MODifiable Effectors of Renin System Activation: Treatment Evaluation

描述（由申请人提供）：25-羟基维生素D （25[OH]D）的降低和尿酸水平的升高与肾素血管紧张素系统的激活、内皮功能障碍和血压升高有关。此外，较低的25(OH)D和较高的尿酸水平与超重和肥胖有关，并且可能是肥胖对肾素血管紧张素系统激活、内皮功能障碍和血压不利影响的潜在介质。然而，补充维生素D和降低尿酸对高血压、心血管和慢性肾脏疾病的潜在机制的影响尚不清楚。中度（肾素系统激活的可调节效应：治疗评估）研究是一项随机、双盲、安慰剂对照的临床试验，将50,000单位/周的维生素D补充剂与安慰剂进行比较，持续8周，或将降尿酸与别嘌呤醇300毫克/天或probenecid 500毫克/天（均在4周剂量滴定至600毫克/天或1000毫克/天）与安慰剂进行比较。超重或肥胖的维生素D缺乏或尿酸水平为5mg /dL的成年人将被纳入研究，主要终点将是肾素血管紧张素系统的激活状态，由血浆肾素活性、血管紧张素II浓度和高钠平衡个体对输注血管紧张素II的肾血浆流量反应决定。次要终点将是通过高分辨率超声测量反应性充血的内皮依赖性扩张，第三终点将是通过动态血压装置测量的24小时收缩压和舒张压。从科学的角度来看，这项试验将提供第一个关于25(OH)D和尿酸对肾素血管紧张素系统激活和内皮功能影响的人体实验数据，这是疾病的两个关键机制。从公共卫生的角度来看，该试验的结果将为旨在预防高血压、心血管疾病和慢性肾脏疾病发病率的战略和未来试验提供信息。

DESCRIPTION (provided by applicant): Both lower 25-hydroxyvitamin D (25[OH]D) and higher uric acid levels are associated with activation of the renin angiotensin system, endothelial dysfunction, and elevation of blood pressure in humans. Furthermore, lower 25(OH)D and higher uric acid levels are associated with overweight and obesity, and may be potential mediators of the adverse effects of adiposity on renin angiotensin system activation, endothelial dysfunction, and blood pressure. However, the effects of vitamin D supplementation and uric acid lowering on these underlying mechanisms of hypertension, cardiovascular and chronic kidney disease are unknown. The MODERATE (MODififable Effectors of Renin system Activation: Treatment Evaluation) study is a randomized, double blind, placebo controlled, clinical trial comparing 50,000 units/week of vitamin D supplementation to placebo for 8 weeks, or comparing uric acid lowering with either allopurinol 300 mg/day or probenecid 500 mg/day (both with a dose titration at 4 weeks to 600 mg/day or 1000 mg/day, respectively) to placebo for 8 weeks. Overweight or obese adults with vitamin D deficiency or uric acid levels e 5 mg/dL will be enrolled, and the primary endpoint will be the activation state of the renin angiotensin system, as determined by the plasma renin activity, angiotensin II concentration, and the renal plasma flow response to infused angiotensin II with individuals in high-sodium balance. The secondary endpoint will be endothelial dependent dilation measured by reactive hyperemia with high resolution ultrasound, and the tertiary endpoint will mean 24 hour systolic and diastolic blood pressure measured with an ambulatory blood pressure device. From a scientific standpoint, this trial will provide the first experimental human data regarding the effects of 25(OH)D and uric acid on renin angiotensin system activation and endothelial function, which are two critical mechanisms of disease. From a public health standpoint, the results of this trial will inform strategies and future trials designed to prevent the incidence of hypertension, cardiovascular and chronic kidney disease.