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

血管生成素作为肾同种异体移植结构和功能的预后标志物的评价

基本信息

批准号：
10487563
负责人：
Sherry George Mansour
金额：
$ 19.3万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10487563
关键词：
ANGPT1 gene Allografting Angiopoietins Animal Model Association Learning Atrophic Biological Biological Markers Biopsy Blood Blood Vessels Blood capillaries Blood specimen Clinical Research Collection Data Development Donor person End stage renal failure Endothelial Cells Enrollment Equilibrium Evaluation Extravasation Family Fibrosis Finding by Cause Folic Acid Future Glomerular Filtration Rate Goals Health Histologic Histology Hospitals Human Impairment Injury Intervention Intervention Studies Kidney Kidney Transplantation Measurement Measures Mediator of activation protein Mission Multicenter Trials National Institute of Diabetes and Digestive and Kidney Diseases Organ Organ Procurements Outcome Pathology Pathway interactions Patients Perioperative Permeability Plasma Postoperative Period Production Prognostic Marker Prospective cohort Protocols documentation Recurrence Renal function Research Role Sampling Specimen Stains Structure TIE-2 Receptor Testing Time Tissue Banks Tissue Grafts Tissues Transplant Recipients Transplantation Tubular formation Urine Vascular Endothelium Waiting Lists antagonist antibody-mediated rejection base cadherin 5 career cell injury clinical care clinical epidemiology cohort effective therapy experience follow-up graft failure graft function improved interstitial ischemic injury junctional adhesion molecule kidney allograft kidney fibrosis participant enrollment prognostic prospective protein biomarkers receptor repaired response risk stratification tool

项目摘要

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.

项目概要/摘要肾移植是终末期肾病 (ESKD) 的主要治疗方法，1 然而，3-5% 的移植失败每年，只有 50% 在十年后仍能发挥功能。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) 的组织学表现不明确，4-7 存在于多达三分之一的活检是在移植后 6 个月进行的。8 此外，内皮细胞损伤在肾脏中很常见在采购过程中由于缺血性损伤而进行移植，9 并导致血管完整性受损和管周毛细血管损失，已被证明会导致 IFTA.9-12 此外，血管完整性已被证实提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 因此，我们建议评估血管生成素家族中捕获血管完整性的两种血管标记物 [Angiopoietin-1 （Angpt-1）和-2（Angpt-2）]在已故供体肾移植的情况下。 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 的平衡：Angpt-2 生产决定了血管的完整性。17 该提案的目标是评估血液是否通过血管生成素测量的血管完整性将是短期和长期移植物功能的预后努力确定未来干预的途径。候选人假设维持血管完整性（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结果。在目标 1 中，我们将前瞻性地招募已故供体移植受者，并使用预现有的受者队列来评估和外部验证围手术期血管生成素的关联具有1年移植功能。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（平均随访约四年）预先存在的 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的关联使用我们的前瞻性入组队列进行 6 个月移植物活检的病理学分析。更具体地说，我们将评估 Angpt-1 和 -2 是否与 6 个月 IFTA、管周毛细血管损失和血管通透性相关关于组织学。了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。