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Mitochondrial Injury Assessed During Normothermic Machine Perfusion Predicts Outcomes and Costs After Liver Transplantation - A Prospective Validation and Cost-Effectiveness Analysis
*Chase J. Wehrle¹, *Elizabeth Dewey², *Chunbao Jiao³, *Keyue Sun³, *Rebecca Panconesi³, *Sangeeta Satish¹, *Omer F. Karakaya³, *Khaled Ali¹, *Minghy Zhang¹, *Mazhar Khalil¹, *Alejandro Pita¹, *Jaekeun Kim¹, *Federico Aucejo¹, *David C. Kwon¹, *Robert Fairchild¹, *Masato Fujiki¹, *Antonio D. Pinna⁴, *David Meierhofer⁵, *Belinda Udeh², *Koji Hashimoto¹, Charles Miller¹, *Andrea Schlegel^1
1Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH; ²Center for Population Health Research, Cleveland Clinic, Cleveland, OH; ³Inflammation & Immunity, Cleveland Clinic, Cleveland, OH; ⁴Transplantation, Cleveland Clinic Florida, Weston, FL; ⁵Genomics, Max Planck Institute, Berlin, Germany

Objectives:
Flavin Mononucleotide (FMN) is a marker of mitochondrial complex-1 injury previously described for viability assessment during hypothermic perfusion (HOPE) in 2019. Recent data demonstrated the utility of FMN in normothermic machine perfusion (NMP), the only ex-situ perfusion technique currently approved for liver transplantation in the US. The marker has not yet been validated in NMP, and its economic impact has not been reported.
Methods:
All transplants with endischemic NMP at our center were included, divided into development (10/2022-1/2024, n=213) and prospective validation (1/2024-7/2024, n=143). Cox-regression and mixed-effects models assessed graft loss, complications and FMN-guided graft discard. Liquid chromatography-mass spectrometry (LC-MS), mitochondrial complex I (anti-NDUFS) and regeneration (anti-Ki67) immunostaining were performed.
Results:
Graft loss was predicted best by perfusate FMN (>1700 samples; c-statistic AUC 0-4hrs NMP: 0.94, 95%CI=0.8670-0.9711) versus traditional markers. Spectroscopy measurements were confirmed with LC-MS (Pearson R=0.9835, 95%CI=0.9495-0.9964). High FMN grafts demonstrate significant complex-1 injury and reduced regenerative capacity on immunohistochemistry [Fig1].
Since implemented prospectively, graft discard is not different (p=0.346). The prospective validation cohort had greater overall donor/graft/recipient risk (Donor&Recipient Age, MELD, DRI, fWIT, DBD vs DCD). Over one-third (n=43, 35%) were DCD-grafts.
Perfusate FMN>1.75mg/mL at 4 hours was independently associated with reduced graft survival and death-censored graft survival. Transplant in the FMN-era was independently associated with improved graft survival on cox regression (HR=6.841, 95%CI 1.447-37.300).
Between-era outcomes analysis was risk-adjusted for the above-mentioned donor/graft/recipient risk. After adjustment, prospective graft assessment with FMN was independently associated with reductions in all complications (OR=0.41, 95%CI 0.09-0.44, p=0.0001), NAS (OR=0.06, 0-0.44, p=0.04), Anastomotic strictures (OR=0.38, 0.15-0.85, p=0.04) and 90-day mortality (OR=0.19, 0-0.30, p=0.03). Similarly, risk-adjusted multivariate linear regression revealed a 44% reduction in 90-day Comprehensive complication index (?=0.78, 95%CI 0.69-0.89, p<0.001).
Patients with highest quintile of FMN 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. Implementation of FMN correlated with an absolute $43k (15%) reduction in 90-day post-LT costs, though not significant ($487K vs. $444K, p=0.078) [Fig2].

Discussion:
Our findings support prospective utilization of FMN-based viability assessment during machine perfusion. Despite higher donor/recipient risk, our center has reduced complications and improved graft survival with FMN-based discard. Reduced transplant costs likely stem from prevention of post-transplant complications.