Planning Grant for Reduction of Uric Acid to Prevent Hypertension (RAPHY) Trial

描述（由申请人提供）：降低尿酸预防高血压（RAPHY试验）（摘要）高血压影响三分之一的美国人口，是心血管疾病的主要原因。尿酸升高始终预示着高血压的发展，并且通常出现在新发高血压中。我们发现近90%的青少年新发高血压与高尿酸有关。在最近的一项双盲研究中，我们发现当血清尿酸降至< 5 mg/dl时，86%的青少年血压恢复正常（而安慰剂组只有3%）。动物尿酸升高也会引起高血压，这是由肾素-血管紧张素系统的激活、内皮功能的抑制（降低一氧化氮）和肾脏血管疾病的发生介导的。此外，临床和实验研究还表明，降低尿酸可能有其他好处，包括改善内皮功能，减少代谢综合征和糖尿病的发生。我们的初步数据表明，尿酸介导的高血压以两步的方式发展，第一步是由肾素-血管紧张素系统介导的可逆血管收缩和内皮NO的减少，第二步是肾传入小动脉的不可逆改变，导致永久性钠依赖性高血压。这些数据表明，年轻人可能有机会预防高血压。因此，我们提出了一项15个中心的临床试验，以检验降低尿酸会降低血压的进行性升高和降低胰岛素抵抗发生率的假设。功效分析表明，我们将需要400名年龄在12-50岁、尿酸水平升高（>6.0 mg/dl）的高血压前期（成人JNC7标准和青少年第四工作组标准）受试者，在治疗1年后和治疗后随访2年后，检测治疗组和对照组之间收缩压或舒张压的5 mmHg差异。主要终点将是12个月和36个月时收缩压和舒张压的变化以及胰岛素抵抗的患病率。青少年和年轻成人联合试验将确定低尿酸疗法的效用和治疗有效的年龄范围。如果这个假设是正确的，这项研究将为减少高血压、肥胖和心血管疾病的流行提供一种新颖而有效的方法，这些疾病目前正困扰着世界人口。

DESCRIPTION (provided by applicant): Reduction of Uric Acid to Prevent Hypertension (RAPHY Trial) (Abstract) Hypertension affects one-third of the US population and is the major cause of cardiovascular disease. An elevated uric acid consistently predicts the development of hypertension and is commonly present in new onset hypertension. We found that nearly 90% of new onset hypertension in adolescents is associated with a high uric acid. In a recent double blind study we found that BP became normal in 86% of such adolescents when serum uric acid was lowered to < 5 mg/dl (vs 3% of placebo-treated subjects). Raising uric acid in animals also causes hypertension which is mediated by activation of the renin-angiotensin system, inhibition of endothelial function (lowering nitric oxide), and the development of vascular disease in the kidneys. Furthermore, both clinical and experimental studies also suggest lowering uric acid may have other benefits, including improvement in endothelial function and a reduction in the development of metabolic syndrome and diabetes. Our preliminary data suggest that uric acid mediated hypertension develops in a two step fashion, first by reversible vasoconstriction mediated by the renin-angiotensin system and reduction of endothelial NO, the second by irreversible alteration of renal afferent arterioles leading to a permanent sodium dependent hypertension. These data suggest that there may be a window of opportunity for the prevention of hypertension in the young. Consequently, we propose a 15-center clinical trial to test the hypotheses that lowering uric acid will reduce the progressive rise in blood pressure and decrease the incidence of insulin resistance. Power analysis indicates that we will need 400 prehypertensive (by JNC7 criteria for adults and 4th Task Force criteria for adolescents) subjects age 12-50 with elevated uric acid levels (>6.0 mg/dl) to detect a 5 mmHg difference in systolic or diastolic BP between treated and control subjects after 1 year of treatment and after 2 years of post treatment follow up. The primary endpoints will be change in systolic and diastolic blood pressure and prevalence of insulin resistance at 12 and 36 months. The combined adolescent and young adult trial will determine the utility of hypouricemic therapy and the age range during which the therapy is effective. If the hypothesis is correct, this study will provide a novel and effective way to reduce the epidemic of hypertension, obesity and cardiovascular disease that current grips the world's population. PUBLIC HEALTH RELEVANCE: Planning Grant: Project Narrative Our preliminary studies in both animal models and human clinical trials suggest that elevated serum uric acid may be causally involved in the development of essential hypertension in adolescents. We propose a multi-center clinical trial to determine if reduction of serum uric acid will prevent the progressive rise in blood pressure in those at highest risk for development of hypertension, patients with pre-hypertension. This trial may provide a new paradigm for preventive therapy of hypertension, a disease that effecting more than 30% of Americans and causes nearly 1 million deaths a year in the USA.