Effect of a defatting pharmacologic cocktail with rapamycin during cold-to-warm ex situ perfusion of discarded human livers: A comparative study.

BACKGROUND

Ex situ perfusion has been shown to improve the preservation of marginal liver grafts. Normothermic conditions allow graft viability evaluation and metabolic modifications, such as drugs injection to modify lipid content. In a previous study, we demonstrated that a pharmacologic defatting cocktail with rapamycin (DFAT) significantly reduced the triglyceride content of steatotic hepatocytes in vitro. The objective of the present study was to test the defatting cocktail in discarded human livers during ex situ perfusion.

METHODS

Discarded livers were perfused according to an uninterrupted cold-to-warm protocol. The defatting cocktail was injected after 30 minutes under normothermic conditions (37 °C), whereas no defatting cocktail was administered to controls. The objective of this study was to evaluate the effect of the defatting cocktail on lipid metabolism and reduction in histologic steatosis. Liver viability was evaluated using UK viability criteria.

RESULTS

Twelve discarded highly marginal livers (median Donor Risk Index 2.02 [1.6-3.47], with a median macrosteatosis of 55% [10%-90%]) underwent cold-to-warm perfusion for a median of 765 minutes (450-1,320). Defatting cocktail injection was performed in 9 livers (vs 3 controls), triggering a marked increase in triglyceride into the perfusate (at 90 minutes +164% vs +23% in controls; P < .001); a reduction of triglyceride content in liver tissue with a peak effect at 30 minutes (-46.6% vs +14.8% in controls, P = .0032); an increase in the hepatic expressions of genes related to lipid export, β-oxidation, and autophagy; and a decrease in that of lipogenesis-related genes. Five livers (41.6%) reached viability criteria, including 3 (33%) in the defatting cocktail group and 2 (67%) in the control group. A 10% reduction of histologic macrosteatosis was observed in the defatting cocktail group vs 0% in controls.

CONCLUSION

Continuous cold-to-warm ex situ perfusion combined with defatting cocktail injection triggers the release of triglycerides and the activation of lipid export, β-oxidation, and autophagy pathways, together with a trend toward steatosis reduction.