F32 Childcare Costs Supplement: Assessment of the Vitamin D Metabolite Ratio as a Therapeutic Target in Clinical Practice

项目摘要/摘要 维生素D代谢受损与骨骼疾病、心血管疾病的风险增加有关 慢性肾脏疾病(CKD)患者的心血管疾病(CVD)和死亡，世界上一个庞大且不断增长的人口 美国。维生素D异常状态的临床评估和治疗是维生素D异常的主要焦点 肾脏病临床护理，但由于缺乏可靠的维生素D充分性衡量标准和 识别哪些人可能对维生素D治疗有反应的能力有限。两个最常见的 用于指导临床决策和治疗的标志物，25-羟基维生素D(25(OH)D)和 甲状旁腺激素(PTH)浓度是维生素D充分性的不完美衡量标准：25(OH)D是一种 与维生素D受体结合的许多下游反应弱相关的非活性代谢物， 而甲状旁腺激素只反映了许多靶器官中的一个，并受到维生素D以外的其他因素的影响 受体激活。对组织水平、功能性维生素D活性的测量可能会更好地定义维生素D 充分性。维生素D活性代谢物1，25(OH)2D与维生素D的结合 受体强烈诱导细胞色素P24A1酶介导25(OH)D的药代动力学清除 通过关键中间体24，25-二羟基维生素D(24，25(OH)2D)。因此，24，25(OH)2D至25(OH)D 比率，也被称为维生素D代谢物比率(VDMR)，已被提出作为衡量CYP24A1- 介导的25(OH)D清除和功能维生素D活性。 总的研究目标是验证VDMR作为25(OH)D清除的标志(目标1)，测试是否 VDMR改变了对补充维生素D的治疗反应(目标2)，以及低VDMR是否 与心血管疾病风险增加有关，心血管疾病是慢性肾脏病的主要死亡原因(目标3)。我会利用3 以社区为基础、种族/民族多样化的补充性队列，具有广泛的肾功能到 完成这些目标：慢性肾脏疾病中25-羟基维生素D的清除研究 (CLEAR)，拥有25(OH)D清除量的黄金标准药代动力学测量的最大队列； 在动脉粥样硬化多种族研究中嵌套口服维生素D3的严格随机临床试验 (MESA)；和慢性肾功能不全队列(CRIC)，这是规模最大、最全面的 集结的CKD特征队列。总之，这项工作将评估VDMR在临床实践中的应用 为慢性肾脏病的维生素D治疗提出了一种“精确医学”的方法。这一项目将被实施 在来自不同学科的研究人员的指导下，在丰富的学术环境中 由华盛顿大学和肾脏研究所共同组成。有组织的培训 本申请中提出的计划和本项目的结果将作为过渡到 职业发展奖，并最终成为一名独立研究人员。

PROJECT SUMMARY/ABSTRACT Impaired vitamin D metabolism is associated with increased risks of bone disease, cardiovascular disease (CVD) and death among patients with chronic kidney disease (CKD), a large and growing population in the United States. The clinical evaluation and treatment of abnormal vitamin D status are a major focus of nephrology clinical care, but are hampered by the lack of reliable measures of vitamin D adequacy and a limited ability to identify individuals who are likely to respond to vitamin D treatment. The two most commonly used markers used to guide clinical decision-making and treatment, 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) concentrations, are imperfect measures of vitamin D adequacy: 25(OH)D is an inactive metabolite with weak correlation with many downstream responses of vitamin D receptor binding, while PTH reflects activity at just one of many target organs and is influenced by factors other than vitamin D receptor activation. Measures of tissue-level, functional vitamin D activity may more optimally define vitamin D adequacy. The binding of 1,25-dihydroxyvitamin D (1,25(OH)2D, the active vitamin D metabolite) to vitamin D receptors strongly induces the CYP24A1 enzyme to mediate the pharmacokinetic clearance of 25(OH)D through the key intermediate 24,25-dihydroxyvitamin D (24,25(OH)2D). Thus the 24,25(OH)2D to 25(OH)D ratio, also called the vitamin D metabolite ratio (VDMR), has been proposed as a novel measure of CYP24A1- mediated 25(OH)D clearance and functional vitamin D activity. The overall study objectives are to validate the VDMR as a marker of 25(OH)D clearance (Aim 1), test whether the VDMR modifies treatment response to vitamin D supplementation (Aim 2) and whether low VDMR is associated with an increased risk of CVD, the prevailing cause of death in CKD (Aim 3). I will leverage 3 complementary community-based, racially/ethnically diverse cohorts with broad ranges of kidney function to accomplish these objectives: the Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease Study (CLEAR), the largest cohort with gold standard pharmacokinetic measurements of 25(OH)D clearance; a rigorous randomized clinical trial of oral vitamin D3 nested within the Multi-Ethnic Study of Atherosclerosis (MESA); and the Chronic Renal Insufficiency Cohort (CRIC), the largest and most comprehensively characterized CKD cohort assembled. In totality, this work will evaluate the use of the VDMR in clinical practice and advance a “precision medicine” approach to vitamin D therapy in CKD. This project will be conducted under the mentorship of investigators from diverse disciplines, within the rich academic environment collectively formed by the University of Washington and the Kidney Research Institute. The structured training plan proposed in this application and the results of this project will serve as a foundation to transition to a Career Development Award and an eventual career as an independent researcher.