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

• 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
• 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

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.

项目摘要/摘要 肾脏移植是终阶段肾脏疾病（ESKD）的主要疗法，1然而，3-5％的移植物失败 每年，只有50％的人在十年时保持运作。2,3最常见的移植物损失表现是 间质纤维化和管状萎缩（IFTA）的组织学发现不佳，4-7存在于 移植后6个月的活检中的三分之一。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引起的移植，9，导致血管完整性受损和 周围毛细管损失已显示出导致IFTA.9-12的毛细血管损失。 建议通过减少白蛋白的微血管泄漏，对肾功能产生保护作用 减少接受者对受损的内皮细胞的反应。9、10、14、15因此，我们提出了 评估血管捕获血管完整性的血管生成素家族中的两个血管标记[Angiopoietin-1 （ANGPT-1）和-2（ANGPT-2）]在死者肾脏移植的情况下。激活ANGPT-1 受体，TIE-2维持血管稳定性和完整性，但Angpt-2是竞争性的拮抗剂Angpt-1， 干扰Angpt-1-Tie-2轴，并促进容器泄漏。16Angpt-1的平衡：Angpt-2 生产决定了血管的完整性。17该提案的目的是评估血液是否存在 血管蛋白测量的血管完整性将是短期和长期移植功能的预后 为了确定未来干预的途径。候选人假设维护 血管完整性（通过ANGPT-1和ANGPT-2测量）将与纤维化较少有关，更好的移植物将 结果。在AIM 1中，我们将前瞻性地注册已故的捐赠者移植接受者，并使用前 现有的接收者队列评估和外部验证围手术期血管生成素的关联 具有1年的移植功能。在AIM 2中，我们将评估在一个时间点测量的血管生成素是否为 与长期移植失败（平均随访约四年）相关 预先存在的首选试验。在AIM 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学人群进行6个月移植活检的病理学。更具体地说，我们将 评估ANGPT-1和-2是否与6个月的IFTA相关，周围毛细管损失和血管渗透性 关于组织学。了解血管蛋白在同种异体移植结果中测量的血管完整性的作用 可能有助于识别未来干预的途径，并风险将受体分层以进行更多针对性的试验和临床 关心。