Bruinsma Bote G, Avruch James H, Sridharan Gautham V, Weeder Pepijn D, Jacobs Marie Louise, Crisalli Kerry, Amundsen Beth, Porte Robert J, Markmann James F, Uygun Korkut, Yeh Heidi
1 Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 2 Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 3 Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Transplantation. 2017 Jul;101(7):1637-1644. doi: 10.1097/TP.0000000000001699.
The ongoing shortage of donor livers for transplantation and the increased use of marginal livers necessitate the development of accurate pretransplant tests of viability. Considering the importance energy status during transplantation, we aimed to correlate peritransplant energy cofactors to posttransplant outcome and subsequently model this in an ex vivo setting.
Sequential biopsies were taken from 19 donor livers postpreservation, as well as 30 minutes after portal venous reperfusion and hepatic arterial reperfusion and analyzed by liquid chromatography-mass spectrometry for energetic cofactors (adenosine triphosphate [ATP]/adenosine diphosphate [ADP]/adenosine monophosphate [AMP], nicotinamide adenine dinucleotide /NAD, nicotinamide adenine dinucleotide phosphate / nicotinamide adenine dinucleotide phosphate , flavin adenine dinucleotide , glutathione disulfide/glutathione). Energy status was correlated to posttransplant outcome. In addition, 4 discarded human donation after circulatory death livers were subjected to ex vivo reperfusion, modeling reperfusion injury and were similarly analyzed for energetic cofactors.
A rapid shift toward higher energy adenine nucleotides was observed following clinical reperfusion, with a 2.45-, 3.17- and 2.12-fold increase in ATP:ADP, ATP:AMP and energy charge after portal venous reperfusion, respectively. Seven of the 19 grafts developed early allograft dysfunction. Correlation with peritransplant cofactors revealed a significant difference in EC between early allograft dysfunction and normal functioning grafts (0.09 vs 0.31, P < 0.05). In the simulated reperfusion model, a similar trend in adenine nucleotide changes was observed.
A preserved energy status appears critical in the peritransplant period. Levels of adenine nucleotides change rapidly after reperfusion and ratios of ATP/ADP/AMP after reperfusion are significantly correlated to graft function. Using these markers as a viability test in combination with ex vivo reperfusion may provide a useful predictor of outcome that incorporates donor, preservation, and reperfusion factors.
目前供肝用于移植的短缺情况持续存在，且边缘性供肝的使用增加，因此需要开发准确的移植前活力检测方法。考虑到移植过程中能量状态的重要性，我们旨在将移植期间的能量辅助因子与移植后结局相关联，并随后在体外环境中对其进行建模。
在19个供肝保存后、门静脉再灌注和肝动脉再灌注30分钟后进行连续活检，并通过液相色谱 - 质谱法分析能量辅助因子（三磷酸腺苷[ATP]/二磷酸腺苷[ADP]/单磷酸腺苷[AMP]、烟酰胺腺嘌呤二核苷酸/NAD、烟酰胺腺嘌呤二核苷酸磷酸/烟酰胺腺嘌呤二核苷酸磷酸、黄素腺嘌呤二核苷酸、谷胱甘肽二硫化物/谷胱甘肽）。能量状态与移植后结局相关联。此外，对4个循环死亡后废弃的供肝进行体外再灌注，模拟再灌注损伤，并同样分析能量辅助因子。
临床再灌注后观察到向更高能量腺嘌呤核苷酸的快速转变，门静脉再灌注后ATP:ADP、ATP:AMP和能量电荷分别增加2.45倍、3.17倍和2.12倍。19个移植物中有7个发生早期移植物功能障碍。与移植期间辅助因子的相关性显示，早期移植物功能障碍和功能正常的移植物之间的能量电荷存在显著差异（0.09对0.31，P<0.05）。在模拟再灌注模型中，观察到腺嘌呤核苷酸变化的类似趋势。
在移植期间维持能量状态似乎至关重要。再灌注后腺嘌呤核苷酸水平迅速变化，再灌注后ATP/ADP/AMP的比率与移植物功能显著相关。将这些标志物用作活力检测并结合体外再灌注可能提供一个有用的结局预测指标，该指标纳入了供体、保存和再灌注因素。
