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Subsections
Transplant Medicine Overview

Transplant Medicine

Transplant Medicine Overview

Background

  • Definition
    • Transfer of an organ/tissue from one person to another (allograft), or from a donor site to another site on the same person’s body (autograft)
    • Allografts can either be from a living or deceased source
  • Synopsis
    • History
      • 1905: First successful corneal transplant
      • 1908: First successful skin-allograft
      • 1950: First successful kidney transplant
      • 1954: First successful living related kidney transplant (between identical twins)
      • 1962: First kidney transplant from deceased donor
      • In 1950s sublethal doses of total body irradiation combined with cortisone was used for transplantations 1
      • In 1959, 6-Mercaptopurine (6-MP) was discovered to suppress the immune system, and 6-MP combined with corticosteroids were used for transplantations 1
      • Azathioprine replaced 6-MP in early 1960s with subsequent decreased toxicity 1
      • Antithymocyte globulin (ATG) was introduced in same period
      • Immunosuppressive effects of Cyclosporine A were discovered in 1972, and the medication was approved in 1980 leading to substantial improvement in successful solid organ
      • transplantations 2
      • Multiple new immunosuppressants have been developed over the past 20 years
    • Current information 3
      • As of October 2014
        • Approx 124,000 people in the USA are on waitlist to receive an organ
          • Of these, approximately 79,500 people are on the active waitlist
      • From January to July 2014
        • Total of 16,884 transplants were performed in the United States
        • Total of 8,279 new donors appeared in the United States
      • Approximately every 10 minutes a new patient is added to the national transplant waiting list
        • On average, 21 patients die every day while waiting on a transplant
        • 1 organ donor can save 8 lives on average
      • The gap between patients needing transplants and donors being added to the donor registry continues to widen

Donatable Organs and Tissues

  • Liver
  • Kidney
  • Heart
  • Lungs
  • Pancreas
  • Small intestine
  • Bones and tendons (musculoskeletal graft)
  • Heart valves
  • Corneas
  • Skin
  • Saphenous veins
  • Corneas and musculoskeletal grafts are the most commonly transplanted tissues, while kidneys, liver, and heart are the most commonly transplanted organs

Source of Organs

  • Living donors
    • Donor remains alive and donates an organ, or part of an organ, that can regenerate or tolerate the higher workload (i.e., kidney, lung lobe, small intestines)
  • Deceased donor are either declared brain dead or circulatory dead, with organs kept artificially alive until they can be excised
  • Brain dead
    • Majority of deceased patients, but < 3% of deaths are due to brain death leading to severe shortage of donor organs
    • Once patient declared brain dead, donation can be considered
  • Circulatory dead
    • Organ donation is primarily possible when patient is severely brain injured and not expected to survive
    • Inferior outcomes compared to organs from brain dead donors

Organ Bank Referral

  • After donor has been identified
    • Hospital staff and regional organ procurement organization (regional OPO or donor bank) will discuss medical status of potential donor and confirm suitability as a donor
      • Usually requires specially trained nurse from regional OPO to go to hospital to assess suitability of donor patient
  • All hospitals are required by law to contact the regional OPO in the event of death or imminent death

Consent

  • Motivation is usually altruistic
    • Altruism is highly valued, and many countries, including the USA, prohibits compensation of donors or their families
  • Families of potential organ donors must be offered option of donating under state and federal law
  • Both hospital staff and representatives from the regional OPO discuss donor options with the family
  • Consent must be given by potential organ donors family, even if a donor card has been signed by the patient
  • If the family consents to donation, a physical exam, along with medical and social history, is taken from the potential donor’s family to assess risk to recipient

Organ Matching Process

  • The majority of deceased donor organs in the United States are allocated to the Organ Procurement and Transplantation Network (OPTN), which is run by the United Network for Organ Sharing (UNOS) 3
  • Individual regional OPOs (all members of OPTN) are responsible for the identification of suitable donors and collection of donated organs
  • UNOS allocates organs based on the method considered most fair by the scientific leadership in the specific field
  • UNOS uses a set policy to make the process of matching organs with recipients as objective as possible. Several factors are considered, including: age, ability of recipient to recover, ABO status, distance, height and weight, size of organ, life support status, listing status, and time on wait list
  • The regional organ procurement organization receives a list of possible matches from UNOS
  • Coordinator at the regional center then calls transplant center for patient at top of list for each organ
  • Recipients transplant surgeon accepts or declines the organ offered, and if declined the patient next on the list is called until all organs are placed

Complications

  • Rejection of graft
    • Hyperacute rejection
      • Occurs within minutes to hours after transplantation
      • Caused by preformed alloantibodies by the recipient, mainly against MHC antigens
    • Acute rejection
      • Occurs within days to months after transplantation
      • Caused by a tissue injury process mediated by alloantibodies and alloreactive T cells, primarily in response to MHC antigens
    • Chronic rejection
      • Occurs within months or years after transplantation
      • Caused by chronic inflammation that triggers proliferation of intimal smooth muscle cells resulting in vascular occlusion and ischemic changes
    • Prevention of graft rejection is achieved by long-term use of immunosuppressive medications, which can lead to drug toxicity, chronic rejection, and immune
  • Side effects of medications
    • Diabetes Mellitus
    • Dyslipidemia
    • Hypertension
    • Gastrointestinal problems
    • Gout
    • Anxiety and depression
    • Sexual problems
    • Excessive hair growth
    • Nephrotoxicity
    • Development of malignancies

ID Issues and Prevention

  • Diminished clinical and radiological findings due to impaired inflammatory response from chronic immunosuppressive therapy
  • More complex antimicrobial therapies due to frequency of drug toxicity and drug interactions
  • Susceptibility to opportunistic infections
  • Increased antimicrobial resistance (VER, MRSA, Pseudomonas, Fungi, and Ganciclovir-resistant CMV) 4
  • Common infections after transplant 4
    • < 4 weeks post-transplant: MRSA, Candida, VRE, Aspergillus, Aspiration, Line infection, C. difficile colitis
    • 1-6 months post-transplant: HSV, CMV, HBV, HCV, EBV, Listeria, TB, PCP, BK virus, Nocardia, Toxoplasma, Strongyloides, Leishmania
    • > 6 months post-transplant: Community-acquired pneumonia, Aspergillus, Dermatophytes, CMV colitis, UTIs
  • Before transplantation vaccinations to be considered includes
    • Measles/Mumps/Rubella
    • Diphtheria/Tetanus/Pertussis
    • Poliovirus
    • Haemophilus influenza B
    • Hepatitis B
    • Pneumococcal
    • Influenza
    • Varicella zoster
    • Human papillomavirus
  • After transplantation, all live vaccines should be avoided. Only consider following vaccines
    • Hepatitis B
    • Pneumococcal
    • Yearly Influenza A
  • Prophylaxis
    • UTIs, PCP, and Nocardia infections: Treat with Trimethoprim-Sulfamethoxazole
    • HSV: Acyclovir
    • CMV: Ganciclovir
    • Risk for systemic or recurrent fungal infections: Fluconazole or Ketoconazole. However, both of these can increase the levels of Cyclosporine and Tacrolimus
    • Oropharyngeal candidiasis: Nystatin suspension or Clotrimazole troches

Immunosuppressive Medications 1

  • Glucocorticoids (Solu-Medrol, Prednisone)
    • Anti-inflammatory and immunosuppressive
    • Used for induction and maintenance of immunosuppression, acute cellular rejection, and antibody-mediated rejection
    • Side effects: Hypertension, dyslipidemia, diabetes, Cushingoid appearance, sleep disturbances, mood changes, impaired wound healing, osteoporosis
  • Azathioprine (Imuran, Azasan)
    • Purine analog that inhibits DNA synthesis, suppressing proliferation of activated T cell lymphocytes
    • Used for maintenance immunosuppression
    • Side effects: Hepatotoxicity, myalgias, malaise, leukopenia which is dose-dependent and reversible, myelosuppression with toxic doses, long-term use associated with basal cell and squamous cell carcinomas.
  • Mycophenolate Mofetil (MMF, CellCept), Mycophenolic acid (MyFortic)
    • Mycophenolate mofetil is a prodrug that is converted to mycophenolic acid, which is now directly available. Blocks purine biosynthesis, thus inhibiting lymphocyte function
    • Used for maintenance immunosuppression
    • Side effects: Dyslipidemia, diabetes, hypocalcemia, hyper-/hypokalemia, hypomagnesemia, abnormal liver function tests, increase in BUN and creatinine, increased incidence of BK virus and BK nephropathy, gastrointestinal symptoms (nausea, diarrhea, abdominal pain), bone marrow suppression (leukopenia and thrombocytopenia)
    • Antacids with aluminum and magnesium block drug absorption from GI tract
  • Cyclosporine (Sandimmune, Neoral, Gengraf)
    • Inhibits calcineurin by binding to cyclophilin, blocking several cytokines and inhibiting T-lymphocyte activation and proliferation
    • Used for maintenance immunosuppression
    • Side effects: Hypertension, dyslipidemia, diabetes, nephrotoxicity, neurotoxicity, gum hyperplasia, hirsutism, tremors, hyperkalemia, TTP (rare), bone marrow suppression, increased risk of malignancies
    • Toxicity worsened by ACE inhibitors and dehydration
    • Narrow therapeutic window with recommended trough levels of 100-300 ng/mL, and 2-hour peak levels < 1200 ng/mL
  • Tacrolimus (Prograf, Astagraf XL, Hecoria)
    • Inhibits calcineurin by binding to FK-binding protein with same effects as Cyclosporine, but 50-100 times more potent.
    • Used for maintenance immunosuppression
    • Side effects: Hypertension, dyslipidemia, diabetes, increased incidence of BK virus and BK nephropathy, nephrotoxicity, neurotoxicity, gum hyperplasia, bone marrow suppression, increased risk of malignancies
    • Recommended trough levels of 5-15 ng/mL
  • Sirolimus (Rapamune), Everolimus (Afinitor, Zortress)
    • Inhibits transduction of signals to the mTOR complex, thus causing immunosuppression and antiproliferation (Everolimus is an active metabolite of Sirolimus with same mechanism)
    • Used for maintenance immunosuppression
    • Side effects: Dyslipidemia, diabetes, hyper-/hypocalcemia, hyperphosphatemia, hypomagnesemia, hyponatremia, abnormal liver function tests, impaired wound healing, flu-like syndrome, acne, bone marrow suppression (thrombocytopenia), can be nephrotoxic if used in combination with Cyclosporine or Tacrolimus
  • Antithymocyte globulin - Equine (Atgam)
    • Polyclonal Ab that causes T-cell depletion by complement-mediated lysis, as well as B-cell apoptosis, interference with dendritic cell function, modulation of adhesion molecules and chemokine receptors, and induction of regulatory T cells
    • Used for induction of immunosuppression, and steroid-resistant rejection
    • Side effects: Induction of cytokine-release syndrome with fever, chills, and sometimes hypotension and pulmonary edema. Profound lymphopenia, thrombocytopenia, abnormal liver function tests, increased risk of CMV and EBV infections, serum sickness, anaphylaxis (rare)
  • Antithymocyte globulin – Rabbit (Thymoglobulin)
    • Polyclonal Ab which acts on T cell surface antigens and depletes CD4 lymphocytes
    • Used for induction of immunosuppression, and acute rejection
    • Side effects: Hypertension, fever, malaise, hyperkalemia, abdominal pain, UTIs, leukopenia, thrombocytopenia, dyspnea
  • Rituximab (Rituxan)
    • Monoclonal Ab against CD20 targeting B cells except plasma cells
    • Used for antibody-mediated rejection, desensitization of HLA-sensitized patients, and ABO-incompatible transplantations
    • Side effects: Hyper-/hypotension, fever, urticaria, hyperglycemia, abdominal pain, ALT elevation, infusion-related reactions (angioedema, bronchospasm, chills, dizziness, fever. headache, BP instability, nausea, vomiting), bone marrow suppression, neutropenic fever
  • Basiliximab (Simulect)
    • Monoclonal antibody against CD25, competitively inhibits IL-2 receptors and activation of T cells
    • Used for induction of immunosuppression
    • Side effects: Abnormal heart sounds, arrhythmia, malaise, fever, skin disorders, acidosis, diabetes, hyper-/hypocalcemia, dyslipidemia, hyper-/hypokalemia, hyperuricemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, hypersensitivity reactions, bone marrow suppression, increased risk of EBV infection
  • Belatacept (Nulojix)
    • Fusion protein blocking CD80/86, thus inhibiting T cell activation
    • Used for maintenance of immunosuppression
    • Side effects: Hypertension, dyslipidemia, diabetes, bone marrow suppression, relatively high incidence of post-transplant lymphoproliferative disorder, increased risk of malignancies
  • Bortezomib (Velcade)
    • Proteasome inhibitor with activity against mature plasma cells
    • Used for antibody-mediated rejections
    • Side effects: Neurotoxicity, headache, fatigue, bone marrow suppression
  • Eculizumab (Soliris)
    • Monoclonal Ab blocking cleavage of complement C5 into pro-inflammatory components
    • Used for antibody-mediated rejections
    • Side effects: Headache, fever, nausea, vomiting, flu-like symptoms, increased sensitivity to light, increased risk of meningococcal meningitis

Contact Information

  • UNOS (United Network for Organ Sharing)
  • US Dept Health and Human Services. Organ Procurement and Transplantation Network
    • Post Office Box 2484, Richmond, Virginia 23218

References

  1. Sandwijk MS van, Bemelman FJ, Ten Berge IJ. Immunosuppressive drugs after solid organ transplantation. Neth J Med. 2013;71(6):281-289
  2. Ruiz P, Maldonado P, Hidalgo Y, et al. Transplant tolerance: new insights and strategies for long-term allograft acceptance. Clin Dev Immunol. 2013;2013:210506
  3. US Dept Health and Human Services. Organ Procurement and Transplantation Network. Available at: https://optn.transplant.hrsa.gov/. [Accessed March 2019]
  4. Fishman JA. Infections in immunocompromised hosts and organ transplant recipients: essentials. Liver Transpl. 2011;17 Suppl 3:S34-37.
  5. AMA. Guidelines for Organ Transplantation. Available at: https://www.ama-assn.org/delivering-care/ethics/guidelines-organ-transplantation. [Accessed March 2019]

Contributor(s)

  1. Stensman, Lars M., MD
  2. Clingenpeel, Joel M., MD, MPH
  3. Sindhwani, Maughan K., MD

Updated/Reviewed: March 2019