Vitamin D Catabolism in Chronic Kidney Disease

描述(由申请人提供)：维生素D代谢受损是降低慢性肾脏疾病(CKD)显着发病率和死亡率的一个有前途的治疗目标。然而，由于缺乏有效的生物标志物，维生素D代谢受损的评估和治疗目前受到限制。我们的初步数据表明，CKD患者维生素D分解代谢减少伴随1，25-二羟基维生素D生成减少，评估维生素D分解代谢可能为指导临床诊断和治疗提供有价值的新工具。我们建议定义跨肾小球滤过率和RACE的维生素D分解代谢，并测试循环中低浓度的24，25-二羟基维生素D是否是CKD患者不良健康结局的可改变的危险因素。金标准药代动力学研究将确定慢性肾脏病患者维生素D分解代谢是否受损以及受损程度如何。现有流行病学研究和临床试验的协同辅助研究将测试24，25-二羟基维生素的相关性 研究维生素D浓度与不良健康后果之间的关系，检查一系列常见维生素D相关干预措施对循环中24，25-二羟基维生素D的影响，并探讨基线24，25-二羟基维生素D浓度是否能确定对此类常见干预措施有生化反应的患者。这一实验组合将全面评估CKD患者的维生素D分解代谢，并确定24，25-二羟基维生素D是否可能填补该人群维生素D代谢的临床评估中的一个重要空白。

DESCRIPTION (provided by applicant): Impaired vitamin D metabolism is a promising therapeutic target to reduce the marked morbidity and mortality of chronic kidney disease (CKD). However, the evaluation and treatment of impaired vitamin D metabolism is currently limited by a lack of effective biomarkers. Our preliminary data suggest that reduced vitamin D catabolism accompanies reduced 1, 25- dihydroxyvitamin D production in CKD and that evaluation of vitamin D catabolism may offer a valuable new tool to guide clinical diagnosis and treatment. We propose to define vitamin D catabolism across glomerular filtration rate and race and test whether a low circulating concentration of 24, 25-dihydroxyvitamin D, the most abundant product of 25-hydroxyvitamin D catabolism by CYP24A1, is a modifiable risk factor for adverse health outcomes in CKD. Gold standard pharmacokinetic studies will define whether and to what extent vitamin D catabolism is impaired in CKD. Synergistic ancillary studies to existing epidemiologic studies and clinical trials will test associations of 24,25-dihydroxyvitamin D concentration with adverse health outcomes, examine the effects of a broad range of common vitamin D-related interventions on circulating 24,25-dihydroxyvitamin D, and explore whether baseline 24,25-dihydroxyvitamin D concentration identifies patients who have biochemical responses to such common interventions. This combination of experiments will comprehensively evaluate vitamin D catabolism in CKD and determine whether 24,25-dihydroxyvitamin D may fill an important void in the clinical assessment of vitamin D metabolism in this population.