外科学课件：器官移植

1、Organ Transplantation,Female, 49y Pretty Rich Single and Sad,Polycystic liver and kidney disease Her mother and elder sister both died of the same disease. On hemodialysis,Comparison to normal liver & kidney,Normal,Polycystic liver and kidney,Removed organs and grafts,Intensive care unit (ICU) and d

2、ischarge,Follow up,Her younger sister suffered from the same disease. History repeated itself.,A New Day Has Come,Organ Transplantation,Overview of transplantation Transplantation immunity and prevention Procurement and preservation of grafts Organ transplantation,History of transplantation,Fantasy

3、stage Empirical study stage Clinical early stage Clinical developing stage,Fantasy stage,2000 ys ago , Bianque “ 剖胸探心，易而治之 ”,Empirical study stage,Alexis Carrel (France) Nobel Prize winner in 1912 for Medicine and physiology,Invented a new technique for vascular anastomosis,Clinical early stage,Jose

4、ph Murray (USA),Kidney transplantation between identical twins, in 1954,Cadaveric kidney transplantation, in 1962,Nobel Prize winner in 1990,Clinical developing stage,Facial Transplantation,France 2005,China 2006,Milestones in Organ transplantation,Fundament,Started in 1960s Developed rapidly during

5、 the last two decades All kinds of transplantations can be performed Over 7000 patients underwent transplantations/year The numbers of transplantation added up to morn than 100,000.,Organ transplantation in China,Conception of transplantation,Transplantation,Transplantation is the moving of viable c

6、ells, tissues or organs from one body to another (or from a donor site on the patients own body), for the purpose of replacing the recipients damaged or failing cell, tissue or organ with a working one from the donor site.,Terms of Transplantation,The transplanted cell, tissue or organ is called gra

7、ft.,The person who donates grafts is called donor.,The person who receives grafts is called recipient.,Autotransplantation Isotransplantation Allotransplantation Xenotransplantation,Classification,According to the genetic difference,Autotransplantation,Transplant back to the same person,Isotransplan

8、tation,Organs or tissues are transplanted from a donor to a genetically identical recipient,Allotransplantation,Organs or tissues are transplanted from a donor to a genetically non-identical member of the same species,Xenotransplantation,Transplanting organs or tissues from one species to another,Cl

9、assification（according to the site of transplants),orthotopic transplantation heterotopic transplantation Paratopic transplantation,Orthotopic Transplantation,Heterotopic Transplantation,Paratopic Transplantation,In situ lateral partial liver transplantation,Classification,According to the character

10、istics of grafts Cell transplantation Tissue transplantation Organ transplantation,Cell Transplantation,haemopoietic stem cell transplantation, MSC transplantation, etc,Tissue Transplantation,Skin, fascia, tendon, etc,Organ Transplantation,According to Applied Techniques,Vascularized transplantation

11、 Pedicled transplantation Dissociated transplantation Infused transplantation,Vascularized Transplantation,Pedicled Transplantation,Latissimus dorsi flap to reconstitute breast,Dissociated Transplantation,Free skin grafting,Infused Transplantation,Question 1,We often heard about the bone marrow tran

12、splantation. What kinds of transplantations does it belong to?,A. isotransplantation,B. Allotransplantation,C. Cell transplantation,D. Tissue transplantation,E. Organ transplantation,F. Dissociated transplantation,G. Infused transplantation,Organ Transplantation,Overview of transplantation Transplan

13、tation immunity Procurement and preservation of grafts Organ transplantation,Transplant immunity,Rejection is the biggest obstacle for transplantation.,Host against invader,Rejection results from the difference of the MHC Ag,Transplantation antigen,MHC antigen (HLA) Class i: HLA-A, B, C, expressed o

14、n cell surface of all nucleated cells and recognized by CD8+ T-cells Class ii: HLA-DR, DQ, DP, expressed on cell surface of APC cells and recognized by CD4+ T-cells mHC antigen (minor histocompatibility antigen) Endothelial glycoproteins ABO blood-group antigens,Key components of the immune system,D

15、irect and indirect recognition of heterogenous antigen,Co-stimulatory Signals,B-cell mediated humoral response,HAR,CR,Ab preexisted,Ab Produced gradually,CsA Tac,OKT3,细胞毒T淋巴细胞相关抗原4融合蛋白(CTLA4-Ig),抗CD154单抗,抗CD25单抗,Sirolimus Everolimus,酪氨酸激酶3（JAK3）抑制剂,MPA,排斥反应信号通路及免疫抑制剂,FK778,抗CD52单抗,FTY720,Aza,Types o

16、f rejection,Hyperacute rejection, HAR Acute vascular rejection Acute rejection, AR Acute cellular rejection Chronic rejection, CR,Hyperacute rejection,Mediated by preformed antibodies recognizing foreign Ag,Occurs within minutes to hours after vascular anastomosis,Result from prior exposure to alloa

17、ntigens from blood transfusions, pregnancy, or previous transplantation,Hyperacute Rejection,Require Immediate removal of transplant,Prevented by transplanting only ABO-compatible grafts,Rapid agglutination of the blood occurs,Rapid thrombotic occlusion of the vascular of the transplanted allograft,

18、Acute Vascular Rejection(Accelerated Rejection),Occurs on day 3-5 post-transplantation Ig G Ab against endothelial antigen and activation of complement T-cell also contribute to the accelerated rejection Lysis of the endothelial cells and infiltration of inflammatory cells,Acute cellular rejection,U

19、sually occurs on day 4-90 PT Caused by mismatched HLA Cellular and humoral immunity involved in this episode,Acute cellular rejection,Clinical symptoms and signs: anemia, edema, hypourocrinia and transplanted kidney dysfunction Laboratory testing +Tissue biopsy,Early diagnosis and treatment are very

20、 important 90% AR can be reverted,Acute Cellular Rejection,The presence of T-cells infiltrating the transplanted tissue,Evidence of structural injury to the transplanted tissue,Injury to the blood vessels in the transplanted tissue,Chronic Rejection,A term used to describe a long-term loss of functi

21、on in transplanted organs. The mechanism of CR is less clearly defined. Proliferation of endothelial cells and smooth muscle cells, thereby leading to luminal occlusion,Chronic rejection,Over 3 months after transplantation Immunological and non-immunological causes involved No effective treatment up

22、 till now Re-transplantation is the only definitive treatment,Prevention of Rejection,ABO blood typing,Pre-existing Ab detection,HLA typing,HLA-A, HLA-B, HLA-DR,Clinical Immunosuppressant,Induction agents Antibodies directed at lymphocytes Maintenance agents Corticosteroid Antiproliferative Agents T

23、-cell-directed immunosuppressants Lymphocyte sequestration,Two polyclonal anti-lymphocyte agents ALG, ATG Two mAbs against IL-2R Simulect, Zenapax One mAb against CD3 cells OkT3,Induction agents,Maintenance agents,Clinical Immunosuppressant,Adrenal Corticosteroid,Antiproliferative Agents,T-cell-dire

24、cted immunosuppressants,Lymphocyte sequestration,Possible mechanism,Suppress the cell-mediated immunity Inhibition of cytokine gene transcription and cytokine secretion Suppress the humoral immunity,Side effects: Hypertension, weight gain, peptic ulcers, cataract formation, hyperglycemia, cushingoid

25、 features, Infections,Adrenal Corticosteroid,Antiproliferative agents,Possible mechanisms: Inhibit purine, DNA, RNA synthesis Inhibit T-cell proliferation and Abs production Side-effects: bone marrow suppression, liver toxicity, gastrointestinal upset and so on.,Azathioprine,Mycophenolate Mofetil,Cy

26、clophosphamide,T-cell-directed immunosuppressants,CsA and FK 506 are calcineurin inhibitors Inhibit the expression of IL-2 and other cytokines, thereby inhibit T-cell activation and proliferation Potencial adverse effects: nephrotoxicity, neurotoxicity, hypertension, etc,cyclosporine,FK506,Sirolimus

27、,Calcineurin inhibitors,Cell cycle arrest,Lymphocyte sequestration FTY720 Increase the expression or change the function of certain adhesion molecules in lymphocyte,Clinical immunosuppressant,Organ Transplantation,Overview of transplantation Transplantation immunity Procurement and preservation of g

28、rafts Organ transplantation,Types of donor,Living donors,Cadaveric (Deceased) donors,Organ perfusion and preservation,Warm ischemia time (WIT): indicates the period from the stop of blood supply of donor organ to the beginning of cold perfusion WIT10 minutes,Cold ischemia time (CIT): indicates the p

29、eriod from cold perfusion to recovery of blood circulation of the grafts, including the whole preservation time,Principles of Organ Preservation,Under low temperature (0-4),Maintain optimal osmotic pressure Carbohydrates, K+, Na+,Reduce ischemia reperfusion injury Agents against oxyradical,Reperfusi

30、on injury: refers to damage to tissue caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damages through the induction of oxidative

31、 stress.,Preservation solution,Solution mimics intracellular fluid Solution mimics extracellular fluid Non intracellular and extracellualr solution,UW solution: high K+, low Na+, mimics intracellular level to minimize diffusion down electrochemical gradients,Overview of transplantation Transplantati

32、on immunity Procurement and preservation of grafts Organ transplantation,Organ Transplantation,Kidney transplantation,Kidney transplantation,Indications: end-stage renal disease (ESRD) Primary diseases: Chronic glomerulonephritis 7090 % Diebetic nephropathy 5% Chronic pyelonephritis 5% Malignant nep

33、hrosclerosis 1% Polycystic kidney disease 1% Other renal disease 1%,Recipient evaluation and preparation,Age: normally 1250 yeas old,Without systemic disease to damage transplanted kidney (e.g. Uncontrolled systemic infection or malignancy),Careful management of other concomitant diseases (e.g. Diab

34、etes, Systemic lupus erythematosus, TB, diffused vasculitis),Contraindications Malignancy Uncontrolled systemic infection Emotional disturbance Obvious Hemorrhagic tendency (PU) Amyloid degeneration ,Recipient evaluation and preparation,CMV antibody titer HIV HBV & HCV Parathyroid evaluation Coagula

35、tion profile ABO and HLA typing Urologic evaluation Gastrointestinal evaluation Psychiatric assessment ,Recipient evaluation and preparation,Donor selection,Immunologic Selections,Non-immunologic Selections,ABO blood group typing,Lymphocytotoxicity cross match test 10%,HLA typing,PRA,Exclusion of sy

36、stemic infections,Exclusion of malignancy, etc,Kidney function,Abnormal anatomy,Age,Kidney transplantation operation,Grafts procurement & preservation Grafts trimming Renal vein management； Renal artery management； Ureter management,Grafts procurement & preservation,Grafts Trimming,Ureter renal arte

37、ry renal vein,Vascular anastomosis,Renal artery,External iliac artery,Renal vein,External iliac vein,Abdominal aorta,Inferior vena cava,Recovery of blood circulation,Ureteroneocystostomy,Living donor kidney normally requires 3-5 days to reach normal functioning level Cadereric donor kidney usually s

38、tretch that interval to 7-15 days,Immunosuppression,Immunosuppresants must be taken for the rest of the patients life The most common medication regimen today: Tacrolimus +mycophenolate+ prednisone or Cyclosprorine, rapamycin, azathioprine AR occurs in 10% to 25% of people after transplantation duri

39、ng the first sixty days,Complications of Renal Transplantation,Transplant Rejection( hyperacute, acute or chronic),Vascular complications (arterial or venous obstruction, bleeding),Infections or sepsis,Urinary complications (Urinomas, urinary obstruction, ATN, etc),Post-transplant lymphoproliferativ

40、e disorder (PTLD),Other side effects of medications,Gastrointestinal inflammation Ulceration of the stomach and esophagus hirsutism hair loss obesity acne diabetes mellitus (type 2) hypercholesterolemia and etc,Prognosis of kidney transplantation,Kidney transplantation is a life-extending procedure.

41、 Deceased donor transplanted kidneys have 1-, 5-, and 10-year survival rates of 89%, 67%, and 40%. The longest-surviving time of the renal grafts exceeded over 40 years in the world and 30 years in China.,Liver transplantation,Liver transplantation,Indications,Contraindications,Metastatic cancer out

42、side liver Active drug or alcohol abuse Active septic infections HIV infection Advanced age and serious heart diseases Etc.,HCC,Acute liver failure,Liver cirrhosis after hepatitis C,Biliary atresia,Liver pompes syndrome,Procurement of Donor Liver,Liver transplantation,Classical liver transplantation

43、,Partial liver transplantation,Auxiliary liver transplantation,Piggy-back liver transplantation,Transplant operation procedures,Hepatectomy,Anhepatic phase,Post-implantation phase,Classical liver transplantation,Piggy-back Liver Transplantation,Post-transplant Management,A short stay in ICU Hemodyna

44、mic stability Respiratory stability Adequate kidney function,Complications after liver transplantation,Primary graft nonfunction Intra-abdominal bleeding Vascular complications Biliary complications Infections,Common complications,Immunologic Aspects,Acute rejection Chronic rejection Recurrent disea

45、ses,Primary Graft Nonfunction,Relate to donor variables, inadequate preservation, prolonged cold ischemia time or humoral immune response Encounted in 2% to 5% liver grafts Characterized by poor synthetic function and severe hepatocyte injury,Primary Nonfunction,Clinical findings: progressive hemody

46、namic instability, multi-organ system failure, and encephalopathy Laboratory finding :demonstrate worsening acidosis, coagulopathy, and extremely elevated enzymes Early re-transplantation needed Failure to find a suitable graft within 7 days is associated with higher morbility and mortality.,Acute r

47、ejection,T-cell mediated acute rejection Occurs at a rate of 30% to 50% within the first 6 months Most often within the first 4 weeks Clinical findings : fever, abdominal pain, elevated liver enzymes and bilirubin Diagnosis confirmed by a liver biopsy 90% of AR can be cured with high-dose of cortico

48、steroids or potent anti-T-cell Abs,Chronic rejection,CR is seen months or years after transplantation Manifested by poor synthetic liver function and hyperbilirubinemia Characterized histologically by paucity of the bile ducts Also described as vanishing bile duct syndrome The etiology is not well understood Commonly irreversible,Long-term results,Prognosis is quite good. Liver transplantation recipients have 1-, 5-, and 8-year survival rates of 91%, 84%, and 78%. The longe