Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion

Abstract

Objective: The aim of this study was to evaluate sequential hypothermic and normothermic machine perfusion (NMP) as a tool to resuscitate and assess viability of initially declined donor livers to enable safe transplantation. Summary Background Data: Machine perfusion is increasingly used to resuscitate and test the function of donor livers. Although (dual) hypothermic oxygenated machine perfusion ([D]HOPE) resuscitates livers after cold storage, NMP enables assessment of hepatobiliary function. Methods: In a prospective clinical trial, nationwide declined livers were subjected to ex situ NMP (viability assessment phase), preceded by 1-hour DHOPE (resuscitation phase) and 1 hour of controlled oxygenated rewarming (COR), using a perfusion fluid containing an hemoglobin-based oxygen carrier. During the first 2.5 hours of NMP, hepatobiliary viability was assessed, using predefined criteria: perfusate lactate <1.7 mmol/L, pH 7.35 to 7.45, bile production >10 mL, and bile pH >7.45. Livers meeting all criteria were accepted for transplantation. Primary endpoint was 3-month graft survival. Results: Sixteen livers underwent DHOPE-COR-NMP. All livers were from donors after circulatory death, with median age of 63 (range 42-82) years and median Eurotransplant donor risk index of 2.82. During NMP, all livers cleared lactate and produced sufficient bile volume, but in 5 livers bile pH remained <7.45. The 11 (69%) livers that met all viability criteria were successfully transplanted, with 100% patient and graft survival at 3 and 6 months. Introduction of DHOPE-COR-NMP increased the number of deceased donor liver transplants by 20%. Conclusions: Sequential DHOPE-COR-NMP enabled resuscitation and safe selection of initially declined high-risk donor livers, thereby increasing the number of transplantable livers by 20%. Trial registration: www.trialregister.nl; NTR5972.

Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials

“…Van Leeuwen et al recently proposed a definition of viability criteria based on both hepatocellular (liver parenchyma) and cholangiocyte (bile duct) function (see section "Hypothermic followed by Normothermic Machine Perfusion"). 66 In addition, we hope that the results of the Viability Testing and Transplantation of marginal Livers (VITTAL study), an ongoing prospective clinical trial, can provide more information on the algorithm to decide which initially discarded liver should be transplanted (NCT02740608; ►Table 2). 67…”

Anticoagulant Management and Synthesis of Hemostatic Proteins during Machine Preservation of Livers for Transplantation

“…NMP is currently applied in an effort to resuscitate marginal liver grafts which would traditionally be declared as unfit for transplantation, or to extend the preservation period. [24][25][26] NMP can be performed immediately after procurement until transplantation, thus significantly minimizing SCS as the preservation modality for these grafts. 27 This procedure reduces IR injury.…”

“…Given the physiological conditions maintained during NMP, donor livers typically resume normal metabolic and synthetic functions, such as lactate clearance, bile production, and synthesis of proteins soon after the initiation of NMP. 24,38 It is widely known that the liver is principally responsible for the synthesis of pro-and anticoagulant proteins along with the components of fibrinolytic system. However, the extent and rate of the synthesis of hemostatic proteins during ex situ NMP is yet to be thoroughly investigated.…”

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

“…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 .…”

“…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 13,22,39 and also helped to define optimal criteria for the final acceptance of these rejected grafts once their viability had been re-assessed. 22 In the case of bicarbonate in bile at 6 h NMP, also only CDmiR-222, and not HDmiR-122, at 2 h showed a strong, but negative, correlation (C), while both miRs were predictive of the bile/perfusate glucose ratio at 6 h (D).…”