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.
Chronic kidney disease is an important worldwide public health problem as the number of patients with kidney disease continues to increase. Patients with moderate to severe kidney disease have a higher risk of cardiovascular death than the general population although the reasons for this increased risk remain unclear. Arterial damage occurs early in the course of kidney disease and is a major factor that contributes to death in these patients. This research proposal will focus on another epidemic in kidney disease patients, vitamin D deficiency, which may be a contributing cause to their increased vascular damage and cardiovascular disease. Vitamin D deficiency has been linked with bone disease as well as diabetes, hypertension, myocardial infarctions, heart failure and arterial dysfunction. This proposal will examine if vitamin D supplementation (nutritional or active vitamin D) improves arterial function in patients with moderate to severe kidney disease. The information gained from this study will add to the knowledge of how to prevent and treat abnormal arterial function in kidney disease patients and will justify future interventional trials on vitamin D supplementation and cardiovascular outcomes in patients with moderate to severe kidney disease.
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