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

项目总结 在美国，已故捐赠者肾脏的平均冷藏时间可以从9小时到30小时不等。 美国因地理位置不同而不同。众所周知，肾脏在冷冻保存之前保存的时间越长 移植，移植后并发症的可能性就越大，如移植功能延迟。这是 尤其是来自老年捐赠者或患有共病的捐赠者的器官--比例不断扩大 美国捐赠者池-在冷藏期间对损伤表现出更高的敏感性。人们对此知之甚少 决定人体器官冷藏损伤速度和程度的机制。这种对知识的缺乏 是开发治疗策略以减少冷藏的临床影响的关键障碍 受伤。我们最近发现，冷藏诱导人的肾脏在肾脏内产生纤维蛋白原。 肾小管细胞。当恢复常温/常氧时，纤维蛋白原被分泌到血管系统中，在那里它 可使红细胞聚集成环形结构，导致微血管病理性堵塞。我们 假设肾纤维蛋白原是冷藏损伤的主要影响因素，因此是一个可行的靶点 以提高冷藏后器官的韧性。前活体器官灌流(EVOP)已成为一项研究和 临床平台提供了在翻译相关的环境中直接检验这一假说的机会。这里, 我们将专门使用人体组织来实现两个目标：1)确定冷- 储存诱导肾脏纤维蛋白原合成；2)评估EVOP作为治疗平台的改善 移植前纤维蛋白原介导的病理改变。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，有可能通过改善 无论是获得器官还是移植后的结果。

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.