Angiotensin II Blockade for Chronic Allograft Nephropathy

描述(申请人提供)：慢性移植物肾病引起的肾移植损失，最近被指定为间质纤维化/肾小管萎缩(IF/TA NOS)，被广泛认为是一个主要问题，随着急性排斥反应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。无论原因如何，组织学上的IF/TA在移植后几个月内几乎普遍存在于同种异体移植物中。目前，一旦IF/TA的临床表现出现，就没有治疗的选择。没有重点改变免疫抑制剂以预防IF/TA NOS的措施尚未经过测试。这项申请要求继续支持一项正在进行的基于肾活检的随机对照试验，该试验已成功完成招募。这项研究是在美国国立卫生研究院的支持下启动的，并继续获得了DSMB的批准，将在本提案的5年内完成退出阶段。这项名为血管紧张素II阻滞剂治疗慢性移植物肾病(ABCAN)的试验将确定，在肾移植后的头5年，血管紧张素受体阻滞剂是否可以防止皮质间质体积扩大(一个准确预测长期移植物功能的指标)和移植物丢失，因为活检证明IF/TA是其主要原因；IF/TA NOS。正在进行的研究将描述IF/TA肾移植中发生的间质超微结构的变化，治疗对这些变化的影响，并将提供IF/TA的发生率和发展的预测因素。我们还将确定血管紧张素II受体阻断对肾小球滤过率下降速度的影响，移植后蛋白尿的发生和进展，以及导致蛋白尿的通透性缺陷的性质。辅助研究还将描述IF/TA的自然历史，并阐明这一重要疾病的早期标志和预测因素。最后，我们将获得一个丰富的尿液、血清、DNA和肾组织存储库，可以与科学界的其他研究人员共享。公共卫生相关性：慢性移植物肾病仍然是肾移植失败和重新透析的主要原因。治疗选择有限，疾病的病程往往是渐进性的。这项试验旨在防止这一过程的一个主要中介，即肾脏皮质间质间隙的扩张，大部分疤痕发生在那里。正在研究的药物氯沙坦已被证明对许多肾脏疾病有效。

DESCRIPTION (provided by applicant): Renal transplant loss due to chronic allograft nephropathy, recently designated as interstitial fibrosis/tubular atrophy not otherwise specified (IF/TA NOS), is widely acknowledged as a major problem that has increased in relative importance as the incidence of early graft loss from acute rejection declined. Histological IF/TA, regardless of the cause, is almost universally present in the allograft within a few months of transplantation. Currently, there are no therapeutic options once the clinical manifestations of IF/TA have developed. Measures not focused on altering immunosuppressants to prevent IF/TA NOS have not been tested. This application requests continued support for an ongoing renal biopsy based randomized controlled trial that has successfully completed recruitment. This study, initiated with NIH support and recipient of continued DSMB approval will complete the exit phase during the 5 years of this proposal. This trial, Angiotensin II Blockade for Chronic Allograft Nephropathy (ABCAN), will determine whether angiotensin II receptor blockade can, in the first 5 post-kidney transplant years, prevent cortical interstitial volume expansion (an accurate predictor of long term graft function) and graft loss from biopsy proven IF/TA particularly its major cause; IF/TA NOS. The ongoing studies will characterize the interstitial ultrastructural compositional changes that occur in renal allografts with IF/TA, the effects of treatment on these changes and will also provide descriptors of the incidence and predictors of the development of IF/TA. We will also determine the impact of angiotensin II receptor blockade on the rate of GFR decline, the incidence and progression of post transplant proteinuria and the nature of the permselectivity defects responsible for the proteinuria. The ancillary studies will also describe the natural history of IF/TA and elucidate early markers and predictors of this important disorder. Lastly, we will have acquired a rich repository of urine, serum, DNA and renal tissue that can be shared with other investigators in the scientific community. PUBLIC HEALTH RELEVANCE: Chronic allograft nephropathy continues to be a major cause of kidney transplant loss and return to dialysis. Treatment options are limited and the course of the disease tends to be progressive. This trial is designed to prevent a major mediator of this process, namely the expansion of the cortical interstitial compartment of the kidney where most of the scarring occurs. The drug being studied, Losartan, has proven efficacious in a number of kidney diseases.