验，比较骨化三醇和胆骨化醇对维生素D不足或缺乏的IIIB期和IV期CKD患者通过肱动脉血流介导扩张（FMD）测量的导管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骨化醇组6个月FMD治疗反应的差异。次要目的是通过测定骨化三醇与胆骨化醇对血浆CRP、IL-6浓度和内皮细胞NF- B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，并每月抽取钙和磷以评估安全性。本研究将回答一个重要的临床问题，即营养（即胆骨化醇）或活性（即骨化三醇）维生素D补充剂是否能改善中度至重度CKD患者的血管内皮功能。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非钙化作用的理解。