Donor Liver Blood Tests and Liver Transplant Outcomes: UK Registry Cohort Study.

BACKGROUND: Safely increasing organ utilization is a global priority. Donor serum transaminase levels are often used to decline livers, despite minimal evidence to support such decisions. This study aimed to investigate the impact of donor "liver blood tests" on transplant outcomes. METHODS: This retrospective cohort study used the National Health Service registry on adult liver transplantation (2016-2019); adjusted regressions models were used to assess the effect of donor "liver blood tests" on outcomes. RESULTS: A total of 3299 adult liver transplant recipients were included (2530 following brain stem death, 769 following circulatory death). Peak alanine transaminase (ALT) ranged from 6 to 5927 U/L (median = 45). Donor cause of death significantly predicted donor ALT; 4.2-fold increase in peak ALT with hypoxic brain injury versus intracranial hemorrhage (adjusted P < 0.001). On multivariable analysis, adjusting for a wide range of factors, transaminase level (ALT or aspartate aminotransferase) failed to predict graft survival, primary nonfunction, 90-d graft loss, or mortality. This held true in all examined subgroups, that is, steatotic grafts, donation following circulatory death, hypoxic brain injury donors, and donors, in which ALT was still rising at the time of retrieval. Even grafts from donors with extremely deranged ALT (>1000 U/L) displayed excellent posttransplant outcomes. In contrast, donor peak alkaline phosphatase was a significant predictor of graft loss (adjusted hazard ratio = 1.808; 1.016-3.216; P = 0.044). CONCLUSIONS: Donor transaminases do not predict posttransplant outcomes. When other factors are favorable, livers from donors with raised transaminases can be accepted and transplanted with confidence. Such knowledge should improve organ utilization decision-making and prevent future unnecessary organ discard. This provides a safe, simple, and immediate option to expand the donor pool.

Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II.

The reaction mechanism of DNA topoisomerase II (TOP2) involves a covalent double-strand break intermediate in which the enzyme is coupled to DNA via a 5'-phosphotyrosyl bond. This normally transient enzyme-bridged break is stabilised by drugs such as mitoxantrone, mAMSA, etoposide, doxorubicin, epirubicin and idarubicin, which are referred to as TOP2 poisons. Removal of topoisomerase II by the proteasome is involved in the repair of these lesions. In K562 cells, inhibiting the proteasome with MG132 significantly potentiated the growth inhibition by these six drugs that target topoisomerase II, and the highest level of potentiation was observed with mitoxantrone. Mitoxantrone also showed the greatest potentiation by MG132 in three Nalm 6 cell lines with differing levels of TOP2A or TOP2B. Mitoxantrone was also potentiated by the clinically used proteasome inhibitor PS341 (Velcade). We have also shown that proteasome inhibition with MG132 in K562 cells reduces the rate of removal of mitoxantrone or etoposide stabilised topoisomerase complexes from DNA, suggesting a possible mechanism for the potentiation of topoisomerase II drugs by proteasomal inhibition.