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Comparison of competing ex vivo preservation techniques and investigation of the mechanisms of graft recovery during ex-vivo perfusion in marginal kidney grafts

边缘肾移植物离体灌注过程中竞争性离体保存技术的比较和移植物恢复机制的研究

基本信息

批准号：
425903082
负责人：
Dr. Laura Ioana Mazilescu
金额：
--
依托单位：
Klinik für Allgemeinchirurgie, Viszeral- und Transplantationschirurgie
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2019
资助国家：
德国
起止时间：
2018-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/425903082?language=en
关键词：
Comparison competing ex vivo preservation

项目摘要

Kidney transplantation represents the treatment of choice for end-stage renal disease. The enormous gap between supply and demand has lead to the more frequent use of organs from extended criteria and donation after circulatory death. A major problem with these marginal grafts is delayed graft function due to an increased susceptibility to ischemia and reperfusion injury, which leads to decreased long-term function. Therefore, the transplant community has focused its efforts on investigating methods for improving the function of these grafts. Normothermic ex-vivo kidney perfusion and oxygenated hypothermic perfusion are promising options to achieve that. In a porcine model of donation after circulatory death, studies have shown that marginal grafts subjected to normothermic ex-vivo kidney perfusion instead of the traditional cold storage demonstrate improved function of the grafts. Also, there is evidence from other animal studies that oxygenated hypothermic perfusion is superior to cold storage. The objective of the present research project is to investigate which method offers the best option for kidney preservation and which mechanisms are involved in the improved donation after circulatory death graft function in perfused grafts over static cold storage. We hypothesize that providing oxygen to the grafts prevents anaerobic metabolism, which results in a reduction in mediators involved in ischemia-reperfusion. However, other novel pathways may also be implicated. Therefore, we will initiate an unbiased examination of gene expression through microarray analysis, to then validate the results using quantitative polymerase chain reaction and then correlate these results with appropriate protein expression studies such as through enzyme-linked immunosorbent assays and Western blots. Also, potential biomarkers that correlate with improved graft function can be identified and these markers may then be utilized to assess the function and health of marginal grafts undergoing ex-vivo perfusion prior to transplant in patients. Finally, we will investigate whether a combination of oxygenated hypothermic perfusion and normothermic ex-vivo kidney perfusion offers a better preservation method in marginal grafts. The results of this study will support the translation of oxygenated hypothermic perfusion and normothermic ex-vivo kidney perfusion to human studies, and a personalized approach could be adopted as marginal grafts deemed unfit for transplant may be subjected to oxygenated hypothermic perfusion and normothermic ex-vivo kidney perfusion for restoration, improvement and assessment of graft function prior to transplantation.

肾移植是终末期肾病的首选治疗方法。供需之间的巨大差距导致了更频繁地使用扩展标准的器官和循环死亡后的捐赠。这些边缘移植物的一个主要问题是移植物功能延迟，这是由于对缺血和再灌注损伤的易感性增加，导致长期功能降低。因此，移植界致力于研究改善这些移植物功能的方法。常温体外肾脏灌流和含氧低温灌流是实现这一目标的有希望的选择。在猪循环死亡后的捐献模型中，研究表明，边缘移植物接受常温体外肾脏灌流，而不是传统的冷藏，移植物的功能得到了改善。此外，来自其他动物研究的证据表明，含氧低温灌流优于冷藏。本研究的目的是探讨哪种方法能提供最佳的肾脏保存方案，以及通过静态冷藏改善循环死亡后供肾功能的机制。我们假设，给移植物提供氧气可以防止无氧代谢，从而导致参与缺血-再灌注的介质减少。然而，也可能牵涉到其他新的途径。因此，我们将通过微阵列分析启动对基因表达的无偏见检查，然后使用定量聚合酶链式反应验证结果，然后将这些结果与适当的蛋白质表达研究相关联，例如通过酶联免疫吸附试验和Western blotts。此外，可以识别与移植物功能改善相关的潜在生物标记物，然后这些标记物可以用于评估患者移植前接受体外灌流的边缘移植物的功能和健康状况。最后，我们将研究氧合低温灌流和常温体外肾灌流相结合的方法是否能为边缘移植物提供更好的保存方法。这项研究的结果将支持氧合低温灌流和常温体外肾灌流在人体研究中的应用，并可采用个性化的方法，因为不适合移植的边缘移植物可能会在移植前接受氧合低温灌流和常温体外肾灌流，以恢复、改善和评估移植物功能。