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The effect of adding pulsatility to gaseous oxygen persufflation during liver preservation was studied in an isolated rat liver model. Livers from male Wistar rats were retrieved 30 min after cardiac arrest of the donor and subjected to 18 h of cold storage. Some grafts were subjected to nonpulsatile or pulsatile gaseous oxygen persufflation. Graft viability was assessed thereafter upon warm reperfusion in vitro (n = 5 per group). Pulsatile persufflation significantly improved parenchymal integrity (enzyme release, bile flow) upon reperfusion, with respect to nonpulsatile persufflation or cold storage (CS) (e.g., max. release of alanine aminotransferase: 44 ± 10 vs. 178 ± 29 vs. 345 ± 100 U/L; pulsatile vs. nonpulsatile persufflation vs. CS).The effect was associated with the prevention of the ischemic decline in gene and protein expression of the vasoprotective Kruppel-like factor 2, increased perfusate levels of the endogenous vasodilator nitric oxide, and reduced portal vascular resistance upon reperfusion, while nonpulsatile persufflation was less effective (e.g., vascular resistance: 1235 ± 108 vs. 1607 ± 155 vs. 2215 ± 208 Pa s/mL; pulsatile vs. nonpulsatile persufflation vs. CS). In conclusion, pulsatile mechanostimulation of the hepatovasculature seems a genuine protective mechanism, affecting early graft recovery upon reperfusion.

The prognosis for recipients of small liver grafts is poor. The aim of this study was to determine the impact of venous systemic oxygen persufflation (VSOP) with nitric oxide (NO) gas for 30% partial liver preservation and transplantation in rats. After we determined optimal NO concentration as 40 ppm in vitro with the isolated perfused rat liver model, we assessed liver injury and regeneration in vivo at 1, 3, 24 and 168 h after transplantation in the following three groups after 3 h-cold storage (n = 20 per group): control group = static storage; VSOP group = oxygen persufflation and VSOP+NO group = oxygen with NO persufflation. The liver graft persufflation was achieved with medical gas via the suprahepatic vena cava; In comparison with control group after transplantation, VSOP+NO preservation (1) increased portal circulation, (2) reduced AST and ALT release, (3) upregulated hepatic endothelial NO synthase, (4) reduced hepatocyte and bileductule damage and (5) improved liver regeneration. These results suggest that gaseous oxygen with NO persufflation is a novel and safe preservation method for small partial liver grafts, not only alleviating graft injury but also improve liver regeneration after transplantation.

Background The University of Wisconsin (UW) solution has been recognized as the gold standard for liver preservation; however, it possesses some limitations, and other solutions exist for organ preservation. The aim of this study was to compare the liver functions of transplanted grafts that had been stored in Celsior and Custodiol solutions. Methods We searched the MEDLINE, EMBASE, LILACS, Cochrane Central Register of Controlled Trials, and SCIELO databases. We included randomized and quasi-randomized, controlled trials that compared the efficacy and safety of Celsior and Custodiol with UW solution for liver preservation in adults. The factors that were considered for analysis were their impacts on primary dysfunction (primary nonfunction and initial poor function), ischemic-type biliary lesions, and patient and graft survival rates. Because of the lack of direct evidence, an indirect comparison of Celsior and Custodiol was calculated. Results We identified 3 randomized controlled trials and 1 quasi-randomized, controlled trial to pool in a meta-analysis of Celsior versus UW solutions. The number of episodes of primary dysfunction was lower in the Celsior group (7.4%) than in the UW group (9.8%), but the difference was not significant (relative risk [RR], 0.68; 95% confidence interval [CI], 0.22–1.97). Two randomized controlled trials compared Custodiol and Wisconsin solutions were identified. The number of episodes of primary dysfunction was also lower in the Custodiol group (3.0%) compared with the Wisconsin group (8.4%), but the difference was not significant (RR, 0.36; 95% CI, 0.08–1.70). An indirect comparison using data from the main analysis revealed no difference between the Celsior and Custodiol solutions (RR, 1.88; 95% CI, 0.57–6.16). Conclusion The Celsior and Custodiol solutions performed similarly to UW solution as preservation solutions in liver transplantation clinical settings.

Background Gaseous insufflation of oxygen via the venous vascular system has proven to be an effective tool for preventing anoxic tissue injury after extended time periods of ischemic liver preservation. Most experimental studies so far have been undertaken in rat models and include a series of pinpricks into postsinusoidal venules as an outlet for the insufflated gas. Here, we describe a simplified technique for minimally invasive liver oxygenation in porcine grafts, representing a hassle-free access to organ oxygenation without vascular lesions. Methods We retrieved livers from Landrace pigs and cold-stored them in histidine-tryptophan-ketoglutarate solution. Subsequent to 18 h preservation, we treated some livers for an additional 2 h with gaseous oxygen, insufflated via silicone tubing inserted into the suprahepatic caval vein. Gas pressure was limited to 18 mm Hg. We occluded the infrahepatic caval vein with a bulldog clamp. Gas bubbles left the graft via the portal vein. We assessed liver integrity by energetic tissue status and by controlled in vitro reperfusion with autologous blood. Results Magnetic resonance imaging demonstrated homogeneous gas distribution in the persufflated tissue without major shunting. Biochemical analyses revealed effective and homogeneous restoration of energetic homeostasis in the ischemic graft before reperfusion. Sinusoidal endothelial clearance of hyaluronic acid was significantly improved upon reperfusion, as was hepatic arterial flow. Parenchymal enzyme loss was concordantly mitigated after minimally invasive liver oxygenation. Conclusions Our results indicate that gaseous oxygen persufflation of the porcine liver is possible without tissue trauma, and significantly enhances post-preservation recovery of the graft.

Background: Ex vivo machine perfusion (MP) can better preserve organs for transplantation. We have recently reported on the first application of an MP protocol in which liver allografts were fully oxygenated, under dual pressures and subnormothermic conditions, with a new hemoglobin-based oxygen carrier (HBOC) solution specifically developed for ex vivo utilization. In those studies, MP improved organ function post-operatively and reduced inflammation in porcine livers. Herein, we sought to refine our knowledge regarding the impact of MP by defining dynamic networks of inflammation in both tissue and perfusate. Methods: Porcine liver allografts were preserved either with MP (n = 6) or with cold static preservation (CSP; n = 6), then transplanted orthotopically after 9 h of preservation. Fourteen inflammatory mediators were measured in both tissue and perfusate during liver preservation at multiple time points, and analyzed using Dynamic Bayesian Network (DyBN) inference to define feedback interactions, as well as Dynamic Network Analysis (DyNA) to define the time-dependent development of inflammation networks. Results: Network analyses of tissue and perfusate suggested an NLRP3 inflammasome-regulated response in both treatment groups, driven by the pro-inflammatory cytokine interleukin (IL)-18 and the anti-inflammatory mediator IL-1 receptor antagonist (IL-1RA). Both DyBN and DyNA suggested a reduced role of IL-18 and increased role of IL-1RA with MP, along with increased liver damage with CSP. DyNA also suggested divergent progression of responses over the 9 h preservation time, with CSP leading to a stable pattern of IL-18-induced liver damage and MP leading to a resolution of the pro-inflammatory response. These results were consistent with prior clinical, biochemical, and histological findings after liver transplantation. Conclusion: Our results suggest that analysis of dynamic inflammation networks in the setting of liver preservation may identify novel diagnostic and therapeutic modalities.

We are writing in response to the article written by Jochmans et al [1]. The article is a comprehensive review on the status of preservation and resuscitation techniques in kidney and liver transplantation. It highlights the need for dynamic techniques of preservation for higher-risk kidney and liver grafts, detailing hypothermic and normothermic perfusion technologies. The review also documents a list of registered clinical trials of these novel techniques in kidney transplantation. The supporting information (S1) also lists the planned or ongoing trials that are unregistered. The authors state that, currently, there are no registered ongoing clinical trials comparing preimplantation normothermic machine perfusion with static cold storage.

The increased demand for organs has led to the increased usage of "higher-risk" kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more susceptible to preservation injury and have a higher risk of unfavourable outcomes. Dynamic, instead of static preservation could allow for organ optimisation, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve and resuscitate vulnerable grafts. Preclinical findings have ignited clinical organ preservation research that investigates dynamic preservation, its various modes (continuous, pre-implantation) and temperatures (hypothermic, sub-, or normothermic). This review outlines the current status of dynamic preservation of kidney and liver grafts and describes on-going research and emerging clinical trials. This article is protected by copyright. All rights reserved. ispartof: American Journal of Transplantation vol:16 issue:9 pages:2545-2555 ispartof: location:United States status: published

The European trial investigating normothermic ex vivo liver perfusion (NEVLP) as a preservation technique for liver transplantation (LT) uses gelofusine, a non-US Food and Drug Administration-approved, bovine-derived, gelatin-based perfusion solution. We report a safety and feasibility clinical NEVLP trial with human albumin-based Steen solution. Transplant outcomes of 10 human liver grafts that were perfused on the Metra device at 37 °C with Steen solution, plus 3 units of erythrocytes were compared with a matched historical control group of 30 grafts using cold storage (CS) as the preservation technique. Ten liver grafts were perfused for 480 minutes (340-580 minutes). All livers cleared lactate (final lactate 1.46 mmol/L; 0.56-1.74 mmol/L) and produced bile (61 mL; 14-146 mL) during perfusion. No technical problems occurred during perfusion, and all NEVLP-preserved grafts functioned well after LT. NEVLP versus CS had lower aspartate aminotransferase and alanine aminotransferase values on postoperative days 1-3 without reaching significance. No difference in postoperative graft function between NEVLP and CS grafts was detected as measured by day 7 international normalized ratio (1.1 [1-1.56] versus 1.1 [1-1.3]; P = 0.5) and bilirubin (1.5; 1-7.7 mg/dL versus 2.78; 0.4-15 mg/dL; P = 0.5). No difference was found in the duration of intensive care unit stay (median, 1 versus 2 days; range, 0-8 versus 0-23 days; P = 0.5) and posttransplant hospital stay (median, 11 versus 13 days; range, 8-17 versus 7-89 days; P = 0.23). Major complications (Dindo-Clavien ≥ 3b) occurred in 1 patient in the NEVLP group (10%) compared with 7 (23%) patients in the CS group (P = 0.5). No graft loss or patient death was observed in either group. Liver preservation with normothermic ex vivo perfusion with the Metra device using Steen solution is safe and results in comparable outcomes to CS after LT. Using US Food and Drug Administration-approved Steen solution will avoid a potential regulatory barrier in North America. Liver Transplantation 22 1501-1508 2016 AASLD.

The traditional philosophy of ex vivo organ preservation has been to limit metabolic activity by storing organs in hypothermic, static conditions. This methodology cannot provide longevity of hearts for more than 4-6 h and is thereby insufficient to expand the number of available organs. Albeit at lower rate, the breakdown of ATP still occurs during hypothermia. Furthermore, cold static preservation does not prevent the permanent damage that occurs upon reperfusion known as ischemia-reperfusion (IR) injury. This damage is caused by increased reactive oxygen species (ROS) production in combination with mitochondrial permeability transition pore (mPTP) opening, highlighting the importance of mitochondria in ischemic storage. There has recently been a major paradigm shift in the field, with emerging research supporting changes in traditional storage approaches. Novel research suggests achieving metabolic homeostasis instead of attempting to limit metabolic activity which reduces IR injury and improves graft preservation. Maintaining high ATP levels and circumventing cold organ storage would be a much more sophisticated standard for organ storage and should be the focus of future research in organ preservation. Given the link between mPTP, Ca2(+), and ROS, managing Ca2(+) influx into the mitochondria during conditioning might be the next critical step towards preventing irreversible IR injury.

Antioxidant agents have the potential to reduce ischemia/reperfusion damage to organs for liver transplantation (LT). In this prospective, randomized study, we tested the impact of an infusion of N-acetylcysteine (NAC) during liver procurement on post-LT outcomes. Between December 2006 and July 2009, 140 grafts were transplanted into adult candidates with chronic liver disease who were listed for first LT, and according to a sequential, closed-envelope, single-blinded procedure, these patients were randomly assigned in a 1/1 ratio to an NAC protocol (69 patients) or to the standard protocol without NAC [71 patients (the control group)]. The NAC protocol included a systemic NAC infusion (30 mg/kg) 1 hour before the beginning of liver procurement and a locoregional NAC infusion (300 mg through the portal vein) just before cross-clamping. The primary endpoint was graft survival. The graft survival rates at 3 and 12 months were 93% and 90%, respectively, in the NAC group and 82% and 70%, respectively, in the control group (P = 0.02). An adjusted Cox analysis showed a significant NAC effect on graft survival at both 3 months [hazard ratio = 1.65, 95% confidence interval (CI) = 1.01-2.93, P = 0.04] and 12 months (hazard ratio = 1.73, 95% CI = 1.14-2.76, P ≤ 0.01). The incidence of postoperative complications was lower in the NAC group (23%) versus the control group (51%, P 1.8), the incidence of primary dysfunction of the liver was lower (P = 0.09) for the NAC group (15%) versus the control group (32%). In conclusion, the NAC harvesting protocol significantly improves graft survival. The effect of NAC on early graft function and survival seems higher when suboptimal grafts are used.

Organ shortage has led to an increased number of transplantations from extended criteria donors. These organs are more vulnerable to ischemia-reperfusion injury. Thus, improvement of organ preservation is needed. HTK is a widely used preservation solution for static cold storage in liver transplantation. The present study was to investigate the beneficial effect of warm HTK donor pretreatment on liver preservation.Male inbred Wistar rats (weighing 230-260 g) served as donors and recipients (n=6/group). Donors of treatment groups received i.v. 0.01 mL/g body weight (BW) warm (21 degree centigrade) HTK systemically 15 minutes prior to cold perfusion. Control groups received 0.01 mL/g BW warm (21 degree centigrade) NaCl 0.9%. Following pretreatment, donors were flushed with 4 degree centigrade cold HTK, livers were explanted and stored in 4 degree centigrade HTK for six hours. Thereafter orthotopic liver transplantation was performed. Recipients were harvested four hours, two and five days after reperfusion and blood and liver tissue samples were obtained. Blood samples were analyzed for AST, ALT, lactate dehydrogenase and bilirubin. Liver histological analysis as well as tissue analysis for pro-MMP2, MMP2 and pro-MMP9 using zymography was conducted.Treatment groups showed significantly lower ALT and lactate dehydrogenase levels as well as significantly lower activities of pro-MMP2, MMP2 and pro-MMP9. Histological analysis revealed only minor damage in all groups.The new concept of warm HTK pretreatment significantly reduced ischemia-reperfusion injury. The reduced ischemia-reperfusion injury was due to MMP inhibition. Warm HTK donor pretreatment is easy to handle and could further improve HTK's potency in liver preservation.

Introduction The gold standard in organ preservation is static cold storage (SCS) using University of Wisconsin solution (UW). Although it is well-known that there is a finite limit to SCS preservation, and that there is a correlation between the adenosine triphosphate (ATP) levels and organ function post-preservation, a quantitative relationship has not been established, which is important in understanding the fundamental limitations to preservation, minimizing cold ischemic injury, and hence maximizing use of the donor organ pool. Aim This study determines the time limits of cellular viability and metabolic function during SCS, and characterizes the relationship between cellular viability and energetic state using clinically relevant techniques in organ preservation. Methods Rat livers were procured and stored using conventional storage in UW solution at 4°C. Viability was assessed by determining the amount of viable hepatocytes and intracellular ATP content after 0, 24, 48, 72, and 120 hours of storage. Results Numbers of viable hepatocytes that were isolated from these livers decreased steadily during SCS. After 5 days, viable hepatocytes decreased from 25.95 × 10 6 to 0.87 × 10 6 cells/gram tissue. Intracellular ATP content decreased from 9.63 to 0.93 moles/g tissue. Statistical analysis of variance established a linear relation for both parameters as a function of time ( P Conclusion The linear correlation between hepatocyte viability, ATP content, and storage time suggests a shared physiological foundation. These findings confirm ATP as direct predictor for organ quality in the context of liver preservation, which will aid quantitative assessment of donor organs for various applications.

Recent in vitro studies of cold-induced cell injury have revealed the detrimental effects of extracellular chloride on cold-stored isolated rat hepatocytes; however, its influence on endothelial cells is beneficial. To determine which of these effects is predominant in vivo, we tested both a chloride-poor variant of a new histidine-tryptophan-ketoglutarate (HTK)–based preservation solution and a chloride-containing variant in a rat liver transplantation model. The study, which was carried out in a blinded fashion with 7 or 8 rats per group, was divided into 2 parts: (1) a comparison of survival in 3 series under different conditions [different microsurgeons, rat strains, cold ischemia times (3, 12, and 24 hours), and warm ischemia times] and (2) an assessment of the microcirculation (30-90 minutes after reperfusion), laboratory data, bile production, and histology. In each of the survival experiments, a (strong) tendency toward prolonged survival was observed with the new chloride-containing solution (50% versus 12.5%, 75% versus 37.5%, and 100% versus 71.4% [chloride-containing vs. chloride-poor], overall P < 0.05). Additionally, the sinusoidal perfusion rates (83.9% ± 4.0% versus 69.2% ± 10.8%, P < 0.01) and the red blood cell velocities in sinusoids (147.7 ± 26.7 versus 115.5 ± 26.0 μm/second, P < 0.05) and in postsinusoidal venules (332.4 ± 87.3 versus 205.5 ± 53.5 μm/second, P < 0.01) were clearly higher with chloride. Moreover, the serum activities of liver enzymes were slightly reduced (not significantly), and bile production was significantly increased. These results suggest an overall beneficial effect of chloride in HTK-based liver preservation solutions. Liver Transpl 17:650-660, 2011. © 2011 AASLD.

The purpose of this prospective, nine-center, non-randomized study was to assess the efficacy and safety of Celsior preservation fluid in liver transplantation using unselected donors. As data comparing allograft outcomes following liver transplantation using Celsior and University of Wisconsin (UW) preservation fluids are limited, we also compared our cohort with matched controls selected from the European Liver Transplant Registry (ELTR) who received total liver grafts preserved with UW solution during the same period. One hundred and forty patients who received livers preserved with Celsior were included. The primary endpoint, graft loss at one-yr post-transplantation, was observed in 24 patients (17.1%) which was not significantly different from the 20.0% pre-defined threshold rate (95% confidence interval [CI] 10.9, 23.4; p=0.398). Predictive factors for graft loss on univariate analysis were moderate-to-severe steatosis on the donor graft (5/22 patients with graft loss vs. 8/107 patients without, p=0.046) and duration of warm ischemia (1.4±1.1 h in patients with graft loss vs. 0.9±0.5 h in patients without, p=0.034). Hepatic artery thrombosis and stenosis occurred in seven (5.0%) and six (4.3%) patients, respectively. The comparison of our patients to 420 ELTR controls showed that one-yr graft survival rates (Celsior: 82.9%, 95% CI 75.8, 88.2; UW: 78.6%, 95% CI 74.4, 82.2) and Kaplan-Meier one-yr graft survival distributions (p=0.285) were similar. Within the cold ischemia time achieved in our study, liver preservation with Celsior appeared efficient and safe. Comparison with ELTR patients suggested that liver allograft survival was similar using Celsior or UW solution for preservation of unselected donor grafts.

Translational medicine has become a priority, but there is still a big difference between the arrival of new treatments and investment. Basic science should not be neglected because the translation from basic research is not sustained in the absence of basic research. The purpose of this literature review was to analyze the translational medicine in the liver transplant field: liver ischemia-reperfusion injury (IRI), immunosuppression, clinical and surgical complications, small-for-size syndrome (SFSS), rejection, and ongoing innovations (liver machine, liver preservation, artificial livers, and regenerative medicine). We performed a systematic literature review that were updated in October 2016. The searches were performed in the Cochrane Central Register of Controlled Trials and Review, PubMed/Medline, Embase, and LILACS databases. All the selected studies on the management of translational medical research in liver transplantation (LT) were analyzed. Initially the search found 773 articles. Methodological viewing and analysis of the articles, followed by the application of scientific models, including translational medicine in the liver transplant field. In conclusions, this review demonstrates the application of scientific research with translation medical benefits regarding the LT. The literature has a great tendency, improvements and investments in the study of translational medicine in LT. Innovative studies and technologies from basic science help to clarify clinical doubts. Moreover, evidence increases the importance of scientific research in quality of clinical practice care.

Intestinal transplantation has become the therapy of choice for patients with intestinal failure and life-threatening complications from total parenteral nutrition. Results, however, remain inferior as compared with other transplant types with the quality of the organ graft as the most important factor of outcome after transplantation. The intestine is extremely sensitive to ischemia. Unfortunately, a relatively long ischemic preservation period is inevitable. The current standard in organ preservation [cold storage (CS) with University of Wisconsin solution] was developed for kidney/liver preservation and is suboptimal for the intestinal graft despite good results for other organs. This review aimed at appraising the results from the use of previously applied and recently developed preservation solutions and techniques to identify key areas for improvement. As the studies available do not reveal the most effective method for intestinal preservation, an optimal strategy will result from a synergistic effect of different vital elements identified from a review of published material from the literature. A key factor is the composition of the solution using a low-viscosity solution to facilitate washout of blood, including amino acids to improve viability, impermeants and colloids to prevent edema, and buffer for pH-homeostasis. Optimizing conditions include a vascular flush before CS and luminal preservation. The most effective composition of the luminal solution and a practical, clinically applicable optimal technique are yet to reach finality. Short-duration oxygenated arterial and/or luminal perfusion have to be considered. Thus, a tailor-made approach to luminal preservation solution and technique need further investigation in transplant models and the human setting to develop the ultimate technique meeting the physiologic demands of the intestinal graft during preservation.

Background: The benefit of carbon monoxide as applied by controlled, continuous gaseous persufflation during liver preservation on postischemic graft recovery was investigated in an isolated rat liver model.Methods: Livers from male Wistar rats were retrieved 30 min after cardiac arrest of the donor and subjected to 18 h of cold storage. Some grafts were subjected to gaseous persufflation with carbon monoxide (CO, dissolved in nitrogen) during static cold storage at a concentration of 50 ppm or 250 ppm. Graft viability was assessed thereafter upon warm reperfusion in vitro.Results: CO-persufflation significantly reduced cellular enzyme loss (maximal at 50 ppm) and functional recovery (bile production and energy charge) upon reperfusion by about 50%. The effect was associated with a reduction of free radical-induced lipid peroxidation, lower vascular perfusion resistance, and improved mitochondrial ultrastructure.Conclusion: Viability of cold stored liver grafts can be notably augmented by gaseous ex vivo application of low dose CO to the isolated organ. (C) 2010 Elsevier Inc. All rights reserved.

This study examined the effects of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) supplementation to University of Wisconsin solution (UW) in steatotic and nonsteatotic livers during cold storage. Hepatic injury and function were evaluated in livers preserved for 24 hours at 4°C in UW and in UW with EGF and IGF-I (separately or in combination) and then perfused ex vivo for 2 hours at 37°C. AKT was inhibited pharmacologically. In addition, hepatic injury and survival were evaluated in recipients who underwent transplantation with steatotic and nonsteatotic livers preserved for 6 hours in UW and UW with EGF and IGF-I (separately or in combination). The results, based on isolated perfused liver, indicated that the addition of EGF and IGF-I (separately or in combination) to UW reduced hepatic injury and improved function in both liver types. A combination of EGF and IGF-I resulted in hepatic injury and function parameters in both liver types similar to those obtained by EGF and IGF-I separately. EGF increased IGF-I, and both additives up-regulated AKT in both liver types. This was associated with glycogen synthase kinase-3β (GSK3β) inhibition in nonsteatotic livers and PPARγ overexpression in steatotic livers. When AKT was inhibited, the effects of EGF and IGF-I on GSK3β, PPARγ, hepatic injury and function disappeared. The benefits of EGF and IGF-I as additives in UW solution were also clearly seen in the liver transplantation model, because the presence of EGF and IGF-I (separately or in combination) in UW solution reduced hepatic injury and improved survival in recipients who underwent transplantation with steatotic and nonsteatotic liver grafts. In conclusion, EGF and IGF-I may constitute new additives to UW solution in steatotic and nonsteatotic liver preservation, whereas a combination of both seems unnecessary. Liver Transpl 16:1098–1111, 2010. © 2010 AASLD.

Primary graft dysfunction still represents a major challenge in liver transplantation. We herein studied in an isolated rat liver perfusion model whether a multidrug donor preconditioning (MDDP) can not only reduce but also completely prevent cold ischemia–reperfusion injury. MDDP included curcumin, simvastatin, N-acetylcysteine, erythropoietin, pentoxyphylline, melatonin, glycine, and methylprednisolone. Postischemic reperfusion was performed after 24 h cold storage in histidine–tryptophan–ketoglutarate solution with 37°C Krebs Henseleit bicarbonate buffer. Cold hepatic ischemia–reperfusion resulted in a massive K+ release, protein loss, and aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase elevation. This was associated with increased malondialdehyde formation, enhanced tumor necrosis factor-alpha and interleukin-6 production, pronounced leukocytic tissue infiltration, and apoptotic cell death. MDDP abolished the inflammation response and was capable of completely preventing the manifestation of parenchymal injury. Thus, MDDP potentiates the protective effects reported after single-drug donor preconditioning and may therefore be an interesting approach to improve the outcome in clinical liver transplantation.

Reversible uncoupling of the mitochondrial electron-transport chain may be one strategy to prevent intracellular oxidative stress during liver cold preservation/warm reperfusion (CP/WR) injury. 2,4-Dinitrophenol (DNP) is a potent water-soluble uncoupling agent for supplementation of the hepatic CP solution. The aim of this work was to investigate the possible influence of DNP in the CP solution on the isolated rat liver state during CP/WR. Livers were subjected to CP at 4 degrees C in sucrose-phosphate based solution (SPS) for 18 h, followed by WR for 60 min in vitro. The final concentration of DNP was 100 mu M. DNP presence during the CP stage led to partial ATP level decrease accompanied by a significant diminution in liver TBARS and a prevention of antioxidant enzyme activity decrease (catalase, GSH-PO, GSH-Red) when compared with livers stored without DNP. After DNP wash-out during WR, an improvement in the mitochondrial functional state (higher respiratory control indices and ATP levels, and a decrease in V-4 respiration rates) were observed. This was concurrent with lower TBARS levels, higher antioxidant enzyme activities and significant increase of bile production. The results suggest that reversible uncoupling may be one way to influence oxidative stress associated with hepatic cold preservation. (C) 2010 Elsevier Inc. All rights reserved.

Purpose of review This review considers the potential of machine perfusion to preserve livers for clinical transplantation, including steatotic or ischaemically damaged grafts and aims to go over the most significant achievements in liver machine perfusion over the last year. To reach acceptance in liver preservation, machine perfusion will need to improve outcomes compared with simple cold storage (SCS), provide objective measures of graft viability, and resuscitate less-than-ideal grafts before transplantation. Recent findings Current machine perfusion protocols comprise both hypothermic (HMP) and normothermic (NMP) approaches. HMP increases energy stores compared to SCS, and NMP shows additional resuscitative potential. Dutkowski transplanted ischaemically damaged pig livers after HMP following SCS, which avoided graft failure observed after SCS alone. Guarrera performed 20 clinical transplants after 4-7 h HMP. Friend has performed porcine transplantations after NMP of 4-20 h and univocally demonstrated the significant resuscitative effects on ischaemically damaged grafts otherwise destined to fail. Whereas NMP promises resuscitative effects, it demands challenging, near-physiologic conditions. Subnormothermic perfusion is being tested as a promising medium in between. Summary Despite recent substantial improvements, liver preservation by machine perfusion remains limited and in contrast to the global revival of kidney machine perfusion. However, liver machine perfusion may be close to returning to clinical practice if it has not already done so. History shows that superiority alone does not guarantee immediate clinical use. Further clear-cut benefits of machine perfusion such as viability assessment will have to be accompanied by usability and human factors, and innovative and improved perfusion solutions applied in novel perfusion protocols.

Here we examine the effect of adding carvedilol (CVD) to University of Wisconsin (UW) solution on the preservation of steatotic and nonsteatotic livers during cold ischemia and after normothermic reperfusion. We used an isolated perfused rat liver model. The following protocols were evaluated. Protocol 1 concerned the effect of CVD after cold ischemia. Steatotic and nonsteatotic livers were preserved for 24 hours in UW solution alone or with CVD. Livers without cold ischemia were used as controls. Transaminases were evaluated in the flushing effluent. Protocol 2 involved the effect of CVD after reperfusion. Both liver types were preserved for 24 hours in UW solution alone or with CVD and then perfused ex vivo for 2 hours at 37 degrees C. Livers flushed and perfused without ischemia were used as controls. Hepatic injury and functionality [transaminases, bile production, and hepatic clearance of sulfobromophthalein (BSP)] were evaluated after reperfusion. In addition, factors potentially involved in hepatic ischemia-reperfusion injury, including oxidative stress (malondialdehyde and superoxide anion levels), mitochondrial damage (glutamate dehydrogenase activity), microcirculatory disorders (flow rate and vascular resistance), and adenosine triphosphate (ATP) depletion, were evaluated after reperfusion. After cold ischemia, steatotic livers preserved in UW solution showed higher transaminase levels than nonsteatotic livers. After reperfusion, steatotic livers preserved in UW solution showed higher transaminase levels and lower bile production and BSP clearance than nonsteatotic livers. Alterations in the perfusion flow rate and vascular resistance, mitochondrial damage, and reduced ATP content were more evident in steatotic livers preserved in UW solution. The addition of CVD to UW solution reduced hepatic injury, obstructed its mechanisms, and improved hepatic functionality in both liver types. We conclude that CVD is a useful additive for UW solution that improves the preservation of steatotic and nonsteatotic livers subjected to prolonged cold ischemia.

Organ shortage limits the applicability of liver transplantation to treat end-stage liver disease, and the use of extended-criteria donors is a necessity in the current era. Donors after cardiac death (DCD) suffer irreversible cardiac arrest prior to donation and represent a potential source of additional organs if properly maintained. DCD undergo an initial period of warm ischemia that provokes cellular alterations. Experimental and clinical studies performed at our center have demonstrated that normothermic extracorporeal membrane oxygenation (NECMO) is effective at maintaining abdominal organs in DCD. NECMO helps stop and even revert some of the changes that occur during warm ischemia and offers the opportunity to evaluate graft viability prior to implantation. Nonetheless, the percentage of organs arising from DCD that are accepted for transplant remains relatively low due to the co-existence of other factors that prohibit their utilization, namely poor perfusion and hepatic steatosis. The use of dual-pump normothermic machine perfusion (NMP) in the ex vivo phase of DCD liver preservation can offer additional benefits over traditional cold storage. In experimental studies, ischemic injury and hepatocellular function are significantly improved in DCD grafts preserved with NMP. Clinical studies on the use of NMP in DCD liver transplantation are under way.

University of Wisconsin solution (UWS) is the gold standard for graft preservation. Celsior solution (CS) is a new solution not as yet widely used in liver grafts. The aim of this study was to compare the liver function of transplanted grafts stored in these 2 preservation solutions. The primary endpoints were the rates of primary nonfunction (PNF) and primary dysfunction (PDF). We performed a prospective and pseudorandomized study that included 196 patients (representing 104 and 92 livers preserved in UWS and CS, respectively) at La Fe University Hospital (Valencia, Spain) between March 2003 and May 2005. PNF and PDF rates, liver function laboratory parameters, postoperative bleeding, vascular and biliary complications, and patient and graft survival at 3 years were compared for the 2 groups. The 2 groups were similar in terms of donor variables, recipient variables, and surgical techniques. The PNF rates were 2.2% and 1.9% in the CS and UWS groups, respectively (P = not significant), and the PDF rates were 15.2% and 15.5% in the CS and UWS groups, respectively (P = not significant). There were no significant differences in the laboratory parameters for the 2 groups, except for alanine aminotransferase levels in month 3, which were lower in the CS group (P = 0.01). No significant differences were observed in terms of complications. Three-year patient and graft survival rates were as follows for years 1, 2, and 3: 83%, 80%, and 76% (patient) and 80%, 77%, and 73% (graft) for the UWS group and 83%, 77%, and 70% (patient) and 81%, 73%, and 67% (graft) for the CS group (P = not significant). In conclusion, this study shows that CS is as effective as UWS in liver preservation. Liver Transpl 15:1709–1717, 2009. © 2009 AASLD.

The continuous shortage of organs necessitates the use of marginal organs from donors with various diseases, including arrhythmia-associated cardiac failure. One of the most frequently used anti-arrhythmic drugs is amiodarone (AM), which is given in particular in emergency situations. Apart from its anti-arrhythmic actions, AM provides anti-oxidative properties in cardiomyocytes. Thus, we were interested in whether AM donor pretreatment affects the organ quality and function of livers procured for preservation and transplantation. Donor rats were pretreated with AM (5 mg/kg of body weight) 10 minutes before flush-out of the liver with a cold (4 degrees C) histidine-tryptophan-ketoglutarate solution (n = 8). Livers were then stored for 24 hours at 4 degrees C before ex situ reperfusion with a 37 degrees C Krebs-Henseleit solution for 60 minutes in a nonrecirculating system. At the end of reperfusion, tissue samples were taken for histology and Western blot analysis. Animals with vehicle only (0.9% NaCl) served as ischemia/reperfusion controls (n = 8). Additionally, livers of untreated animals (n = 8) not subjected to 24 hours of cold ischemia served as sham controls. AM pretreatment effectively attenuated lipid peroxidation, stress protein expression, and apoptotic cell death. This was indicated by an AM-mediated reduction of malondialdehyde, heme oxygenase-1, and caspase-3 activation. However, AM treatment also induced mitochondrial damage and hepatocellular excretory dysfunction, as indicated by a significantly increased glutamate dehydrogenase concentration in the effluate and decreased bile production. In conclusion, AM donor pretreatment exerts anti-oxidative actions in liver preservation and reperfusion. However, these protective AM actions are counteracted by an induction of mitochondrial damage and hepatocellular dysfunction. Accordingly, AM pretreatment of donors for anti-arrhythmic therapy should be performed with caution. Liver Transpl 15:763-775, 2009. (C) 2009 AASLD.

Microcirculatory failure after cold liver preservation and reperfusion impairs tissue oxygenation and causes additional organ damage. Hemoglobin-glutamer (HbG) 200 is a hemoglobin-based oxygen carrying solution capable to improve organ oxygenation. The aim of this study was to evaluate its potential to decrease reperfusion injury after cold liver preservation. Therefore, Wistar rat livers were stored at 4 degrees C for 24 h and reperfused in the isolated perfused rat liver model with a sanguineous perfusate for 180 min. The perfusate consisted of rat blood and Krebs-Henseleit solution (Group A), supplemented by either HES 6% (Group B), or HbG (Groups C and D). In Group D heme oxygenase (HO) activity was blocked by intraperitoneal tin protoporphyrin-IX application before organ harvest. HbG supplementation increased the perfusate hemoglobin by 3,3 g/dL. After 180 min reperfusion perfusate alanine aminotransferase levels (72 +/- 27 micro/L) were significantly reduced in Group C, compared with Groups A and B (140 +/- 28 micro/L and 203 +/- 62 micro/L, respectively). These results correlated with a significant increase of HO-1 expression and activity during reperfusion. These effects could be abolished by tin protoporphyrin-IX application. HbG has been proven to be effective to reduce cold liver preservation-reperfusion injury. The positive effect on reperfusion injury depends on the induction of HO-1, which increases the bilirubin production, an important antioxidant acting as intracellular radical scavenger.

BACKGROUND AND AIM We previously reported that hypothermic machine perfusion (HMP) for liver preservation is feasible, but hepatic microcirculatory dysfunction and significant liver damage remain major obstacles in its application when the preservation is extended to 24 h. The underlying injury mechanism is not well understood. The present study sought to investigate the role of thromboxane A(2) (TXA(2)) in the pathogenesis of liver injury after prolonged HMP. METHODS Livers isolated from Sprague-Dawley rats were subjected to continuous machine perfusion with University of Wisconsin (UW) solution at a flow rate of 0.4 mL/min/g liver at 4 degrees C for 24 h. A specific TXA(2) synthase inhibitor, OKY-046 (OKY), was added to UW solution during the preservation period and to the Krebs-Henseleit buffer during reperfusion. The performance of the livers after preservation was evaluated using an isolated liver perfusion system with Krebs-Henseleit buffer at a flow rate of 15 mL/min at 37 degrees C for 30 min. RESULTS Prolonged HMP induced a significant release of TXA(2) into the portal circulation as indicated by markedly increased levels of TXB(2) in the perfusate during reperfusion (at 30 min, 1447.4 +/- 163.6 pg/mL vs 50.91 +/- 6.7 pg/mL for control). Inhibition of TXA(2) synthesis with OKY significantly decreased releases of TXA(2) (69.8 +/- 13.4 pg/mL) concomitant with reduced lactate dehydrogenase (LDH) releases (at 30 min, HMP + OKY: 144.9 +/- 27.9 U/L; HMP: 369.3 +/- 68.5 U/L; simple cold storage or SCS: 884.4 +/- 80.3 U/L), decreased liver wet/dry weight ratio (HMP + OKY vs SCS and HMP: 3.6 +/- 0.3 vs 4.4 +/- 0.1 and 3.9 +/- 0.2, respectively) and increased hyaluronic acid uptake (at 30 min, HMP + OKY vs SCS, HMP: 33.1 +/- 2.9% vs 13.9 +/- 3.6%, 18.6 +/- 2.4%, respectively). Liver histology also showed significant improvement in tissue edema and hepatocellular necrosis with OKY compared with HMP without OKY. CONCLUSION The results demonstrate that TXA(2) is involved in the development of hepatocellular injury induced by HMP, and inhibition of TXA(2) synthesis during preservation and reperfusion protects liver hepatocytes and sinusoidal endothelial cells from injuries caused by prolonged HMP.

Due to the sharp increase in liver transplant candidates and the subsequent shortage of suitable donor livers, an extension of the current donor criteria is necessary. Simple cold storage, the current standard in organ preservation has proven to be insufficient to preserve extended criteria donor livers. Therefore a renewed interest grew toward alternative methods for liver preservation, such as hypothermic machine perfusion and normothermic machine perfusion. These "new" preservation methods were primarily assessed in rat models, and only a few clinically relevant large animal models have been described so far. This review will elaborate on these alternative preservation methods.

Hypothermic machine perfusion (HMP) has the potential to improve recovery and preservation of Donation after Cardiac Death (DCD) livers, including uncontrolled DCD livers. However, current perfusion solutions lack the needed substrates to improve energy recovery and minimize hepatic injury, if warm ischemic time (WIT) is extended. This proof-of-concept study tested the hypothesis that the University of Wisconsin (UW) solution supplemented with anaplerotic substrates, calcium chloride, thromboxane A2 inhibitor, and antioxidants could improve HMP preservation and minimize reperfusion injury of warm ischemic livers. Preflushed rat livers subjected to 60 min WIT were preserved for 5 h with standard UW or supplemented UW (SUW) solution. Post preservation hepatic functions and viability were assessed during isolated perfusion with Krebs-Henseleit solution. Livers preserved with SUW showed significantly (p < .001) improved recovery of tissue ATP levels (micromol/g liver), 2.06 +/- 0.10 (mean +/- SE), as compared to the UW group, 0.70 +/- 0.10, and the level was 80% of that of fresh control livers (2.60 +/- 0.13). At the end of 1 h of rewarming, lactate dehydrogenase (U/L) in the perfusate was significantly (p < .05) lower in the SUW group (429 +/- 58) as compared to ischemia-reperfusion (IR) (781 +/- 12) and the UW group (1151 +/- 83). Bile production (microg/min/g liver) was significantly (p < .05) higher in the SUW group (280 +/- 13) as compared to the IR (224 +/- 24) and the UW group (114 +/- 14). The tissue edema formation assessed by tissue wet-dry ratio was significantly (p < .05) higher in UW group. Histology showed well-preserved hepatic structure in the SUW group. In conclusion, this study suggests that HMP with SUW solution has the potential to restore and preserve livers with extended WIT.

This study compares the effects of machine perfusion (MP) at different temperatures with simple cold storage. In addition, the role of Ca(2+) levels in the MP medium was evaluated. For MP, rat livers were perfused for 6 hours with Krebs-Henseleit (KH) solution (with 1.25 or 2.5 mM CaCl(2)) at 4 degrees C, 10 degrees C, 20 degrees C, 25 degrees C, 30 degrees C, or 37 degrees C. For cold storage, livers were perfused in situ and preserved with Celsior solution at 4 degrees C for 6 hours. The reperfusion period (2 hours at 37 degrees C) was performed under the same conditions used for MP-preserved and cold storage-preserved livers. Hepatic enzyme release, bile production, adenosine triphosphate (ATP) levels, and morphology were evaluated during MP and reperfusion. MP at 37 degrees C caused marked enzyme release; the same findings were obtained during reperfusion. By contrast, MP temperature lowering induced a significant decrease in liver damage. High levels of biliary gamma-glutamyltransferase and lactate dehydrogenase were found with MP at 4 degrees C and 10 degrees C but not with MP at 20 degrees C. When a KH-1.25 mM CaCl(2) solution was used during MP at 20 degrees C, very low enzyme release was observed and significantly lower hepatic damage was present at the end of the reperfusion period in comparison with cold storage. The same results were obtained when ruthenium red, a calcium uniporter blocker, was added to KH-2.5 mM CaCl(2). ATP levels were higher and morphology was better in liver preserved with KH-1.25 mM CaCl(2). MP at 20 degrees C with KH-1.25 mM CaCl(2) resulted in better quality liver preservation, improving hepatocyte and endothelial biliary cell survival, in comparison with cold storage. This raises the need to reconsider the temperature and calcium levels to be used during liver MP.

Coskun, Abdurrahman/0000-0002-1273-0604; WOS: 000248729900010 PubMed: 17517073 Aim: To evaluate the protective effect of L-carnitine on liver tissue preserved in University of Wisconsin (UW) solution. Methods: Twenty Wistar Albino rats were divided into two groups, a control (UW) group and a UW Plus L-carnitine group. Retrieved liver grafts were preserved in UW and UW Plus L-carnitine solutions at +4 degrees C. Preservation solution samples were assessed at 2, 24, 36, and 48 h to measure alanine aminotransferase and acid phosphatase activity. Tissue injury was scored on paraffin sections. Results: No micro or macrovacuolar fat droplets were observed in the tissue slices. L-Carnitine effectively decreased enzyme release when added to UW solution (P < 0.05). Conclusion: in addition to fatty liver, L-carnitine might be a metabolic adjunct in preservation solutions for non-fatty liver within UW solution.

University of Wisconsin (UW) solution has been recognized as the gold standard in liver preservation, but its limitations are becoming obvious, such as risk of biliary complications and its high cost. Alternatively, the effects of histidine-tryptophan-ketoglutarate (HTK), such as improved biliary protection and low cost, have been observed. This systematic review is conducted to compare the efficacy and safety of these 2 solutions. Databases from 1966 to June 2006 were searched. Randomized clinical trials (RCTs) and cohort studies comparing HTK and UW solutions for liver transplantation were included. Ten articles including 11 comparisons (1,200 patients) met the inclusion criteria, containing 2 RCTs and 9 cohort studies. No marked differences existed between the 2 groups in patient and graft survival rates, acute rejection, primary nonfunction, primary dysfunction, delayed graft function, and ALT and AST levels after transplantation. The only positive result was observed in the bile production after deceased donor liver transplantation (DDLT), which was statistically significantly higher in HTK group than that of UW group (95% confidence interval, 18.65-57.47; P=0.0001). Although the difference in biliary complications between the 2 groups did not reach statistical significance, HTK was thought to be more effective for biliary tract flush and prevention of biliary complications in some studies. There was no statistically significant difference of effects (except bile production) between HTK and UW. But trends were documented in some studies for the superiority of HTK in biliary tract flush, prevention of biliary complications, and cost saving. Adequately powered RCTs with longer follow-up periods are required to evaluate the long-term effect of these 2 solutions.

Effective preservation of liver grafts is the first essential step for successful liver transplantation. Insufficient perfusion leads to ischemic-type biliary lesions after transplantation. Perfusion of the graft can be performed either in situ or ex situ, with gravity flow or pressure-controlled. Mainly University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions are used widespread in clinical liver transplantation. Due to a persistent lack of data, we performed this systematic investigation of in situ and ex situ perfusion of liver grafts with HTK (low-viscous) and UW (high-viscous) solutions at different pressure steps on the perfusion solution (gravity flow, 50, 100, 150, and 200 mm Hg). End points were perfusion flow and pressure in the hepatic artery. A pig model was used with n = 8 pigs randomized to each (HTK and UW) group. In situ perfusion was ineffective for both solutions at any pressure on the perfusate bag. Ex situ perfusion showed significantly improved flow and pressure in the hepatic artery and, therefore, was highly effective. No major differences between HTK and UW solutions could be detected. Therefore, an additional ex situ perfusion of the hepatic artery should be mandatory in every liver procurement.

© 2015 Kato et al. Hepatic ischemia and reperfusion injury (IRI) is an inflammatory condition and a significant cause of morbidity and mortality after surgery. Matrix metalloproteinases (MMPs) have been widely implicated in the pathogenesis of inflammatory diseases. Among the different MMPs, gelatinases (MMP-2 and MMP-9) are within the most prominent MMPs detected during liver IRI. While the role of MMP-9 in liver damage has been fairly documented, direct evidence of the role for MMP-2 activity in hepatic IRI remains to be established. Due to the lack of suitable inhibitors to target individual MMPs in vivo, gene manipulation is as an essential tool to assess MMP direct contribution to liver injury. Hence, we used MMP-2-/-deficient mice and MMP-2+/+wild-type littermates to examine the function of MMP-2 activity in hepatic IRI. MMP-2 expression was detected along the sinusoids of wild-type livers before and after surgery and in a small population of leukocytes post-IRI. Compared to MMP-2+/+mice, MMP-2 null (MMP-2-/-) mice showed exacerbated liver damage at 6, 24, and 48 hours post-reperfusion, which was fatal in some cases. MMP-2 deficiency resulted in upregulation of MMP-9 activity, spontaneous leukocyte infiltration in naïve livers, and amplified MMP-9-dependent transmigration of leukocytes in vitro and after hepatic IRI. Moreover, complete loss of MMP-2 activity impaired the degradation of poly (ADP-ribose) polymerase (PARP-1) in extensively damaged livers post-reperfusion. However, the administration of a PARP-1 inhibitor to MMP-2 null mice restored liver preservation to almost comparable levels of MMP-2+/+mice post-IRI. Deficient PARP-1 degradation in MMP-2-null sinusoidal endothelial cells correlated with their increased cytotoxicity, evaluated by the measurement of LDH efflux in the medium. In conclusion, our results show for the first time that MMP-2 gene deletion exacerbates liver IRI. Moreover, they offer new insights into the MMP-2 modulation of inflammatory responses, which could be relevant for the design of new pharmacological MMP-targeted agents to treat hepatic IRI.

Aims We have compared hypothermic oxygenated machine perfusion (HOPE) with simple cold storage (SCS) in liver preservation with a porcine model of donor after cardiac death (DCD). Methods A DCD model was developed in 10 hybrid pigs by apnea. Livers were harvested after 30 min of warm ischemia (WI) and randomly preserved using HOPE (HOPE group, five pigs, dual perfusion via portal vein and hepatic artery) or SCS (SCS group, five pigs) methods. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose, lactic acid, and pyruvic acid were measured by microdialysis analyzer. Results Histological morphology of liver tissue was significantly affected by 30 min of WI. HOPE significantly delayed histological morphology change and cell apoptosis. Release of ALT and AST was significantly higher in SCS group compared to HOPE group (p

The effectiveness of liver preservation solutions remains in evidence. Cold ischemia time, steatosis, expanded criterion donors, operational cost, and survival represent important roles in its success. In a prospective cohort study between August 2009 and April 2014, 178 patients were allocated into an Institut Georges Lopez – 1 (IGL-1) solution group (63.5%) or histidine-tryptophan-ketoglutarate (HTK) group (36.5%). There were no differences among recipient’s characteristics including age, skin color, gender, Model for End-stage Liver Disease score, acute rejection, cholestasis, and reperfusion syndrome incidences. Also, donors, age average, skin color, donor risk index, time in intensive care unit, hemodynamic variables, infections, and steatosis incidences were similar. The average cold ischemia time was 494 minutes in the IGL-1 group and 489 minutes in the HTK group ( P = .77). Alanine aminotransferase and aspartate aminotransferase serum levels on the first postoperative day were 707 and 1185 mg/dL, respectively, with IGL-1 and 1298 and 2291 mg/dL, respectively, with HTK ( P = .016) and similar at day 15 ( P > .88). The incidence of delayed graft function was 4.5% with IGL-1 and 4.6% with HTK ( P = .90). The incidence primary nonfunction was 2.7% with IGL-1 and 3.1% with HTK ( P = .71). The incidence of perioperative death was 11.5% with IGL-1 and 13.8% with HTK ( P = .94). The survival in 30 months was 86% in IGL-1 group and 82% in HTK group ( P = .66). Both preservation solutions are efficient to liver transplantations with deceased donors. Major prospective trials are necessary to evaluate each preservation solution’s particularities. The preservation solution availability in each transplantation center must guide its use at the present moment.

Prolonged oxygen deprivation corresponding to the ischemic period is observed during liver resection, transplantation, and trauma and subsequent oxygen restoration always leads to reperfusion injury. In particular, the ischemic period represents an inevitable event during conventional organ preservation before transplantation and the magnitude and severity of reperfusion injury depend on the time of liver preservation. Faced with the increasing shortage of donor organs for transplantation, there is renewed interest in marginal livers, such as those obtained from donation after circulatory death or fatty livers, which are particularly susceptible to ischemia/reperfusion (I/R) injury. The decreased tolerance towards I/R observed in fatty livers has not been fully elucidated yet, and underlying mechanisms appear different in lean and steatotic livers. The paper of A. Matsuda et al. proposed the use of activated protein C (APC), an anticoagulant, found to induce an initial attenuation of tissue damage by inhibiting inflammatory cell infiltration and sinusoidal endothelial injury in normal liver. Of interest, in steatotic mice livers, APC did not affect initial liver damage but attenuated late damage, suggesting the existence of an additional pathway to the anti-inflammatory cytoprotective effect of APC which may occur via activation of adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. A further attempt to reduce the fatty liver susceptibility was reported by E. Pantazi et al. that used a peroxisome proliferator-activated receptor α (PPARα) agonist WY-14643. PPARα is a nuclear receptor highly expressed in liver and it functions as a lipid sensor. Treatment with WY-14643 reduced liver injury in fatty rat livers, enhanced the deacetylase enzyme sirtuin 1 (SIRT1), recently found to be a target for preventing I/R, and prevented endoplasmic reticulum stress. M. Bejaoui et al. investigated the use of polyethylene glycols (PEGs) that, besides their usefulness as oncotic agents in preservation solution, have been shown to protect against cold injury and ischemic damage. The intravenous PEG 35 administration by a unique dose protected steatotic rat liver grafts against the deleterious effects of cold storage and the subsequent reperfusion. The rationale for the intravenous administration of PEG 35 was to induce a pharmacological preconditioning effect; its protective mechanisms are related to preservation of mitochondria and the induction of protective cell signaling pathways (eNOS, Akt, and AMPK). An additional model of liver preconditioning by pharmacological induction of adenosine A2a receptor (A2aR) was reported by E. Alchera et al. The analysis of the molecular changes induced by A2aR stimulation revealed multiple mechanisms of liver cell protection that can be both immediate (early preconditioning) and delayed (late preconditioning). Note that the A2aR activation also protects against lipotoxicity by preventing lipoapoptosis in primary rat hepatocytes. Among the hepatic mechanisms involved in the development of I/R, mitochondrial dysfunction represents a crucial cellular event contributing to I/R injury. As reported by K. Go et al., the elimination of abnormal and dysfunction mitochondria by mitophagy appears to increase both the quality of the mitochondria and cell survival. Although the mechanisms underlying the onset and propagation of mitophagy remain elusive, this event represents an early adaptive response to facilitate cell survival during I/R. Articles published in this issue not only help to identify new pharmacological approaches for improving liver function during ischemia/reperfusion damage but also stimulate the identification of molecular mediators of hepatic injury. Mariapia Vairetti Hartmut Jaeschke Diethard Monbaliu Jae-Sung Kim Andrea Ferrigno

Background Curcumin has profound antioxidant and anti-inflammatory properties. This research assessed the effect of curcumin on liver preservation. Methods Sprague-Dawley rat livers were flushed with different preservation solutions [Euro-Collins solution (EC), phosphate buffer saline (PBS), University of Wisconsin solution (UW)] with or without curcumin (25-200 microM) and stored at 4 degrees C for 24-48 hours. Livers were then perfused for 120 minutes via the portal vein with oxygenated Krebs-Henseleit bicarbonate buffer solution at a pressure of 18 cm H2O in a perfusion apparatus. The livers in the normal (NL) group were flushed with EC, PBS, or UW, then immediately perfused (zero preservation time). Results We found that curcumin at 100 microM concentration had the optimal preservation characteristics. Portal flow rates and bile production were significantly higher and liver enzymes (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) were significantly lower in the EC+C livers and PBS+C livers than in the EC or PBS with optimum concentration of 100 microM of curcumin. Comparing UW+C vs. UW livers, at 24 hours there was no difference in these parameters; however, at 36 hours and 48 hours, portal flow rates and bile production were significantly higher in UW+C livers. Conclusions We found that curcumin has inherent organ preservation quality as it enhanced liver preservation in PBS. In addition, curcumin enhanced the preservation quality of EC and UW solutions, thereby extending the preservation time while maintaining the organ quality.