Controlled Trial of Renin Angiotensin Blockade in ADPKD

描述(由申请人提供)： 建议研究的总体假设是，旨在多水平阻断肾素血管紧张素系统的强化干预策略(血管紧张素II受体相互作用由血管紧张素II AT1受体阻滞剂或ARB，血管紧张素II转换酶抑制剂或ACEI产生血管紧张素II，血管紧张素II AT1受体密度和细胞内信号转导由3-羟基-3-甲基戊二酰辅酶A还原酶或他汀类抑制剂)将减缓肾功能正常或接近正常的患者的肾囊性疾病的进展。这一策略的成功与否将取决于纠正常染色体显性遗传性多囊肾病(ADPKD)相关的肾内血流动力学改变的程度(先导研究)，以及轻、中度肾功能不全患者的肾功能下降(30-60ml/min/1.73 m2)(主要研究)。主要研究的主要终点将是肾功能正常或接近正常的患者的肾脏体积增加15%或囊腔体积增加30%，以及轻度至中度肾功能不全患者的肾小球滤过率减少50%或血清肌酐增加一倍。将获得肾血流量(RBF)、肾血管阻力(RVR)和动脉顺应性的MR测定，以确定治疗干预后的血流动力学变化在多大程度上可以预测它们在延缓肾囊性疾病的进展或肾功能下降方面的成功。类似的方法将用于确定新的降压疗法在ADPKD中的潜在价值。主要研究的方案将在500名患者中进行，其中250名在梅奥诊所招募，150名在KUMC招募，100名在克利夫兰诊所招募。这些患者中约有一半的肾功能正常或接近正常，一半的患者有轻度到中度的肾功能不全。试点研究的方案将只在梅奥诊所进行。

DESCRIPTION (provided by applicant): The overall hypothesis of the proposed studies is that an intensified interventional strategy aimed at blocking the renin angiotensin system at multiple levels (angiotensin II-receptor interaction by an angiotensin II AT1-receptor blocker or ARB, angiotensin II generation by an angiotensin I converting-enzyme inhibitor or ACEI, an angiotensin II AT1-receptor density and intracellular signaling by inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase or statin) will slow down the progression of the renal cystic disease in patients with normal or near-normal renal function (GFR > 60ml/min/1.73m2) and the decline of renal function in patients with mild to moderate renal insufficiency (30-60 ml/min/1.73 m2) (Main Study) and that the success of this strategy will be predicted by the extent to which it corrects the intrarenal hemodynamic alterations associated with autosomal dominant polycystic kidney disease (ADPKD) (Pilot Study). The primary end-points for the Main Study will be a 15% increase in kidney volume or a 30% increase in cyst volume measured by MR in patients with normal or near-normal renal function and a 50% reduction in GFR or a doubling in serum creatinine in patients with mild to moderate renal insufficiency. MR determinations of renal blood flow (RBF), renal vascular resistance (RVR) and arterial compliance will be obtained to ascertain the extent to which the hemodynamic changes in response to therapeutic interventions can predict their success in delaying the progression of the renal cystic disease or the decline of renal function. Similar methodology will be used to ascertain the potential value of novel antihypertensive therapies in ADPKD. The protocols for the Main Study will be conducted in 500 patients, 250 recruited at the Mayo Clinic, 150 recruited at KUMC, and 100 at the Cleveland Clinic. Approximately one-half of these patients will have normal or near-normal renal function and one-half have mild to moderate renal insufficiency. The protocols for the Pilot Study will be conducted only at the Mayo Clinic.