Hypothermic machine perfusion with metformin-University of Wisconsin solution for ex vivo preservation of standard and marginal liver grafts in a rat model

AIM To compare the effect of University of Wisconsin(UW) solution with or without metformin, an AMP-activated protein kinase(AMPK) activator, for preserving standard and marginal liver grafts of young and aged rats ex vivo by hypothermic machine perfusion(HMP).METHODS Eighteen young(4 mo old) and 18 aged(17 mo old)healthy male SD rats were selected and randomly divided into three groups: control group, UW solution perfusion group(UWP), and UW solution with metformin perfusion group(MUWP). Aspartate aminotransferase(AST), alanine aminotransferase(ALT), lactate dehydrogenase(LDH), interleukin-18(IL-18), and tumor necrosis factor-alpha(TNF-α) in the perfused liquid were tested. The expression levels of AMPK and endothelial nitric oxide synthase(e NOS) in liver sinusoidal endothelial cells were also examined.Additionally, microscopic evaluation of the harvested perfused liver tissue samples was done. RESULTS AST, ALT, LDH, IL-18 and TNF-α levels in the young and aged liver-perfused liquid were, respectively,significantly lower in the MUWP group than in the UWP group(P < 0.05), but no significant differences were found between the young and aged MUWP groups.Metformin increased the expression of AMPK and e NOS protein levels, and promoted the extracellular release of nitric oxide through activation of the AMPK-e NOS mediated pathway. Histological examination revealed that in the MUWP group, the extent of liver cells and tissue damage was significantly reduced compared with the UWP group.CONCLUSION The addition of metformin to the UW preservative solution for ex vivo HMP can reduce rat liver injury during cold ischemia, with significant protective effects on livers, especially of aged rats.

Different ischemic preconditioning for rat liver graft: protection and mechanism

OBJECTIVE: To investigate the protective mechanism of different ischemic preconditioning (IPC) to ischemia/reperfusion (I/R) injury of rat liver graft. METHODS: 192 Wistar rats were randomly divided into 4 groups (48 rats in each group): control group (group C), experimental group 1 (group E_1), experimental group 2 (group E_2), and experimental group 3 (group E_3). IPC was not carried out in group C. In the experimental groups, IPC was carried out by blocking blood flow of the portal vein and hepatic artery and then reperfusion by removal of the clamp before donor liver was resected. Group E_1: 5-minute ischemia and 10-minute reperfusion; Group E_2: 5-minute ischemia and 5-minute reperfusion and one more the same procedure; Group E_3: 10-minute ischemia and 15-minute reperfusion. Four hours after IPC, liver transplantations were performed. Recipient blood and graft samples were obtained to determine the levels of ALT, AST, TNF-α and apoptosis index at 0.5, 2, 6, 24 hours after portal vein reperfusion. RESULTS: At 0.5, 2 hours after portal vein reperfusion, the levels of TNF-α in the experimental groups E_1, E_2, and E_3 were significantly lower than in the control group (P<0.05), and the levels in group E_2 were significantly lower than in groups E_1 and E_3 (P<0.05). At 24 hours, the levels of TNF-α in group E_2 were significantly lower than in groups C, E_1 anti E_3 (P<0.05). At 2 and 6 hours, apoptosis index in the experimental groups E_1, E_2, and E_3 was significantly less than in the control group (P<0.05). Apoptosis index in group E_2 was significantly less than groups E_1 and E_3(P<0.05). At 24 hours apoptosis index in the experimental groups E_1, E_2 , and E_3 was significantly less than in the control group (P<0.05). CONCLUSIONS: Ischemic preconditioning could attenuate liver graft injury by decreasing apoptosis of hepatocytes and production of TNF-α. The method of IPC with 5-minute ischemia, 5-minute reperfusion and one more the same procedure is a better way to protect liver graft from ischemia-reperfusion injury.

Nuclear factor-KB decoy oligodeoxynucleotides attenuates ischemia/reperfusion injury in rat liver graft

AIM: To evaluate the protective effect of NF-κB decoy oligodeoxynucleotides (ODNs) on ischemia/reperfusion (I/R) injury in rat liver graft. METHODS: Orthotopic syngeneic rat liver transplantation was performed with 3 h of cold preservation of liver graft in University of Wisconsin solution containing phosphorothioated double-stranded NF-κB decoy ODNs or scrambled ODNs. NF-κB decoy ODNs or scrambled ODNs were injected intravenously into donor and recipient rats 6 and 1 h before operation, respectively. Recipients were killed 0 to 16 h after liver graft reperfusion. NF-κB activity in the liver graft was analyzed by electrophoretic mobility shift assay (EMSA). Hepatic mRNA expression of TNF-α, IFN-γ and intercellular adhesion molecule-1 (ICAM-1) were determined by semiquantitative RT-PCR. Serum levels of TNF-α and IFN-γ were measured by enzyme-linked immunosorbent assays (ELISA). Serum level of alanine transaminase (ALT) was measured using a diagnostic kit. Liver graft myeloperoxidase (MPO) content was assessed. RESULTS: NF-κB activation in liver graft was induced in a time-dependent manner, and NF-κB remained activated for 16 h after graft reperfusion. NF-κB activation in liver graft was significant at 2 to 8 h and slightly decreased at 16 h after graft reperfusion. Administration of NF-κB decoy ODNs significantly suppressed NF-κB activation as well as mRNA expression of TNF-α, IFN-γ and ICAM-1 in the liver graft. The hepatic NF-κB DNA binding activity [presented as integral optical density (IOD) value] in the NF-κB decoy ODNs treatment group rat was significantly lower than that of the I/R group rat (2.16±0.78 vs 36.78 ±6.35 and 3.06±0.84 vs 47.62± 8.71 for IOD value after 4 and 8 h of reperfusion, respectively, P<0.001). The hepatic mRNA expression level of TNF-α, IFN-γ and ICAM-1 [presented as percent of p-actin mRNA (%)] in the NF-κB decoy ODNs treatment group rat was significantly lower than that of the I/R group rat (8.31 ±3.48 vs 46.37±10.65 and 7.46± 3.72 vs 74.82±12.25 for hepatic TNF-a mRNA, 5.58±2.16 vs 50.46±9.35 and 6.47±2.53 vs 69.72±13.41 for hepatic IFN-y mRNA, 6.79 ±2.83 vs 46.23±8.74 and 5.28±2.46 vs 67.44±10.12 for hepatic ICAM-1 mRNA expression after 4 and 8 h of reperfusion, respectively, P<0.001). Administration of NF-κB decoy ODNs almost completely abolished the increase of serum level of TNF-α and IFN-γ induced by hepatic ischemia/reperfusion, the serum level (pg/mL) of TNF-α and IFN-γ in the NF-kB decoy ODNs treatment group rat was significantly lower than that of the I/R group rat (42.7±13.6 vs 176.7±15.8 and 48.4±15.1 vs 216.8±17.6 for TNF-α level, 31.5±12.1 vs 102.1±14.5 and 40.2±13.5 vs 118.6±16.7 for IFN-γ level after 4 and 8 h of reperfusion, respectively, P<0.001). Liver graft neutrophil recruitment indicated by MPO content and hepatocellular injury indicated by serum ALT level were significantly reduced by NF-κB decoy ODNs, the hepatic MPO content (A655) and serum ALT level (IU/L) in the NF-κB decoy ODNs treatment group rat was significantly lower than that of the I/R group rat (0.17±0.07 vs 1.12 ±0.25 and 0.46±0.17 vs 1.46±0.32 for hepatic MPO content, 71.7±33.2 vs 286.1±49.6 and 84.3±39.7 vs 467.8±62.3 for ALT level after 4 and 8 h of reperfusion, respectively, P< 0.001). CONCLUSION: The data suggest that NF-κB decoy ODNs protects against I/R injury in liver graft by suppressing NF-κB activation and subsequent expression of proinflammatory mediators.

Emerging concepts in liver graft preservation

The urgent need to expand the donor pool in order to attend to the growing demand for liver transplantation has obliged physicians to consider the use of suboptimal liver grafts and also to redefine the preservation strategies. This review examines the different methods of liver graft preservation, focusing on the latest advances in both static cold storage and machine perfusion(MP). The new strategies for static cold storage are mainly designed to increase the fatty liver graft preservation via the supplementation of commercial organ preservation solutions with additives. In this paper we stress the importance of carrying out effective graft washout after static cold preservation, and present a detailed discussion of the future perspectives for dynamic graft preservation using MP at different temperatures(hypothermia at 4 ℃, normothermia a t 3 7 ℃ and subnormothermia at 20 ℃- 2 5 ℃). Finally, we highlight some emerging applications of regenerative medicine in liver graft preservation. In conclusion, this review discusses the "state of the art" and future perspectives in static and dynamic liver graft preservation in order to improve graft viability.

Using old liver grafts for liver transplantation: Where are the limits?

The scarcity of ideal liver grafts for orthotopic liver transplantation(OLT) has led transplant teams to investigate other sources of grafts in order to augment the donor liver pool. One way to get more liver grafts is to use marginal donors, a not well-defined group which includes mainly donors > 60 years, donors with hypernatremia or macrosteatosis > 30%, donors with hepatitis C virus or hepatitis B virus positive serologies, cold ischemia time > 12 h, non-heart-beating donors, and grafts from split-livers or living-related donations. Perhaps the most practical and frequent measure to increase the liver pool, and thus to reduce waiting list mortality, is to use older livers. In the past years the results of OLT with old livers have improved, mainly due to better selection and maintenance of donors, improvements in surgical techniques in donors and recipients, and intra- and post-OLT management. At the present time, sexagenarian livers are generally accepted, but there still exists some controversy regarding the use of septuagenarian and octogenarian liver grafts. The aim of this paper is to briefly review the aging process of the liver and reported experiences using old livers for OLT. Fundamentally, the series of septuagenarian and octogenarian livers will be addressed to see if there is a limit to using these aged grafts.

How to protect liver graft with nitric oxide

Organ preservation and ischemia reperfusion injury as- sociated with liver transplantation play an important role in the induction of graft injury. One of the earliest events associated with the reperfusion injury is en- dothelial cell dysfunction. It is generally accepted that endothelial nitric oxide synthase (e-NOS) is cell-pro- tective by mediating vasodilatation, whereas inducible nitric oxide synthase mediates liver graft injury after transplantation. We conducted a critical review of the literature evaluating the potential applications of regu- lating and promoting e-NOS activity in liver preservation and transplantation, showing the most current evidenceto support the concept that enhanced bioavailability of NO derived from e-NOS is detrimental to ameliorate graft liver preservation, as well as preventing subse- quent graft reperfusion injury. This review deals mainly with the beneficial effects of promoting "endogenous" pathways for NO generation, via e-NOS inducer drugs in cold preservation solution, surgical strategies such as ischemic preconditioning, and alternative "exogenous" pathways that focus on the enrichment of cold storage liquid with NO donors. Finally, we also provide a basic bench-to-bed side summary of the liver physiology and cell signalling mechanisms that account for explaining the e-NOS protective effects in liver preservation and transplantation. ? 2011 Baishideng. All rights reserved.

Reuse of liver grafts following the brain death of the initial recipient

AIM: To determine if there is a reasonable prospect of success of a re-use liver transplantation.METHODS: We systematically searched for reports of liver graft re-use using electronic searches of PubMed and Web of Knowledge. We performed hand searches of references lists of articles reporting re-use of grafts.RESULTS: A systematic review of the literature reveals 28 liver transplantations using previously transplanted grafts. First and second recipients ranged in age from 4 to 72 years and 29 to 62 years respectively. Liver disease in the first recipient was varied including 5(18%) patients with fulminant liver failure who died subsequently of cerebral edema. The second transplanta-tion was performed after a median interval of 5 d(one day-13 years). Viral hepatitis was present in 3(11%) of the initial recipients and in 8(29%) of final recipients. Hepatocellular carcinoma was present in 6(21%) of the final recipients. Early survival after the final transplantation was 93%, whereas long-term survival was 78% with a mean follow-up of 23.3(3-120) mo.CONCLUSION: Outcomes of transplantation using previously transplanted grafts in this select population are similar to those seen with conventional grafts.

Feasibility of using marginal liver grafts in living donor liver transplantation

Liver transplantation(LT) is one of the most effective treatments for end-stage liver disease caused by related risk factors when liver resection is contraindicated. Additionally,despite the decrease in the prevalence of hepatitis B virus(HBV) over the past two decades,the absolute number of HBs Ag-positive people has increased,leading to an increase in HBV-related liver cirrhosis and hepatocellular carcinoma. Consequently,a large demand exists for LT. While the wait time for patients on the donor list is,to some degree,shorter due to the development of living donor liver transplantation(LDLT),there is still a shortage of liver grafts. Furthermore,recipients often suffer from emergent conditions,such as liver dysfunction or even hepatic encephalopathy,which can lead to a limited choice in grafts. To expand the pool of available liver grafts,one option is the use of organs that were previously considered "unusable" by many,which are often labeled "marginal" organs. Many previous studies have reported on the possibilities of using marginal grafts in orthotopic LT; however,there is still a lack of discussion on this topic,especially regarding the feasibility of using marginal grafts in LDLT. Therefore,the present review aimed to summarize the feasibility of using marginal liver grafts for LDLT and discuss the possibility of expanding the application of these grafts.

Liver graft preservation methods during cold ischemia phase and normothermic machine perfusion

The growing demand for donor organs requires measures to expand donor pool.Those include extended criteria donors, such as elderly people, steatotic livers,donation after cardiac death, etc. Static cold storage to reduce metabolic requirements developed by Collins in late 1960 s is the mainstay and the golden standard for donated organ protection. Hypothermic machine perfusion provides dynamic organ preservation at 4°C with protracted infusion of metabolic substrates to the graft during the ex vivo period. It has been used instead of static cold storage or after it as short perfusion in transplant center. Normothermic machine perfusion(NMP) delivers oxygen, and nutrition at physiological temperature mimicking regular environment in order to support cellular function. This would minimize effects of ischemia/reperfusion injury.Potentially, NMP may help to estimate graft functionality before implantation into a recipient. Clinical studies demonstrated at least its non-inferiority or better outcomes vs static cold storage. Regular grafts donated after brain death could be safely preserved with convenient static cold storage. Except for prolonged ischemia time where hypothermic machine perfusion started in transplant center could be estimated to provide possible positive reconditioning effect. Use of hypothermic machine perfusion in regular donation instead of static cold storage or in extended criteria donors requires further investigation. Multicenter randomized clinical trial supposed to be completed in December 2021. Extended criteria donors need additional measures for graft storage and assessment until its implantation. NMP is actively evaluating promising method for this purpose.Future studies are necessary for precise estimation and confirmation to issue clinical practice recommendations.

Impact of small-for-size liver grafts on medium-term and long-term graft survival in living donor liver transplantation: A meta-analysis

BACKGROUND Small-for-size grafts (SFSGs) in living donor liver transplantation (LDLT) could optimize donor postoperative outcomes and also expand the potential donor pool. Evidence on whether SFSGs would affect medium-term and long-term recipient graft survival is lacking. AIM To evaluate the impact of small-for-size liver grafts on medium-term and longterm graft survival in adult to adult LDLT. METHODS A systematic review and meta-analysis were performed by searching eligible studies published before January 24, 2019 on PubMed, EMBASE, and Web of Science databases. The primary outcomes were 3-year and 5-year graft survival. Incidence of small-for-size syndrome and short term mortality were also extracted. RESULTS This meta-analysis is reported according to the guidelines of the PRISMA 2009 Statement. Seven retrospective observational studies with a total of 1821 LDLT recipients were included in the meta-analysis. SFSG is associated with significantly poorer medium-term graft survival. The pooled odds ratio for 3-year graft survival was 1.58 [95% confidence interval 1.10-2.29, P = 0.014]. On the other hand, pooled results of the studies showed that SFSG had no significant discriminatory effect on 5-year graft survival with an odds ratio of 1.31 (95% confidence interval 0.87-1.97, P = 0.199). Furthermore, incidence of small-for-size syndrome detected in recipients of SFSG ranged from 0-11.4% in the included studies. CONCLUSION SFSG is associated with inferior medium-term but not long-term graft survival. Comparable long-term graft survival based on liver graft size shows that smaller grafts could be accepted for LDLT with appropriate flow modulatory measures. Close follow-up for graft function is warranted within 3 years after liver transplantation.

Liver grafts from hepatitis B surface antigen-positive donors: A review of the literature

The scarcity of available organs and the gap between supply and demand continue to be the main limitations of liver transplantation. To relieve the organ shortage, current transplant strategies have implemented extended criteria, which include the use of liver from patients with signs of past or present hepatitis B virus(HBV) infection. While the use of liver grafts from donors with evidence of past HBV infection is quite limited, some data have been collected regarding the feasibility of transplanting a liver graft from a hepatitis B surface antigen(HBs Ag) positive donor. The aim of the present work was to review the literature regarding liver transplants from HBs Ag-positive donors. A total of 17 studies were identified by a search in Medline. To date, HBs Ag positive grafts have preferentially been allocated to HBs Ag positive recipients. The large majority of these patients continue to be HBs Ag positive despite the use of immunoglobulin, and infection prevention can only be guaranteed by using antiviral prophylaxis. Although serological persistence is evident, no significant HBV-related disease has been observed, except in patients coinfected with delta virus. Consistently less data are available for HBs Ag negative recipients, although they are mostly promising. HBs Agpositive grafts could be an additional organ source for liver transplantation, provided that the risk of reinfection/reactivation is properly prevented.

Effect of ulinastatin donor-pretreatment on liver graft during cold preservation in rats

Background Donor-pretreatment with ulinastatin may influence the liver graft during cold preservation. The aim of this research was to determine whether pretreatment of donor liver with Ulinastatin can attenuate cold preservation injury,and to explore the mechanism by which Ulinastatin affects the donor liver graft.Methods One hundred and forty-four Wistar rats were divided into the Ulinastatin treatment group （T group） pretreated with Ulinastatin 50 000 U/kg and control group （C group） treated with 0.9% normal saline via peritoneal injection prior to the anesthetization. After the abdominal cavity was opened and perfused with cold Ringer＇s lactate solution, the liver was harvested. The harvested liver was preserved in cold Ringer＇s lactate solution for 0, 2, 6, 24 hours, at which time the liver tissue was sampled for determination of dry weight and wet weight, Na＋-K＋-ATPase and Ca2＋-ATPase activity, lactic acid dehydrogenase （LDH） activity, lactic acid and malondialdehyde levels. Light microscopy and electron microscopy were used to observe liver morphology. The liver cold-preservation solution was taken for measurement of aspartate aminotransferase （AST） and alanine transaminase （ALT） levels. Correlation between ATPase activity and lactic acid level was analyzed by SPSS 13.0 for Windows.Results The morphology in the T group had improved cell boundaries vs. The C group at each time point. Dry weight to wet weight in the T group was lower than in the C group at 6 hours （P 〈0.05）, but the difference was not significant at 24 hours. ALT levels in the T group were lower than that in the C group at 6 hours （P 〈0.05） and 24 hours （P 〈0.01）. AST levels in the T group were lower than those in the C group at 2 hours （P〈0.05）, 6 hours （P 〈0.01） and 24 hours （P 〈0.01）.Na＋-K＋-ATPase activity in the T group was higher than in the C group and the mean difference between two groups was significant at 0 hour （P 〈0.05） and 2 hours （P 〈0.05）. Ca2＋-ATPase activity in the T group was higher than in the C group with the mean difference between two groups significant at 2 hours （P 〈0.05）. The T group had increased lactic acid levels at 0 hour （P 〈0.01） and 2 hours （P 〈0.05） compared with the C group, but there was no influence on the LDH activity at the same time. There were no obvious differences in the levels of malondialdehyde between the two groups at any time point. A linear correlation between Na＋-K＋-ATPase activity and lactic acid levels （r=0.295, P 〈0.05） was found.Conclusions Donor-pretreatment with ulinastatin may protect the cells in a liver graft from ischemia injury during cold preservation; the mechanism may be due to its promotion for cell glycolysis and its preservation of ATPase activity.

Risk factors, surgical complications and graft survival in liver transplant recipients with early allograft dysfunction

Background: Early allograft dysfunction (EAD) is a severe complication after liver transplantation. The associated risk factors and complications have re-gained recent interest. This study investigated risk factors, survival and complications associated with EAD in a large liver transplant center in Latin America. Methods: Retrospective, unicenter, cohort, based on data from adult patients undergoing first deceaseddonor liver transplant from January 2009 to December 2013. EAD was defined by one or more of the following:(i) bilirubin ≥10 mg/dL on postoperative day 7;(ii) international normalized ratio ≥1.6 on postoperative day 7, and (iii) alanine aminotransferase or aspartate aminotransferase > 2000 IU/L within the first seven days after transplant. Results: A total of 602 patients were included;of these 34.2% developed EAD. Donor risk factors were male ( P = 0.007), age between 50 and 59 years ( P = 0.034), overweight ( P = 0.028) or grade I obesity ( P = 0.012), sodium > 157 mmol/L ( P = 0.002) and grade IV ischemia/reperfusion injury ( P = 0.002). Cold ischemia time ≥10 h ( P = 0.008) and warm ischemia time ≥40 min ( P = 0.013) were the surgical factors. Male ( P < 0.001) was the only recipient protective factor. Compared with the non-EAD group, patients with EAD were submitted to more reoperations (24.3% vs. 13.4%, P = 0.001) and had higher graft loss rates (37.9% vs. 21.2%, P < 0.001), with similar patient survival rates ( P = 0.238). Conclusions: EAD risk factors are related to donor, surgical procedure and recipient. Donor risk factors for EAD were male, age between 50 and 59 years, donor overweight or grade Ⅰ obesity, sodium > 157 mmol/L and grade Ⅳ ischemia/reperfusion injury. Cold ischemia time ≥10 h and warm ischemia time ≥40 min were the surgical risk factors. Male was the only recipient protective factor. Patients with EAD had higher reoperations and graft loss rates.

Protocol liver biopsy is the only examination that can detect mid-term graft fibrosis after pediatric liver transplantation

AIM:To assessed the clinical significance of protocol liver biopsy(PLB)in pediatric liver transplantation(LT).METHODS:Between July 2008 and August 2012,89and 55 PLBs were performed in pediatric patients at two and five years after LT,respectively.We assessed the histopathological findings using the Metavir scoring system,including activity(A)and fibrosis(F),and we identified factors associated with scores of≥A1 and≥F1.Our results clarified the timing and effectiveness of PLB.RESULTS:The incidences of scores of≥A1 and≥F1 were 24.7%and 24.7%,respectively,at two years after LT and 42.3%and 34.5%,respectively,at five years.Independent risk factors in a multivariate analysis of a score of≥A1 at two years included≥2 h ofcold ischemic time,no acute cellular rejection and an alanine amino transaminase(ALT)level of≥20 IU/L(P=0.028,P=0.033 and P=0.012,respectively);however,no risk factors were identified for a score of≥F1.Furthermore,no independent risk factors associated with scores of≥A1 and≥F1 at five years were identified using multivariate analysis.A ROC curve analysis of ALT at two years for a score of≥A1 demonstrated the recommended cutoff value for diagnosing≥A1 histology to be 20 IU/L.The incidence of scores of≥A2 or≥F2 at two years after LT was 3.4%(three cases),and all patients had an absolute score of≥A2.In contrast to that observed for PLBs at five years after LT,the incidence of scores of≥A2 or≥F2 was 20.0%(11 cases),and all patients had an absolute score of≥F2.In all cases,the dose of immunosuppressants was increased after the PLB,and all ten patients who underwent a follow-up liver biopsy improved to scores of≤A1 or F1.CONCLUSION:PLB at two years after LT is an unnecessary examination,because the serum ALT level reflects portal inflammation.In addition,immunosuppressive therapy should be modulated to maintain the ALT concentration at a level less than 20 IU/L.PLB at five years is an excellent examination for the detection of early reversible graft fibrosis because no serum markers reflect this finding.

Outcomes of right-lobe and left-lobe living-donor liver transplantations using small-for-size grafts

AIM To analyze the outcomes of living-donor liver transplantation(LDLT) using left-lobe(LL) or right-lobe(RL) small-for-size(SFS) grafts.METHODS Prospectively collected data of adult patients who underwent LDLT at our hospital in the period from January 2003 to December 2013 were reviewed. The patients were divided into the RL-LDLT group and the LL-LDLT group. The two groups were compared in terms of short-and long-term outcomes, including incidence of postoperative complication, graft function, graft survival, and patient survival. A SFS graft was defined as a graft with a ratio of graft weight(GW) to recipient standard liver volume(RSLV)(GW/RSLV) of < 50%. The Urata formula was used to estimate RSLV.RESULTS Totally 218 patients were included for analysis, with 199 patients in the RL-LDLT group and 19 patients in the LL-LDLT group. The two groups were similar in terms of age(median, 53 years in the RL-LDLT group and 52 years in the LL-LDLT group, P = 0.997) but had significantly different ratios of men to women(165:34 in the RL-LDLT group and 8:11 in the LL-LDLT group, P < 0.0001). The two groups were also significantly different in GW(P < 0.0001), GW/RSLV(P < 0.0001), and graft cold ischemic time(P = 0.007). When it comes to postoperative complication, the groups were comparable(P = 0.105). Five patients died in hospital,4(2%) in the RL-LDLT group and 1(5.3%) in the LLLDLT group(P = 0.918). There were 38 graft losses, 33(16.6%) in the RL-LDLT group and 5(26.3%) in the LL-LDLT group(P = 0.452). The 5-year graft survival rate was significantly better in the RL-LDLT group(95.2% vs 89.5%, P = 0.049). The two groups had similar 5-year patient survival rates(RL-LDLT: 86.8%, LL-LDLT: 89.5%, P = 0.476).CONCLUSION The use of SFS graft in LDLT requires careful tailormade surgical planning and meticulous operation. LLLDLT can be a good alternative to RL-LDLT with similar recipient outcomes but a lower donor risk. Further research into different patient conditions is needed in order to validate the use of LL graft.

Graft-versus-host disease after liver transplantation:A comprehensive literature review

AIM:To determine the factors affecting mortality in patients who developed graft-versus-host disease (GvH) after liver transplantation (LT) METHODS:We performed a review of studies of GvH following LT published in the English literature and accessed the PubMed, Medline, EBSCO, EMBASE, and Google Scholar databases Using relevant search phrases, 88 articles were identified. Of these, 61 articles containing most of the study parameters were considered eligible for the study. Risk factors were first examined using a univariate Kaplan-Meier model, and variables with a significant association (P < 0 05) were then subjected to multivariate analyses using a Cox proportional-hazards model RESULTS:The 61 articles reported 87 patients, 58 male and 29 female, mean age, 40.4 ± 15.5 years (range:8 mo to 74 years), who met the inclusion criteria for the present study. Deaths occurred in 59 (67.8%) patients, whereas 28 (32.2%) survived after a mean follow-up period of 280.8 ± 316.2 d (range:27-2285 d). Among the most frequent symptoms were rash (94.2%), fever (66.6%), diarrhea (54%), and pancytopenia (54%). Theaverage time period between LT and first symptom onset was 60.6 ± 190.1 d (range: 2-1865 d). The Kaplan-Meier analysis revealed that pancytopenia (42.8% vs 59.3%,P = 0.03), diarrhea (39.2%vs 61.0%,P = 0 04), age difference between the recipient and the donor (14.6 ± 3.1 yearsvs 22.6 ± 2.7 years,P < 0.0001), and time from first symptom occurrence to diagnosis or treatment (13.3 ± 2.6 mo vs 15.0 ± 2.3 mo, P < 0.0001) were significant factors affecting mortality, whereas age, sex, presence of rash and fever, use of immunosuppressive agents, acute rejection before GvH , etiological causes, time of onset, and donor type were not associated with mortality risk The Cox proportional-hazards model, determined that an age difference between the recipient and donor was an independent risk factor (P = 0 03; hazard ratio, 7.395, 95% confidence interval, 1.2-46.7). CONCLUSION:This study showed that an age difference between the recipient and donor is an independent risk factor for mortality in patients who develop GvH after LT.

Effect of donor age on graft function and longterm survival of recipients undergoing living donor liver transplantation

BACKGROUND： Donor shortage is the biggest obstacle in organ transplantation. Living donor liver transplantation（LDLT） has been considered as a valuable approach to shortening waiting time. The objectives of this study were to investigate the feasibility of utilizing donors older than 50 years in LDLT and to evaluate the graft function and recipient survival.METHODS： All LDLT cases（n=159） were divided into the older（donor age ≥50 years, n=10） and younger（donor age 〈50 years,n=149） donor groups. Donor graft and recipient condition pre-,intra- and post-operation were compared between the two groups.In particular, graft functions and recipient survivals were analyzed.RESULTS： The median donor age was 58.5（52.5-60.0） years in the older donor group and 25.0（23.0-32.0） in the younger donor group. There was no significant difference in cold ischemic time, anhepatic phase and operation time between the older and younger donor groups（P〉0.05）. However, the volume of red blood cell transfused in operation was greater in the older donor group than in the younger donor group（1900 vs 1200 m L, P=0.023）. The 1-, 3- and 5-year graft survival rates were 90%, 80% and 80% for the older donor group, and 92%, 87% and 87% for the younger donor group, respectively（P=0.459）.The 1-, 3- and 5-year survival rates were 100%, 90% and 90% for recipients with older grafts, and 93%, 87% and 87% for those with younger grafts, respectively（P=0.811）.CONCLUSION： It is safe for a LDLT recipient to receive liver from donors older than 50 years, and there is no significant adverse effect on graft function and long-term patients’ survival.

Early graft dysfunction following adult-to-adult livingrelated liver transplantation:Predictive factors and outcomes

AIM:To describe a condition that we define as early graft dysfunction(EGD)which can be identified preoperatively. METHODS:Small-for-size graft dysfunction following living-related liver transplantation(LRLT)is characterized by EGD when the graft-to-recipient body weight ratio(GRBWR)is below 0.8%.However, patients transplanted with GRBWR above 0.8%can develop dysfunction of the graft.In 73 recipients of LRLT(GRBWR>0.8%),we identified 10 patients who developed EGD.The main measures of outcomes analyzed were overall mortality,number of re-transplants and length of stay in days(LOS).Furthermore we analyzed other clinical pre-transplant variables,intraoperative parameters and post transplant data.RESULTS:A trend in favor of the non-EGD group(3-mo actuarial survival 98%vs 88%,P=0.09;3-mo graft mortality 4.7%vs 20%,P=0.07)was observed as well as shorter LOS(13 d vs 41.5 d;P=0.001)and smaller requirement of peri-operative Units of Plasma (4 vs 14;P=0.036).Univariate analysis of pre- transplant variables identified platelet count,serum bilirubin,INR and Meld-Na score as predictors of EGD. In the multivariate analysis transplant Meld-Na score (P=0.025,OR:1.175)and pretransplant platelet count(P=0.043,OR:0.956)were independently associated with EGD. CONCLUSION:EGD can be identified preoperatively and is associated with increased morbidity after LRLT. A prompt recognition of EGD can trigger a timely treatment.

Auxiliary partial liver transplantation for acute liver failure using "high risk" grafts: Case report

Acute liver failure(ALF) is a reversible disorder that is associated with an abrupt loss of hepatic mass, rapidly progressive encephalopathy and devastating complications. Despite its high mortality, an emergency liver transplantation nowadays forms an integral part in ALF management and has substantially improved the outcomes of ALF. Here, we report the case of a 32-year-old female patient who was admitted with grade Ⅳ hepatic encephalopathy(coma) following drug-induced ALF. We performed an emergency auxiliary partial orthotopic liver transplantation with a "high risk" graft(liver macrovesicular steatosis approximately 40%) from a living donor. The patient was discharged on postoperative day 57 with normal liver function. Weaning from immunosuppression was achieved 9 mo after transplantation. A follow-up using CT scan showed a remarkable increase in native liver volume and gradual loss of the graft. More than 6 years after the transplantation, the female now has a 4-year-old child and has returned to work full-time without any neurological sequelae.

Living donor liver transplantation using dual grafts:Ultrasonographic evaluation

AIM: To evaluate the dual-graft living donor liver transplantation (LDLT) with ultrasonography, with special emphasis on the postoperative complications. METHODS: From January 2002 to August 2007, 110 adult-to-adult LDLTs were performed in West China Hos- pital of Sichuan University. Among them, dual-graft implantations were performed in six patients. Sonographic findings of the patients were retrospectively reviewed. RESULTS: All the six recipients survived the dual-graft adult-to-adult LDLT surgery. All had pleural effusion. Four patients had episodes of postoperative abdominal complications, including fluid collection between the grafts in three patients, intrahepatic biliary dilatation in two, hepatofugal portal flow of the left lobe in two, and atrophy of the left lobe in one. CONCLUSION: Although dual-graft LDLT takes more efforts and is technically complicated, it is safely feasible. Postoperative sonographic monitoring of the recipient is important.