Angiotensin II Blockade

描述（由申请人提供）：慢性同种异体移植肾病（CAN）导致的肾移植失败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物丢失的发生率下降，该问题的相对重要性有所增加。包括明尼苏达大学在内的多个中心的研究表明，在排除因功能正常的移植物而死亡的患者后，多达80%的患者将因CAN而重返透析。目前，一旦CAN的临床表现出现，就没有治疗选择。预防CAN的测试措施尚未得到解决。本研究的主要目的是探讨肾素-血管紧张素-醛固酮系统（RAAS）在CAN发病中的作用。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受体阻断剂阻断该系统在延缓许多内源性肾脏疾病的损伤和进展方面产生了有益的结果。本研究专门研究了血管紧张素II受体阻滞剂Iosartan在预防肾移植受者的5年、随机、双盲、安慰剂对照研究中活检证实的CAN导致的皮质间质体积扩张（长期移植物功能的准确预测因子）和移植物丢失方面的长期获益。本临床试验将直接检验以下假设：阻断肾素血管紧张素醛固酮系统将通过独立的降血压机制提供实质性获益，即阻断致炎途径、抗蛋白尿作用、改善超滤和可能的一些免疫调节作用。拟定的研究还将描述CAN肾移植物中发生的间质超微结构组成变化、治疗对这些变化的影响，并提供移植肾小球病发生率和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移植物丢失速率的影响，移植后蛋白尿的发生率和进展，导致蛋白尿的选择性渗透缺陷的性质，还将探索蛋白尿与CAN移植物丢失的相关性。本试验还将有助于建立移植受者RAAS的谱，并探讨两个基因多态性，ACE和TGF-β和CAN之间的关系。这些研究应有助于描述CAN的自然史、性质和发病机制，阐明这种重要疾病的早期标志物和预测因子，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.