个体化免疫抑制治疗在肾移植的疗效观察

目的：探讨个体化免疫抑制治疗对肾移植患者的临床价值。方法：将肾移植患者分为个体化组(42例)和常规组(50例),分别采用个体化免疫抑制治疗和常规免疫抑制治疗,并对术后两组的临床指标进行比较。结果：个体化组比较常规组,术后肝功能损害、高血糖、胃肠功能紊乱、呼吸系统感染、急性排斥反应发生率均明显降低(P＜0．05);而巨细胞病毒感染发生率及移植肾切除人数无差异(P＞0．05)。结论：个体化免疫抑制治疗既能维持免疫抑制效果,又能最大限度减少药物不良反应,对肾移植患者有较好治疗价值。     

个体化免疫抑制方案在肝移植高危受者中的应用

目的　评价高危受者肝移植后采用个体化免疫抑制方案的意义。方法　根据受者术前情况的不同制定不同的免疫抑制方案 ,比较采用个体化免疫抑制方案的高危受者与采用常规免疫抑制方案的高危受者和普通受者肝移植术后肾功能衰竭、急性排斥反应、感染发生率 (包括细菌、真菌、巨细胞病毒感染 )以及院内死亡率。结果　采用个体化免疫抑制方案的高危受者肝移植术后肾功能衰竭、细菌及真菌感染的发生率以及院内死亡率均较采用常规免疫抑制方案的高危受者显著降低 (P<0 .0 5) ,与采用常规免疫抑制方案的普通受者相比 ,两个组上述指标的差异无显著性。结论　采用个体化免疫抑制方案较常规免疫抑制方案有更高的安全性 ,可以提高高危受者的肝移植成功率。     

肝移植术后长期存活慢性肾功能损害受者的免疫抑制方案个体化应用

目的探讨肝移植术后长期存活慢性肾功能损害受者应用个体化免疫抑制方案的疗效。方法选择18岁以上、肝移植术后2年以上、入组前采用以他克莫司(FK506)为基础免疫抑制方案、肝功能正常而肾功能损害的受者,共32例。根据免疫功能评分和白细胞计数制定个体化免疫抑制方案,以FK06用量最小化为原则,转换为麦考酚吗乙酯(MMF)或西罗莫司,并调整其用量。调整后至少每个月随访1次,进行肝功能、肾功能、血常规检查和免疫功能评估。结果 32例受者经个体化免疫抑制方案治疗,随访(24.3±7.6)个月,个体化治疗后各时段的肾小球滤过率(GFR)均较此前有明显提高(均为P<0.01),以调整用药后1个月最明显。无发生排斥反应。结论根据免疫功能评分和白细胞计数制定个体化免疫方案,使FK506用量最小化,可以有效改善肝移植术后长期存活的受者的肾功能,并不增加排斥反应的发生率。     

优化肝移植术后免疫抑制治疗方案

免疫抑制剂的毒副作用常常是影响肝移植受者长期生存的危险因素.免疫抑制个体化治疗是目前肝脏移植综合治疗的热点和难点.免疫抑制治疗已从仅着眼于移植术后抗免疫排斥反应,逐步向追求患者和移植物长期存活、药物副作用最小化、优化患者生命质量,同时降低患者经济负担方向发展.通过掌握各类免疫抑制剂特点及毒副作用,正确有效地评估受者的免疫状态,结合患者自身病理生理状况,有针对性地选择免疫抑制治疗方案,达到药物剂量最小化,实现个体化给药方案.     

个体化免疫抑制治疗的理论与实践

新型免疫抑制剂在降低急性排斥反应发生率的同时,也因其狭窄的治疗指数以及药代动力学、药效动力学的个体差异而导致的药物毒性,很大程度上影响了移植物以及受者的长期存活。免疫抑制个体化治疗的概念产生于需要尽量减少药物的不良反应的同时又要优化这些药物的疗效。因中毒剂量与有效剂量之间的差距很小,故免疫抑制个体化治疗非常重要,并且越来越受到移植界的重视。基因多态性可影响药物的药代动力学和药效学特性,所以器官移植受者对药物的反应可能会因个体间基因多态性而有所不同。因此,个体化治疗就是以每个受者的信息为基础决定治疗策略,根据受者的基因组成、表达变化以及药物的治疗效果、不良反应等不同个性,对每个受者进行最适宜的治疗。     

CYP3A基因多态性与肾移植后早期钙调磷酸酶抑制剂的应用

免疫抑制不足或过度是早期移植肾功能丧失的主要原因之一,移植后1年内若能避免发生急性排斥反应,将会有助于提高移植物的长期存活率[1].钙调磷酸酶抑制剂(CNI)为目前大多数实体器官移植术后免疫抑制剂方案的基础,但因其治疗窗狭窄,个体间药代动力学差异显著以及药效动力学与药物浓度的相关性差等特点,其临床应用受到限制[1-4].因此,如何根据个体需要而个体化使用CNI,以优化免疫抑制剂的效果,减少毒性等不良反应,依然是实体器官移植面临的一个难题[4-5].     

肝肠联合移植1例报告

目的探讨肝肠联合移植的术式、免疫抑制治疗方案与效果。方法对一中年男性短肠综合征患者施行辅助性肝肠联合移植，术后患者免疫抑制治疗采用甲波尼龙(MP)、环孢素A(CsA)、环磷酰胺(CTX)与抗淋巴细胞球蛋白(ALG)处理。结果术后观察期内移植物存活良好。结论本例采用的免疫抑制治疗方案是成功的，且手术方法操作较为简便、易行。     

麻醉药物代谢酶CYP450酶系基因组学研究进展

遗传多态性是造成个体对药物反应差异的重要因素之一,其中CYP450酶系的基因多态性可能导致种族间及个体间对同一底物代谢能力的不同.现就镇静安定药、吸入麻醉药、局麻药、镇痛药的药物效应与CYP450基因多态性的相关性进行综述,为临床个体化给药,实现个体优化治疗提供新思路.     

肾移植术后常规免疫抑制方案下发生他克莫司肾毒性的影响因素

目的 探讨在常规免疫抑制方案下和正常血药浓度范围内肾移植受者发生他克莫司(Tac)肾毒性的影响因素及其对个体化治疗的指导意义。方法 回顾分析132例肾移植术后2年内按照Tac常规剂量(0.15～0.3 mg·kg-1·d-1)和血Tac浓度维持在8～11 μg/L,并坚持随访的首次肾移植受者的资料。Tac肾毒性经移植肾活检和临床实验室检测结果诊断。根据是否发生Tac肾毒性,分为肾毒性组和对照组。对可能的影响因素,包括受者的年龄、性别、是否发生过移植肾功能延迟恢复、药物暴露量、用药时间、肝功能异常、血清白蛋白水平、红细胞比容以及多药耐药基因(MDR1)和细胞色素P450酶3A5(CYP3A5)基因等共10项指标进行多因素回归分析。结果 在常规免疫抑制剂方案下和正常血药浓度范围内,Tac肾毒性发生率为18.9％(25/132)。经单因素和多因素分析,肝功能异常(RR=3.05,95％可信区间为0.879～11.533,P=0.024)、血清白蛋白水平(RR=0.966,95％可信区间为0.994～1.006,P=0.018)、红细胞比容(RR=0.999,95％可信区间为0.998～1.000,P= 0.032)、CYP3A5基因多态性（RR= 0.777,95％可信区间为0.023～6.798,P=0.032）及MDR1基因多态性(RR=0.654,95％可信区间为0.053～7.109,P=0.017)是导致Tac肾毒性的独立危险因素。结论 肾移植后在常规免疫抑制方案下及正常血药浓度内,肝功能异常是导致Tac肾毒性最主要的危险因素,白蛋白水平低下、红细胞比容降低也是导致Tac肾毒性的影响因素,此外还应考虑受者CYP3A5及MDR1的基因多态性,以实现个体化免疫抑制治疗。     

个体化免疫抑制方案在心脏移植高危患者中的应用

目的 探讨个体化免疫抑制方案在心脏移植高危患者中的应用.方法 回顾分析2001年9月至2006年12月51例在围手术期合并HBV感染、糖尿病、肾功能不全或肺部感染的心脏移植病例,全组患者术前均采用达利珠单抗进行免疫诱导治疗,基础免疫抑制方案为环孢霉素A(CsA)、硫唑嘌呤(Aza)或吗替麦考酚酯(MMF)和泼尼松的三联方案.其中术前合并HBV感染10例,术后强调使用MMF,术后1个月停用泼尼松;术前合并糖尿病9例,术后并发移植后糖尿病4例,术后强调使用CsA,不用FK506,减量使用或停用泼尼松,配合胰岛素治疗;术前肾功能不全16例,术后常规使用MMF,术后第5～19天开始使用CsA;术后并发肺部感染12例,减量或暂停使用CsA、MMF和泼尼松.结果 术前合并HBV感染10例,随访1年肝功能稳定,1例于术后第13个月发生急性排斥反应.糖代谢异常13例,术后血糖控制满意,随访6个月无急性排斥反应发生.术前肾功能不全16例,随访1个月无急性排斥反应发生,肾功能恢复正常.术后并发肺部感染12例,2例死于严重的肺部感染,其他患者均存活;随访1个月,1例患者于术后第17天发生急性排斥反应.结论 免疫抑制方案的个体化能使心脏移植的高危患者平稳渡过围手术期,不会增加急性排斥反应的发生率.     

The Impact of IL28B Genetic Variants on Recurrent Hepatitis C in Liver Transplantation: Significant Lessons from a Dual Graft Case

IL28B genetic polymorphism is related to interferon‐sensitivity in chronic hepatitis C, but the significance of grafts carrying different genotypes from recipients is still unclear in liver transplantation. A 51‐year‐old Japanese male carrying a minor genotype underwent dual liver transplantation for liver cirrhosis due to hepatitis C virus (HCV). The left lobe graft carried a major genotype, and the right a minor genotype. He achieved virological response during the course of pegylated‐interferon and ribavirin therapy against recurrent hepatitis C for 2 years, but HCV relapsed immediately at the end of the therapy. Two years after antiviral therapy, liver biopsy was performed from each graft. The specimens showed A1F0 in the left lobe graft and A2F2 in the right. Moreover, quantitative polymerase chain reaction was performed using RNA extracted from each specimen to see there was no HCV RNA in the left lobe whereas there was in the right. This case provides clear evidence that IL28B genetic variants determine interferon sensitivity in recurrent hepatitis C following liver transplantation, which could result in new strategies for donor selection or for posttransplant antiviral therapy to HCV positive recipients.     

Diagnosis of 6 Mercaptopurine Hepatotoxicity Post Liver Transplantation Utilizing Metabolite Assays

Azathioprine and 6-mercaptopurine (6 MP) are commonly used as immunosuppression postsolid organ transplantation. Recently, a better understanding of the metabolism of these drugs has developed. 6 Mercaptopurine is metabolized by thiopurine methyl transferase (TPMT) which is under the control of a common genetic polymorphism. Genetic testing and measurement of levels of 6 MP metabolites allow identification of patients at risk of toxicity. We report two cases of cholestatic hepatocellular injury associated with 6 MP toxicity occurring after orthotopic liver transplantation. Cholestasis developed after the introduction of 6 MP. Patients underwent extensive investigation and 6 MP toxicity was considered only after all other causes had been excluded. Thiopurine methyl transferase alleles identified on genetic testing were normal as were the 6 thioguanine levels. However, 6-methyl mercaptopurine levels were significantly elevated into the toxic range. Cholestasis resolved within a few weeks of drug withdrawal. 6 Mercaptopurine hepatotoxicity can present with a variety of clinical, biochemical and histological manifestations post OLT and should be considered as a cause of liver enzyme elevation. Monitoring of 6 MP metabolite levels in addition to TPMT allele testing is useful to prevent 6 MP toxicity and to help guide therapy.     

Hepatocyte transplantation: clinical experience and potential for future use

Hepatocyte transplantation has been proposed as a method to support patients with liver insufficiency. There are three main areas where the transplantation of isolated hepatocytes has been proposed and used for clinical therapy. Cell transplantation has been used: 1) for temporary metabolic support of patients in end-stage liver failure awaiting whole organ transplantation, 2) as a method to support liver function and facilitate regeneration of the native liver in cases of fulminant hepatic failure, and 3) in a manner similar to gene therapy, as a "cellular therapy" for patients with genetic defects in vital liver functions. We will briefly review the basic research that leads to clinical hepatocyte transplantation, the published clinical experience with this experimental technique, and some possible future uses of hepatocyte transplantation.     

Association between a polymorphism in the IL-12p40 gene and cytomegalovirus reactivation after kidney transplantation

BACKGROUND: Cytomegalovirus (CMV) infection is associated with a significant rate of morbidity after organ transplantation. The genetic factors influencing its occurrence have been little investigated. IL-12 plays a crucial role in anti-infectious immune responses, especially by stimulating IFNgamma production. An A-to-C single nucleotide polymorphism (SNP) within the 3'-untranslated region of the IL-12p40 gene has been characterized and was reported to be both functionally and clinically relevant. However, the impact of this single nucleotide polymorphism on events after organ transplantation has never been reported. METHODS: In this study, we investigated the impact of the 3'-untranslated region polymorphism on the occurrence of CMV infection in 469 kidney recipients transplanted at the University Hospital of Tours between 1995 and 2005. The polymorphism was genotyped using the restriction fragment length polymorphism method and CMV infection was determined by pp65 antigenemia. RESULTS: Multifactorial Cox regression analysis demonstrated that the presence of the C allele was an independent risk factor for CMV infection (OR=1.52, P=0.043), the risk being even higher when study was restricted to patients with positive CMV serological status before the graft and who did not receive any CMV prophylaxis (OR=1.88, P=0.028). CONCLUSIONS: This study identified a new genetic risk factor for CMV reactivation after kidney transplantation. The results of our study suggest that C carriers might especially benefit from CMV prophylaxis.     

Liver Transplantation from an Identical Twin without Immunosuppression, with Early Recurrence of Hepatitis C

Hepatitis C virus reinfection after liver transplantation is universal and more severe than in nontransplant patients. Rejection episodes and immunosuppressive agents are considered risk factors for deterioration of recurrent hepatitis C. We report 2 cases of living donor liver transplantation for patients with hepatitis C-related cirrhosis who received right-lobe grafts from an identical twin. Thanks to genetic identity, no immunosuppressive drugs were administered during or after transplantation without rejection. Hepatitis C virus RNA kinetics showed a rapid increase following transplantation and liver biopsies 1 month after transplantation showed acute lobular hepatitis in both cases. Antiviral therapy using interferon alpha and ribavirin was started immediately, and both cases showed virological and histological response. In conclusion, avoidance of immunosuppression did not delay hepatitis C recurrence following transplantation, while early antiviral therapy without risk of rejection or immunosuppression led to successful viral eradication.     

Severe venoocclusive disease after liver transplantation treated with transjugular intrahepatic portosystemic shunt

Venoocclusive disease (VOD) is due to hepatic sinusoidal lining injury leading to portal hypertension; its incidence after liver transplantation is about 2%. When severe, it does not respond to medical therapy and has a high mortality; retransplantation is the only therapeutic option. However, there are no detailed data regarding the use of transjugular intrahepatic portosystemic shunt for VOD after liver transplantation. We describe two patients who developed severe VOD after liver transplantation, failed defibrotide therapy, and were treated by transjugular intrahepatic portosystemic shunt (TIPS). The portal hypertension resolved completely and one had full histological recovery. We believe that TIPS should be attempted as it may resolve progressive portal hypertension and the hepatic congestion, while allowing the clinician time for listing for further liver transplantation if the patient fails to respond.     

系统治疗在肝癌术前新辅助治疗中应用进展

近年来，肝癌的系统治疗进展迅速，新的免疫治疗药物、靶向药物不断涌现，新的治疗理念和治疗方案不断创新。但关于系统治疗应用于肝癌术前的方案选择和疗效分析，探讨相对较少。肝癌的新辅助系统治疗按其目的和后续手术方式可分为可切除性肝癌的新辅助系统治疗、不可切除肝癌的转化治疗和肝移植术前的降期或桥接治疗。新辅助系统治疗策略的制定需基于术前诊断特别是病理学诊断、多学科讨论及分子肿瘤学委员会讨论、系统的疗效评估、科学的终点选择及术中术后的全过程管理。由于肝癌肝移植涉及系统免疫调节和免疫微环境重塑，其综合治疗的方案、方式都处于探讨阶段。新辅助治疗用于肝癌肝移植的术前降期或术前桥接在免疫治疗时代，是亟需探讨的重要问题。     

Historical aspects of hepatocyte transplantation

Hepatocyte transplantation has been used for temporary metabolic support of patients in end-stage liver failure awaiting whole organ transplantation as a method to support liver function and facilitate regeneration of the native liver in cases of fulminant hepatic failure and as a "cellular therapy" for patients with genetic defects in vital liver functions. The aim of this paper was to discuss the basic research that led to clinical hepatocyte transplantation, the published clinical experience with this experimental technique, and some possible future uses of hepatocyte transplantation.     

肝细胞癌肝移植供肝选择策略

供肝数量不足是制约肝移植发展的主要因素,更是制约肝细胞癌肝移植治疗的突出因素。既往对肝细胞癌肝移植的研究多集中在受者选择标准、降期治疗、免疫抑制方案等方面,近年来研究发现供肝的选择对肝细胞癌肝移植术后肿瘤复发也有显著影响。笔者从临床供肝的主要类型、肝细胞癌肝移植适应证的把握、适应证内肝细胞癌肝移植和超适应证肝细胞癌肝移植的供肝选择以及供肝选择对肝细胞癌肝移植预后的影响进行深入探讨。     

Apparent Remission of a Solitary Metastatic Pulmonary Lesion in a Liver Transplant Recipient Treated with Sorafenib

Hepatocellular carcinoma (HCC) remains a significant disease worldwide and its incidence is expected to increase. In selected patients, liver transplantation offers a 5‐year patient survival between 48% and 75%. However, HCC recurrence occurs in approximately 20% of transplant recipients. No therapy has proven efficacious in decreasing the risk of recurrence after transplantation. Sorafenib, a multitargeted tyrosine kinase inhibitor, has been shown to improve survival in patients with advanced HCC that have no history of liver transplantation. We report complete remission of HCC in a 54‐year‐old man who developed biopsy‐proven lung metastasis after liver transplantation treated with sorafenib.