HLA-A, -B, and -DR – most important in recipient/donor matching

•  HLA-DR – most important overall (HLA = human leukocyte antigen)

  ABO blood compatibility – generally required for all transplants (except liver)

  Cross-match – detects preformed recipient antibodies to the donor organ by mixing recipient serum with donor lymphocytes → if these antibodies are present, it is termed a positive cross-match and hyperacute rejection would likely occur with TXP

  Panel reactive antibody (PRA)

•  Technique identical to cross-match; detects preformed recipient antibodies using a panel of HLA typing cells

•  Get a percentage of cells that the recipient serum reacts with → a high PRA (> 50%) is often a contraindication to TXP (increased risk of hyper-acute rejection)

•  Transfusions, pregnancy, previous transplant, and autoimmune diseases can all increase PRA

  Mild rejection – pulse steroids

  Severe rejection – steroid and antibody therapy (ATG or daclizumab)

  Skin cancer – #1 malignancy following any transplant (squamous cell CA #1)

  Post-transplant lympho-proliferative disorder (PTLD) – next most common malignancy following transplant (Epstein-Barr virus related)

•  Tx: withdrawal of immunosuppression; may need chemotherapy and XRT for aggressive tumor

DRUGS

  Mycophenolate (MMF, CellCept)

•  Inhibits de novo purine synthesis, which inhibits growth of T cells

•  Side effects: myelosuppression

•  Need to keep WBCs > 3

•  Used as maintenance therapy to prevent rejection

•  Azathioprine (Imuran) has similar action

  Steroids – inhibit inflammatory cells (macrophages) and genes for cytokine synthesis (IL-1, IL-6); used for induction after TXP, maintenance, and acute rejection episodes

  Cyclosporin (CSA)

•  Binds cyclophilin protein and inhibits genes for cytokine synthesis (IL-2, IL-4, etc.); used for maintenance therapy

•  Side effects: nephrotoxicity, hepatotoxicity, tremors, seizures, hemolytic-uremic syndrome

•  Need to keep trough 200–300

•  Undergoes hepatic metabolism and biliary excretion (reabsorbed in the gut, get entero-hepatic recirculation)

  FK-506 (Prograf, tacrolimus)

•  Binds FK-binding protein; actions similar to CSA but more potent

•  Side effects: nephrotoxicity, more GI symptoms and mood changes than CSA, much less entero-hepatic recirculation compared to CSA

•  Less rejection episodes in Kidney TXP’s w/ FK-506 compared to CSA

•  Need to keep trough 10–15

  Sirolimus (Rapamycin)

•  Binds FK-binding protein like FK-506 but inhibits mammalian target of rapamycin (mTOR); result is that it inhibits T and B cell response to IL-2

•  Used as maintenance therapy

  Anti-thymocyte globulin (ATG)

•  Equine (ATGAM) or rabbit (Thymoglobulin) polyclonal antibodies against T cell antigens (CD2, CD3, CD4)

•  Used for induction and acute rejection episodes

•  Is cytolytic (complement dependent)

•  Need to keep WBCs > 3

•  Side effects: cytokine release syndrome (fever, chills, pulmonary edema, shock) – steroids and Benadryl given before drug to try to prevent this

  Zenapax (daclizumab) – human monoclonal antibody against IL-2 receptors

•  Used for induction and acute rejection episodes

•  Is not cytolytic

TYPES OF REJECTION

  Hyperacute rejection (occurs within minutes to hours)

•  Caused by preformed antibodies that should have been picked up by the cross-match

•  Activates the complement cascade and thrombosis of vessels occurs

•  Tx: emergent re-transplant (or just removal of organ if kidney)

  Accelerated rejection (occurs < 1 week)

•  Caused by sensitized T cells to donor antigens

•  Tx: ↑ immunosuppression, pulse steroids, and possibly antibody Tx

  Acute rejection (occurs 1 week to 1 month)

•  Caused by T cells (cytotoxic and helper T cells)

•  Tx: ↑ immunosuppression, pulse steroids, and possibly antibody Tx

  Chronic rejection (months to years)

•  Partially a type IV hypersensitivity reaction (sensitized T cells)

•  Antibody formation also plays a role

•  Leads to graft fibrosis

•  Tx: ↑ immunosuppression – no really effective treatment

KIDNEY TRANSPLANTATION

  Can store kidney for 48 hours

  Need ABO type compatibility and cross-match

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