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

项目概要/摘要 肾移植是终末期肾病的主要治疗方法，但移植失败率为3- 5 移植物丢失最常见的表现是： 间质纤维化和肾小管萎缩（IFTA）的组织学表现不佳，4-7， 在移植后6个月的活组织检查中，多达三分之一。8此外，内皮细胞损伤在肾脏中很常见， 移植由于缺血性损伤在采购，9并导致受损的血管完整性， 肾小管周围毛细血管损失，这已被证明会导致IFTA。9 -12此外， 建议通过减少白蛋白的微血管渗漏对肾功能产生保护作用13，以及 减少受体对受损内皮细胞的同种免疫反应。9，10，14，15出于这个原因，我们建议 评价血管生成素家族中捕获血管完整性的两种血管标记物[血管生成素-1 （Angpt-1）和-2（Angpt-2）]。Angpt-1的激活 受体Tie-2维持血管稳定性和完整性，但Angpt-2，Angpt-1的竞争性拮抗剂， 干扰Angpt-1-Tie-2轴，并促进血管渗漏。16 Angpt-1：Angpt-2的平衡 生产决定血管的完整性。17本提案的目标是评估血液是否 血管生成素测量的血管完整性将预测短期和长期移植物功能 以确定未来干预的途径。候选人假设， 血管完整性（通过Angpt-1和Angpt-2测量）将与较少的纤维化和更好的移植物相关 成果。在目标1中，我们将前瞻性地招募已故的供体移植受体，并使用预- 现有接受者队列，以评价和外部验证围手术期血管生成素的相关性 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 与长期移植失败相关（平均随访约4年）， 既存FAVORIT试验。在目标3中，我们将测试围手术期血管生成素与组织 使用我们的前瞻性入组队列对6个月移植物活检进行病理学检查。具体来说，我们将 评价Angpt-1和Angpt-2是否与6个月IFTA、肾小管周围毛细血管损失和血管通透性相关 在组织学上。了解血管生成素测量的血管完整性在同种异体移植结局中的作用 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研究。 在乎

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.