【作者】 苗芸；

【导师】 于立新；

【作者基本信息】 第一军医大学 ， 泌尿外科， 2007， 博士

【摘要】 背景自从1906年Mathieu报道首例肾移植开始，人类对器官移植的探索从未停止过，随着外科技术的日臻完善以及新型免疫抑制剂的不断更新，器官移植在临床已经作为部分器官功能衰竭的替代性治疗手段。同时，因为所涉及医学理论同外科技巧的复杂性与难度，器官移植又被称为21世纪医学领域的珠穆朗玛峰。目前，临床移植对器官移植的关注焦点不仅限于排斥反应的控制，还注重患者以及危重患者的长期生存质量，如：对多器官联合移植的研究、移植相关肿瘤发生的分析、ABO血型不相符的器官移植，移植术后心血管并发症的防治、移植受者妊娠等等。本文对多器官联合移植（以肝肾联合移植为例）以及移植相关肿瘤（以并发肺癌为例）的研究分述如下：第一部分肝肾联合移植的临床经验第一章肝肾联合移植的临床经验第二章肝肾联合移植中肝脏对肾脏的保护作用第二部分器官移植并发肺癌患者的生存分析第一章器官移植后肺癌患者的生存分析第二章肺癌患者器官移植后的生存分析第一部分肝肾联合移植的临床经验第一章肝肾联合移植的临床经验目的：探讨肝肾联合移植的适应证，手术技术，治疗经验以及并发症的防治。方法：2001年10月至2006年6月进行肝肾联合移植18例。男13例，女5例。年龄41-71岁，平均57.9岁。原发病：多囊肝、多囊肾并尿毒症8例，酒精性肝硬化合并尿毒症2例，乙型肝炎肝硬化合并尿毒症7例，肾移植术后14年丙型肝炎肝硬化导致肝衰伴移植肾功能不全尿毒症1例。肝移植采用经典非转流原位肝移植术式和背驮式肝移植术式，肾移植为常规术式。病肝切除时注意细致分离第三肝门、创面及时止血。以抗胸腺淋巴细胞免疫球蛋白或白介素-2受体单克隆抗体作为免疫诱导，术后服用他克莫司、霉酚酸酯以及激素维持免疫抑制治疗。患者门诊随访，复查血、尿常规，肝肾功能，他克莫司血药浓度以及移植物B超等项目。随访时间2个月～4年10个月。结果：18例手术均取得成功。16例存活至今，肝肾功能正常，其中存活4年10个月者1例，存活3年以上者2例，2年以上者6例，1年以上者4例，1年以内3例。1例49岁患者术后1年6个月死于心肌梗塞，1例52岁患者术后1年1个月死于肺部巨细胞病毒（CMV）感染。术后发生急性排斥反应1例，继发性出血1例，心肌梗塞1例（死亡），胸腔积液4例，肺部感染3例（1例死亡）。除死亡病例外，所有并发症经相应治疗后逆转治愈。结论：肝肾联合移植是肝肾功能衰竭的有效治疗手段。娴熟的手术技巧、围手术期细心管理、并发症的及时诊治是肝肾联合移植成功的关键。第二章肝肾联合移植中肝脏对肾脏的保护作用目的：探讨肝肾联合移植中肝脏对肾脏的保护作用。方法：回顾分析2001年10月至2006年6月接受肝肾联合移植的18例患者，并以同一供体的对侧肾脏所完成的单独肾移植18例受者作为对照，2组间患者年龄、性别、血型、冷热缺血时间、人类白细胞抗原（HLA）配型、肾病原发病、免疫抑制方案等条件基本相匹配。对2组间移植肾急性排斥反应（AR）、慢性排斥反应（CR）、移植肾功能延迟恢复（DGF）的发生率以及出院时患者血清肌酐（Cr）改善水平进行比较。结果：肝肾联合移植组AR和DGF发生率明显均低于单独肾移植组，统计学差异显著（5.56％vs 33.3％P=0.035；0 vs 27.8％P=0.045）；肝肾联合移植组CR发生率明显低于单独肾移植组，但统计学差异不明显（0 vs 11.1％P=0.486）。出院时平均Cr水平肝肾联合移植组明显优于单独肾移植组，统计学差异显著（77.6±23.4umol／L vs 123.1±23.8umol／L P=0.000）。结论：肝肾联合移植中肝脏对肾脏具有保护作用，能够维持良好的移植肾功能。第二部分器官移植并发肺癌患者的生存分析肺癌在普通人群中为第二位高发肿瘤，并且已经成为全球因肿瘤导致死亡的最主要原因。在美国，无论在男性还是女性，肺癌都已列为头号肿瘤杀手，其导致的死亡率为70／100000。在欧盟，肿瘤致死的病因中，1／3为肺癌。在中国，男性中因肺癌导致的死亡率为33／100000，并且在今后的几十年还会继续上升。器官移植的受者中，恶性肿瘤已经成为非常重要的并发症，发病率为平均每年1-2％，其中皮肤癌、淋巴瘤、肾癌等，发病率高达5-10％，并且随着移植后免疫抑制时间的延长，发病风险每年增加1-2％。在器官移植受者中新发肺癌以及肺癌后接受器官移植的患者生存情况并不清楚，文献报道仅限于单中心的小样本调查。本文以Israel Penn国际移植肿瘤登记处（Israel Penn International Transplant Tumor Registry，IPITTR）录入的器官移植术后新发肺癌患者（662例）以及肺癌后接受器官移植的患者（28例）的临床资料，对影响患者生存率的因素进行分析。第一章：器官移植后肺癌患者的生存分析目的：了解器官移植后新发肺癌患者影响其生存率的各类因素。方法：对1968年11月至2006年12月向Israel Penn International Transplant Tumor Registry报告的器官移植后新发肺癌病例的存活时间进行多因素分析。采用SPSS 11.5统计软件。以Cox回归模型分析多种因素对生存时间的影响，Kaplan-Meier法比较肿瘤分期对生存时间的影响。P值小于0.05认为具有统计学差异。结果：662例患者于器官移植后平均第44个月（0-1054）时诊断肺癌。总体存活率为33％。患者移植时年龄偏大（P=0.033），病理诊断为小细胞肺癌（P=0004）以及接受ATG／ALG／OKT₃抗体诱导治疗（P=0.032）的患者死亡风险升高，并具有统计学意义。外科手术切除肿瘤病灶（P=0.000）、化疗（P=0.001）可以改善患者的生存率，并具有统计学意义。依据病理分期，四期肿瘤患者生存时间具有统计学差异（P=0.000）。患者性别、种族、诊断时年龄、移植-诊断时间、供器官类型、移植器官种类、以及除抗体类以外的免疫抑制剂类型同患者的生存时间无统计学相关性。结论：1．免疫抑制使得肺癌进展迅速，预后差。2．移植时年龄较大、病理类型为小细胞肺癌、经ATG／ALG／OKT₃抗体诱导治疗、以及晚期肿瘤使得患者死亡风险升高；3．外科切除、化疗可以改善患者生存率；4．以常规方法治疗肿瘤的同时减少免疫抑制剂用量。停用抗代谢药物，通常根据患者血药浓度减少25-50％CNI剂量；5．器官移植后对于有吸烟史的高危患者群应密切注意肺部的随访；6．我国可借鉴IPITTR模式建立相应的移植登记处，以便资料汇总、分析，有助于移植受者的治疗及随访。第二章：肺癌患者器官移植后的生存分析目的：了解肺癌患者器官移植后的生存情况。方法：对1968年11月至2006年12月向Israel Penn International Transplant Tumor Registry报告的肺癌患者接受器官移植后存活时间进行多因素分析。采用SPSS 11.5统计软件。以Cox回归模型分析多种因素对生存时间的影响。P值小于0.05认为具有统计学差异。结果：1968年11月至2006年12月期间，IPITTR共有28例移植前既发肺癌患者，因病理分期资料不完全，其对生存时间的影响未纳入分析。患者性别、种族、诊断以及移植时年龄、诊断-移植时间、供器官类型、移植器官种类、免疫抑制剂类型以及肿瘤复发同患者的生存时间均无统计学相关性。移植术后出现6例肺癌复发（21％），均在术后5年内复发。死亡9例，均在移植后5年内死亡，总体生存率为68％，死亡率为32％。结论：1．结合文献，仅早期肺癌患者肿瘤切除后可作为器官移植受者，且移植后存活率并不理想。2．普通人群中肺癌患者的生存曲线于诊断后5年开始趋于平缓，因此建议肺癌患者接受器官移植的等待时间为至少5年。更多还原

【Abstract】 Explores in organ transplantation have been continuing since the first kidneytransplantation in human was reported in 1906. With the development of surgicaltechnique and immunosuppression agents, organ transplantation has been the highestand hardest field in medical science. Current clinic focuses of transplantation are onlong-term outcome and intense recipients as well as acute and chronic rejection, suchas multiple organ transplantation, transplant-related malignance, cardiovasculardisease post transplantation and pregnancy in recipients. This article will provide theresearch on combined liver-kidney transplantation and analysis of multivariatefactors that influence survival with lung cancer in recipients as follows:PartⅠExperience with combined liver-kidney transplantationChapterⅠExperience with combined liver-kidney transplantationChapterⅡA liver graft from the same donor protect a kidney in combinedliver-kidney transplantationPartⅡAnalysis of multivariate factors that influence survival with lungcancer in recipientsChapterⅠMultivariate risk factors survival analysis of de novo lung cancerin organ transplant recipients ChapterⅡMultivariate risk factors survival analysis of pre-existing lungcancer in organ transplant recipientsPartⅠExperience with combined liver-kidney transplantationChapterⅠExperience with combined liver-kidney transplantationObjective To describe the indications, surgical techniques, clinical experiences andtreatment of complications of combined liver-kidney transplantation （CLKT）.Methods 18 cases subject to CLKT from Oct 2001 to June 2006 were reviewed inour center. 13 men and 5 women. Median age 57.9ys, age range 41 to 71ys. Primarydiseases as follow: 8 polycystic liver and kidney with uremia, 2 alcoholic cirrhosiswith uremia, 7 liver cirrhosis led by Hepatitis B with uremia, 1 liver cirrhosis led byHepatitis C and grafted renal failure 14 years after transplantation. Livertransplantations were performed with piggyback style or standard techniques withoutveno-venous bypass. Kidney transplantation followed routines. Care should be takenon third hepatic portal during hepatectomy. Immunosuppressive therapy includedATG or basilimab as introduction and Tacrolimus/Mycophenolate mofetil/steroid.The period of follow up ranges from 2 months to 4 years and 10 months.Results All the 18 operations were completed successfully. 16 are alive till nowwith good liver and kidney function. Among the 16 cases, the longest survival time is4 years and 10 months, 2 patients’ are over 3 years, 6 are over 2 years, 3 are over 1year and 3 are within 1 year. ldied of myocardial infarction on the eighteenth monthafter Tx. The other died of cytomegalovirus （CMV） infection of lung on thirteenthmonth. Complications included 1 acute rejection, 1 secondary hemorrhage, 1myocardial infarction, hydrothorax in 4, and pulmonary infection in 3. Except for 2dead cases, other compilations were rescued after therapy.Conclusions CLKT is an effective treatment method for liver and renal function failure. Proficient surgical skill and immediate management of complications arecrucial for successful CLKT.ChapterⅡA liver graft from the same donor protect a kidney in combinedliver-kidney transplantationObjective To compare the improvement of renal graft function of combined liver-kidney transplantation（CLKT） and kidney alone transplantation（KAT）.Methods The data of 18 CLKT and 18 contralateral kidney alone transplantationswere analyzed. The two groups Were matched in the following variables: age, gender,blood type, cold and warm ischemic time of the grafts, human leukocyte antigen（HLA）, primary renal disease, and use of immunosuppressants. Incidences of acuterejection, chronic rejection, delayed graft function and improved serum creatinine （Cr）on discharge were compared.Results The rates of acute rejection and delayed graft function were much lower inCLKT than that in KAT with significant difference （5.56% vs 33.3% P=0.035; 0vs 27.8% P=0.045）. CR incidence was lower in CLKT without significantdifference （0 vs 11.1% P=0.486） . There was much lower Cr lever in CLKT thanthat in KAT （77.6±23.4umol/L vs 123.1±23.8umol/L P=0.000）.Conclusions Analysis of the data indicates an allograft enhancing perfect effect ofliver transplantation on the renal allograft in combined liver- kidney transplantation. PartⅡAnalysis of multivariate factors that influence survivalwith lung cancer in recipientsLung cancer ranks among the most commonly occurring malignancies and currentlyis the leading cause of cancer-related deaths worldwide. In the United States, lungcancer is the most common cause of cancer-related deaths in men as well in women,with an incidence approximating 70 per 100,000 in individuals. Lung cancercurrently accounts for one-third of all cancer-related deaths in the European Union.In China, the mortality rate from lung cancer in males now approximates 33 per100,000, and death rates are expected to substantially increase over the next severaldecades. Transplant recipients develop malignancies at a rate of 1-2%approximately per year but this is higher （5-10%） for certain types of cancer （skin,lymphoma, kidney） and the overall rate of 1-2% increases in subsequent years withlonger exposure times to immunosuppressive drugs. However, the effects of organtransplantation on lung cancer incidence in recipients are unclear, literatures onwhich are limited to single center and small samples. Multivariate risk factorssurvival analysis of organ transplantation recipients with de novo （n=662） andpre-existing （n=28） lung cancer reported to the Israel Penn International TransplantTumor Registry from November 1968 to December 2006 was performed.ChapterⅠMultivariate risk factors survival analysis of de novo lung cancer inorgan transplant recipients Objective To investigate the risk factors that influence survival of de novo lungcancer in organ transplant recipientsMethods Multivariate risk factors survival analysis of lung cancer post organtransplantation reported to the Israel Penn International Transplant Tumor Registryfrom November 1968 to December 2006 was performed.Results Lung cancer presented 44 months （median） （range 0-1054） in 662 patientspost organ transplantation. Overall survival was 33%. Death risks were increased forthose who were older （P=0.033） at transplant, diagnosed with small cell lung cancer（P=0.004）, and administered with ATG/ALG/OKT₃ （P=0.032） for induction therapy.Surgery （P=0.000） and chemotherapy （P=0.001） were associated with increasedsurvival. Stage makes difference in survival time in recipients （P=0.000）. Nodifferences in death risk for age at diagnoses, gender, race, time from transplantationto diagnosis, donor type, transplantation organ and other immunosuppression wereidentified.Conclusion1. Lung cancer takes rapid progress and grim outcome under immunosuppression.2. Death risk was increased for patients with older age at transplantation, histology ofsmall cell lung cancer, induction therapy with ATG/ALG/OKT₃ and later stage oftumor.3. Death risk was improved for those receiving surgery and chemotherapy.4. We would suggest immunosuppression regulation with discontinuation of antimetabolites, and 25-50％reduction in CNI dose.5. Close surveillance is needed for the recipients that used to be heavy smokers.6. Similar registry as IPITTR should be set up in China transplant community forbetter outcome and follow up for the transplant recipients.ChapterⅡMultivariate risk factors survival analysis of pre-existing lungcancer in organ transplant recipientsObjective To investigate the risk factors that influence survival of pre-existing lungcancer in organ transplant recipientsMethods Multivariate risk factors survival analysis of pre-existing lung cancer inorgan transplant recipients reported to the Israel Penn International Transplant TumorRegistry from November 1968 to December 2006 was performed.Results The IPITTR has reviewed a series of 28 cases of pre-existing lung cancer intransplant recipients. Stage data were not included for analysis because of incompleterecords. No differences in death risk for age at diagnoses or transplantation, gender,race, wait time from diagnosis to transplantation, donor type, transplantation organand immunosuppression agents were identified. Recurrences in 6 （21％） patientsoccurred within 5 years post transplantation. 9 patients died within 5 years. Overallsurvival was 68％and mortality was 32％. Conclusion1. In literature, transplantation is generally acceptable for only patients with earlystage disease. Overall survival rate has not been good.2. Survival cures of lung cancer do not begin to flatten until 5 years post diagnosis ingeneral populations. We would recommend 5 years of disease free prior totransplantation.更多还原