5. TRANSPLANT DRUGS

Organ transplant

is a vital treatment option for patients with terminal/end-stage organ failures (e.g., kidney, heart, liver, and lung), improving quality of life and saving lives.

Cadaveric transplantation

TYPES OF ORGAN TRANSPLANTATION

A healthy organ from a deceased person is transplanted into a patient with end-stage organ failure.

Living-donor transplantation

A kidney or a portion of the liver from a living donor is transplanted into a patient with end-stage kidney or liver disease

Types of Organ Transplants: Autograft

transplant of tissue to the same person. Examples: skin grafts, vein extraction for CABG, stem cell autograft, storing blood for future surgery, rotationplasty (distal joint replaces a more proximal one, e.g., foot to knee).

Types of Organ Transplants: Allograft and allotransplantation

Transplant of an organ or tissue between two genetically non-identical members of the same species. Most human tissue and organ transplants are allografts

Challenge: The recipient's immune system identifies the organ as foreign and attempts to destroy it, causing transplant rejection. The risk can be estimated by measuring the Panel reactive antibody level.

Types of Organ Transplants: Isograft

Subset of allografts where organs or tissues are transplanted from a donor to a genetically identical recipient (e.g., identical twin). Isografts do not trigger an immune response.

Types of Organ Transplants: Xenograft and xenotransplantation

Transplant of organs or tissue from one species to another.

• Examples: Porcine heart valve transplant (common and successful), attempted piscine-primate islet tissue transplant for diabetes research.

• Risks: Often extremely dangerous due to increased risk of non-functional compatibility, rejection, and disease carried in the tissue.

• Current research includes transplanting human fetal hearts and kidneys into animals to address organ shortage.

Types of Organ Transplants: Domino transplants

Used in patients with cystic fibrosis (CF) needing lung replacement, where a heart-lung block is transplanted. The recipient's healthy original heart can then be transplanted into a second recipient.

Types of Organ Transplants: ABO-incompatible transplants (ABOi)

• Possible in very young children (generally under 12 months, sometimes up to 24 months) due to an underdeveloped immune system.

• Graft survival and mortality are similar between ABOi and ABO-compatible (ABOc) recipients.

• Important factors: recipient must not have produced isohemagglutinins and have low levels of T cell-independent antigens.

• UNOS regulations allow ABOi transplantation in children under two years of age if isohemagglutinin titers are 1:4 or below, and if no matching ABOc recipient is available.

• Studies suggest the window for ABOi transplantation may be prolonged by exposure to nonself A and B antigens.

• If retransplantation is needed, the recipient may receive a new organ of either blood type.

Hypersensitivity Reactions

An exaggerated immune response triggered by interaction with an antigen (allergen).

Type I

Hypersensitivity Reactions

Immediate reaction mediated by IgE antibodies (e.g., anaphylaxis)

Type II

Hypersensitivity Reactions

Cytotoxic reaction mediated by IgG or IgM antibodies (e.g., hemolytic transfusion reaction)

Type III

Hypersensitivity Reactions

Reaction mediated by immune complexes (e.g., serum sickness)

Type IV

Hypersensitivity Reactions

Delayed reaction mediated by cellular response (e.g., contact dermatitis, transplant rejection).

Transplant Rejection (Host-versus-graft disease)

• Occurs when the recipient's immune system attacks and destroys the transplanted tissue, recognizing it as foreign.

• Determining molecular similitude (histocompatibility) between donor and recipient.

• Use of immunosuppressant drugs after transplant.

Transplant Rejection (Host-versus-graft disease) Can be lessened by:

• Cellular immunity

• Humoral immunity

Mechanism: An adaptive immune response involving:

Cellular immunity

Mediated by killer T cells inducing apoptosis of target cells.

Humoral immunity

Mediated by activated B cells secreting antibody molecules.

Type IV ("delayed") hypersensitivity reaction

Transplant rejection is a_____mediated by T cells. The recipient’s T cells become alloreactive, recognizing Major Histocompatibility Complex (MHC) antigens on the donated organ, and promote local immune and inflammatory responses.

Immunosuppression

Reduction of the activation or efficacy of the immune system. This is the goal of medication therapy after transplant to prevent organ rejection.

The immune system

____________remains the biggest barrier to transplantation due to its effective mechanisms against foreign organisms

Underlying premise

Use multiple drugs that alter different aspects of the immune system.

Challenges with Immunosuppressant Drugs

Not always effective, expensive, must be taken daily, and associated with toxic effects. (These are common reasons for non-compliance)

Induction Therapy

• Provides intense immunosuppression.

• Drugs diminish antigen presentation and T-cell response, reducing acute rejection risk during the initial transplant period. (T cells are crucial white blood cells in the adaptive immune response).

MEDICATION FOR INDUCTION THERAPY: Basiliximab

• Mechanism of Action: A monoclonal antibody that acts as an interleukin-2 (IL-2) receptor antagonist. It specifically binds to the alpha subunit (CD25) of the IL-2 receptor on the surface of activated T lymphocytes, preventing IL-2 from binding. IL-2 is essential for T-cell activation and proliferation, so blocking its receptor inhibits T-cell activation and thus suppresses the immune response.

• Indications: Kidney transplants.

• Route: Parenteral.

Calcineurin Inhibitors: MEDICATIONS FOR MAINTENANCE THERAPY

Mechanism of Action: Suppress the immune system by binding to cytoplasmic proteins (e.g., cyclophilin for cyclosporine, FKBP-12 for tacrolimus) that then inhibit calcineurin phosphatase. Calcineurin is essential for the activation of nuclear factor of activated T-cells (NFAT), which is crucial for the transcription of genes encoding IL-2 and other cytokines necessary for T-cell activation and proliferation. By inhibiting calcineurin, these drugs prevent the activation of T-cells.

Calcineurin Inhibitors: MEDICATIONS FOR MAINTENANCE THERAPY- Cyclosporine

• SE: Mild to moderate hypertension, hirsutism, tremor.

• AE: Mild nephrotoxicity, hepatotoxicity.

• Note: Grapefruit should be avoided (can increase drug levels). Transplant recipients should not receive live vaccines because their suppressed immune system is not capable of developing a protective response against the disease process, potentially leading to infection.

Calcineurin Inhibitors: MEDICATIONS FOR MAINTENANCE THERAPY- Tacrolimus

Mechanism of Action: Similar to cyclosporine, it binds to FKBP-12, inhibiting calcineurin and thus preventing T-cell activation and cytokine production.

MEDICATIONS FOR MAINTENANCE THERAPY: Costimulation Blockers

• Belatacept

• Mechanism of Action: A selective T-cell costimulation blocker. It binds to CD80 and CD86 receptors on antigen-presenting cells (APCs), thereby blocking the essential CD28-mediated costimulatory signal required for full T-cell activation. Without this second signal, T-cells become anergic (non-responsive) or undergo apoptosis, leading to immunosuppression.

• Adverse Reactions (AR): Can affect the immune system, may cause certain white blood cells to grow out of control, may increase the risk for developing serious (even fatal) infections or certain cancers (e.g., post-transplant lymphoproliferative disorder - PTLD). Other ARs: pale skin, lightheadedness, rapid heart rate, chest tightness, high/low potassium, high blood sugar, or dangerously high blood pressure.

MEDICATIONS FOR MAINTENANCE THERAPY: Mammalian Target of Rapamycin (mTOR) Inhibitors

• Sirolimus (Rapamune)

Mechanism of Action: Binds to the immunophilin FKBP-12, forming a complex that inhibits the mammalian target of rapamycin (mTOR). mTOR is a critical kinase involved in cell growth, proliferation, and metabolism. By inhibiting mTOR, sirolimus blocks signal transduction pathways that lead to T-cell and B-cell proliferation, thus suppressing the immune response. It also inhibits the response to cytokines like IL-2.

MEDICATIONS FOR MAINTENANCE THERAPY: Purine Antimetabolites

• a. Azathioprine (Imuran, Thioprine

• Mechanism of Action: A prodrug that is converted to 6-mercaptopurine (6-MP), which then inhibits purine nucleotide synthesis. Purines are essential building blocks for DNA and RNA. By interfering with their synthesis, azathioprine primarily inhibits the proliferation of rapidly dividing cells, including T and B lymphocytes, thus suppressing the immune response.

• Indications: Prevention of kidney transplant rejection.

• Drug half-life: 5 hours.

• Route: PO.

• AR: Increased risk of neoplasia (cancers), pancreatitis, abdominal pain, immunosuppression (leading to increased infection risk).

MEDICATIONS FOR MAINTENANCE THERAPY: Inosine Monophosphate Dehydrogenase (IMPDH) Inhibitors

• Mycophenolate mofetil

• Mechanism of Action: A prodrug that is rapidly converted to mycophenolic acid (MPA). MPA is a potent, selective, non-competitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme critical for the de novo synthesis of guanosine nucleotides. Lymphocytes are highly dependent on this de novo pathway for purine synthesis (unlike other cells which can use salvage pathways). By blocking IMPDH, mycophenolate selectively inhibits the proliferation of B and T lymphocytes, thus suppressing the immune response. It may also inhibit the recruitment of leukocytes to inflammatory sites.

• Route: PO and IV.

MEDICATIONS FOR MAINTENANCE THERAPY: Corticosteroids

• Prednisone

• Mechanism of Action: A synthetic glucocorticoid. It exerts broad immunosuppressive and anti-inflammatory effects by binding to intracellular glucocorticoid receptors. This binding leads to the altered expression of numerous genes. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability. It suppresses the immune system by reducing the activity and volume of the lymphatic system, inhibiting cytokine production (e.g., IL-1, IL-2, IL-6, TNF-α), and reducing lymphocyte proliferation and function.

• Route: PO.

• Long-term use may lead to: Impaired wound healing, Cushing syndrome, glaucoma and cataracts, Kaposi sarcoma (increased risk in immunosuppressed), growth suppression in children.

Transplant rejection

Occurs when the immune system of the transplant recipient attacks the transplanted organ because it recognizes foreign tissues and attempts to destroy them

Antithymocyte globulin (rabbit), or ATG rabbit

DRUGS FOR TRANSPLANT REJECTION

Mechanism of Action: A polyclonal (depleting) antibody preparation derived from rabbits immunized with human thymocytes. It contains antibodies that recognize and bind to multiple T-cell surface proteins (e.g., CD2, CD3, CD4, CD8, CD25, CD45), leading to their depletion from circulation (via complement-dependent lysis and opsonization) and functional inactivation. This broad depletion of T-cells provides profound immunosuppression.

Muromonab-CD3

DRUGS FOR TRANSPLANT REJECTION

• Mechanism of Action: A monoclonal antibody that binds specifically to the CD3 complex on the surface of T lymphocytes. The CD3 complex is part of the T-cell receptor complex and is essential for T-cell activation. Binding of muromonab-CD3 to CD3 initially causes activation but then leads to the internalization or modulation of the CD3 complex, functionally deleting T cells from the circulation and rendering them unresponsive, thereby preventing their role in rejection.

• Route: IV.

• Severe Reactions (SR): Anaphylaxis, Stevens-Johnson Syndrome (a severe skin reaction).

live vaccines

Transplant recipients receiving these drugs should NOT receive

infections

Immunosuppressed transplant recipients are highly vulnerable to various____

Bacterial - Pneumocystis jiroveci pneumonia (PJP)

DRUGS FOR INFECTION

• Life-threatening illness in immunocompromised patients.

• Prophylaxis: Routine prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) is used to reduce morbidity and mortality of PJP following transplantation.

  • Mechanism of Action (TMP-SMZ): A synergistic combination that inhibits bacterial (and protozoal/fungal) folic acid synthesis. Trimethoprim inhibits dihydrofolate reductase, and sulfamethoxazole inhibits dihydropteroate synthase, both essential enzymes in the folate metabolic pathway required for nucleic acid and protein synthesis.

  • TMP-SMZ taken once every morning can make skin more sensitive to sunlight. Use SPF 25.

Fungal - Nystatin

DRUGS FOR INFECTION

• Used to treat thrush (oral candidiasis) in the mouth and esophagus.

• Typically for patients on high-dose immunosuppression and stopped when the steroid dose is below 20mg per day.

• Mechanism of Action: A polyene antifungal that binds to ergosterol (a sterol component of fungal cell membranes), creating pores that cause leakage of intracellular components and fungal cell death.

• Administration: Before administering, the nurse must instruct the patient to: Shake the suspension, swish the dose around the mouth (allowing it to coat the mouth), and do not eat/drink within 30 minutes afterward.

Viral - Cytomegalovirus (CMV) infection

DRUGS FOR INFECTION

• Most common viral infection to develop post-transplant and plays a significant role in organ rejection.

• Prophylaxis: Patient must receive antiviral prophylaxis with oral ganciclovir (for 3-6 months).

  • Mechanism of Action: A synthetic guanine nucleoside analog. It is phosphorylated intracellularly by viral (and host) kinases to its active triphosphate form. Ganciclovir triphosphate then competitively inhibits viral DNA polymerase and is incorporated into viral DNA, leading to chain termination and inhibition of viral DNA synthesis.

• If untreated, CMV can cause complications in the liver, kidney, heart, lungs, and eyes.

NURSING PROCESS: PATIENT-CENTERED COLLABORATIVE CARE (Organ Transplants: Immunosuppression)

• ASSESSMENT:

  • Clinical signs of rejection (e.g., fever, pain/tenderness at transplant site, swelling, organ dysfunction).

  • Risk factors for infection (e.g., fever, chills, cough, abnormal lab values).

  • Nutritional status, including weight and history of weight loss.

• DIAGNOSIS:

  • Ineffective Protection related to the possibility of transplant rejection.

  • Risk for Infection related to immunosuppression.

• PLANNING:

  • The transplant recipient will remain free of infection.

  • The transplanted organ will function optimally without signs of rejection.

• INTERVENTIONS:

  • Monitor vital signs (VS), weight, and glucose levels regularly.

  • Educate the patient to avoid anyone with an active infection and to be careful not to injure themselves (due to impaired healing and infection risk).

  • Emphasize strict adherence to hygiene practices (e.g., handwashing, oral care).

• EVALUATION:

  • Adherence to the immunosuppressive drug regimen.

  • Freedom from infection and transplant rejection.

  • Optimal functioning of the transplanted organ.