PRINCIPLES OF Transplantation Surgery M K Alam MS, FRCS Professor of Surgery Al Maarefa Colleges

ILOs Define terminologies used in organ transplantation At the end of this presentation students should be able to: Define terminologies used in organ transplantation Describe the immunological basis of organ transplantation, organ matching, & immunosuppression. Summarize indications, contraindications, and outcome of common organ transplantation.

History of organ transplantation Rapidly expanding & important surgical specialty 300 AD: Cosmos & Damian attempted a leg transplant. 1778: John Hunter coined the term ‘transplant’ 1933: Voronoy 1st human renal transplant- failed due to ABO incompatibility 1945: Hume 1st short-lived functioning renal allograft 1950: Lawler 1st long-term survivor renal transplant 1963: Starzl 1st human liver allograft 1967: Starzl 1st long-term survivor liver transplantation 1967: Barnard 1st successful heart transplant 1981: Shumway 1st successful heart-lung transplant 1988: Grant 1st long-term survivor of small bowel transplant

Transplantation Indication- when no alternative treatments are available Improves quality of life Improves survival Cooperation of several disciplines Surgeons, anaethetists, immunologists & physicians

Two main obstacles to transplantation Recipients immune response Shortage of donor organs

Terminology Autograft: Free transplantation of tissue from one part of the body to another in the same individual. Isograft: Transfer of tissue between genetically identical individual- identical twins. Allograft: Organ transplanted from individuals of same species- main class of transplantation in humans Xenograft: Organ transfer between dissimilar species. Tissue is chemically treated to make it non-antigenic (porcine heart valve).

Terminology Orthotopic graft: Donor organ transplanted to the diseased organ site- liver. Heterotopic graft: Donor organ transplanted at a site different from normal anatomical position. Kidney in iliac fossa. Artificial (hybrid) organ implantation: Bio-artificial organs (combination of biomaterials & living cells)- experimental technique

Donor organs Cadaver graft: Organs retrieved from an individual pronounced brain dead according to a defined criteria, while heart continue to beat, ventilatory & other support maintained Living donors: -Related donors- parent or siblings -Unrelated donors- voluntary or to make money

Basic immunology of organ transplantation Auto & isografts - do not elicit immune response. Genetic differences between donor & recipient-major importance. Main antigens triggering rejection are coded in a group of genes known as- MHC (major histocompatibility complex). Located on short arm of chromosome 6 MHC class 1 are on all nucleated cells & platelets-(named HLA A,B, & C) MHC class 2 on B-cells, macrophage, monocyte & antigen-presenting cells (APC)- HLA DR, DP & DQ Blood group antigens (ABO system) can also trigger humoral rejection.

Immune response Inflammation- center of rejection process. Reperfusion→ endothelial activation→ infiltration of inflammatory cells particularly macrophages.

Afferent arm of immune response Presentation of donor HLA antigens to recipient’s T-cells receptor (TCR) “allorecognition” leads to T-cell activation. Recognized as foreign by recipient T-cells. Clonal expansion of T-cells. Differentiation T- cells into: CD4 positive (helper): Helping B-cell → plasma cells to make antibody, and activate phagocytosis. CD8 positive (effector)- Control level and quality of immune response. CD4- central role in rejection process.

Efferent arm of immune response Donor organ damage- efferent arm response Humoral mechanism- antibody produced by B- lymphocytes (under influence by cytokines released by T-cells CD4) bind foreign antigen → cell lysis. Cellular mechanism- by cytotoxic T-cells, macrophage, natural killer cells (large granular lymphocyte) & neutrophils.

Clinical patterns of rejection Hyperacute: Within 24 hours due to preformed antibody (IgG) against donor HLA antigens. Overcome by pre-transplant screening. Acute: within 6 months in up to 50% grafts. Characterized by infiltration of activated T cells and inflammatory cells. Chronic: >6 months, progressive decline in function. Multifactorial damage-(immune mediated, toxicity from immunosuppression, viral infection) cellular atrophy, fibrosis.

Organ matching ABO compatibility: ABO red cell antigen is also expressed on most tissue cells. HLA tissue typing: HLA antigen A,B,& DR on the donor and recipient on lymphocytes HLA typing most useful in renal transplant Direct cross match- incubating donor lymphocyte with recipient plasma. Detects preformed antibodies.

Organ retrieval Cadaver: Heart beating, ventilation supported Retrieval after cardiac arrest, rapid organ perfusion Organ function in donors established. e.g. Kidney Normal urine output (except oliguria due to dehydration), analysis, urea & creatinine. Live related: Kidney, liver, pancreas, lung, small intestine. Must justify operative risk.

General contraindication to organ donation Age > 90 HIV disease Disseminated cancer Melanoma Treated cancer within 3 years of donation Neurodegenerative disease due to infection- CJD

Organ specific contraindication to organ donation Liver: Acute hepatitis, cirrhosis, portal vein thrombosis. Kidney: Chronic kidney disease, long term dialysis, renal malignancy, previous renal transplant. Pancreas: Insulin dependent diabetes, pancreatic malignancy

Immunosuppression Achieve a balance between prevention of rejection and morbidity-side effects, risk malignancy Steroids: 1st line for acute rejection. Side effects of long term use. Azathioprine (AZA): For acute cellular rejection in renal transplant. Myelosuppression, GI symptoms. Mycophenolate mofetil: Prevents lymphocyte activation, replaced AZA in renal transplant Calcineurin inhibitors: Cyclosporin- acts by inhibiting cytokines which activates lymphocytes. Nephrotoxicity, hypertension, hyperglycemia, hyperlipidemia. Tacrolimus- Better outcome in kidney & liver transplant. Nephrotoxic, neurotoxic, diabetes, alopecia. Sirolimus: Inhibits T cell activation. Limited use due to toxicity Antibody: Induction therapy at the time of transplantation to provide immediate immunosuppression after transplantation.( antithymocyte globulin, alemtuzumab, interleukin-2 antibody)

Complications of immunosuppression Susceptibility to infections: TB, candida, pneumocytis carinii, cytomegalovirus, EB virus, measles, herpes. Risk of malignancy: SCC, Lymphoma Specific side effects of individual agent or regimen.

Organ donation Deceased donation- according to country rules Donor management: Cardiovascular stability, and maintaining organ function- optimal fluid, maintaining BP, & minimal inotrope support. Organ preservation: Cold storage by intravascular flush with chilled preservation fluid- UW fluid (University of Wisconsin) or Eurocollins solution. Preservation time- Kidney 24 hrs. , liver 20 hrs.

Renal transplantation Indication: End stage renal disease Patient assessment: Absolute contraindications- malignancy, active infection. Relative contraindications- advance age, severe cv disease, non-compliance with immunosuppressive therapy. Diabetes, hypertension, amyloidosis can also affect the transplanted kidney. Outcome: 1- year graft survival 90% 5- year graft survival 70% Peri-operative mortality- 2-5%

Liver transplantation Indication: Chronic liver disease with signs of decompensation (OV, ascites, jaundice, coagulopathy, SBP, hypoalbuminaemia) Common aetiology : Adults- alcohol, HBV, HCV, primary biliary cirrhosis, sclerosing cholangitis, HCC, acute liver failure due to paracetamol toxicity, viral. Children- biliary atresia, Wilson’s disease. Patient assessment: Expected 50% chance of 5 year post-transplant survival.

Liver transplantation Living donor: A portion of liver removed for transplant in children or small recipient. Donor liver regenerates to full size and function. Donor mortality- 0.5%. Post-op. management of rejection: Usually around day 7- rising transaminases. Biopsy to confirm rejection. Treated by methylprednisolone for 3 days. Complete rejection rare. Outcome: 1 year survival 90%, 5-year survival 66% . Need for long term immunosuppression. Most patients report good quality of life.

Pancreas transplantation Indication: Type I diabetes mellitus SPK – simultaneous pancreas- kidney transplant PTA- pancreas transplant alone Outcome: 1-year pancreas graft survival 82%. Pancreatic islets cell transplantation- more then one pancreas is needed to treat one patient.

Heart & lung transplant Heart: Coronary related heart failure, cardiomyopathy, valvular disease, congenital HD. Lung: COPD, cystic fibrosis, pulmonary fibrosis. Most challenging of all transplants. Outcome: Heart- 65% at 5 years, 50% at 10 years & 30% at 15 years. Lung- 50% at 5 years and 25% at 10 years.

Thank you!