Nicotinamide Adenine Dinucleotide as a Potential Biomarker for Graft Viability During Normothermic Machine Perfusion: An Ex Vivo Rodent Study

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Abstract
Background: The shortage of donor organs has increased the use of extended criteria donor (ECD) grafts in liver transplantation. Normothermic machine perfusion (NMP) could be used as a platform for real‐time quality assessment, which is crucial since ECD grafts are more susceptible to ischemia–reperfusion injury (IRI). As nicotinamide adenine dinucleotide (NAD + ) is a central mediator of cellular antioxidativedefense, reduced intracellular NAD (iNAD + ) levels in grafts sustaining greater injury may reflect diminished antioxidative capacity and could serve as a marker to assess graft quality. This study aimed to investigate iNAD + in comparison to existing damage‐associated parameters for liver graft quality in a small animal NMP model simulating ECD conditions through advanced donor age, prolonged cold ischemia time (CIT), and donation after circulatory death (DCD). Methods: Fifty‐nine male Sprague–Dawley rat livers were analyzed across six experimental groups defined by donor age (3 months [young] or 12 months [elderly]), procurement modality (standard procurement or donation after circulatory death [DCD]), and cold ischemia time (CIT; 6 h or 12 h), followed by 6 h of NMP. No livers were excluded from analysis. iNAD + levels were quantified using a colorimetric enzymatic assay. Results: Perfusate iNAD + levels continuously rose over time during NMP and differed significantly between intervention groups ( p = 0.003). iNAD+ correlated negatively with ALT levels (R = −0.36, p = 0.024) and liver tissue necrosis in grafts (perfusate R = −0.24, p = 0.17; tissue R = −0.19, p = 0.2), although these associations did not reach statistical significance. Long CIT, higher donor age, and DCD procurement were associated with lower iNAD+ levels. iNAD+ did not correlate with lactate clearance or bile production (both p > 0.05). A non‐significant trend toward a positive association between iNAD+ and glucose metabolism was observed ( R = 0.29, p = 0.077). Discussion: Higher perfusate iNAD+ levels were associated with better organ performance, consistent with iNAD+ reflecting the graft's antioxidative metabolic capacity. Lower iNAD+ levels in elderly and DCD grafts aligned with established damage markers. Perfusate iNAD+ may therefore offer a complementary tool for evaluating metabolic activity and organ performance during NMP, pending prospective validation.

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