Transplantation Surgery M K Alam MS, FRCS

ILOs At the end of this presentation students should be able to: Define terminology used in transplantation surgery. Describe immunological basis of organ transplantation. State steps in organ matching & retrieval. Describe methods of immunosuppression. State in brief about individual organ transplantation.

Transplantation No alternative treatments are available Improves quality of life and Improves survival Needs cooperation of several disciplines- surgeons, anaethetists, immunologists & physicians

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

Terminology (Graft types) 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(Graft techniques) Orthotopic graft: Donor organ transplanted to the diseased organ site- liver transplant. 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: Organ retrieved from an individual who has been pronounced dead according to a defined criteria. Living donors: -Related donors- parent or siblings -Unrelated donors- voluntary or to make money

Immune response Auto & isografts - do not elicit immune response. Inflammation- at the center of rejection process. Reperfusion→ endothelial activation→ infiltration of inflammatory cells particularly macrophages. Major histocompatibility complex encodes transplant antigen which are similar to serum HLA (human leucocyte antigen)

Afferent arm of immune response Presentation of donor MHC antigen to recipient T-cells receptor (TCR) 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. B-cell 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). 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 provided rapid organ perfusion can be achieved. Organ function in donors must be established. e.g. Kidney- normal urine output (except oliguria due to dehydration), analysis, urea & creatinine. Live related: Kidney, liver

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 (Creutzfeldt–Jakob disease or bovine spongiform encephalopathy or BSE)

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 of drugs , risk of developing malignancy) Steroids: 1st line for acute rejection. Side effects of long term use. Azathioprine (AZA): Used 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.

Complications of immunosuppression Increased susceptibility to infection- 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. 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!