Wehrle Chase J, Satish Sangeeta, Dewey Elizabeth, Nadeem Muhammad A, Sun Keyue, Jiao Chunbao, Khalil Mazhar, Pita Alejandro, Kim Jaekeun, Aucejo Federico, Kwon David Ch, Fujiki Masato, Pinna Antonio D, Udeh Belinda, Miller Charles, Hashimoto Koji, Schlegel Andrea
Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Inflammation and Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Ann Surg. 2025 Jul 21. doi: 10.1097/SLA.0000000000006822.
Flavin mononucleotide (FMN), a marker of mitochondrial complex 1 injury, has not yet been validated for its predictive value of outcomes and economic impact.
Normothermic machine perfusion (NMP) is the only ex-situ perfusion technique currently approved for liver transplantation in the US. Optimal graft viability assessment on this approach remains controversial.
All liver transplants at our center were included, divided into static-cold storage (SCS, n=418), NMP (OrganOx Metra ) with traditional viability criteria (10/2022-1/2024, n=213) and prospective viability assessment using FMN (NMP+FMN, 1/2024-87/2024, n=143). Perfusate fluorescence spectroscopy was performed to quantify FMN during NMP. Spectroscopy results were correlated with tissue analyses. Standard risk factors and clinically relevant core outcomes were collected for analysis. Groups were propensity-matched, and posttransplant outcomes including economics were assessed using inverse-probability of treatment weighting (IPTW). Mixed-effects models assessed complications, graft loss and FMN-guided liver utilization. A decision-analytic model was used to assess the cost-benefit of NMP and FMN-testing.
Graft loss was predicted best by perfusate FMN (>1700 samples; c-statistic AUC 0-4hrs NMP: 0.96, 95%CI:0.93-0.97, P <0.0001) versus traditional viability markers. High FMN grafts demonstrated significantly more mitochondrial injury measured in tissues at the end of NMP. Since implemented prospectively, FMN-based viability assessment during NMP lead to a comparable liver utilization rate of NMP=94 vs. NMP+FMN=90% ( P =0.346) despite higher overall donor and recipient risk. Over one-third (n=43, 35%) were livers from donation after circulatory death donors (DCD). Elevated perfusate FMN of >1.75μg/mL at 4hours was independently associated with reduced graft survival and death-censored graft survival. Liver transplants in the FMN-era were independently associated with improved graft survival on cox regression (HR:6.841, 95%CI:1.447-37.300, P <0.001). Risk-adjusted outcomes including biliary and overall complications, major (Clavien>IIIA) complications, liver-related major complications, and graft loss were improved with FMN-based viability testing. Overall morbidity measured by comprehensive complications index (CCI) was reduced with NMP but did significantly decrease with additional FMN-use compared to SCS. Such results were upheld when DBD and DCD grafts were evaluated independently. Liver transplantations with high FMN livers demonstrated greater cumulative costs ( P <0.001). On mixed-effects modelling, 44% percent of transplant-related cost variation was explained by FMN in the top quintile (>1.75μg/mL). Risk-matched FMN-tested DBD grafts specifically demonstrated incremental 16% reduction in major complications with net $33,657 saving per graft in the decision-analytic model while DCD grafts demonstrated 30% improvement in major complications and an incremental cost-reduction of $53,563 per graft.
Our findings support routine utilization of FMN-based viability assessment during NMP. Despite higher donor/recipient risk, our center has reduced complications and improved graft survival with FMN-based decision making. Reduced transplant costs likely stem from a reduction of post-transplant complications.
黄素单核苷酸（FMN）作为线粒体复合物1损伤的标志物，其对预后的预测价值及经济影响尚未得到验证。
常温机器灌注（NMP）是美国目前唯一批准用于肝移植的体外灌注技术。这种方法的最佳移植物活力评估仍存在争议。
纳入我们中心所有的肝移植病例，分为静态冷保存组（SCS，n = 418）、采用传统活力标准的NMP组（OrganOx Metra，2022年10月至2024年1月，n = 213）和使用FMN进行前瞻性活力评估的组（NMP + FMN，2024年1月至87月，n = 143）。在NMP期间进行灌注液荧光光谱分析以定量FMN。光谱结果与组织分析相关联。收集标准风险因素和临床相关的核心结局进行分析。对各组进行倾向匹配，并使用治疗权重逆概率（IPTW）评估包括经济学在内的移植后结局。混合效应模型评估并发症、移植物丢失和FMN指导的肝脏利用情况。使用决策分析模型评估NMP和FMN检测的成本效益。
与传统活力标志物相比，灌注液FMN对移植物丢失的预测最佳（>1700个样本；c统计量AUC 0 - 4小时NMP：0.96，95%CI：0.93 - 0.97，P <0.0001）。在NMP结束时，高FMN移植物在组织中表现出明显更多的线粒体损伤。自前瞻性实施以来，尽管供体和受体总体风险较高，但NMP期间基于FMN的活力评估导致NMP的肝脏利用率与NMP + FMN相当，分别为94%和90%（P = 0.346）。超过三分之一（n = 43，35%）的肝脏来自循环死亡后捐赠者（DCD）。4小时时灌注液FMN>1.75μg/mL独立与移植物存活率降低和死亡删失的移植物存活率降低相关。在Cox回归中，FMN时代的肝移植独立与移植物存活率提高相关（HR：6.841，95%CI：1.447 - 37.300，P <0.001）。基于FMN的活力检测改善了风险调整后的结局，包括胆道和总体并发症、主要（Clavien>IIIA）并发症、肝脏相关主要并发症和移植物丢失。通过综合并发症指数（CCI）衡量的总体发病率在NMP时降低，但与SCS相比，额外使用FMN时并未显著降低。当独立评估DBD和DCD移植物时，这些结果仍然成立。高FMN肝脏的肝移植显示出更高的累积成本（P <0.001）。在混合效应模型中，FMN在前五分之一（>1.
