丙型肝炎病毒阳性受者肾移植后的安全性分析

背景：对于丙肝病毒阳性患者接受肾移植后安全性的问题是目前大家关注的热点。目的：丙型肝炎病毒感染者接受肾移植后临床观察及处理对策。方法：纳入22例患者,肾移植前肝炎病毒RNA均为阳性,其中14例患者肝功能轻度升高。移植后定期检测患者的肝、肾功能,积极防治可能的排斥反应。主要观察患者一般情况、肝、肾功能、肝炎病毒基因学情况及死亡率。结果与结论：移植后随访6~36个月,20例患者移植后4周~6个月内出现不同程度的肝功能异常,予护肝治疗后肝功能均恢复正常,1例移植后HCV-RNA阳性患者,因自行改变抗排斥方案于移植后1.5年出现严重的肝功能衰竭而死亡;4例患者移植后应用干扰素和利巴韦林治疗,HCV-RNA转阴,其余18例患者HCV-RNA均呈阳性,需长期护肝治疗。表明,对丙肝病毒阳性受者,移植后应进行严格的随访,出现肝功能异常时,及时采取相应处理和护肝治疗。     

乙肝病毒携带者肾移植术后的处理

目的:探讨乙肝病毒携带者肾移植术后的处理。方法:12例患者中,11例术前检查均为HBsAg(+)、HBeAb(+)、HBcAb(+),1例HBsAg(+)、HBeAg(+)、HBcAb(+),乙肝病毒DNA阴性,术后常规服用拉米呋啶。结果:术后随访4～12个月,8例患者于术后2周内出现程度不同的肝功能异常,均以丙氨酸氨基转移酶和天冬氨酸氨基转移酶升高为主,乙肝病毒DNA检测呈阴性,经调整免疫抑制剂用量,并给予护肝治疗,患者的肝功能恢复正常。结论:乙肝病毒携带者接受肾移植术后,出现肝功能异常时,应正确区分是病毒性肝损害还是药物性肝损害,及时采取相应处理,并给予护肝治疗。     

肾移植术后乙型肝炎病毒拉米夫定耐药的治疗

目的:观察肾移植术后乙型肝炎病毒患者发生拉米夫定耐药后,应用新一代核苷类抗乙型肝炎病毒药物阿德福韦和恩替卡韦的治疗效果。方法:选择2001-05/2006-09于南方医科大学南方医院器官移植科就诊的乙型肝炎病毒感染并发生病毒多聚酶催化域YMDD基序变异,对拉米夫定耐药的肾移植患者4例,患者均知情同意。定期复查血清丙氨酸转氨酶、天冬氨酸转氨酶、总胆红素、乙型肝炎病毒DNA定量及乙型肝炎病毒YMDD变异情况,先后采用拉米夫定、阿德福韦及恩替卡韦进行治疗,并观察其治疗效果。结果:①4例患者分别随访16,26,63,67个月,移植肾功能良好。②4例患者分别在服用拉米夫定14,24,51和62个月(术后12个月)时出现乙型肝炎病毒YMDD变异,乙型肝炎病毒DNA升高至105～109拷贝/mL,肝功能异常。2例加用阿德福韦3个月后撤除拉米夫定,单用阿德福韦治疗,乙型肝炎病毒DNA均降为104拷贝/mL,肝功能正常,其中1例单用阿德福韦9个月后乙型肝炎病毒YMDD变异转阴,另1例单用阿德福韦2个月,乙型肝炎病毒YMDD变异仍为阳性;2例停用拉米夫定,直接换为恩替卡韦,其中1例2个月后肝功能正常,乙型肝炎病毒DNA阴性,乙型肝炎病毒YMDD变异阴性,另1例服药2个月后肝功能正常,乙型肝炎病毒DNA降为104拷贝/mL,乙型肝炎病毒YMDD变异仍为阳性。结论:新型抗乙型肝炎病毒药物阿德福韦和恩替卡韦可有效抑制拉米夫定耐药的乙型肝炎病毒复制,有利于乙型肝炎病毒阳性肾移植患者长期存活。     

肾移植术后并发肝功能损害防治体会（附5例报告）

本文总结了1987年-2000年53例同种异体肾移植术后5例并发肝功能损害病例的治疗体会，认为在移植前选择合适的病人。移植后在出现肝功能异常前掌握好CS—A的用量，慎用硫唑瞟呤，术后及时测定CS—A的血药浓度及肝、肾功能的变化，是预防肝功能损害的重要条件，认为在肾移植术后出现肝功能损害后，在治疗肝功能损害的同时，应把保护植肾功能、防止排斥反应与治疗肝功能损害同等看待，也是肾移植成功的必要条件。     

减少或撤除环孢素A的免疫抑制方案在HBV-DNA阳性肾移植患者中的应用

目的 探讨减少或撤除环孢素A(CsA)的免疫抑制方案在乙型病毒性肝炎DNA阳性肾移植患者中的应用价值.方法 对我院2004年1月至2007年12月64例肾移植术后HBV-DNA阳性患者初始免疫抑制剂的治疗方案进行总结,分为:①环孢素A(CsA)+霉酚酸酯(MMF)组(A组),CsA的谷值CO在200～250 mg/ml,MMF用量在1.0～1.5g/d;②普乐可复(FK506)+MMF组(B组),FKS06的谷值浓度维持在7～9 ng/ml,MMF用量在1.0～1.5 g/d;③低剂量CsA+西罗莫司(SRL)组(C组),CsA的谷值CO在150ng/ml左右,CO维持750 ng/ml左右,SRL浓度维持在6～10 ng/ml.所有病例应用恩替卡韦抑制HBV-DNA的复制和常规保肝利胆治疗,随访6个月.结果 三组肾移植术后急性排斥反应的发生率差异无统计学意义(P>0.05),A组有12例(80%)患者出现肝功能异常,HBV-DNA转阴者8例(53%),应用恩替卡韦抑制乙型肝炎病毒复制和加强护肝治疗后,有7例肝功能好转,其中肝功能恢复缓慢且HBV-DNA持续阳性者2例改为FK506+MMF的治疗方案,3例改为低剂量CsA+SRL的治疗方案.B组有5例(20%)患者出现肝功能异常,HBV-DNA转阴者18例(75%).C组有4例(16%)患者出现肝功能异常,HBV-DNA转阴者18例(72%).结论 减少或撤除CsA的免疫抑制方案对于HBV-DNA阳性的肾移植患者是安全有效的,不增加排斥反应的发生,也不加重肝功能的损害.     

乙型肝炎病毒感染者肾移植前肝穿刺活检与预后分析

背景:乙肝病毒感染者肾移植手术国内有较多报道,但乙肝病毒感染者肾移植前肝穿刺活检观察有限.目的:对慢性肾功能衰竭合并不同程度慢性乙型病毒性肝炎患者进行肾移植前肝穿刺活检,移植后2年随访观察转归情况.方法:对接受肾移植的21例乙型肝炎病毒感染的尿毒症患者进行肝穿刺活检.根据肝活检组织病理学改变,分为轻度(n=9)、中度(n=7)、重度(n=5)3组.肾移植后随访观察2年.3组中各有2例进行重复肝活检组织病理学检查.结果与结论:轻度慢性乙型肝炎组在随访2年中各项观察指标均无明显变化.中度慢性乙型肝炎组从移植后3个月开始谷氨酰转肽酶活性明显高于正常水平,随访至终点时,2例重复肝活检病理显示已处于重度病变.重度慢性乙型肝炎组从移植后3个月开始谷氨酰转肽酶活性持续高于正常水平;18个月开始,血清白蛋白水平低于正常值,球蛋白水平高于正常值;随访至终点时,有4例呈肝硬化改变.提示不同程度的慢性乙型病毒性肝炎患者肾移植后预后不同,肝活检是评价肝脏病变程度的重要手段,具有指导肾移植选择的作用.     

肾移植后他克莫司与五酯胶囊合用致高血钾症1例

背景:肾移植患者由于免疫抑制剂的药物肝毒性,肝功能异常发生率高,对临床出现肝功能异常者,需护肝治疗.但合用护肝药必须监测免疫抑制剂浓度.目的:探讨肾移植患者他克莫司与五酯胶囊合用对他克莫司浓度及血生化的的影响.方法:回顾性分析1例以他克莫司为免疫抑制剂的肾移植患者加服及停用五酯胶囊时他克莫司浓度及肾功能、血生化变化.患者因"慢性肾小球肾炎,慢性肾功能不全"于1998-06起行血液透析治疗.2000-08行同种异体尸体肾移植,移植后免服他克莫司+吗替麦考酚酯+泼尼松.移植后4个月患者出现肝功能异常,加用联苯双酯.2010-07-25患者停用联苯双酯,改服五酯胶囊.2010-07-29患者停用五酯胶囊.结果与结论:服用他克莫司的肾移植受者,合用五酯胶囊,他克莫司血浓度显著升高.由5.3 ng/L升至24.7 ng/L,并合并高血钾症,停用五酯胶囊1周,他克莫司浓度由24.7 ng/L.降至6.1 ng/!.,血钾由6.4 mmol/L.降至4.6 mmol/L.提示移植肾功能稳定的肾移植受者,在加用五酯胶囊,必须严密监测他克莫司血浓度及肝肾功能、电解质,及时调整他克莫司片用量,保护移植肾功能.     

干扰素联合利巴韦林治疗肾移植术前丙型肝炎12例分析

目的 观察a-干扰素联合利巴韦林治疗肾移植术前丙型病毒性肝炎患者的疗效及安全性.方法 采用a-干扰素135 μg每周1次皮下注射,同时口服利巴韦林600 mg/d,治疗12例肾移植术前并发丙型病毒性肝炎患者24周,并每月复查血常规、肝功能、肾功能和HCV-RNA.结果 在治疗12周后有6例患者出现血清ALT转为正常,HCV-RNA阴性(＜100拷贝/ml)的早期应答,在治疗结束后10例患者出现完全应答,2例出现部分应答.治疗过程中12例患者维持血液透析治疗,血肌酐在原有水平波动,未见明显增高.结论 a-干扰素联合利巴韦林对肾移植术前丙型病毒性肝炎患者具有较好的临床疗效,未加重肾功能损害,值得临床进一步推广应用.     

脑死亡器官捐献移植过程中的问题

背景:采用国际标准的供肾来源,即脑死亡无偿肾脏捐献可缓解目前肾移植中供肾的严重短缺问题。近年脑死亡无偿器官捐献及移植已在中国成功开始实施,但在脑死亡无偿器官捐献肾移植方面的报道较少。目的:探讨脑死亡器官捐献肾移植在中国的可行性及保证移植成功的必要条件。方法:总结2007-01/2010-07脑死亡器官捐献肾移植12例患者的经验和体会,包括供者/供肾的评估、供肾的摘取与保存、肾移植情况、移植后受者肾功能及并发症、住院时间、生活质量等。结果与结论:12例脑死亡器官捐献肾移植受者中10例在移植后2～5d肾功能恢复正常,移植后14～21d出院;2例出现肾功能延迟恢复,分别于移植后10,15d肾功能正常,移植后第28天出院。在2～42个月随访过程中,8例患者肾功能均正常,尿蛋白阴性,已从事正常工作,生活质量良好;2例出现蛋白尿,但肾功能正常;1例肾功能正常,肝功能异常,经治疗好转;1例在术后3个月死于严重肺部感染。提示,脑死亡器官捐献肾移植在中国可以得到开展;脑死亡供者必须有满意的血流动力学和尿量及良好的肾功能才能作为理想的肾移植供体;选择最佳移植时机,重视移植后系统性随访,才能确保脑死亡无偿器官捐献肾脏移植成功。     

肾移植术后重症肝炎(附12例报告)

目的：探讨重症肝炎对肾移植患者存活的影响。方法：对12例肾移植术后发生重症肝炎患者的临床资料进行分析。结果：12例患者均为慢性重症肝炎，病原学检测均有乙肝病毒感染且病毒处于复制状态，7例于移植术前感染，5例于术后感染，其中2例同时合并丙肝病毒感染，均为移植术后感染。治疗按重症肝炎方案进行，12例患者死亡11例，好转1例，死亡率达91.1％。结论：肾移植术后发生重症肝炎病情危重，并发症多，治疗困难，死亡率高，因此移植术前应了解患者有无病毒携带及病毒性肝炎，术后密切监测肝功能，出现肝功能异常后及时诊治。     

他汀类药物在糖尿病患者心血管事件一级预防中的新证据和新指南

大量的循证医学证据证实了他汀类药物的心血管事件二级预防作用。但是,他汀类药物在心血管事件一级预防中患者是否获益目前仍有争论。糖尿病本身是冠心病的等危症,无心血管疾病的糖尿病患者使用他汀类药物进行心血管事件一级预防应视为非糖尿病患者的二级预防。如此推论,糖尿病患者使用他汀类药物进行心血管事件一级预防应该获得肯定。临床真实情况是否如此？近期陆续发表的一些研究,用部分临床研究证据对其进行了初步的分析和探索。     

Serum hepatitis C virus (HCV) RNA: a reliable tool for evaluating HCV- related liver disease in anti-HCV-positive blood donors with persistently normal alanine aminotransferase values

BACKGROUND: The significance of hepatitis C virus (HCV) antibodies in blood donors with persistently normal alanine aminotransferase (ALT) levels requires evaluation. STUDY DESIGN AND METHODS: The serum and the liver were assayed for HCV RNA. Liver histology was analyzed in 14 HCV- positive subjects who had repeatedly normal ALT values over a follow-up period of at least 3 months. RESULTS: HCV RNA was not detected in liver and serum, and liver histology showed minimal changes in more than one- half of the subjects (8/14), even if third-generation recombinant immunoblot assay was positive; this demonstrated that HCV can be eradicated spontaneously. Moderately histopathological liver lesions were usually found in HCV RNA-positive subjects (6/14), but one subject had active disease that required interferon therapy; this shows that chronic hepatitis may be present in HCV-positive individuals despite repeatedly normal transaminase values. HCV genotypes other than 1b (II) were usually identified, and the presence or absence of serum and liver HCV RNA correlated completely in all 14 patients. CONCLUSION: Serum HCV RNA should be assayed in those HCV-positive donors having repeatedly normal transaminase activity; if it is positive, indicating an ongoing HCV infection, a liver biopsy should be performed to measure the degree of the liver disease and determine the appropriate antiviral therapy.     

A new HCV core antigen assay based on disassociation of immune complexes: an alternative to molecular biology in the diagnosis of early HCV infection

BACKGROUND: An EIA based on immune complex disassociation of nucleocapsid proteins of HCV has been developed to detect and quantify HCV core antigen. STUDY DESIGN AND METHODS: To evaluate whether this new assay (trak-C, Ortho Clinical Diagnostics) could be an alternative to NAT during the window period, its sensitivity in this context was assessed, and its performance was compared with that of a first-generation HCV core antigen assay dedicated to the blood screening (HCV core antigen ELISA). Studied populations included nine HCV RNA-positive, HCV antibody-negative blood donors and 23 hemodialysis patients who underwent an HCV seroconversion. From these individuals, 81 samples (23 HCV RNA-negative and 58 HCV RNA-positive) sequentially collected during the phase before seroconversion were tested. RESULTS: The nine blood donor samples were positive for the presence of HCV core antigen by the trak-C, and 6 of 8 tested were positive for the presence of HCV core antigen by blood screening ELISA. In the hemodialysis cohort, the 23 HCV RNA-negative samples were negative with the two HCV core antigen assays. Among the 58 HCV RNA-positive samples, 46 of 57 (80.7%) tested were positive for the presence of HCV core antigen with the blood screening assay, and 57 of 58 (98.2%) were positive for the presence of HCV core antigen with the trak-C. The mean delays in detecting HCV infection between trak-C and the appearance of HCV antibodies, between HCV RNA testing and trak-C, and between trak-C and HCV core antigen ELISA were 58.2, 0.24, and 3.33 days, respectively. CONCLUSION: Trak-C was more sensitive than the blood screening assay and had similar performance to HCV RNA assay in the window period. Trak-C could constitute an alternative to NAT for the diagnosis of HCV infection during the window period, especially when molecular biology procedures cannot be implemented.     

Early antiviral treatment of hepatitis C virus recurrence after liver transplantation in HIV-infected patients

OBJECTIVE: To investigate the efficacy of early antiviral treatment for hepatitis C virus (HCV) recurrence in HIV/HCV-coinfected patients undergoing liver transplantation for end-stage liver disease. METHODS: Open prospective trial of early treatment of HCV recurrence in consecutive HIV/HCV-coinfected patients transplanted at a tertiary hospital in Barcelona between 2002 and 2004. All patients had indication for liver transplantation, no previous CDC class C HIV-associated opportunistic events, a CD4+ T-cell count >100cells/microl, and undetectable plasma HIV RNA on highly active antiretroviral therapy. Treatment with pegylated interferon-alpha2b (1.5 microg/kg/week) and ribavirin (800-1000 mg/day) was given for 24 to 48 weeks, as soon as HCV recurrence was histologically documented. RESULTS: Of six patients who underwent transplant, five patients surviving the early post-transplantation period developed HCV recurrence, presenting as severe cholestatic hepatitis in three, and were started on antiviral treatment a median of 12 weeks (range: 5-31) after transplantation. After a median follow-up of 24 months all treated patients were alive. Biochemical response was achieved in all patients, although only one achieved a sustained virological response. Mild rejection before HCV recurrence occurred in two cases. Treatment was well tolerated with no episodes of rejection or mitochondrial toxicity. No patient required modification of the antiretroviral regimen. Liver biopsies performed in patients without virological response, 12-34 months after transplantation, showed cirrhosis in two and moderate chronic active hepatitis in the remainder. CONCLUSIONS: Despite early antiviral treatment, severe HCV recurrence after liver transplantation may compromise long-term survival in HIV-infected patients. Improved treatment strategies for these patients are urgently required.     

Adoptive immunotherapy with liver allograft–derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice

After liver transplantation in HCV-infected patients, the virus load inevitably exceeds pre-transplantation levels. This phenomenon reflects suppression of the host-effector immune responses that control HCV replication by the immunosuppressive drugs used to prevent rejection of the transplanted liver. Here, we describe an adoptive immunotherapy approach, using lymphocytes extracted from liver allograft perfusate (termed herein liver allograft–derived lymphocytes), which includes an abundance of NK/NKT cells that mounted an anti-HCV response in HCV-infected liver transplantation recipients, despite the immunosuppressive environment. This therapy involved intravenously injecting patients 3 days after liver transplantation with liver allograft–derived lymphocytes treated with IL-2 and the CD3-specific mAb OKT3. During the first month after liver transplantation, the HCV RNA titers in the sera of recipients who received immunotherapy were markedly lower than those in the sera of recipients who did not receive immunotherapy. We further explored these observations in human hepatocyte–chimeric mice, in which mouse hepatocytes were replaced by human hepatocytes. These mice unfailingly developed HCV infections after inoculation with HCV-infected human serum. However, injection of human liver–derived lymphocytes treated with IL-2/OKT3 completely prevented HCV infection. Furthermore, an in vitro study using genomic HCV replicon–containing hepatic cells revealed that IFN-γ–secreting cells played a pivotal role in such anti-HCV responses. Thus, our study presents what we believe to be a novel paradigm for the inhibition of HCV replication in HCV-infected liver transplantation recipients.     

Reliability of the third-generation recombinant immunoblot assay for hepatitis C virus

BACKGROUND: In a confirmatory laboratory, the second-generation recombinant immunoblot assay (RIBA-2) was replaced by the third- generation RIBA (RIBA-3) in March 1993. The aim of this validation study was to compare the sensitivity and specificity of RIBA-2 and RIBA- 3 in a routine setting, by using a validated hepatitis C virus (HCV) RNA polymerase chain reaction to establish plasma viremia. STUDY DESIGN AND METHODS: RIBA-2 testing was performed (March 1991-March 1993) in 593 HCV RNA-positive and 1498 HCV RNA-negative subjects. RIBA-3 testing was performed (March 1993-May 1994) in 220 HCV RNA-positive and 530 HCV RNA-negative subjects. All samples reacted for anti-HCV in enzyme- linked immunosorbent assay. RESULTS: In HCV RNA-positive individuals, the sensitivity of RIBA-3 was significantly higher than that of RIBA-2 (99.5% vs. 93.3%, p = 0.0005). This was not caused by inclusion of the NS5 antigen, but by a higher sensitivity of the antigens c33 and c100 (RIBA-2: 94.3% and 62.6%; RIBA-3: 99.5% and 88.6%). Replacement of the c22 and c100 recombinant proteins by synthetic peptides significantly reduced nonspecific reactivity against these antigens (p < 0.0001). Unfortunately, increased nonspecific reactivity against the modified c33 antigen and the new NS5 antigen canceled out this effect. Two-band reactivity occurred more often in nonviremic persons than in viremic persons (32.7% vs. 8.2%, p < 0.0001). Risk factors for HCV infection were less frequently observed in 11 blood donors with two-band reactivity than in 6 blood donors with other positive RIBA-3 patterns (18% vs. 83%, p = 0.03). CONCLUSION: The higher sensitivity of RIBA-3 significantly reduced the number of indeterminate test results in HCV RNA-positive persons. Confirmatory laboratories must be aware of the frequent occurrence of nonspecific, isolated reactivity and even nonspecific, two-band reactivity in anti-HCV enzyme-linked immunosorbent assay-reactive blood donors.     

HCV RNA in blood donors with isolated reactivities by third-generation RIBA

BACKGROUND: The objective of this collaborative study was to learn the proportion of HCV RNA-positive samples obtained from a population of donors with isolated anti-HCV reactivities by third-generation RIBA (RIBA-3) (indeterminate results). STUDY DESIGN AND METHODS: During a 2-year period, 11 blood transfusion centers kept all samples with indeterminate RIBA-3 results to test them by PCR, using both local and commercial techniques. RESULTS: Of the 758 RIBA-3 indeterminate samples, 10 (1.3%) were positive for HCV RNA: 3. 3 percent (6/180) and 1.3 percent (4/317) of samples with anti-core or anti-NS3 reactivity, respectively, and none of the 52 and 209 samples with anti-NS4 or anti-NS5 reactivity, respectively. HCV RNA-positive donors with anti-core reactivity were infected with different subtypes (1 with HCV subtype 1b, 1 with 2, 1 with 2a/2c, 2 with 3a, and 1 with 5a), and a follow-up indicated a chronic-carrier state in two of the six donors. Acute hepatitis was diagnosed in three of the four donors with anti-NS3 reactivity alone. Two of these three were IV drug users and were infected with subtype 1a. CONCLUSION: HCV RNA-positive donors with indeterminate results in RIBA-3 are extremely rare, but they do exist. They were observed only when either anti-core or anti-NS3 was present. With such a RIBA-3 profile, PCR testing remains necessary to reveal an eventual acute or chronic HCV infection.     

肝肾联合移植后前列地尔的早期应用

背景:近来有文献报道,前列地尔可促进移植肾功能的恢复,降低肾功能恢复延迟与急性排斥反应发生率,减少死亡率。目的:观察肝肾联合移植后早期应用前列地尔对移植物功能恢复的影响。方法:选择6例肝肾联合移植患者作为实验组,移植过程中及移植后3周内给予前列地尔30μg/d,同期选择4例移植过程中及移植后不给予前列地尔的肝肾联合移植患者作为对照。观察两组患者移植后尿量、血肌酐、肌酐清除率、丙氨酸氨基转移酶、天冬氨酸转移酶、总胆红素、直接胆红素、移植肾血流阻力指数、胆汁引流量情况。结果与结论:实验组患者移植后尿量、肌酐清除率、胆汁引流量均大于对照组(P<0.05),丙氨酸氨基转移酶、天冬氨酸转移酶、总胆红素、直接胆红素浓度、肌酐浓度及移植肾血流阻力指数均明显低于对照组(P<0.05)。结果证实前列地尔对肝肾联合移植后移植肝、肾功能的早期恢复有积极的意义。