BACKGROUND: Donation after circulatory death (DCD) liver grafts are known to be predisposed to primary nonfunction and ischemic cholangiopathy. Many DCD grafts are discarded because of older donor age or long warm ischemia times. Thus, it is critical to improve the quality of DCD liver grafts. Here, we have tested whether an enriched oxygen carrier added to the preservation solution can prolong graft survival and reduce biliary damage. METHODS: We assessed the adenosine triphosphate (ATP) content decay of mouse liver grafts after cold ischemia, warm ischemia, and combined warm+cold ischemia. In addition, we used a rat model of liver transplantation to compare survival of DCD grafts preserved in high-oxygen solution (preoxygenated perfluorocarbon [PFC] + University of Wisconsin [UW] solution) versus lower oxygen solution (preoxygenated UW solution). RESULTS: Adenosine triphosphate levels under UW preservation fall to less than 10% after 30 minutes of warm ischemia. Preoxygenated UW solution with PFC reached a significantly higher PaO2. After 45 minutes of warm ischemia in oxygenated UW + PFC solution, grafts showed 63% higher levels of ATP (P = 0.011). In addition, this was associated with better preservation of morphology when compared to grafts stored in standard UW solution. Animals that received DCD grafts preserved in higher oxygenation solution showed improved survival: 4 out of 6 animals survived long-term whereas all control group animals died within 24 hours. CONCLUSIONS: The additional oxygen provided by PFC during static cold preservation of DCD livers can better sustain ATP levels, and thereby reduce the severity of ischemic tissue damage. PFC-based preservation solution extends the tolerance to warm ischemia, and may reduce the rate of ischemic cholangiopathy.

Primary hyperoxaluria type 1 (PH1) is a rare liver enzymatic defect that causes overproduction of plasma oxalate. Accumulation of oxalate in the kidney and subsequent renal failure are fatal to PH1 patients often in pediatric age. Combined liver and kidney transplantation is the therapy of choice for end-stage renal disease due to PH1. Levels of plasma oxalate remain elevated for several months after liver transplantation, as the residual body oxalate is slowly excreted. Patients with persistent hyperoxaluria after transplant often require hemodialysis, and accumulation of residual oxalate in the kidney can induce graft dysfunction. As the native kidneys are the main target of calcium oxalate accumulation, we postulated that removal of native kidneys could drastically decrease total body oxalate levels after transplantation. Here, we report a case of bilateral nephrectomy at the time of combined liver-kidney transplantation in a pediatric PH1 patient. Bilateral nephrectomy induced a rapid decrease in plasma oxalate to normal levels in less than 20 days, compared to the several months reported in the literature. Our results suggest that removal of native kidneys could be an effective strategy to decrease the need for hemodialysis and the risk of renal dysfunction after combined liver-kidney transplantation in patients with PH1.

As donor organ shortages persist, functional machine perfusion is under investigation to improve preservation of the donor liver. The transplantation of donation after circulatory death (DCD) livers is limited by poor outcomes, but its application may be expanded by ex vivo repair and assessment of the organ before transplantation. Here we employed subnormothermic (21 degrees C) machine perfusion of discarded human livers combined with metabolomics to gain insight into metabolic recovery during machine perfusion. Improvements in energetic cofactors and redox shifts were observed, as well as reversal of ischemia-induced alterations in selected pathways, including lactate metabolism and increased TCA cycle intermediates. We next evaluated whether DCD livers with steatotic and severe ischemic injury could be discriminated from 'transplantable' DCD livers. Metabolomic profiling was able to cluster livers with similar metabolic patterns based on the degree of injury. Moreover, perfusion parameters combined with differences in metabolic factors suggest variable mechanisms that result in poor energy recovery in injured livers. We conclude that machine perfusion combined with metabolomics has significant potential as a clinical instrument for the assessment of preserved livers.