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S-Nitrosated human serum albumin (SNO-HSA) is useful in preventing liver ischemia/reperfusion injury, and SNO-HSA should thus be able to prevent cell injury during liver transplantation. However, the potential protective effect of SNO-HSA on a combination of cold and warm ischemia, which is obligatory when performing liver transplantation, has not been examined. Therefore, we evaluated the protective effect of SNO-HSA added to University of Wisconsin (UW) solution during cold or/and warm ischemia in situ and in vitro. First, we observed that apoptotic and necrotic cell death were increased during cold and warm ischemia, respectively. SNO-HSA, which possesses anti-apoptosis activity at low NO concentrations, can inhibit cold ischemia injury both in situ and in vitro. In contrast, SNO-HSA had no significant effect on warm liver ischemia injury which, however, can be reduced by UW solution. We also demonstrated that the cellular uptake of NO from SNO-HSA can occur during cold ischemia resulting in induction of heme oxygenase-1 within 3h of cold ischemia. Our results indicate that treatment with SNO-HSA or UW solution alone is not sufficient to inhibit liver injury during a period of both cold and warm ischemia. However, a combination of SNO-HSA and UW solution can be used to prevent the two types of ischemia. SNO-HSA-added UW solution could be very useful in transplantation, because the previously imposed constraints on preservation time can be removed. This is a great advantage in a situation as the present one with increased utilization of scarce donor organs for more recipients.
Copyright © 2013 Elsevier Inc. All rights reserved.
Breakthroughs in basic and clinical science in solid organ transplantation were presented at the American Transplant Congress 2011. Key areas of presentation included the pathogenesis of late allograft failure, immune regulation and tolerance, pathways in allograft injury, electing appropriate patients for transplantation, determining the best allocation schemes to maximize effective utilization, organ preservation, monitoring the alloimmune response and immunosuppressive management. In this review, we present highlights of the meeting. These presentations demonstrate the exciting promise in translating from the bench to affect patient care.
©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
Complications of liver transplantation are not limited to acute and chronic rejection, and recurrence of original disease, but include surgical complications, most commonly hepatic artery occlusion, infections, and development of de novo malignancies. In the early posttransplantation period, procurement/preservation injury, non-immunologic injury to the graft during harvesting and implantation, is manifested by centrilobular hepatocyte pallor and cholestasis but rarely leads to significant graft dysfunction. Ischemic complications, such as hepatic artery thrombosis, are more serious complications and may lead to early graft loss or biliary stricture. Infectious complications generally occur in the mid-to-late period after transplantation; cytomegalovirus (CMV) remains a common pathogen. Human herpes 6 virus infection has been implicated in allograft dysfunction, but is usually seen in the setting of co-infection with CMV. De novo malignancies are emerging as a significant cause of mortality after liver transplantation; risk is cumulative, and increases with time posttransplantation. Development of such malignancies in the setting of solid organ transplantation is multifactorial, and is related to individual and regional predispositions to malignancy, pre-transplantation disease states, recipient viral status, and use and intensity of immunosuppression regimens.
HYPOTHESIS - Donor, technical, and recipient risk factors cumulatively impact survival and health-related quality of life after liver transplantation.
DESIGN - Retrospective study.
SETTING - Tertiary care center.
PATIENTS - A total of 483 adults undergoing primary orthotopic liver transplantation between January 1, 1991, and July 31, 2003.
MAIN OUTCOME MEASURES - Graft and patient survival, Karnofsky functional performance scores, Medical Outcomes Study Short Form 36 Health Survey scores, and Psychosocial Adjustment to Illness Scale scores as influenced by potential risk factors including donor age, weight, warm ischemia time, cold ischemia time (CIT), sex, United Network for Organ Sharing (UNOS) status (1 or 2A vs 2B or 3), recipient age and disease, bilirubin level, and creatinine level.
RESULTS - Five-year graft survival was 72% for recipients of donors younger than 60 years and 35% for recipients of donors 60 years and older (P<.001). A CIT of 12 hours or more was associated with shorter 5-year graft survival (71% vs 58%; P = .004). Five-year graft survival for UNOS status 2B or 3 was 71% vs 60% for status 1 or 2A (P = .02). A comparable pattern was seen for patient survival in relation to donor age (P = .003), CIT (P = .005), and urgency status (P = .03). Urgent UNOS status, advanced donor age, and prolonged CIT were independently associated with shorter graft and patient survival (P<.05). Functional performance and health-related quality of life were not affected by donor, recipient, or technical characteristics.
CONCLUSIONS - Combining advanced donor age, urgent status, and prolonged CIT adversely affects graft and patient survival, and the cumulative effects of these risk factors can be modeled to predict posttransplant survival.
The effects of various tissue preservation buffers on cytochrome P450 (P450)-mediated activities of microsomes prepared from fresh surgical liver samples were examined. Two individual human liver samples were obtained, and three portions of each were preserved in one of three solutions: phosphate buffer, Krebs-Heinseleit solution, or University of Wisconsin solution. Microsomes were prepared within 24 h, 3 days, and 7 days after the resection of the samples. Marker P450 activities were measured. Liver microsomes prepared within 24 h displayed similar ethoxyresorufin O-deethylation, bufuralol 1'-hydroxylation (BF 1'-OH), and chlorzoxazone 6-hydroxylation activities in all preservation solutions, whereas S-mephenytoin 4'-hydroxylation and midazolam 1'-hydroxylation activities displayed some variation depending on the preservation buffer used. Most of the marker P450 activities were stable for 3 days after removal from surgical patients and declined at 7 days; however, a decline in BF-1'OH activity was observed even at day 3. These results suggest P450-specific activity depends on the method by which human liver samples are preserved. Moreover, the results of these studies establish the minimum tissue preservation criteria that, when met, qualify the drug disposition data generated from subcellular fractions derived from a particular surgical tissue sample.
BACKGROUND - Ischemic-preconditioning is a process whereby a brief ischemic episode confers a state of protection against subsequent long-term ischemia-reperfusion injury. Ischemic preconditioning has been studied in heart and liver ischemia-reperfusion injury; however, few studies have been performed in the model of preservation-reperfusion injury in liver transplantation. The current study was designed to evaluate the ability of ischemic preconditioning to protect liver grafts from long-term preservation-reperfusion injury.
METHODS - Male Sprague Dawley rats were used as donors and recipients of orthotopic liver transplantation. Ischemic preconditioning was done by interruption of the portal vein and hepatic artery for 5, 10, and 20 min (5-10, 10-10, and 20-10 groups). Reflow was initiated by removal of the clamp for another 10 min in all groups. The liver was removed and placed in a bath with Euro-Collins solution for different preservation times. Tolerance of the transplanted liver to cold ischemia was determined by survival time and liver function tests. Rat tumor necrosis factor was analyzed by a bioassay. Nomega-Nitro-L-arginine methyl ester, L-arginine, or adenosine was administered to block or stimulate the synthesis of nitric oxide (NO) in the rats that received long-term-preserved liver grafts.
RESULTS - Twenty percent of syngeneic rats (n=10) that received a liver graft with a 16-hr cold ischemia time in Euro-Collins solution survived for more than 1 day and 10% survived for more than 5 days. In contrast, 87.5% of rats (n=8) that received a liver graft with ischemic preconditioning (10-10 group) and 16 hr of cold ischemia survived for more than 1 day and 75% for more than 5 days. Recipients of liver grafts with ischemic preconditioning had significantly reduced levels of serum aspartate transaminase and tumor necrosis factor-alpha, as well as increased bile flow, compared with recipients of liver grafts without ischemic preconditioning. Blockage of the NO pathway using Nomega-nitro-L-arginine methyl ester, a stereospecific competitive inhibitor of NO formation, attenuated the protective effect of ischemic preconditioning. Administration of one of two precursors of NO synthesis, L-arginine or adenosine, prolonged the survival of rats that received 16-hr-preserved liver grafts. In addition, L-arginine synergized with short-term ischemic pre conditioning (5-10 group) to increase the survival of rats that received a liver graft with a 16-hr cold ischemia time, and the survival rate was 83% after 5 days. Finally, prolonged ischemic preconditioning (> or = 20 min; 20-10 group) resulted in liver damage and loss of function.
CONCLUSION - The current results show that ischemic preconditioning protects the liver graft from subsequent long-term cold preservation-reperfusion injury in a rat liver transplantation model. The protective role of ischemic preconditioning may be mediated by the endogenous production of NO.
BACKGROUND & AIMS - Low temperature preservation causes unique liver injuries to the sinusoidal lining cells characterized by endothelial cell detachment and rounding and Kupffer cell activation. These changes are similar to those observed during the early stages of angiogenesis. The aim of this study was to investigate if cold preservation injury is caused by the activation of angiogenic mechanisms.
METHODS - Livers were obtained from rats pretreated with three well-known antiangiogenic agents (minocycline, interferon alfa-2b, and fumagillin) and were stored for various durations in cold preservation solutions. The effects of the drugs were evaluated by morphometric assessment of endothelial cell injury in H&E, trypan blue, and immunostained (TIE2/Tek) biopsy specimens. Graft functions and survival were evaluated in isolated perfused rat liver and arterialized orthotopic liver transplantation models.
RESULTS - Sinusoidal lining cell integrity and viability were significantly improved in animals pretreated with the drugs. Reperfusion injury and survival were also better in pretreated animals. Interferon alfa was the most potent agent, reducing injury even in livers preserved in the current most commonly used solution (University of Wisconsin solution).
CONCLUSIONS - Cold preservation injury of liver may be the results of angiogenic mechanisms. This novel observation provides a rationale for improved liver preservation using antiangiogenic agents.