A New Era of Decision Making in Liver Transplantation: A Prospective Validation and Cost-Effectiveness Analysis of FMN-Guided Liver Viability Assessment During Normothermic Machine Perfusion.

OBJECTIVES

Flavin mononucleotide (FMN), a marker of mitochondrial complex 1 injury, has not yet been validated for its predictive value of outcomes and economic impact.

SUMMARY OF BACKGROUND DATA

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.