Evaluation of Angiopoietins as Prognostic Markers of Kidney Allograft Structure and Function

项目摘要/摘要 肾移植是终末期肾病(Eskd)的主要治疗方法，1然而，3-5%的移植肾失败。 每年只有50%的移植物仍在运作。2，3移植物丢失的最常见表现是 间质纤维化和肾小管萎缩(IFTA)的组织学特征不佳，4-7例出现在 移植后6个月，多达三分之一的活组织检查。8此外，内皮细胞损伤在肾脏中很常见 在采购过程中因缺血损伤而进行的移植，9并导致血管完整性受损和 管周毛细血管丢失，已被证明导致IFTA。9-12此外，血管完整性已被 被认为通过减少白蛋白的微血管渗漏对肾脏功能产生保护作用13，以及 减少受体对受损内皮细胞的同种免疫反应。为此，我们建议 评价血管生成素家族中捕捉血管完整性的两种血管标志物[血管生成素1 (Angpt-1)和-2(Angpt-2)]。血管紧张素转换酶1的激活 受体Tie-2维持血管的稳定性和完整性，而Angpt-1的竞争性拮抗剂Angpt-2， 干扰Angpt-1-Tie-2轴，促进血管泄漏。16 Angpt-1：Angpt-2的平衡 生产决定血管的完整性。17这项提议的目标是评估血液是否 血管生成素测定的血管完整性将预测移植物的短期和长期功能 以努力确定未来干预的途径。候选人假设维持 血管完整性(由Angpt-1和Angpt-2测量)将与较少的纤维化和更好的移植物相关 结果。在目标1中，我们将前瞻性地登记已故的捐赠者移植接受者，以及使用预 评估和外部验证围手术期血管生成素相关性的现有受者队列 移植物功能1年。在目标2中，我们将评估在单个时间点测量的血管生成素是否 与长期移植失败(平均随访约四年)有关的研究 先前存在的Favorit审判。在目标3中，我们将测试围手术期血管生成素与组织的相关性。 使用我们的预期登记队列进行为期6个月的移植物活检的病理学研究。更确切地说，我们将 评估Angpt-1和-2是否与6个月的IFTA、肾小管周围毛细血管丢失和血管通透性有关 在组织学方面。理解血管生成素测量的血管完整性在同种异体移植结果中的作用 可能有助于确定未来干预的途径，并对接受者进行风险分层，以进行更有针对性的试验和临床 关心。

Project Summary/Abstract Kidney transplantation is the main therapy for end stage kidney disease (ESKD),1 however, 3-5% of grafts fail yearly and only 50% remain functioning at ten years.2,3 The most common manifestations of graft loss are poorly characterized histologic findings of interstitial fibrosis and tubular atrophy (IFTA), 4-7 which are present in up to a third of biopsies 6-month after transplant.8 Furthermore, endothelial cell injury is common in kidney transplantation due to ischemic injury during procurement,9 and leads to impaired vessel integrity and peritubular capillary loss, which have been shown to lead to IFTA.9-12 In addition, vessel integrity has been proposed to have a protective impact on kidney function by reducing microvascular leakage of albumin13, and reducing the recipient alloimmune response to damaged endothelial cells.9, 10, 14, 15 For this reason, we propose to evaluate two vascular markers in the Angiopoietin family capturing blood vessel integrity [Angiopoietin-1 (Angpt-1), and -2 (Angpt-2)] in the setting of deceased-donor kidney transplantation. Activation of the Angpt-1 receptor, Tie-2, maintains vessel stability and integrity, but Angpt-2, a competitive antagonist to Angpt-1, interferes with the Angpt-1-Tie-2 axis, and promotes vessel leakage.16 The balance of Angpt-1: Angpt-2 production determines the integrity of blood vessels.17 The goal of this proposal is to evaluate if blood vessel integrity as measured by Angiopoietins will be prognostic of short and long-term graft function in an effort to identify pathways for future intervention. The candidate hypothesizes that maintaining vessel integrity (as measured by Angpt-1 and Angpt-2) will be associated with less fibrosis, and better graft outcomes. In aim 1, we will prospectively enroll deceased donor transplant recipients as well as use a pre- existing cohort of recipients to evaluate and externally validate the associations of perioperative Angiopoietins with 1-year graft function. In aim 2, we will evaluate if Angiopoietins measured at a single time point are associated with long-term graft failure (mean follow up of about four years) by using bio-specimens from the pre-existing FAVORIT trial. In aim 3, we will test the associations of perioperative Angiopoietins with tissue pathology on 6-month graft biopsies using our prospective enrollment cohort. More specifically, we will evaluate if Angpt-1 and -2 are associated with 6-month IFTA, peritubular capillary loss and vessel permeability on histology. Understanding the role of vessel integrity as measured by Angiopoietins in allograft outcomes may help identify pathways for future intervention and risk stratify recipients for more targeted trials and clinical care.