Development of Clinical Criteria for Functional Assessment to Predict Primary Nonfunction of High‐Risk Livers Using Normothermic Machine Perfusion

Abstract

Increased use of high‐risk allografts is critical to meet the demand for liver transplantation. We aimed to identify criteria predicting viability of organs, currently declined for clinical transplantation, using functional assessment during normothermic machine perfusion (NMP). Twelve discarded human livers were subjected to NMP following static cold storage. Livers were perfused with a packed red cell–based fluid at 37°C for 6 hours. Multilevel statistical models for repeated measures were employed to investigate the trend of perfusate blood gas profiles and vascular flow characteristics over time and the effect of lactate‐clearing (LC) and non‐lactate‐clearing (non‐LC) ability of the livers. The relationship of lactate clearance capability with bile production and histological and molecular findings were also examined. After 2 hours of perfusion, median lactate concentrations were 3.0 and 14.6 mmol/L in the LC and non‐LC groups, respectively. LC livers produced more bile and maintained a stable perfusate pH and vascular flow >150 and 500 mL/minute through the hepatic artery and portal vein, respectively. Histology revealed discrepancies between subjectively discarded livers compared with objective findings. There were minimal morphological changes in the LC group, whereas non‐LC livers often showed hepatocellular injury and reduced glycogen deposition. Adenosine triphosphate levels in the LC group increased compared with the non‐LC livers. We propose composite viability criteria consisting of lactate clearance, pH maintenance, bile production, vascular flow patterns, and liver macroscopic appearance. These have been tested successfully in clinical transplantation. In conclusion, NMP allows an objective assessment of liver function that may reduce the risk and permit use of currently unused high‐risk livers.

Cell‐free microRNAs as early predictors of graft viability during ex vivo normothermic machine perfusion of human donor livers

“…Often livers, declined for transplantation on subjective assessment by the transplant surgeon, were shown to display minimal morphological changes after histological examination . We set out to evaluate the histological observations described earlier and correlate these data with relative miRNA levels and the HDmiR122/CDmiR222 ratio. Suzuki injury scores at the start and end of NMP were compared with our early predictors HDmiR‐122, CDmiR‐222, and their ratio in perfusate at 30 minutes.…”

“…Mergental et al proposed composite viability criteria based on analysis of 12 discarded human livers. Multilevel statistical analysis showed that lactate clearance stratified his cohort in 2 distinct groups with pH and bile production as discriminative parameters . It should, however, be noted that in studies where livers were transplanted after NMP, these parameters tend to vary extensively and are not predictive for transplant outcome after NMP alone .…”

“…The liver grafts used in this study were not transplanted after preservation; hence, post‐transplantation data are not available. Recent studies, however, showed that the use of NMP for viability assessment of otherwise discarded grafts was clinically feasible and also helped to define optimal criteria for the final acceptance of these rejected grafts once their viability had been re‐assessed . As a consequence, the clinical parameters for hepato‐cholangiocellular injury and function were used as mere viability markers to correlate with relative miR values .…”

“…Overall, the current study showed that poor quality liver grafts with high hepato-cholangiocellular injury (defined as high AST and LDH peaks in perfusate and bile, respectively) and low hepato-chol- Machine perfusion is a technique that is rapidly making its way into the clinic and can be applied for various purposes. NMP not only offers the possibility to perform viability testing of high-risk livers in order to select transplantable organs, 8,13,[21][22][23] but also results in a lower rate of organ discard and lower levels of graft injury after NMP compared to SCS. 24 In the early detection of hepatic injury during machine perfusion, miRs in perfusate offer several advantages.…”

“…Often livers, declined for transplantation on subjective assessment by the transplant surgeon, were shown to display minimal morphological changes after histological examination. 21 We set out to evaluate the histological observations described earlier 22 and correlate these data with relative miRNA levels and the HDmiR122/ Figure 2A). The relative CDmiR-222 levels, but not the relative HDmiR-122 levels, at 30 minutes NMP were also significantly associated with the Suzuki injury score after 6 hours of NMP (P < .05) (data not shown).…”