An extensive evaluation of hepatic markers of damage and regeneration in controlled and uncontrolled donation after circulatory death

Abstract

Livers from donations after circulatory death (DCDs) are very sensitive to ischemia/ reperfusion injury and thus need careful reconditioning, such as normothermic regional perfusion (NRP). So far, its impact on DCDs has not been thoroughly investigated. This pilot cohort study aimed to explore the NRP impact on liver function by evaluating dynamic changes of circulating markers and hepatic gene expression in 9 uncontrolled DCDs (uDCDs) and 10 controlled DCDs. At NRP start, controlled DCDs had lower plasma levels of inflammatory and liver damage markers, including α-glutathione s-transferase, sorbitol-dehydrogenase, malate dehydrogenase 1, liver-type arginase-1, and keratin-18, but higher levels of osteopontin, sFas, flavin mononucleotide, and succinate than uDCDs. During 4hour NRP, some damage and inflammatory markers increased in both groups, while IL-6, HGF, and osteopontin increased only in uDCDs. At the NRP end, the tissue expression of early transcriptional regulators, apoptosis, and autophagy mediators was higher in uDCDs than in controlled DCDs. In conclusion, despite initial differences in liver damage biomarkers, the uDCD group was characterized by a major gene expression of regenerative and repair factors after the NRP procedure. Correlative analysis among circulating/tissue biomarkers and the tissue congestion/necrosis degree revealed new potential candidate biomarkers.

Sequential Normothermic Regional Perfusion and End-ischemic Ex Situ Machine Perfusion Allow the Safe Use of Very Old DCD Donors in Liver Transplantation

“…Many centers prefer shortening NRP to 120 min, while we report a median of 5 h. It is our opinion that if flows are adequate and stable, prolonging perfusion to 4–6 h provides an in-depth assessment without negative effect on organ quality, as the reduced metabolic activity of very old graft can slowly recover after the ischemic damage. Recently, Basta et al 22 published an extensive evaluation of hepatic markers of damage and regeneration in DCD during NRP, showing that NRP allows the safe preservation and proper perfusion of the graft and induces response mechanisms proportional to the severity of the damage and with the capacity to restore metabolic functions and promote a program of liver regeneration and repair. 23…”

“…Many centers prefer shortening NRP to 120 min, while we report a median of 5 h. It is our opinion that if flows are adequate and stable, prolonging perfusion to 4-6 h provides an in-depth assessment without negative effect on organ quality, as the reduced metabolic activity of very old graft can slowly recover after the ischemic damage. Recently, Basta et al 22 -, not applicable; AKI, acute kidney injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bil, bilirubin; BMI, body mass index; CCI, comprehensive complication index; CIT, cold ischemia time; CVA, cerebrovascular accident; D-HOPE, dual hypothermic oxygenated machine perfusion; EAD, early allograft dysfunction; ETOH, alcoholic; F, female; FFP, fresh frozen plasma; FWIT, functional warm ischemia time; GGT, gamma-glutamyl transpeptidase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICU, intensive care unit; IU, international units; LT, liver transplantation; M, male; MELD, Model for End-Stage Liver Disease; MP, machine perfusion; NASH, nonalcoholic steatohepatitis; NMP, normothermic machine perfusion; NRP, normothermic regional perfusion; PNF, primary nonfunction; PRBC, packed red blood cell; PRS, postreperfusion syndrome; TWIT, total warm ischemia time.…”