Mechanisms and Ex Vivo Repair of Cold-Storage Injury in Human Kidney Allografts

人肾同种异体移植物冷藏损伤的机制和离体修复

• 批准号: 10338146
• 负责人: Gregory T Tietjen
• 金额: $ 50.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-28 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338146
• 关键词: Acute-Phase Proteins; Aging; Area; Biological Assay; Biopsy; Biopsy Specimen; Cells; Clinical; Collaborations; Cryopreservation; Development; Donor person; Ensure; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Extrahepatic; Fibrinogen; Geographic Locations; Glomerular Filtration Rate; Goals; Grant; Hepatic; Histopathology; Human; Image; Injury; Interleukin-6; Kidney; Kidney Transplantation; Knowledge; Logistics; Mediating; Mediator of activation protein; Methods; Molecular; Organ; Organ Culture Techniques; Organ Donor; Organ Transplantation; Outcome; Pathologic; Pathology; Patients; Perfusion; Persons; Pharmacology; Physiological; Plasminogen; Prevention; Production; Proteins; Quantitative Microscopy; Regimen; Renal function; Reperfusion Therapy; Research; Scientist; Shock; Specimen; TNF gene; Testing; Therapeutic; Time; Tissue Transplantation; Tissues; Transcript; Translating; Translations; Transplant Recipients; Transplantation; Tubular formation; Urine; Work; X-Ray Computed Tomography; biobank; biological adaptation to stress; comorbidity; cytokine; delayed graft function; experimental study; genomic platform; glomerular filtration; human tissue; improved; in vivo; kidney allograft; kidney cortex; mortality; normoxia; organ injury; post-transplant; repaired; resilience; response; restoration; single-cell RNA sequencing; targeted treatment; therapeutic development; tissue culture; transcriptome sequencing; wasting

PROJECT SUMMARY The average duration of cold-storage for deceased-donor kidneys in the U.S. can range from ~9 to >30 hrs in the U.S. depending on geographic location. It is well established that the longer a kidney is stored cold prior to transplant, the greater the likelihood of post-transplant complications like delayed graft function. This is particularly true for organs from aging donors or donors with co-morbidities—an ever-expanding proportion of the U.S. donor pool—which display increased sensitivity to injury during cold storage. Little is known about the mechanisms that determine the rate and extent of cold-storage injury in human organs. This lack of knowledge presents a critical barrier to the development of therapeutic strategies to reduce the clinical impact of cold-storage injury. We have recently discovered that cold storage induces human kidneys to produce fibrinogen within renal tubular cells. Upon restoration of normothermia/normoxia, fibrinogen is secreted into the vasculature where it can aggregate erythrocytes in a rouleaux formation leading to pathologic plugging of microvessels. We hypothesize that renal fibrinogen is a major effector of cold-storage injury and therefore represents a viable target to improve organ resilience after cold storage. Ex Vivo Organ Perfusion (EVOP) has emerged as a research and clinical platform providing an opportunity to directly test this hypothesis in a translationally relevant setting. Here, we will exclusively use human tissues to achieve two objectives: 1) Determine the mechanism by which cold- storage induces renal fibrinogen synthesis; and 2) Evaluate EVOP as a therapeutic platform to ameliorate fibrinogen-mediated pathology pre-transplant. Successful completion of these objectives will establish a new paradigm for prevention of cold-storage-induced organ injury with the potential to save patient lives by improving both access to organs and post-transplant outcomes.

项目摘要 在美国，死亡供体肾脏冷藏的平均持续时间范围为约9至>30小时， 美国根据地理位置。众所周知，肾脏在冷冻前储存的时间越长， 移植后并发症的可能性越大，如移植功能延迟。这是 尤其是来自老年供体或患有共病的供体的器官- 在冷藏过程中对损伤表现出更高的敏感性。很少有人知道的 决定人体器官冷藏损伤的速率和程度的机制。人们缺乏了解 这对开发治疗策略以减少冷藏的临床影响是一个关键障碍 损伤我们最近发现，冷藏诱导人肾产生纤维蛋白原， 管状细胞在恢复正常体温/正常氧时，纤维蛋白原分泌到血管系统中， 可以聚集红细胞形成红细胞叠连，导致微血管的病理性堵塞。我们 假设肾纤维蛋白原是冷藏损伤主要效应物，因此是一个可行的靶点 以提高冷藏后器官的弹性。离体器官灌注（EVOP）已成为一项研究， 临床平台提供了一个机会，直接测试这一假设在一个预防相关的设置。在这里， 我们将专门使用人体组织来实现两个目标：1）确定冷- 储存诱导肾纤维蛋白原合成;和2）评价EVOP作为改善 纤维蛋白原介导的病理学。成功完成这些目标将建立一个新的 预防冷藏引起的器官损伤的范例，通过改善 获取器官和移植后的结果。