Rapamycin Attenuates Liver Graft Injury in Cirrhotic Recipient—The Significance of Down-Regulation of Rho-ROCK-VEGF Pathway

To investigate whether rapamycin could attenuate hepatic I/R injury in a cirrhotic rat liver transplantation model, we applied a rat orthotopic liver transplantation model using 100% or 50% of liver grafts and cirrhotic recipients. Rapamycin was given (0.2 mg/kg, i.v.) at 30 min before graft harvesting in the donor and 24 h before operation, 30 min before total hepatectomy and immediately after reperfusion in the recipient. Rapamycin significantly improved small-for-size graft survival from 8.3% (1/12) to 66.7% (8/12) (p = 0.027). It also increased 7-day survival rates of whole grafts (58.3%[7/12] vs. 83.3%[10/12], p = 0.371). Activation of hepatic stellate cells was mainly found in small-for-size grafts during the first 7 days after liver transplantation. Rapamycin suppressed expression of smooth muscle actin, which is a marker of hepatic stellate cell activation, especially in small-for-size grafts. Intragraft protein expression and mRNA levels of vascular endothelial growth factor (VEGF) were down-regulated by rapamycin at 48 h both in whole and small-for-size grafts. Consistently, mRNA levels and protein expression of Rho and ROCK I were decreased by rapamycin during the 48 h after liver transplantation. In conclusion, rapamycin attenuated graft injury in a cirrhotic rat liver transplantation model by suppression of hepatic stellate cell activation, related to down-regulation of Rho-ROCK-VEGF pathway.     

Prolongation of canine liver allograft survival by a novel immunosuppressant, FTY720: effect of monotherapy and combined treatment with conventional drugs

BACKGROUND: The immunosuppressive effect and other properties of a novel immunosuppressant, FTY720, have been studied mostly in the experimental transplantation of various extrahepatic organs. In this experiment, we evaluated the antirejection potency and adverse effects of this agent on liver grafts using a canine liver transplantation model. METHODS: Forty-eight orthotopic liver transplantations were performed by the standard technique under a veno-venous bypass. Liver recipients were divided into two studies: a single-dose study with FTY720 at various doses and a combined dose study with conventional immunosuppressants (cyclosporine or tacrolimus) alone and combined with FTY720. Survival, biochemical and hematological tests, blood levels of immunosuppressants, and postmortem histology were determined. RESULTS: The median survival of untreated control animals was 9 days, whereas treatment with FTY720 at a dose of 0.1 mg/kg/day prolonged graft survival to 49.5 days. FTY720 at 1 mg/kg/day showed a slight but insignificant prolongation to 16 days, but when the dose was increased to 5 mg/kg/day, the graft was rejected at 10 days. The combination of FTY720, 0.1 mg/kg/day, with a subtherapeutic dose of cyclosporine, 5 mg/kg/ day, prolonged median animal survival from 40 days with cyclosporine alone to 74 days. A combination of FTY720 (0.1 mg/kg/day) with tacrolimus (0.5 mg/kg/ day) compromised animal survival, reducing survival from 83.5 days with tacrolimus alone to 30.5 days due to infectious complication and emaciation by overimmunosuppression. No evident drug-induced side effects were observed. CONCLUSIONS: FTY720 has a potent immunosuppressive effect when used alone at 0.1 mg/kg/day in canine liver transplantation. FTY720 is a promising candidate for future clinical application in orthotopic liver transplantation.     

Long-term Graft Acceptance in Rat Heart Transplantation by CTLA4Ig Gene Transfection Combined with FTY720 Treatment

CTLA4Ig strongly adheres to B7 molecules on antigen-presenting cells to block intracellular signal transduction via CD28 on helper T cells, which eventually inhibits immune responses. We have demonstrated that the administration to recipient animals of adenoviral vectors containing CTLA4Ig gene (adCTLA4Ig) prolonged graft survival, although the gene expression diminished in a time-dependent manner and the grafts were finally rejected. In addition, recipient animals treated with FTY720, a new immunosuppressant, exhibited a decrease in the number of peripheral lymphocytes due to apoptosis. In this study, we performed adCTLA4Ig transfection combined with FTY720 treatment in heart-grafted rats to determine if the combination could induce a mutual effect on graft survival. The recipient animals were given injections of 1 x 10(9) plaque-forming units of adCTLA4Ig via the tail vein immediately after grafting. On the day before transplantation we administered FTY720 orally to some of these animals at a dosage of 5 mg/kg and again on the day of transplantation. The median graft survival period in the adCTLA4Ig-only group was 27 days, whereas that in the combination group was markedly prolonged to 56 days. Of 15 grafts, 5 survived indefinitely. In these groups we observed detectable levels of CTLA4Ig in the sera 49 days after grafting; the levels were always higher in the combination group than in the adCTLA4Ig-only group. As a result, this study revealed that FTY720 and adCTLA4Ig have a potent mutual effect on graft survival during rat heart transplantation. Furthermore, it is highly possible that FTY720 enhances gene expression of adCTLA4Ig, which may be related to the long-term acceptance of grafts.     

Impaired hepatic regeneration by ischemic preconditioning in a rat model of small-for-size liver transplantation

OBJECTIVE: Graft size is one of the major risk factors in adult-to-adult living donor liver transplantation and rapid regeneration is an essential post-operative requirement. Ischemic preconditioning (IPC) has been shown to be an effective strategy in the reduction of hepatic ischemia-reperfusion injury and stimulation of liver regeneration. This study was designed to evaluate the effects of IPC on liver regeneration in small-for-size liver grafts. METHODS: We employed a rat orthotopic liver transplantation model using small-for-size (30%) grafts, in the presence or absence (control) of IPC (10 min of ischemia followed by 15 min of reperfusion). Survival rate, graft injury, hepatocellular proliferation, cell cycle progression, Stat3 activation, as well as TNF-alpha and IL-6 expression were assessed. RESULTS: IPC significantly enhanced the extent of graft injury and hindered hepatic regeneration in small-for-size liver grafts. The 7-day survival rate was also reduced by IPC, but failed to reach statistical significance. IPC did not affect TNF-alpha levels, but significantly decreased the elevation of IL-6 after reperfusion. These findings were correlated with down-regulation of cyclin E and cyclin D1, and decreased numbers of PCNA-positive nuclei in IPC grafts. These results were inconsistent with Stat3 activation, as P-Stat3 exhibited a stronger and prolonged pattern of expression in the IPC group, compared to controls. CONCLUSIONS: Ischemic preconditioning may impair liver regeneration in small-for-size liver grafts by decreasing IL-6 and blunting cell cycle progression, through a mechanism at least partially independent of Stat3.     

FTY720介导淋巴细胞凋亡抑制小肠移植的移植物抗宿主免疫反应

目的 探讨免疫调节药物FTY720对小肠移植后急性移植物抗宿主病（GVHD）的治疗效果及其作用机制.方法 应用Wistar-Furth（WF）大鼠作为供体,WF和ACI大鼠的子代（F1）作为受体,同种异基因异位全小肠移植的技术方法建立GVHD的动物模型.移植受体分为实验组和对照组,每组6只.实验组从移植手术当日开始予以FTY720治疗,持续14 d;对照组在相同的时间段口服蒸馏水.术后第15天,提取受体靶器官肝脏、小肠及移植物小肠的淋巴细胞,应用免疫组织化学（免疫组化）TUNEL法和流式细胞仪检测两组淋巴细胞凋亡的变化.结果 对照组大鼠术后均死亡于GVHD,平均生存时间（16.0±1.7）d,实验组大鼠均长期成活超过100 d,两组差异具有统计学意义（P＜0.01）.免疫组化TUNEL法检测结果显示,实验组肝脏和移植物小肠黏膜的淋巴细胞凋亡比率均明显高于对照组,差异具有统计学意义（P＜0.05）.流式细胞技术分析结果显示,实验组大鼠移植物小肠黏膜内凋亡的淋巴细胞百分比为19.4%,明显高于对照组的11.8%（P＜0.05）;而肝脏凋亡的淋巴细胞百分比两组差异无统计学意义（P＞0.05）.结论 FTY720可能通过诱导淋巴细胞的凋亡,减少和抑制GVHD对靶器官的损害,改善移植大鼠的预后.     

Attenuation of acute phase shear stress by somatostatin improves small-for-size liver graft survival.

The major concern of living donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be developed. To investigate the protective effect of somatostatin related to hemodynamic stress on small-for-size liver graft injury, we applied a treatment regimen of low-dose somatostatin in a rat orthotopic liver transplantation model using small-for-size grafts (median, 38.7%; range, 35-42%). Somatostatin was given at 5 minutes before total hepatectomy and immediately after reperfusion in the recipient (20 microg/kg). Graft survival, portal hemodynamics, intragraft gene expression and hepatic ultrastructural changes were compared between the rats with or without somatostatin treatment. Seven-day graft survival rates in the somatostatin treatment group were significantly improved compared to the control group (66.7% vs. 16.7%, P = 0.036). In the treatment group, portal pressure and hepatic surface blood flow were significantly decreased within the first 30 minutes after reperfusion, whereas in the control group, transient portal hypertension and excessive hepatic blood flow were observed. Intragraft expression (both messenger RNA and protein) of endothelin-1 was significantly downregulated accompanied with upregulation of heme oxygenase-1 and A20. Better preservation of liver function was found in the treatment group. Hepatic ultrastructure, especially the integrity of sinusoids, was well protected in the treatment group. In conclusion, low-dose somatostatin rescues small-for-size grafts from acute phase injury in liver transplantation by attenuation of acute-phase shear stress that resulted from transient portal hypertension.     

FTY720 Prevents Anti-CD4 mAb-Induced Tolerance but Cannot Reverse Established Tolerance in a Rat Kidney Transplantation Model

FTY720 is highly effective in various models of transplantation and autoimmunity. In order to find drugs that act synergistically with a tolerance-inducing nondepleting anti-CD4 mAb we studied this combination in a strong DA to LEW kidney transplantation model. Rats were treated with 0.3 mg/kg of FTY720 for 14 days and anti-CD4 mAb RIB5/2, alone or in combination. After kidney transplantation serum creatinine and blood lymphocyte counts were monitored. Immunohistology, ELISPOT and TaqMan trade mark -PCR analysis of biopsies were performed. Short-term application of RIB5/2 but not FTY720 induced long-term survival of kidney transplants. Moreover, the combination of FTY720 + RIB5/2 prevented tolerance induction. In the combination group serum creatinine levels increased 1 week after cessation of therapy and all rats died from uremia within 72 days. Intragraft immunohistology, ELISPOT and real-time RT-PCR analysis at day 21 demonstrated an enhanced T-cell infiltration and activation but a diminished up-regulation of protective genes in the grafts from recipients receiving the combination therapy. In contrast, delayed application of FTY720 to RIB5/2-treated rats did not interact with RIB5/2-induced tolerance. In summary, FTY720 is powerful in preventing intragraft infiltration by naive T cells but this might also affect the early development of graft-protecting regulatory T cells and tolerance induction.     

A new immunosuppressant, FTY720, in canine kidney transplantation: effect of single-drug, induction and combination treatments

Three different types of treatment were conducted to clarify the properties of a novel immunomodulator, FTY720, in canine kidney allograft models. Survival, biochemical and hematological tests, pharmacokinetics, and histopathology of grafts and extra-renal organs were analyzed. Accompanying a remarkable reduction in circulating lymphocytes, single-drug treatment of FTY720, ranging from 0.05 to 10 mg/kg, exhibited significant prolongation of graft survival without a dose-dependent effect. Short-course induction with FTY720 at 5 mg/kg per day exhibited similar anti-rejection effects as did single-drug treatment but no advantage in rescuing ongoing rejection. In combination with cyclosporine (CsA; 5 mg/kg) or tacrolimus (FK; 0.5 mg/kg), FTY720 had an additive effect. Trough blood concentrations of FTY720 were linearly correlated with dose. No animal showed critical adverse effects at any point. FTY720 holds promise as a candidate in a new category of drugs that can be combined with conventional agents for induction and maintenance immunosuppression in clinical organ transplantation.     

Protective effects of FTY720 on chronic allograft nephropathy by reducing late lymphocytic infiltration

BACKGROUND: Lymphocytic infiltration is obvious throughout early and late stages of chronic allograft nephropathy. Early infiltrating lymphocytes are involved in initial insults to kidney allografts, but the contribution of late infiltration to long-term allograft attrition is still controversial. Early application of FTY720 reduced the number of graft infiltrating lymphocytes, and inhibited acute rejection. The present study investigated the potential of FTY720 to reduce the number of infiltrating lymphocytes even at a late stage, and, thus, slow the pace of chronic allograft nephropathy. METHODS: Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients with an initial 10-day course of cyclosporine A (1.5 mg/kg/day). FTY720, at a dose of 0.5 mg/kg/day, or vehicle was administered to recipients either from weeks 12 to 24 or from 20 to 24 after transplantation. Animals were harvested 24 weeks after transplantation for histologic, immunohistologic, and molecular analysis. RESULTS: FTY720, either initiated at 12 or 20 weeks after transplantation, reduced urinary protein excretion, and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, and intimal proliferation of graft arteries at 24 weeks after transplantation. Furthermore FTY720 markedly suppressed lymphocyte infiltration and decreased mRNA levels of interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and platelet-derived growth factor-B (PDGF-B) but enhanced the number of apoptotic cells in grafts. CONCLUSIONS: FTY720 ameliorated chronic allograft nephropathy even at advanced stages. Furthermore, our data suggest that this effect was achieved by a reduction of graft infiltrating lymphocytes.     

Combined FTY720/cyclosporine A treatment promotes graft survival and lowers the peripheral lymphocyte count in DA to lewis heart and skin transplantation models

OBJECTIVE: The immunomodulator, FTY720, lowers the peripheral lymphocyte count (PLC) by inducing migration of circulating lymphocytes to secondary lymphoid organs. We investigated the efficacy of mono- vs. combined-FTY720/CsA therapy on graft survival (GS) and on lowering the PLC in a solid organ and a skin graft model, using strains with strong MHC disparity. Methods: Heterotopic cardiac or tail skin grafting was performed using the DA (RT1a) to Lewis (RT1(1)) rat strain combination. FTY720 was administered as a single daily dose by gavage alone or in combination with subcutaneously delivered CsA. PLC, body weight and drug concentrations were determined on day 7, 28, or the day of rejection. MAIN FINDINGS: In placebo-treated animals the heart and skin allografts rejected after 6 and 8 days. FTY720 delayed rejection of both the solid organ and skin grafts. The maximal effect was achieved at 1 mg x kg(-l) x day(-1) FTY720, resulting in a median survival time (MST) of 14 days for both allotransplants comparable to the effect achieved by 1 mg x kg x day(-1) CsA in both models. In the cardiac graft experiment with CsA co-administration, doses of 0.3 and 1 mg/kg were used. Under these conditions very small doses of FTY720 were effective in maintaining grafts throughout the treatment period. Adding higher FTY720 doses to the 1 mg x kg(-1) x day(-1) CsA was needed to effectively extend the skin GS, e.g. 0.3 mg x kg(-l) x day(-1) FTY720 prolonged GS from 13 to 47.5 days MST, i.e. well beyond the 28 day-treatment period. CsA did not influence the PLC at clinically relevant doses. FTY720 lowered the PLC significantly and dose-dependently, at doses lower than those needed for the prolongation of both cardiac and skin GS with FTY720 monotherapy. In rats with skin grafts the PLC was markedly lowered up to 1 mg x kg(-1) x day(-1) FTY720, whereas, in the heart model, it was lowered up to 0.1 mg x kg(-1) x day(-1). Independently of the graft type, within the combination regimens 0.3 mg x kg(-1) x day(-1) FTY720 achieved a maximal PLC depletion. CONCLUSIONS: Combining FTY720 and CsA was very well tolerated with respect to weight gain and lack of any clinically detectable infections. In the strain combination used FTY720 monotherapy was less effective than previously reported in maintaining grafts. The two-drug regimens extended strikingly the GS for both models. However, the prolongation of the heart GS was smoothly dose-related with FTY720 doses ranging from 0.01 to 1 mg x kg(-1) x day(-1) , whereas, the skin graft prolongation was modest at doses up to 0.1 mg x kg(-1) x day(-1) and remarkably enhanced at 0.3 and 1 mg x kg(-1) x day(-1) FTY720.     

表达HGF的骨髓间充质干细胞促进小移植肝早期肝再生

目的 建立大鼠小体积肝移植模型,输注表达人肝细胞生长因子(human hepatocyte growth factor,hHGF)的骨髓间充质干细胞(mesenchymal stem cells,MSCs),研究其在移植早期对小移植肝促再生作用.方法 将已建立的表达hHGF和绿色荧光蛋白(green fluorescence protein,GFP)的MSCs,分别命名为HGF/MSCs,GFP/Mscs.建立大鼠30%肝移植模型.受体分为4组,实验组输注5×106HGF/MSCs;对照组则分别输注相同体积的生理盐水(PS),5×106 GFP/MSCs或1.0×109 pfu含hHGF的重组腺病毒液(Ad-HGF).分别于术后1,3,5,7 d各组随机抽取5只大鼠处死.取血检测血清ALT和hHGF.记录移植物湿重.取肝组织检测hHGF、c-met表达,以及肝细胞凋亡和增殖活性.另每组15只,分组同上,用于观察生存期.结果 PS组大鼠7 d生存率33.3%;组织学及血清学检查示术后肝脏损伤重,汇管区单核细胞浸润多;而实验组大鼠7 d生存率为73.3%.肝脏损伤轻,炎性细胞浸润少;实验组移植肝再生较PS组明显增加.结论 大鼠部分肝移植后,输注HGF/MSCs能够保护小体积移植肝,促进小移植肝再生,提高7 d生存率.     

FK 409 ameliorates small-for-size liver graft injury by attenuation of portal hypertension and down-regulation of Egr-1 pathway

OBJECTIVE: To investigate whether low-dose nitric oxide donor FK 409 could attenuate small-for-size graft injury in liver transplantation using small-for-size grafts. SUMMARY BACKGROUND DATA: The major concern of live donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be investigated. METHODS: We employed a rat orthotopic liver transplantation model using small-for-size (40%) graft. FK 409 was given at 30 minutes before graft harvesting (2 mg/kg) to the donor and immediately after reperfusion (1 mg/kg) to the recipient (FK group). Graft survival, intragraft genes expression, portal hemodynamics, and hepatic ultrastructural changes were compared between the 2 groups. RESULTS: Seven-day graft survival rates in the FK group were significantly improved compared with those of rats not receiving FK 409 (control group; 80% versus 28.6%, P = 0.018). In the FK group, portal pressure was significantly decreased within the first 60 minutes after reperfusion whereas in the control group, transient portal hypertension was observed. Intragraft expression (both mRNA and protein) of early growth response-1, endothelin-1, endothelin-1 receptor A, tumor necrosis factor-alpha, macrophage-inflammatory protein-2, and inducible nitric oxide synthase was significantly down-regulated accompanied with up-regulation of heme oxygenase-1, A20, interferon-gamma-inducible protein-10, and interleukin-10 during the first 24 hours after reperfusion. Hepatic ultrastructure, especially the integrity of sinusoids was well protected in the FK group. CONCLUSIONS: Low-dose FK 409 rescues small-for-size grafts in liver transplantation by attenuation of portal hypertension and amelioration of acute phase inflammatory response by down-regulation of Egr-1, together with prior induction of heat shock proteins.     

The effect of FTY 720 on engraftment in a model of spontaneous allograft acceptance

Further development in organ transplantation requires the utilization of new immunosuppressive drugs that-in addition to being effective against rejection-do not block tolerance. We previously reported that FTY 720, a drug that alters lymphocyte trafficking, has marked anti-rejection properties. We now investigate how FTY 720 influences tolerance in a model of graft acceptance by donor-specific blood transfusion (DSBT). Two different transplant models--heart transplantation (Htx) and intestinal transplantation (Itx)--were studied. We performed orthotopic Itx and heterotopic Htx using fully mismatched inbred male RA (RT1(p)) and PVG (RT1(c)) rats as donors and recipients. Tolerance was induced by DSBT on pre-transplant day -12. To test the effect of FTY 720 on DSBT-induced tolerance, we administered FTY 720 orally prior to DSBT. Itx: control rats succumbed to rejection at 18+/-4 days. DSBT alone prolonged survival to 101.9+/-18 days (P<0.05 vs untreated). Long-term survivors were tolerant (acceptance of secondary donor-specific Htx). Adjunction of FTY 720 prior to DSBT reduced survival to 55.9+/-44.7 days (P<0.05). However, long-term survivors still accepted secondary donor-specific Htx. Htx: control rats survived 9+/-0.6 days. DSBT alone prolonged survival indefinitely (>120 days) and induced tolerance (acceptance of secondary donor-specific Htx). Unlike in Itx, adjunction of FTY 720 prior to DSBT did not reduce Htx survival. Acceptance of secondary donor-specific Htx was not influenced by FTY 720. In Itx, FTY 720 counteracts the beneficial effect of pre-transplant DSBT and triggers acute rejection of primary, but not secondary grafts. In Htx, however, FTY 720 allows full development of tolerance. The mechanisms by which FTY 720 causes rejection in primary intestinal but not in heart grafts need to be elucidated.     

大鼠小体积肝移植后肝细胞再生的研究

目的 探讨小体积肝移植术后肝再生的情况。方法 建立大鼠30％原位肝移植模型,实验分为肝切除（PH）组、全肝移植（0LT）组和30％小体积肝移植（30％POLT）组,观察1w生存率,并于术后1、2、3、7d检测肝细胞增殖活性、肝功能和肝组织学变化。结果 各组1w生存率均为100％;30％POLT组术后2d达到增殖高峰,峰值与PH组无差异（P〉0．05）;其肝功能酶学指标在术后1、3d明显升高,组织学见肝细胞核分裂极其活跃。结论 冷缺血1h的30％供肝和肝切除后肝脏具有同样的增殖活性,仅增殖高峰稍晚;较短的冷缺血时间以及熟练的手术技术可能对小体积供肝的再生起重要作用。     

FTY720 Pretreatment Reduces Warm Hepatic Ischemia Reperfusion Injury Through Inhibition of T-Lymphocyte Infiltration

Ischemia and reperfusion (IR) injury remains a significant problem in clinical liver transplantation. We investigated the effects of lymphocyte depletion with FTY720 in models of warm hepatic IR. Using 60-min partial warm hepatic IR, three groups of rats were studied: Sham--laparotomy alone; Control--water p.o. x 3 d before ischemia; Treatment--FTY720 p.o. x 3 d before ischemia. Animals were sacrificed for analysis at 6 h and 24 h post reperfusion. The effect of FTY720 pretreatment on survival was also studied using 150 min total hepatic IR with portojugular shunt. FTY720 treatment significantly reduced serum glutamic pyruvic transaminase and peripheral blood lymphocytes compared to controls at 6h and 24h (p < 0.0005). Histological grade was significantly improved in treated livers vs. controls (p < 0.05). CD3 immunocytochemical analysis revealed a significant reduction in T-cell infiltration in FTY720-treated livers (p < 0.0002). No difference in tissue myeloperoxidase levels was observed. Seven-day survival was significantly improved in treated rats vs. controls following total hepatic ischemia (p < 0.05). In conclusion, FTY720 ameliorates the biochemical and histological manifestations of hepatic IR by preventing T-lymphocyte infiltration and prolongs survival following a more severe ischemic insult. Myeloperoxidase data suggest this mechanism is independent of neutrophil activation. These results indicate that T lymphocytes are pivotal mediators in hepatic IR and may have important implications in liver transplantation.     

小体积肝移植的基础研究进展

目的介绍小体积肝移植术后移植物损伤机理及移植物保护措施。方法复习和总结了相关文献资料并作综述。结果小体积肝移植术后过高的门静脉压力导致移植物机械性损伤,并通过改变肝窦微循环状态及激活各类细胞因子使移植物损伤进一步加重。通过手术或药物的方法降低门静脉压力可对移植物起一定的保护作用。结论了解小体积肝移植术后移植物损伤机理对于临床提高活体肝移植的效果具有积极的意义。     

采用不含肝中静脉的右半肝行成人间活体肝移植

目的探讨采用不含肝中静脉的右半肝行成人间活体肝移植的可行性及安全性。方法2002年1月至2005年8月,我院施行了16例成人间右半肝活体肝移植,术中采用了不含肝中静脉的右半肝移植物,同时进行了一系列改良的手术技术包括肝右静脉的重建,右肝下静脉的重建,肝中静脉分支的搭桥等改进。结果全组供者无严重并发症及死亡。前2例受者中,1例发生肝静脉吻合口狭窄,1例因发生小肝综合征,死于肝功进行性恶化。后14例受者中发生并发症5例:急性排斥反应,肝动脉栓塞,胆漏,左膈下脓肿及肺部感染各1例;1例再移植术后肺部感染死于MODS。14例中除肝右静脉与下腔静脉(IVC)直接吻合外,其中5例加行右肝下静脉重建,另5例采用自体大隐静脉搭桥行肝中静脉分支与IVC重建,保证了右肝的流出道通畅。移植物与受者重量比(GRWR)为0.72%~1.15%,11例<1.0%,其中2例<0.8%,无小肝综合征发生。结论采用了改进的手术技术,特别是肝静脉流出道的充分重建可有效的避免小肝综合征,从而使采用不含肝中静脉的活体右半肝移植成为安全可靠的手术方式。