Patient Oriented Studies of Vitamin D in Chronic Kidney Disease

描述(由申请人提供)：维生素D缺乏症在晚期慢性肾脏疾病(CKD)患者中非常普遍。心血管疾病(CVD)和感染是慢性肾脏病(CKD)和终末期肾病(ESRD)发病率和死亡率的主要原因。候选人的实验室(Ravi Thadhani，MD，MPH)产生的证据表明，CVD的进展和免疫反应的改变与CKD/ESRD中维生素D水平不足有关。在塔哈尼博士的指导下，一项面向患者的全面研究计划试图从机理和临床相关终点方面调查维生素D生物学和补充策略之间的关系。这项申请描述了候选人和他的受训者将追求的三项研究中的三个独特目标(每项研究都有不同的资金来源支持)：(1)在DIVINE中--NIH赞助的营养维生素D试验--他的团队将确定ESRD患者的营养维生素D缺乏是否会导致巨噬细胞功能和体外感染反应的改变；(2)Primo是一项行业赞助的试验，涉及活性维生素D与3/4 CKD期患者的左心室肥厚[LVH]、舒张期功能和心脏住院治疗。在Primo中，他的团队将确定25-羟基维生素D(25D)和成纤维细胞生长因子-23(FGF-23)的基线水平是否与LVH的进展或不消退有关；以及(3)在Lucid--加拿大卫生研究院支持的ESRD事件的前瞻性队列中--他的团队将检查活性维生素D是否导致冠状动脉过度钙化。通过支持候选人对K24奖项的请求，以患者为导向的重要问题将得到解决。此外，塔哈尼博士在指导、教学和研究方面有着堪称典范的记录，他将获得必要的保护时间，指导由新一代临床研究员和肾病学学生组成的个人。

DESCRIPTION (provided by applicant): Vitamin D deficiency is highly prevalent in patients with advanced chronic kidney disease (CKD). Cardiovascular disease (CVD) and infection are the top causes of morbidity and mortality in CKD and end- stage renal disease (ESRD). Evidence generated by the candidate's (Ravi Thadhani, MD, MPH) laboratory has linked CVD progression and altered immune response to inadequate vitamin D levels in CKD/ESRD. Under Dr. Thadhani's direction, a comprehensive patient-oriented research program seeks to investigate the relationship between vitamin D biology and supplementation strategies in terms of mechanistic and clinically relevant endpoints. This application describes three unique aims in three studies (each backed by separate funding sources) that will be pursued by the candidate and his trainees: (1) in DIVINE - an NIH sponsored trial of nutritional vitamin D - his team will determine whether nutritional vitamin D deficiency in ESRD patients leads to altered macrophage function and ex-vivo response to infection; (2) in PRIMO - an industry sponsored trial of active vitamin D and left ventricular hypertrophy [LVH], diastolic function, and cardiac hospitalization in patients with stage 3/4 CKD - his team will determine if baseline levels of 25-hydroxy vitamin D (25D) and fibroblast growth factor-23 (FGF-23) are linked to progression or lack of regression of LVH; and (3) in LUCID - a prospective cohort of incident ESRD subjects supported by the Canadian Institutes of Health - his team will examine whether active vitamin D leads to excess coronary artery calcification. By supporting the candidate's request for this K24 award, important patient-oriented questions will be addressed. Moreover, Dr. Thadhani, with an exemplary record of mentorship, teaching and research, will be afforded the necessary protected time to mentor individuals who comprise a new generation of clinical research fellows and students in Nephrology.