MODifiable Effectors of Renin System Activation: Treatment Evaluation

描述（由申请方提供）：较低的25-羟基维生素D（25[OH]D）和较高的尿酸水平均与人的肾素血管紧张素系统激活、内皮功能障碍和血压升高相关。此外，较低的25（OH）D和较高的尿酸水平与超重和肥胖有关，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的不良影响的潜在介质。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。适度（可调节的肾素系统激活效应物：治疗评价）研究是一项随机、双盲、安慰剂对照的临床试验，比较了50，000单位/周的维生素D补充剂与安慰剂，持续8周，或比较别嘌呤醇300 mg/天或丙磺舒500 mg/天的降尿酸作用（均在4周时剂量滴定至600 mg/天或1000 mg/天）至安慰剂，持续8周。将入组超重或肥胖且维生素D缺乏或尿酸水平<5 mg/dL的成人，主要终点将是肾素血管紧张素系统的激活状态，通过血浆肾素活性、血管紧张素II浓度和高钠平衡个体对输注血管紧张素II的肾血浆流量反应确定。次要终点将是通过高分辨率超声反应性充血测量的内皮依赖性扩张，第三终点将是使用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第一个人体实验数据，这是疾病的两个关键机制。从公共卫生的角度来看，这项试验的结果将为预防高血压、心血管和慢性肾脏疾病的发病率的策略和未来的试验提供信息。 公共卫生相关性：缺乏维生素D和血液中尿酸含量较高的人可能有患高血压、心脏病和肾脏疾病的风险，因为他们的身体会产生不适当的某些激素，而且他们的血管不能正常运作。超重或肥胖的人更容易缺乏维生素D和尿酸水平高。这项研究将确定是否给予维生素D补充剂或药物来降低超重或肥胖人群的尿酸水平，可以逆转一些最终可能导致高血压，心脏病发作和肾脏疾病的激素和血管异常。

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. PUBLIC HEALTH RELEVANCE: People with vitamin D deficiency and higher blood levels of a compound called uric acid may be at risk for developing high blood pressure, heart attacks, and kidney disease because their bodies produce inappropriate amounts of certain hormones and because their blood vessels do not function normally. People who are overweight or obese are more likely to have vitamin D deficiency and high levels of uric acid. This study will determine whether giving vitamin D supplements or medication to lower uric acid levels to overweight or obese people can reverse some of the hormone and blood vessel abnormalities that ultimately could cause high blood pressure, heart attacks, and kidney disease.