Angiotensin II Blockade

描述（由申请人提供）：慢性同种异体肾病（CAN）导致的肾移植损失被广泛认为是一个主要问题，随着急性排斥反应导致的早期移植损失发生率的下降，该问题的相对重要性也在增加。包括明尼苏达大学（University of Minnesota）在内的多个中心的研究表明，在排除因移植功能正常而死亡的患者后，多达80%的患者将因CAN而再次接受透析。目前，一旦CAN的临床表现发展，就没有治疗选择。预防CAN的检测措施尚未得到解决。本项目的总体目的是研究肾素-血管紧张素-醛固酮系统（RAAS）在CAN发展中的作用。该系统在许多实验和临床肾脏疾病的进展中起着重要作用。此外，用血管紧张素转换酶抑制剂和血管紧张素II受体阻滞剂阻断该系统，在许多内源性肾脏疾病中产生了延缓损伤和进展的有益结果。本研究对肾移植受者进行了一项为期5年的随机、双盲、安慰剂对照研究，专门研究了血管紧张素II受体阻滞剂Iosartan在预防肾皮质间质体积扩张（长期移植物功能的准确预测因子）和活检证实的移植物损失方面的长期益处。该临床试验将直接验证肾素-血管紧张素-醛固酮系统的阻断将通过独立的降血压机制提供实质性的益处，即阻断胫腓通路、抗蛋白尿作用、改善高滤过以及可能的一些免疫调节作用。拟议的研究还将描述CAN异体肾移植中发生的间质超微结构变化，治疗对这些变化的影响，并提供移植肾小球病变发生率和发展预测因素的完整描述。这些研究还将确定血管紧张素II受体阻断对肾小球滤过率下降速率的影响，以及肾小球大小对CAN移植物损失速率的影响，移植后蛋白尿的发生率和进展，导致蛋白尿的pero选择性缺陷的性质，并将探索蛋白质与CAN移植物损失的关系。该试验还将有助于构建移植受者RAAS的概况，并探索ACE和TGF-b与CAN两种基因多态性之间的关系。这些研究将有助于描述CAN的自然历史、性质和发病机制，阐明这一重要疾病的早期标志物和预测因素，并可能确定一种安全有效的预防策略。

DESCRIPTION (provided by applicant): Renal transplant loss due to chronic allograft nephropathy (CAN) is widely acknowledged as a major problem that has increased in relative importance as the incidence of early graft loss from acute rejection has declined. Studies from various centers, including the University of Minnesota, suggest that, after excluding patients dying with a functioning graft, as many as 80% of patients who will return to dialysis do so because of CAN. At the present time there are no therapeutic options once the clinical manifestations of CAN have developed. Testing measures to prevent CAN have not been addressed. The overall purpose of this project is to investigate the role of the renin-angiotensin-aldosterone system (RAAS) in the development of CAN. This system plays an important role in the progression of many experimental and clinical renal diseases. Furthermore, blockade of this system with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers has yielded beneficial results in retarding injury and progression in numerous intrinsic renal diseases. This study specifically investigates the long term benefit of the angiotensin II receptor blocker, Iosartan, in the prevention of cortical interstitial volume expansion (an accurate predictor of long term graft function) and graft loss from biopsy proven CAN in a 5 year, randomized, double masked, placebo controlled study of kidney transplant recipients. This clinical trial will directly test the hypothesis that blockade of the renin angiotensin aldosterone system will provide a substantial benefit through blood pressure lowering independent mechanisms, namely, interruption of tibrogenic pathways, anti-proteinuric actions, amelioration of hyperfiltration and possibly some immunomodulatory effects. The proposed studies will also characterize the interstitial ultrastructural compositional changes that occur in the renal allografts with CAN, the effects of treatment on these changes and provide a complete description of the incidence and predictors for the development of transplant glomerulopathy. These studies will also determine the impact of angiotensin II receptor blockade on the rate of decline of glomerular filtration rate, as well as the impact of glomerular size on the rate of graft loss from CAN, the incidence and the progression of post transplant proteinuria, the nature of the permselectivity defects responsible for the proteinuria and will also explore the association of proteinuna with graft loss from CAN. This trial will also help construct a profile for the RAAS in the transplant recipients and explore the relationship between two genes polymorphisms, ACE and TGF-b and CAN. These studies should help to describe the natural history, nature and pathogenesis of CAN, elucidate early markers and predictors of this important disorder and, perhaps, define a safe and useful preventative strategy.