医、技学院(华盛顿医疗手册培训-器官移植)

1、Solid Organ Transplant Medicine Dr. Bai Xue-li The Department of HBP Surgery and Liver TransplantationContentsSolid Organ Transplant Basics1Graft Rejection2Complications3Special Considerations4In 1954, Prof. achieved the first successful kidney transplantation from one identical twin to another with

2、out using anti-rejection drugs The first successful kidney transplantation； The first living organ transplantation； The first relative kidney transplantation; The first organ transplantation between identical twins1990HistoryHistoryDr. Thomas E. Starzl 1963 first liver transplantationProf. Christiaa

3、n Barnard1967 first heart transplantationDr. James D. Hardy1963 first lung transplantation General PrinciplesA surgical operation where a failing or damaged organ in the human body is removed and replaced with a new oneA treatment, not a cure, for end-stage organ failure of the kidney, liver, pancre

4、as, heart and lung Solid Organ Transplant BasicsOrthotopic: lung/heart/liverHeterotopic: kidneySurgical Options Autograft: from one part of the body to another Isograft, Syngenic: between two genetically identical individuals Allograft: between two genetically dissimilar individuals of the same spec

5、ies Xenograft: between two species Graft All organs remain in short supply with increasing waiting times for potential recipients Living-donor transplants are considered as a partial solution to organ shortage Xenotransplantation is not a viable option in the near futureGeneral Principles Immunologi

6、c considerations prior to the transplant must be fully evaluated Including ABO compatibility, HLA typing, and some degree of immune response testing to the proposed donorGeneral PrinciplesEvaluation of the recipient Cause of organ failure Treatment for organ failure prior to transplantation Type and

7、 date of transplant CMV status of donor and recipient Initial immunosuppression, particularly use of antibody-based induction therapy Evaluation of the recipient Initial and current function of transplant：nadir creatinine, FEV1, ejection fraction, synthetic function and transaminases, etc. Complicat

8、ions of transplantation ：surgical problems, acute rejection, infections, chronic organ dysfunction, etc. Current immunosuppression regimen and recent drug levels Treatment Immunosuppressionpromote acceptance of a graft (induction therapy)prevent rejection (maintenance therapy)reverse episodes of acu

9、te rejection (rejection therapy) Complicationsinfectionmalignancynonimmune toxicity：nephrotoxicity, diabetes mellitus, bone disease, gout, hyperlipidemia, cardiovascular disease, or neurotoxicityImmunosuppressive agents 1 1、Glucocorticoids：methylprednisolone mechanisms immunosuppressive and anti-inf

10、lammatory inhibition of cytokine transcription induction of lymphocyte apoptosis downregulation of adhesion molecule and MHC expression side effects diabetes mellitus Cushing syndrome osteoporosis Peptic ulcer2、Antiproliferative agents: Azathioprine, MPA Azathioprinemechanisms: metabolized to 6-merc

11、aptopurine inhibits the synthesis of DNA; suppresses the proliferation of activated lymphocytesadverse effects: myelosuppression MPA:MPA, MMFmechanisms: inhibits the rate-limiting step in de novo purine synthesis; selectively inhibits lymphocytes proliferation adverse effects: gastrointestinal distu

12、rbances, hematologic disturbances3 3、Calcineurin inhibitors (CNI)：Cyclosporine (CsA), Tacrolimus CsAmechanisms：blockade of interleukin-2 and other cytokine transcription; inhibition of T-lymphocyte activation and proliferationside effect：nephrotoxicity(30%), hirsutism, hypertension, glucose intolera

13、nce, hyperlipidemia FK506 (first choice for liver transpl)mechanisms： blockade of interleukin-2 transcription, inhibition of T-lymphocyte activation and proliferationside effect：nephrotoxicity, neurotoxic and diabetogenic(more than CsA), hypertension4 4、Sirolimusmechanisms： inhibits the activation o

14、f a regulatory kinase, mammalian target of rapamycin (mTOR); prohibits T-cell progression from the G1 to the S phase of the cell; Anti-HCCside effect：No nephrotoxicity and neurotoxicity gastrointestinal symptoms hyperlipidemia anemia5 5、Polyclonal antibodies : : Antithymocyte globulin （ATG）, Antilym

15、phocyte globulin（ALG） 6 6、Monoclonal antibodies: : OKT3，Anti-interleukin-2 receptor monoclonal antibodies（Daclizumab, Basiliximab ）mechanisms：competitively inhibit CD25 and thereby inhibit activation of T cellsPreventing infection Trimethoprim/sulfamethoxazole：prevents urinary tract infections, Pneu

16、mocystis jiroveci pneumonia, and Nocardia infections Acyclovir：prevents HSV and varicella-zoster，ineffective in CMV prophylaxis Ganciclovir or valganciclovir: prevents reactivation of CMV infection Fluconazole or ketoconazole：systemic fungal infections or recurrent localized fungal infections Graft

17、RejectionHyperacuteRejection Graft RejectionChronicRejectionAcuteRejectionGraft RejectionHyperacute rejection: : occurs within 24 hours after transplantationmediated by pre-existing antibodies specific for graft antigensmassive recruitment of neutrophils occurs followed by rapid inflammationABO inco

18、mpatibilityGraft RejectionAcute rejection: : occurs in the first few days to months after transplantation, 80-90% in the first monthMediated by T cells immune responseMassive infiltration by macrophages and lymphocytesGraft RejectionChronic rejection: :occurs in months to years after transplantation

19、mediated by humoral and cell responseschronic vascular rejection and vascular endothelial injury; organ degeneration and dysfunction not induced by immune response Acute Rejection, Kidney occur in the 1st year after transplantation，in only 10% of patients;if donot receive induction therapy, 20-30% R

20、easons：inadequate drug levels, noncompliance, or less common forms of rejection (such as antibody-mediated rejection or plasma cell rejection) mediated by the cellular immune system and T lymphocytes specific pathologic changes: lymphocytic interstitial infiltrates, tubulitis, and arteritisAcute Rej

21、ection, Kidney Diagnosis: percutaneous renal biopsy; excluding calcineurin inhibitor nephrotoxicity (trough and/or peak levels and associated signs), infection(urinalysis and culture), and obstruction (renal ultrasound) Manifestations: elevated serum creatinine (initial symptom), decreased urine out

22、put, increased edema, or worsening hypertension；Constitutional symptoms (fever, malaise, arthralgia, painful or swollen allograft) are uncommonAcute Rejection, Lung Of the solid organ transplants, the lung is the most immunogenic organ. The majority of patients have at least one episode of acute rej

23、ection. development of chronic rejection (bronchiolitis obliterans syndrome) occurs frequently and most commonly in the first few months after transplantation Diagnosis: fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsiesAcute Rejection, Lung Manifestations: nonspecific;

24、fever, dyspnea, and a nonproductive cough；chest radiograph is usually unchanged；Change in pulmonary function testing is not specific for rejection, but a 10% or greater decline in forced vital capacity or forced expiratory volume in 1 second, or both, is usually clinically significant must distingui

25、sh rejection from infection! Tough symptoms are similar, treatments are markedly differentAcute Rejection, Hearttwo to three episodes of acute rejection in the first year after transplantation; 50% to 80%, at least one rejection episode, most commonly in the first 6 months. Diagnosis: endomyocardial

26、 biopsy performed during routine surveillance or as prompted by symptoms；irreplaceable; repeated endomyocardial biopsies, severe tricuspid regurgitationManifestations: symptoms and signs of left ventricular dysfunction- dyspnea, paroxysmal nocturnal dyspnea, orthopnea, syncope, palpitations, new gal

27、lops, and elevated jugular venous pressureMany patients are asymptomaticAcute Rejection, Liver occurs within the first 3 months after transplant and often in the first 2 weeks after the operation generally reversible and does not portend a potentially serious adverse outcome as in other organs commo

28、nly experience acute allograft rejection, with at least 60% having one episodeAcute Rejection, Liver Diagnosis: liver biopsy Manifestations: mild, only a slight elevation in transaminases；severe, develop to liver failure: fever, malaise, anorexia, abdominal pain, ascites, decreased bile output, elev

29、ated bilirubin, and elevated transaminases. Differential diagnosis: primary graft nonfunction, preservation injury, vascular thrombosis, biliary anastomotic leak, or stenosis肝汇管区内大量以淋巴细胞为主的炎性肝汇管区内大量以淋巴细胞为主的炎性细胞浸润，并可见小叶间胆管上皮炎性细胞浸润，并可见小叶间胆管上皮炎性细胞浸润形成导管上皮炎损伤细胞浸润形成导管上皮炎损伤肝小叶间静脉血管内皮炎，内皮层有淋肝小叶间静脉血管内皮炎，内皮层

30、有淋巴细胞浸润并呈内皮水肿巴细胞浸润并呈内皮水肿Chronic Allograft Dysfunction accounts for the vast majority of late graft losses; mediated by immune and nonimmune factors slowly progressive, insidious; major obstacle to long-term graft survival Pathologic characterization：gradual vascular and ductal obliteration, parenchy

31、mal atrophy, and interstitial fibrosis Diagnosis: often difficult and generally requires a biopsy Treatment: if established, no effective therapy; require a second solid organ transplant; aimed at prevention Company Logo Graft RejectionGeneralPrinciplesDiagnosisManifestationsTreatment-Chronic Allogr

32、aft DysfunctionAccounts for the vast majority of late graft losses and is the major obstacle to long-term graft survival Difficult Require a biopsy Mediated by immune and nonimmune factorsUnique No effective therapy A second solid organ transplant PreventionComplicationsInfectionsRenal DiseaseMalign

33、ancyCMVHepatitis BHepatitis CEBVFungusParasiteComplicationsSkin cancerLip CancerLymphoproliferative DiseaseBronchogenic CarcinomaKaposi SarcomaUterine/Cervical CarcinomaRenal Cell CarcinomaAnogenital Neoplasms Company LogoComplications-InfectionsTreatmentTreatmentDiagnosisPolymerase Chain Reaction (

34、PCR) - Blood Sample Valganciclovir 450 to 900 mg PO bid Ganciclovir 2.5 to 5.0 mg/kg bid IVadjusted for Renal FunctionvCMV Hyperimmune globulin+Ganciclovir Organ Involvement Foscarnet / Cidofovir Ganciclovir Resistant Complications-InfectionsHepatitisLamivudinTextRibavirinInterferonv Hepatitis Bv He

35、patitis COral Fluconazole Play a role in the development of posttransplant lymphoproliferative diseaseImmunosuppression Oral Fluconazole Complications-Infectionsv EBVv Fungusv ParasiteCompany LogoTiming and Etiology of Posttransplant InfectionsTime PeriodInfectious ComplicationEtiology6 month posttr

36、ansplantCommunity-acquired infectionsBacterialTick-borne diseaseChronic progressive infectionHepatitis B, Hepatitis C, Cytomegalovirus Epstein-Barr virus, Papillomavirus Polyoma virus (BK)Opportunistic infectionsP. Jiroveci, L. monocytogenes Nocardia asteroides, Cryptococcus neoformans Aspergillus s

37、pp., West Nile virusCompany LogoComplications Renal disease The leading cause of allograft loss in renal transplant recipients Calcineurin inhibitor (CsA, Tacrolimus) Nephrotoxicity Chronic renal insufficiency End-stage renal disease (ESRD)Company LogoComplications Malignancy Three-to fourfold highe

38、r than general population Skin and lip cancers 40-50% in transplant recipients Risk factors: immunosuppression, UV radiation, HPV Develop at younger age Recommend: protective clothing, sunscreens avoid sun exposure Diagnosis: examination of the skinCompany LogoComplications Malignancy Posttransplant

39、 lymphoproliferative disease 1/5 of all malignancies after transplantation Risk factors: antilymphocyte therapy Majority: large-cell non-Hodgkin lymphomas of the B-cell type Presentation: atypical Diagnosis: requires a high index of suspicion followed by a tissue biopsy Treatment: reduction or withdrawal of immunosuppression chemotherapyCompany LogoSpecial Considerations Drug Interactions Important drug interactions are always a concern