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: 8680229
• 负责人: Jessica B Kendrick
• 金额: $ 15.71万
• 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/8680229
• 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; endothelial dysfunction; 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）：肯德里克博士目前是科罗拉多大学丹佛健康科学中心的首席肾脏科研究员，其主要感兴趣的领域是维生素D失调及其与慢性肾脏病（CKD）患者的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具有坚实的基础，并在同行评审的期刊上完成并发表了矿物代谢领域的几项观察性研究，从而获得了研究设计，数据分析和手稿写作的经验和技能。她在国家会议上的研究中介绍了许多摘要和口头演讲，并与她的导师米歇尔·康乔尔（Michel Chonchol）博士一起参加了NIH赞助的NIH随机对照临床试验。她为她的研究项目获得了为期2年的Amgen奖学金赠款，该研究项目对1133例患者进行了观察性研究，在该研究中，她彻底研究了25-羟基维生素D（25（OH）D）和1,25-二羟基维生素D之间的关系（1,25（OH）2D）与所有自行死亡人性疾病有关。她的直接职业目标是在矿物质代谢领域建立自己的独立调查员。她的长期职业目标是成为一名成功的临床研究员和院士，并在CKD患者的矿物质代谢和血管疾病中建立并指导外部资助的临床研究。为了成为一名成功的独立研究者，肯德里克博士将通过其主要导师，丹佛大学医学副教授，肾脏疾病临床研究主任Chonchol博士Chonchol博士，肾脏疾病和高血压部门的临床研究主任Chonchol博士，一名经验丰富的临床研究员，一名具有Mineral Meteral Metabolism of cv的临床研究员，CVD。她还将通过她的同事Douglas Seals博士Douglas Seals博士，科罗拉多大学的综合医学教授Douglas Seals博士，在科罗拉多大学的科罗拉多大学，一项经验丰富且经验丰富的血管病理学研究剂。她将通过咨询导师，科罗拉多大学公共卫生学院的教职员工Kim McFann博士Kim McFann博士进行实验设计和统计分析的额外培训。她还将通过咨询导师，科罗拉多大学健康科学中心医学教授Tomas Berl博士进行进一步的培训。 Berl博士在进行临床试验的经验丰富的经验，并且已经是合作研究小组的成员已有20多年了，现在在执行委员会任职。她已经完成了公共卫生科学证书，并在其中参加了生物统计学，流行病学，研究设计和道德的课程。她正在参加公共卫生硕士课程，并将在奖励期的头两年完成该学位。她已经拥有硕士学位所需的42个学分中的21个。她还将参与其他活动，这些活动将增强她的学术生涯，包括教学和出版物的机会。她已经完成了通过科罗拉多州IRB和公共卫生课程负责研究的培训，并将在整个奖励期内继续接受培训。肯德里克（Kendrick）博士将有75-85％的保护时间，以致力于K23奖的拟议研究活动。她还将由肾脏科为她提供研究协调员，该研究人员将帮助患者招募和随访，并将协助该提案中计划的测量。 CVD是CKD患者死亡率的主要原因，大动脉损伤是这些患者死亡的主要因素。我们假设在IIIB和IV期慢性肾脏疾病患者（CKD）中，维生素D功能不全或缺乏症的使用将导致与胆固醇补充相比，将改善血管内皮功能。我们将对128例患者进行一项前瞻性，随机，双盲试验，比较骨化三醇与胆钙化酚在IIIB期和IV期IV期CKD患者中的影响或缺乏症对管道动脉内皮依赖性依赖的维生素D不足或缺乏对手臂介导的动脉内皮扩张（EDD）。主要结果是响应治疗后6个月的FMD中骨化三醇和胆固醇基团之间的差异。次要目的集中在探索维生素D是否通过确定骨化三醇与胆钙化酚对CRP，IL-6和NF-？b的内皮细胞表达的血浆浓度对NF-？b的血浆浓度的影响，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值，并将每月绘制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（即胆固醇）或活性（即钙三醇）维生素D补充是否可以在直接头部进行比较的中度至重度CKD中提高血管内皮功能。此外，将使用临床和体外方法来确定维生素D影响血管内皮功能的机制，这将增强我们对维生素D的非钙质作用的理解。