Metabolomics Differences of the Donor Livers Between In Situ and Ex Situ Conditions During Ischemia-free Liver Transplantation

Abstract

Background. Ischemia-free liver transplantation (IFLT) has been innovated to avoid graft ischemia during organ procurement, preservation, and implantation. However, the metabolism activity of the donor livers between in the in situ and ex situ normothermic machine perfusion (NMP) conditions, and between standard criteria donor and extend criteria donor remains unknown. Methods. During IFLT, plasma samples were collected both at the portal vein and hepatic vein of the donor livers in situ during procurement and ex situ during NMP. An ultra-high performance liquid chromatography-mass spectrometry was conducted to investigate the common and distinct intraliver metabolite exchange. Results. Profound cysteine and methionine metabolism, and aminoacyl-tRNA biosynthesis were found in both in situ and ex situ conditions. However, obvious D-arginine and D-ornithine metabolism, arginine and proline metabolism were only found in the in situ condition. The suppressed activities of the urea cycle pathway during ex situ condition were confirmed in an RNA expression level. In addition, compared with extend criteria donor group, standard criteria donor group had more active intraliver metabolite exchange in metabonomics level. Furthermore, we found that the relative concentration of p-cresol, allocystathionine, L-prolyl-L-proline in the ex situ group was strongly correlated with peak alanine aminotransferase and aspartate aminotransferase at postoperative days 1–7. Conclusions. In the current study, we show the common and distinct metabolism activities during IFLT. These findings might provide insights on how to modify the design of NMP device, improve the perfusate components, and redefine the criteria of graft viability.

Twelve-hour normothermic liver perfusion in a rat model: characterization of the changes in the ex-situ bio-molecular phenotype and metabolism

“…Recently, distinctive liver metabolic pathways were identified during clinical ex-situ perfusion 43 . Interestingly, our data support these findings and add some insights into these metabolic mechanisms.…”

“…Since no oxidative damage was detected in cell components, this finding suggests that the endogenous anti-oxidant factors successfully counteracted the production of reactive oxygen species. However, these observations collectively point out the need to develop tailored strategies for exogenous supplementation during the NMP procedure 16 , 43 . This appears a key aspect as the availability of metabolic substrates is essential to trigger liver regeneration and inflammation resolution 46 , otherwise the same adaptive mechanisms could lead to cell death and possible liver failure.…”

Assessment of Mitochondrial Respiration During Hypothermic Storage of Liver Biopsies Following Normothermic Machine Perfusion

“…Furthermore, it has already been shown in small animal models that NMP leads to altered metabolomic signatures in liver tissue which affect mitochondrial biochemical pathways, such as reduced succinate levels. This holds also potential for using different perfusion models and various optimizing supplements to positively influence liver metabolism during NMP [ 24 , 25 ]. The second major difference is the quality of the organs.…”

Twelve-hour Normothermic Liver Perfusion in a Rat Model: Characterization of the Changes in the Ex-situ Bio-molecular Phenotype and Metabolism

“…Recently, distinctive liver metabolic pathways were identi ed during clinical ex-situ perfusion 50 . Interestingly, our data support these ndings and add some insights into these metabolic mechanisms.…”