• Clinical science

Transplantation

Abstract

Transplantation is the process of transferring an organ or a part thereof (known as a graft) from one donor to him/herself (autologous transplantation) or to another recipient (allogenous transplantation if the individuals are not identical twins). In addition to being subject to strict legal requirements, the donor and recipient must be histocompatible in allogenous transplantations in order to minimize the risk of transplant rejection. Because the major histocompatibility complex (MHC) is only perfectly matched in isotransplantation (involving the transfer of genetically identical tissue, e.g., from an identical twin), allogenous transplantation subsequently requires immunosuppressive therapy.

Transplantation biology

  • Graft: the organ or part thereof that is transplanted
  • Donor: the individual from whom the graft is harvested
  • Recipient: the individual who receives the graft

Transplant immunology

Major histocompatibility complex (MHC) and Human leukocyte antigen (HLA)

Human leukocyte antigen (HLA)

  • Definition: Proteins present on the surface of all cells that display antigenic peptides as a normal physiological function so that they can be recognized by T-lymphocytes s either self or non-self antigens.
  • Structure
    • Extracellular domain
      • Polymorphic zone: has a cleft / groove for antigen presentation
      • Nonpolymorphic zone: site at which T-cell receptors bind
    • Intracellular domain
  • Types of HLA
    • Class I HLA
      • Present on all nucleated cells
      • The polymorphic zone presents antigens derived from within the cell.
      • The nonpolymorphic zone binds to CD8 T lymphocytes.
    • Class II HLA
      • Usually restricted to antigen-presenting cells (e.g., dendritic cells, macrophages, B cells)
      • The polymorphic zone presents antigens from the extracellular environment.
      • The nonpolymorphic zone binds to CD4 T lymphocytes.
  • Clinical importance: During the maturation process of T lymphocytes in the thymus gland, T cells that recognize self-derived peptides (including peptides derived from self-HLA molecules) are removed, thus preventing autoimmunity.

Allorecognition

  • Definition: recognition of a foreign antigen as a non-self antigen by a host
  • Types of allorecognition
    • Indirect allorecognition: HLA molecules on an allograft are extremely different from those of the recipient and are thus treated as foreign antigens by the antigen-presenting cells of the recipient → The antigens are broken down and presented by the antigen-presenting cells.
    • Direct allorecognition: HLA molecules on the allograft are exceptionally strong antigens and can directly stimulate the T cells without being broken down and presented by the antigen-presenting cells of the recipient.
  • Clinical importance: Activation of a particular T-cell by a foreign HLA peptide results in clonal proliferation of that type of T lymphocytes; , a process that is mediated by IL-2 acute rejection
    • Activated cytotoxic (CD8) T cells recognize other HLA class I molecules on all cells in the donor graft and cause target cell death by releasing molecules such as perforin and granulozyme.
    • Activated helper (CD4) T cells recognize HLA class II molecules on dendritic cells within the transplanted organ.

Prerequisites for organ matching

Rh compatibility is not required for solid organ transplantation. Both Rh compatibility and ABO compatibility are not essential for hematopoietic stem cell transplantation!

Types of grafts based on histocompatibility between donor and recipient
Type Definition Examples
Autograft
  • Graft originates from the patient him/herself
Isograft
  • Graft originates from a genetically identical person (identical twin)
Allograft
  • Graft originates from genetically different person
Xenograft
  • Graft originates from different species (e.g., pig)

Immunosuppressive therapy is not required for autograft transplantation!

References:[1]

Solid organ transplantation

Organ procurement

  • Deceased donors
    • The organ is harvested from brain-dead donor (BDD) or donor after cardiac death (DCD) .
    • The United Network for Organ Sharing (UNOS) is responsible for organ matching and allocation of organs to candidates on a waiting list.
    • Waiting time
      • Definition: the time period from the entry of a potential transplant candidate on the UNOS list to the allocation of an organ
      • Average waiting times
    • Contraindications for organ donation
    • The following conditions are NOT contraindications to organ donation:
      • Low-grade, localized tumors without evidence of metastasis at the time of death
      • History of malignancy with a disease-free duration > 5 years
      • Hepatitis B or C infection
      • HIV infection
      • Hypertension, diabetes, and/or elderly patients
  • Living donors
    • The organ is surgically harvested from a living donor (usually a relative) at the time of the transplant surgery.
    • Only kidney transplantation and liver transplantation can be performed using grafts from living donors.
    • Advantages
      • Donor is in good general condition
      • Minimal waiting time
      • Preoperative and perioperative immunomodulation is possible in the recipient.
      • Short cold ischemia time
      • High degree of HLA compatibility if the donor is related to the recipient
    • Disadvantages: increased morbidity and mortality in the donor

Organ preservation

  • A harvested organ should be preserved using special hypothermic solutions (e.g., University of Wisconsin solution) until the organ can be transplanted.
    • Extracellular solutions (high Na+, low K+): e.g., Bretschneider (HTK) solution
    • Intracellular solutions (low Na+, high K+): e.g., University of Wisconsin (UW) solution, St. Thomas' cardioplegia solution
  • Ischemic times
    • Warm ischemia time: the time from the withdrawal of life support in the donor to the initiation of cold organ preservation
    • Cold ischemia time: the time from the initiation of cold organ preservation to the warming of the organ within the recipient following restoration of blood perfusion

A prolonged ischemic time increases the risk of organ dysfunction in the post-transplant period!

Site of organ transplantation

Orthotopic
  • The graft is placed in the normal anatomic position.
  • The diseased or non-functional organ that is being replaced is removed.
Heterotopic
  • The graft is placed in a site other than the normal anatomic position.
  • The non-functional organ is usually left in place.
Paratopic
  • The donor organ is placed close to the normal anatomic position.

Post-transplant immunosuppressive therapy

Immunosuppressive therapy is a balancing act: Too much immunosuppression, and the risk of infection increases. Too little, and the risk of rejection increases!

References:[2][3][4]

Renal transplantation

  • Number of procedures: ∼ 19,000 cases in 2016
  • Indication: patients with end-stage kidney disease (CKD 5)
  • Contraindications
    • Absolute
      • Unsuitable vascular anatomy
        • Aortobifemoral bypass or an aortoiliac stent graft that extends to both external iliac arteries
        • Circumferential calcification of the iliac vessels
        • Iliac vein and inferior vena cava thrombosis
      • Active infection (e.g., tuberculosis, invasive fungal infections, osteomyelitis)
      • Malignancy in the past 2 years
      • BMI ≥ 50 kg/m2
      • Active alcohol or substance abuse (except tobacco)
      • Lack of adequate social support (e.g., patient in a nursing home, homeless patient)
    • Relative
      • Age < 1 year or > 75 years
        • Diseases of the lower urinary tract
    • Specific contraindications for living donors

Two healthy, fully functioning kidneys are an essential requirement for kidney donation by a living donor!

1-year survival rate 2-year survival rate 5-year survival rate
Cadaveric graft 88% 81% 71%
Graft from living donor 94% 93% 84%

Renal transplantation is superior to dialysis in end-stage renal disease (ESRD)!

References:[5][6]

Liver transplantation

  • Prognosis

References:[5][7][8]

Cardiac transplantation

Survival rates 1-year survival rate 3-year survival rate 5-year survival rate
Primary transplants 87% 79% 72%
Retransplants 82% 67% 58%

References:[5][9][10][11]

Hematopoietic stem cell transplantation

Hematopoietic stem cell

Hematopoietic stem cell graft Source Risk of graft-vs-host disease Engraftment
Bone marrow transplant
  • Bone marrow aspiration from the posterior superior iliac spine
  • Lowest
  • By 3 weeks
Peripheral blood stem cell transplant
  • Pheresis of peripheral blood after administering a myeloid growth factor (e.g., G-CSF, GM-CSF) or plerixafor (a CXRC4 antagonist) for 4–5 days
  • Highest
  • By 2 weeks
Umbilical cord blood transplant
  • Low
  • By 4 weeks

Types of HSCT

  • Number of procedures: ∼ 20,000 cases in 2015
Autologous stem cell transplantation Allogenous stem cell transplantation
Definition
Indications
Preferred source for graft
Advantages
Disadvantages

Procedure

  1. Preparation of a hematopoietic stem cell graft from the donor using bone marrow aspirate, peripheral blood, or umbilical cord blood
  2. Transplant preparative regimen: recipient preparation using high-dose chemotherapy and/or total body irradiation
  3. Intravenous injection of the harvested hematopoietic stem cells
  4. Stem cell engraftment
  5. In allogenous stem cell transplantation: regimen to prevent graft-vs-host disease (see “Prevention” in graft-versus-host disease)

When considering a regimen to prevent graft-versus-host disease following allogenous HSCT for hematological malignancies, the risk of graft-versus-host disease should always be weighed against the loss of a beneficial graft-vs-tumor effect, and the risk of graft failure due to drug toxicity!

Complications

The mortality rate of allogenous stem cell transplantation is declining, but is still as high as 50%!

References:[5][12][13]

Complications

Graft-related

Graft rejection

  • Definition: graft failure as a result of damage to the graft by the host's immune response (host-versus-graft disease)
  • Types of graft rejection
Type of transplant rejection Hyperacute rejection Acute rejection Chronic rejection
Frequency
Onset
  • < 48 hours after transplantation (usually within minutes to hours)
  • < 6 months after transplantation (usually within days to weeks)
  • > 6 months after transplantation (usually after a few years)
Pathophysiology
Clinical findings
  • Intraoperative assessment: swelling of the organ as soon as perfusion is restored
  • Slow, progressive loss of organ function
Diagnosis
  • Biopsy: small vessel thrombosis and graft infarction
Prevention
  • Preoperative cross-matching and ABO grouping
  • If an ABO incompatible living donor is considered because a compatible donor is not available:
  • Irreversible process with no known prevention
Treatment
  • Graft removal
  • Graft removal, and retransplantation

Graft rejection presents as a failure of the transplanted organ and is very difficult to distinguish from other post-transplant complications. A biopsy is required to confirm the diagnosis!

Graft-versus-host disease

  • Definition: damage to the host as a result of a systemic inflammatory reaction induced by T lymphocytes present in the graft
  • Etiology
    • Allogenous hematopoietic stem-cell transplantation
    • Small bowel transplantation
    • Transfusion of non-irradiated blood products
  • Types of graft-versus-host disease
Acute graft-versus-host disease Chronic graft-versus-host disease
Epidemiology
  • Incidence
    • Without prophylaxis: 70–100%
    • With prophylaxis: 9–50%
Onset
  • < 100 days after transplantation
  • > 100 days after transplantation
Pathophysiology
  • Mostly unknown
Clinical presentation
  • Pruritic or painful maculopapular rash (70% of cases) that involves the ears, nape of the neck, shoulder, soles, and palms
  • Nausea, vomiting, diarrhea, and/or cramping abdominal pain (74% of cases)
  • Hepatic dysfunction: jaundice
  • Less commonly: lagophthalmos, hemorrhagic conjunctivitis, conjunctival pseudomembrane formation
Diagnostics
Prevention
  • Antithymocyte globulin for three days before the transplantation
  • Cyclosporine for 6 months after transplant and one of the following:
    • Methotrexate on post-transplant days 3, 6, and 11 with leucovorin rescue (myeloablative conditioning)
    • Mycophenolate mofetil for 1–3 months (reduced intensity conditioning)
Treatment
Affected organ Severity of acute graft-versus-host disease
Major clinical finding Stage I Stage II Stage III Stage IV

Skin

  • Exanthema
  • < 25% of body surface area
  • 25–50% of the surface area of the body
  • > 50% of the surface area of the body
  • Exanthema + blistering

Intestines

  • > 500 mL/d
  • > 1000 mL/d
  • > 1500 mL/d

Liver

  • 2–3 mg/dL
  • 3–6 mg/dL
  • 6–15 mg/dL
  • > 15 mg/dL
Classification according to the Glucksberg criteria. A score indicating the severity of GvHD can be calculated based on clinical findings.

The skin, intestines, and liver are the most commonly affected organs in graft-versus-host disease!

Immunosuppression-related

Post-transplant infections

Etiology

Early-onset

(< 1 month after transplantation)

Late-onset 1–6 months
6–12 months
> 12 months

Prevention of post-transplant infections

The symptoms of CMV infections can appear similar to those of transplant rejection. Differentiating between conditions can be tricky!

Post-transplant malignancy

  • Incidence: 0.4% following organ transplantation
  • Common malignancies

References:[5][2][1][14][15][16][17][18][19][20][21][22]

We list the most important complications. The selection is not exhaustive.

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  • 8. Squires RH, Ng V, Ekong U et al. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the Am. Ass. for the Study of Liver Diseases, Am. Soc. of Transplantation and the North Am. Soc. for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology. 2014; 60(1): pp. 362–398. doi: 10.1002/hep.27191.
  • 9. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. url: http://www.jhltonline.org/pb/assets/raw/Health%20Advance/journals/healun/ISHLT_GUIDELINE.pdf Accessed February 21, 2017.
  • 10. Mancini D, Lietz K. Selection of Cardiac Transplantation Candidates in 2010. Circulation. 2010; 122: pp. 173–183. doi: 10.1161/CIRCULATIONAHA.109.858076.
  • 11. Canter CE, Shaddy RE, Bernstein D et al. Indications for heart transplantation in pediatric heart disease. Circulation. 2007; 115(5): pp. 658–676. doi: 10.1161/CIRCULATIONAHA.106.180449.
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  • 13. Al-Jaroudi D. XY Chromosome in Acute Lymphocytic Leukemia Female with Secondary Amenorrhea. Cancer Science & Research: Open Access. 2015; 2(1). doi: 10.15226/csroa.2015.00113.
  • 14. Martin PJ, Rizzo JD, Wingard JR et al. First- and Second-Line Systemic Treatment of Acute Graft-versus-Host Disease: Recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012; 18(8): pp. 1150–1163. doi: 10.1016/j.bbmt.2012.04.005.
  • 15. AD K, SJ K, CP L, CP M, TC P, Webber P. Textbook of Organ Transplantation. Hoboken, NJ: John Wiley & Sons; 2014.
  • 16. Fishman JA. Evaluation for infection before solid organ transplantation. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/evaluation-for-infection-before-solid-organ-transplantation?source=see_link%20and%20https:%2F%2Fwww.cdc.gov%2Fmmwr%2Fpreview%2Fmmwrhtml%2Frr4910a1.htm. Last updated December 14, 2016. Accessed March 27, 2017.
  • 17. Goljan EF. Rapid Review Pathology. Philadelphia, PA: Elsevier Saunders; 2018.
  • 18. Le T, Bhushan V,‎ Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017.
  • 19. Williams WW, Taheri D, Tolkoff-Rubin N, Colvin RB. Clinical role of the renal transplant biopsy. Nat Rev Nephrol. 2012; 8(2): pp. 110–121. doi: 10.1038/nrneph.2011.213.
  • 20. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global Perspective. Biol Blood Marrow Transplant. 2009; 15(10): pp. 1143–1238. doi: 10.1016/j.bbmt.2009.06.019.
  • 21. Valenzuela NM, Reed EF. Antibodies in transplantation: the effects of HLA and non-HLA antibody binding and mechanisms of injury. Methods Mol Biol. 2013; 1034: pp. 41–70. doi: 10.1007/978-1-62703-493-7_2.
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  • Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm. Updated October 20, 2000. Accessed March 27, 2017.
last updated 11/19/2018
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