8. Transplantation Basic Concepts: Brain Death, Indications, Immunosuppression

I. Basic Concepts

• Transplantation: Transfer of cells, tissues or organs from donor to recipient to restore missing/damaged function
• Main indication: End-stage irreversible organ failure or selected malignant/metabolic disease
• Goal: Restore organ function → Improve survival and QOL when other treatment is insufficient

Types of Transplant

• Autograft: Same individual, e.g. skin graft
• Isograft: Monozygotic twins
• Allograft: Same species, genetically non-identical → Most organ transplants
• Xenograft: Different species → Experimental/limited because of strong immune barrier
• Orthotopic: Same anatomical location, e.g. heart, liver, lung
• Heterotopic: Different location, e.g. kidney/pancreas in iliac fossa

Donors and Allocation

1. Living donor

• Genetically related or non-genetically/emotionally related
• Criteria: Healthy, acceptable age/BMI, no active infection, tumor-free interval, no alcoholism; non-smoker for lung donation
• Organs/tissues: Kidney, liver segment, bone marrow/hematopoietic stem cells
• Advantages: Elective timing, shorter ischemic time, better planning, lower delayed graft function

2. Deceased donor

• Donation after brain death or circulatory death
• Common grafts: Kidney, liver, heart, lung, pancreas, intestine

• Compatibility/allocation: ABO, HLA-A/B/DR, crossmatch, organ size, urgency, pediatric priority, waiting time and cold ischemic time

II. Brain Death and Consent

• Brain death: Complete, irreversible loss of all brain function, including brainstem function
• Cause of coma must be known and confounders excluded, e.g. sedatives, intoxication, hypothermia, severe metabolic disorder
• Importance: Brain-dead patient can donate organs while circulation is maintained on life support

Causes

• Primary: Brain injury with raised intracranial pressure, intracranial bleeding, stroke, brain tumor
• Secondary: Brain hypoxia/ischemia after cardiorespiratory arrest, severe hypoxia or shock

Clinical Criteria

• Irreversible coma / loss of consciousness
• Absence of brainstem reflexes: Pupillary, corneal, gag/cough and oculovestibular reflexes
• Apnea: No spontaneous breathing during apnea test
• Ancillary tests if required by protocol: EEG or cerebral blood-flow test

Consent Process

• Explicit consent / opt-in: Donation requires direct consent during life or legal authorization
• Presumed consent / opt-out: Donation assumed unless the person refused during life
• Hungarian practice: Presumed consent for deceased donation; written objection prevents organ removal
• Living donation: Always requires free, informed donor consent and donor safety protection

III. Indications

• General indication: End-stage organ failure or selected malignant/metabolic disease with expected survival/QOL benefit
• Recipient must tolerate surgery and lifelong follow-up/immunosuppression

Common Organ Indications

• Kidney: End-stage renal disease, usually GFR <15 ml/min/1.73 m2 or dialysis dependence

• Causes: Diabetes, hypertension, glomerulonephritis, polycystic kidney disease

• Liver: End-stage liver disease/cirrhosis, acute liver failure, selected HCC within criteria

• Causes: HBV, HCV, alcohol-associated liver disease, NASH/MASLD, autoimmune disease, Wilson disease

• Heart: End-stage heart failure, usually NYHA IV, refractory to maximal treatment
• Lung: End-stage pulmonary disease: COPD, pulmonary fibrosis, cystic fibrosis, pulmonary hypertension
• Pancreas: Type 1 diabetes with severe complications; often combined with kidney transplant
• Small intestine: Short bowel syndrome / intestinal failure with severe parenteral nutrition complications
• Bone marrow / hematopoietic stem cells: Leukemia, lymphoma, aplastic anemia, immunodeficiency, selected genetic diseases

IV. Immunosuppression and Graft Rejection

• Purpose: Prevent rejection while minimizing infection, malignancy and drug toxicity
• Solid organ transplantation usually requires lifelong immunosuppression
• Combination of drugs → Lower dose of each drug + different mechanisms

Immunosuppression

1. Induction therapy: Strong perioperative immunosuppression → Reduce acute rejection

• Agents: Anti-thymocyte globulin (ATG), basiliximab, high-dose corticosteroids
• Rituximab: Selected antibody-mediated/desensitization protocols

2. Maintenance therapy: Long-term lower-dose immunosuppression

• Calcineurin inhibitors: Tacrolimus, cyclosporine A
• Antiproliferative agents: Mycophenolate mofetil, azathioprine
• mTOR inhibitors: Sirolimus, everolimus
• Corticosteroids: Prednisolone

Graft Rejection

1. Hyperacute: Minutes-hours

• Preformed recipient antibodies against donor ABO/HLA antigens → Immediate graft thrombosis/failure
• Rare because of ABO testing and crossmatch

2. Acute: Days-weeks/months

• T-cell mediated mostly; can be antibody-mediated
• Kidney example: Oliguria/anuria, high BP, fluid retention, rising creatinine/BUN, graft tenderness
• Treatment: Temporary increase in immunosuppression, usually high-dose steroids +/- ATG/antibody-directed therapy

3. Chronic: Months-years

• Chronic immune injury → Fibrosis/vasculopathy → Progressive graft dysfunction/loss
• Kidney example: Rising creatinine/BUN, proteinuria, electrolyte imbalance, fatigue

Side Effects of Immunosuppression

• Infections: Bacterial, viral, fungal, opportunistic pathogens such as CMV
• Nephrotoxicity: Especially calcineurin inhibitors
• Malignancy: Skin cancer, post-transplant lymphoproliferative disease (PTLD)
• Metabolic complications: Diabetes, hyperlipidemia, hypertension
• Bone marrow suppression and wound-healing problems depending on drug group