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: 10551857
• 负责人: SANJAY KULKARNI
• 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/10551857
• 关键词: Acute-Phase Proteins; Aging; Area; Biological Assay; Biopsy; Biopsy Specimen; Blood Vessels; Cells; Clinical; Collaborations; Cryopreservation; Development; Donor person; 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; Mediating; Mediator; Methods; Molecular; Organ; Organ Culture Techniques; Organ Donor; Organ Transplantation; Outcome; Pathologic; Pathology; Patients; Perfusion; Persons; Physiological; Plasminogen; Predisposition; Prevention; Production; Proteins; Quantitative Microscopy; Regimen; Renal function; Reperfusion Therapy; Research; Scientist; Shock; Specimen; TNF gene; Testing; Therapeutic; 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; natural hypothermia; normoxia; organ injury; pharmacologic; 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，死者释放肾脏的平均冷藏持续时间范围为〜9至> 30 hrs 美国取决于地理位置。已经确定的是，肾脏在冷储存之前的越长 移植，移植后并发症（如延迟移植功能）的可能性越大。这是 对于来自老龄化捐助者或合并症的捐助者的器官尤其如此 - 不断扩大的比例 美国捐助者池（表现出对冷藏过程中受伤的敏感性提高）。关于 确定人体器官冷藏损伤速率和程度的机制。缺乏知识 为发展冷藏临床影响的治疗策略的发展带来了关键的障碍 受伤。我们最近发现，冷存储会诱导人肾脏在肾脏内产生纤维蛋白原 结节细胞。恢复正常温度/常氧症后，将纤维蛋白原分泌到脉管系统中 可以在Rouleaux形成中聚集红细胞，从而导致微血管的病理塞。我们 假设肾纤维蛋白原是冷藏损伤的主要效应因子，因此代表了一个可行的目标 冷藏后的器官弹性。体内器官灌注（EVOP）已成为一项研究， 临床平台提供了一个在翻译相关的环境中直接检验该假设的机会。这里， 我们将专门使用人体组织实现两个目标：1）确定冷 - 存储诱导肾纤维蛋白原合成； 2）评估EVOP作为改善的治疗平台 纤维蛋白原介导的病理前移植。这些目标的成功完成将建立一个新的 预防冷藏诱导器官损伤的范式，有可能通过改善挽救患者生命 都可以访问器官和移植后的结果。