Transplantation

Transplantation is the process of transferring an organ or part of an organ (known as a graft) from one donor to either him/herself (autologous transplantation) or another recipient (allogenous transplantation) or their genetically identical recipient (isograft transplantation). In addition to being subject to strict legal requirements, the donor and recipient must be histocompatible in allogenous transplantations 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., between identical twins), allogenous transplantation subsequently requires immunosuppressive therapy.

Transplant immunology

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

• HLA: a gene cluster on chromosome 6 that codes for MHC molecules
• MHC: 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 as either self or non-self antigens
• Types of MHC
  • The HLA I cluster codes for class I MHC molecules and consists of three loci: HLA-A, HLA-B, and HLA-C.
  • The HLA II cluster codes for class II MHC molecules and also consists of three loci: HLA-DR, HLA-DP, and HLA-DQ.
• See “Major histocompatibility complex” for more details.

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 then 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 lymphocyte, a process that is mediated by IL-2 and leads to 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.
    • The activated helper T cells recruit recipient macrophages to the graft.
    • The activated helper T cells help the plasma cells produce alloantibodies → damage the target cell directly or induce antibody-dependent cell-mediated cytotoxicity

Prerequisites for organ matching

Cross-matching (transplantation)

• Recipient serum is examined for preformed antibodies (donor-specific antibodies) against donor T and B lymphocytes
  • A negative cross-match against T and B cells indicates a lower risk of rejection reactions; therefore, transplantation may be performed.
  • A negative cross-match against T cells but a positive cross-match against B cells indicates a higher risk of acute rejection, but transplantation may still be performed with a high level of caution.
  • A positive cross-match against donor T and B lymphocytes indicates a high risk of hyperacute rejection; therefore, the transplantation must not be performed.

ABO compatibility

• Hematopoietic stem cell transplantation
  • ABO compatibility is preferred but incompatibility can be tolerated.
  • ∼ 40% of allogenous stem cell transplantations are performed despite ABO incompatibility.
• Solid organ transplantation: ABO compatibility is required.

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

Histocompatibility

• Principle
  • MHC matching at the HLA-DR, HLA-A, and HLA-B loci
  • Matching of HLA-C, HLA-DP, and HLA-DQ is preferred but not always required.
• Coding of mismatch degree (HLA-DR, HLA-A, and HLA-B)
  • 0: no mismatch
  • 1: mismatch on either the paternal or maternal chromosome
  • 2: mismatch on both the paternal and maternal chromosome
  • 000: a complete match
  • 222: a complete mismatch
• Odds of histocompatibility
  • For a sibling, the probability that the patient has an HLA compatible sibling is 1 - (0.75)ⁿ (where n is the number of siblings).
  • Between two randomly chosen, nonrelated individuals: 1 in 10,000

Immunosuppressive therapy is not required for autograft transplantation.

Organ procurement

Deceased donors

• Overview
  • The organ is harvested from a brain-dead donor (BDD) or donor after cardiac death (DCD).
  • The United Network for Organ Sharing (UNOS) is responsible for organ matching and the allocation of organs to candidates on a waiting list.
• Waiting time: time period from the entry of a potential transplant candidate on the UNOS list to the allocation of an organ
  • Kidney: 5 years
  • Liver: 11 months
  • Heart: 4 months
  • Lung: 4 months
  • Pancreas: 2 years
  • Kidney/ pancreas: 1.5 years
• Contraindications for organ donation
  • Malignancy
    • Non-curable or metastatic
    • High risk of transmission (e.g., melanomas, choriocarcinomas)
  • Donor sepsis
  • Transmissible spongiform encephalopathies (prion diseases such as Creutzfeldt-Jakob disease)
  • Cardiac arrest occurring before brain death
• NOT contraindications to organ donation
  • Hepatitis B or C infection
  • Low-grade, localized tumors without evidence of metastasis at the time of death
  • History of malignancy with a disease-free duration > 5 years
  • HIV infection ^[1][2]
  • Hypertension, diabetes
  • Advanced age

Living donors

• Overview
  • The organ is 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
  • Preoperative and perioperative immunomodulation is possible in the recipient.
  • Short cold ischemia time
  • Minimal waiting time
  • High degree of HLA compatibility if the donor is related to the recipient
• Disadvantages: increased morbidity and mortality in the donor

Organ preservation

Hypothermic solutions

• Extracellular solutions (e.g., Bretschneider solution): ↑ Na⁺, ↓ K⁺
• Intracellular solutions (e.g., University of Wisconsin solution, St. Thomas cardioplegia solution): ↓ Na⁺, ↑ K⁺

Ischemic times

• Warm ischemia time: time from the withdrawal of life support in the donor to the initiation of cold organ preservation
• Cold ischemia time: time from the initiation of cold organ preservation to the warming of the organ within the recipient following the restoration of blood perfusion

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

Transplantation sites

Post-transplant immunosuppressive therapy

Overview

• Intense immunosuppression in the early postoperative period (3–6 months)
• To minimize drug toxicity, use low doses of multiple drugs rather than high doses of a few drugs.
• Avoid excessive immunosuppression that increases the risk of post-transplant infections and post-transplant malignancy.

Phases

1. Induction therapy using anti-T-lymphocyte antibodies
   • Nondepleting antibodies (monoclonal): basiliximab
   • Lymphocyte-depleting antibodies (polyclonal): thymoglobulin
2. Maintenance therapy: commonly via a triple-drug regimen
   • Corticosteroids
   • Calcineurin inhibitor (e.g., cyclosporine or tacrolimus)
   • Antiproliferative agents (e.g., azathioprine, mycophenolate mofetil, sirolimus)

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

Overview

• Number of procedures: 23,401 in 2019 in the US
• Indication: patients with end-stage renal 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
      • Thrombosis of iliac vein and inferior vena cava
    • Active infection (e.g., tuberculosis, invasive fungal infections, osteomyelitis)
    • Malignancy in the past 2 years
    • BMI ≥ 50 kg/m²
    • Active alcohol or substance use (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
  • Pregnancy
  • Psychiatric diseases or psychosocial problems
  • Diseases potentially leading to kidney damage
    • Proteinuria > 300 mg/day
    • Hypertension that does not respond to treatment
    • Diabetes mellitus
• Technique
  • The left kidney is preferred in living-donor kidney transplantations because it has a longer renal vein.
  • Kidney transplants are transplanted heterotopically in the iliac fossa since this position holds several advantages over orthotopic implantation.
    • The transplanted kidney can be more easily palpated, biopsied, and evaluated via ultrasound.
    • Vascular anastomosis with the inguinal arteries is easier.
    • Distance between the ureter and bladder is shorter.

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

The left kidney is preferred for living-donor transplantation as it has a longer renal vein.

Complications

• Acute tubular necrosis
• Graft rejection
• Post-transplant infection
• Vascular ^[3]
  • Early
    • Renal vein thrombosis ^[4]
    • Renal artery thrombosis
  • Late: renal artery stenosis
• Urological
  • Urinary leakage
  • Urinary tract obstruction
• Lymphocele
• Calcineurin-induced nephrotoxicity

Post-transplant care

• Serial monitoring of renal function tests
• See “Post-transplant immunosuppressive therapy.”
• See “Prevention of post-transplant infections.”

Diagnostic algorithm for renal dysfunction following renal transplantation

1. Consider prerenal causes of acute renal failure.
   • In hypotensive or normotensive patients, measure the BUN:creatinine ratio to rule out dehydration.
   • In hypertensive patients, consider renal artery stenosis and perform Doppler ultrasonography.
2. Measure urine protein and order a dipstick urine test for hematuria.
   • Hematuria or proteinuria: renal biopsy
   • No hematuria or proteinuria
     • If the patient is not taking anticalcineurins: renal biopsy
     • If the patient is taking anticalcineurins: measure serum anticalcineurin levels
       • ↑ Anticalcineurin levels: Reduce anticalcineurin dose and remeasure creatinine.
       • Unchanged anticalcineurin levels (i.e., within the target range): Perform renal and bladder ultrasound to rule out obstruction.
       • ↓ Anticalcineurin levels: Carry out a renal biopsy.

Prognosis

The graft functions stays functional for ∼ 14 years, longer if received from a living donor.

Renal transplantation has a better prognosis than dialysis in end-stage renal disease.

Overview ^[5]

• Number of procedures: 8,896 in 2019 in the US
• Indications
  • Hepatocellular carcinoma without metastatic disease and with either one lesion measuring ≤ 5 cm or three lesions each measuring ≤ 3 cm
  • Fulminant hepatic failure
  • Decompensated cirrhosis with a MELD score ≥ 15
    • Hepatitis C
    • Alcoholic cirrhosis
    • Primary biliary cirrhosis
    • Primary sclerosing cholangitis
    • Biliary atresia
    • Hemochromatosis
    • α1-antitrypsin deficiency
    • Wilson disease
  • Severe metabolic dysfunction due to liver-related diseases with systemic manifestations (e.g., Crigler-Najjar syndrome type I, glycogen storage disorders types I, III, IV)
• Contraindications
  • MELD score < 15
  • Alcohol or drug use disorder
  • Hepatocellular carcinoma with metastatic spread
  • Intrahepatic cholangiosarcoma
  • Severe cardiac or pulmonary disease
  • HIV/AIDS
  • Extrahepatic malignancy
  • Uncontrolled sepsis
  • Fulminant hepatic failure with a sustained ICP > 50 mm Hg or CPP < 40 mm Hg
  • Lack of adequate social support
• Technique: orthotopic transplantation
  • Transfer of the entire organ from a BDD
  • Split-liver transplantation from a living donor or BBD

Complications

• Graft rejection
• Post-transplant infections
• Post-transplant malignancy
• Vascular complications
  • Hepatic artery thrombosis ^[6]
  • Portal vein thrombosis
  • Postoperative hemorrhage
• Biliary complications
  • Biliary leakage
  • Biliary stricture

Diagnostic algorithm in the case of clinical or laboratory features of hepatic dysfunction

• < 6 months post-transplant: duplex ultrasonography to identify biliary or vascular pathology
  • No evidence of biliary dilation or vascular pathology: liver biopsy
  • Evidence of biliary dilation: ERCP or percutaneous transhepatic cholangiography
• > 6 months post-transplant: liver biopsy

Post-transplant care

• Serial monitoring of liver function tests, including ALP
• See “Post-transplant immunosuppressive therapy.”
• See “Prevention of post-transplant infections.”

Prognosis

• High mortality rate within first postoperative year due to the greatest immunosuppression and subsequent infections
• 5-year survival rate: ∼ 80%
• Very good prognosis for pediatric liver transplantation

Overview ^[7][8][9]

• Number of procedures: 3552 in 2019 in the US
• Indications
  • End-stage heart failure (NYHA class IV) and an ejection fraction < 20% with no other viable treatment option
  • Otherwiese untreatable, intractable, life-threatening ventricular arrhythmias
  • Hypoplastic left heart syndrome
  • Severe Ebstein anomaly
  • Pulmonary atresia
  • Heterotaxy lesions
• Contraindications
  • Absolute contraindications
    • AIDS with recurrent opportunistic infections
    • Malignancy within the past 5 years
    • Obstructive lung disease with an FEV₁ < 1 L/min
    • Pulmonary hypertension
      • Pulmonary artery systolic pressure > 60 mm Hg
      • Mean transpulmonary gradient > 15 mm Hg,
      • Pulmonary vascular resistance > 6 Wood units
    • Active SLE, sarcoidosis, or amyloidosis with multisystem involvement
    • ESRD or irreversible hepatic failure if cardiac transplantation alone is being considered
  • Relative contraindications
    • Any active infection (except device-related infection in individuals with ventricular assist devices)
    • Age > 72 years
    • FEV₁ < 40% of the normal value
    • Pulmonary infarction in the past 6–8 weeks
    • Heparin-induced thrombocytopenia in the last 100 days
    • Chronic renal failure (creatinine > 2.5 mg/dL)
    • Hepatic dysfunction (bilirubin > 2.5 mg/dL, serum transaminase more than 3 times the upper limit, or INR > 1.5 without warfarin)
    • Active peptic ulcer disease
    • Severe malnutrition (BMI < 18 kg/m²)
    • Morbid obesity (BMI > 35 kg/m²)
    • Severe diabetes mellitus
    • Uncontrolled hypertension
    • Severe peripheral vascular disease
    • Abdominal aortic aneurysm > 6 cm
    • Symptomatic carotid stenosis
    • Irreversible neurological disease
    • Mental illness
    • Drug, tobacco, or alcohol consumption in the past 6 months
• Technique: A graft from a deceased donor is transplanted orthotopically.
  1. Midline sternotomy
  2. Systemic anticoagulation and cardiopulmonary bypass with therapeutic hypothermia
  3. The aorta is cross-clamped and the recipient heart is excised at the level of the mid-atrium, leaving the pulmonary veins and vena cava intact.
  4. Creation of an atrial cuff in the donor heart
  5. Anastomosis of the atrial cuff first with the remnant of the recipient's left atrium, then the right atrium.
  6. Anastomosis of the pulmonary artery and aorta
  7. Closure of the midline sternotomy, rewarming the patient, and weaning off of cardiopulmonary bypass

Complications

• Post-transplant infection
• Graft rejection
  • Hyperacute and accelerated rejection → cardiogenic shock
  • Acute rejection → arrhythmias, heart failure
  • Chronic rejection → acquired transplant vasculopathy → accelerated coronary artery disease → angina, low stress tolerance
• Pulmonary hypertension → right heart failure

Post-transplant care

• Surveillance endomyocardial biopsies to identify rejection reactions
• See “Post-transplant immunosuppressive therapy.”
• See “Prevention of post-transplant infections.”

Prognosis

Overview ^[10]

• Number of procedures: 2714 in 2019 in the US
• Indication: patients with advanced lung disease refractory to maximal medical or surgical therapy, disabling symptoms during activities of daily living, and risk of death > 50% over the next 2 years
  • COPD
  • Idiopathic pulmonary fibrosis
  • Genetic disorders such as CF and α1-antitrypsin deficiency
  • Idiopathic pulmonary arterial hypertension (IPAH)
  • Sarcoidosis
  • Lymphangioleiomyomatosis
  • Pulmonary Langerhans cell histiocytosis
• Contraindications
  • Absolute
    • Malignancy in the past 2 years
    • Chronic advanced illnesses (e.g., heart, renal, or hepatic insufficiency)
    • Uncontrolled or untreatable pulmonary or extrapulmonary infection
    • Poor cardiac function
    • Acute medical conditions, such as sepsis, myocardial infarction, or liver failure
    • Uncorrectable bleeding diathesis
    • HIV infection, ongoing HBV, HCV, or TB infections
    • Significant chest wall or spinal deformity
    • BMI ≥ 35
    • History of nonadherence to medical therapy
    • Psychiatric conditions or psychosocial problems
    • Lack of adequate social support
    • Severely limited functional status with poor rehabilitation potential
    • Active alcohol, tobacco, or substance use disorder
  • Relative
    • Age > 75 years
    • BMI 30–35
    • Progressive or severe malnutrition
    • Severe, symptomatic osteoporosis
    • Prior chest surgery with lung resection
    • Infection with highly resistant or virulent bacteria, fungi, and/or certain strains of mycobacteria
• Techniques: A graft from a deceased donor is transplanted orthotopically.
  • Bilateral orthotopic lung transplantation (BOLT) is the preferred procedure.
  • In a single-lung transplant, the right lung or the lung with the worse pulmonary function is chosen for replacement.
• Types of lung transplant
  • Lobe ^[11]
  • Single-lung
  • Double-lung
  • Heart-lung

Complications

• Pneumonia
• Primary graft dysfunction due to ischemia-reperfusion injury
• Airway anastomotic complications
  • Bronchial necrosis and dehiscence
  • Tracheobronchomalacia
  • Excess granulation tissue
  • Focal infection
  • Stenosis
  • Fistula
• Chronic graft dysfunction → bronchiolitis obliterans syndrome and restrictive allograft syndrome
• Malignancy
  • Nonmelanoma skin cancer
  • Post-transplant lymphoproliferative disease
  • Kaposi sarcoma, malignancy of the colon, breast, or bladder)

Post-transplant care

• Pulmonary rehabilitation
• Serial monitoring of lung function tests (e.g., PFT, CT scan of the chest, bronchoscopy)
• See “Post-transplant immunosuppressive therapy.”
• See “Prevention of post-transplant infections.”

Prognosis

• Median survival for all adult recipients: 5.7 years
• 1-year survival rate: 78%
• 5-year survival rate: 51%

Hematopoietic stem cell

• A stem cell that can give rise to all lines of blood cells via hematopoiesis.
• Excellent regenerative capacity
• Ability of homing to the bone marrow following intravenous injections

Types of hematopoietic stem cell transplantation (HSCT)

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
   • Rationale
     • To eradicate the underlying disease
     • To prevent graft rejection in the setting of allogenous HSCT
   • Regimens
     • Severe combined immunodeficiency: No recipient preparation is required.
     • Aplastic anemia: antithymocyte globulin and high-dose cyclophosphamide
     • Thalassemia, sickle cell anemia: antithymocyte globulin, high-dose cyclophosphamide, and busulfan
     • Malignancies: various combinations of total body irradiation, antithymocyte globulin, cyclophosphamide, busulfan, melphalan, thiotepa, carmustine, and etoposide
3. Intravenous injection of the harvested hematopoietic stem cells
4. Stem cell engraftment
   • Definition: anatomical and functional incorporation of transfused hematopoietic stem cells in the recipient's bone marrow
   • Factors that affect the success rate of engraftment
     • Earlier engraftment
       • A myeloid growth factor (e.g., G-CSF, GM-CSF) may be used to accelerate stem cell engraftment by 3–5 days.
       • Peripheral blood stem cell transplant
     • Delayed engraftment
       • Methotrexate, which is used to prevent GvHD, delays stem cell engraftment by 3–5 days.
       • Umbilical cord stem cell transplant
   • Confirmation
     • Increase in granulocyte count beyond 500 cells/μL
     • FISH or analysis of STNRs after PCR: evidence of chimerism in peripheral leukocytes
5. In allogenous stem cell transplantation: regimen to prevent GvHD

Complications

• Graft failure
  • Primary graft failure: stem cell engraftment failure
  • Secondary graft failure: graft failure after stem cell engraftment
• GvHD
• Immunosuppression-related complications
  • Post-transplant infections
  • Post-transplant malignancy

The mortality rate of allogenous stem cell transplantation is declining but is still as high as 50%.
When considering a regimen to prevent GvHD following allogenous HSCT for hematological malignancies, the risk of GvHD 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 after transplantation can be divided into graft-related (graft rejection, graft-versus-host disease) and immunosuppression-related complications (infection, malignancy).

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

Graft rejection

• Definition: graft failure as a result of damage to the graft by the host's immune response

Graft rejection manifests 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 (GvHD)

• Definition: damage to the host as a result of a systemic inflammatory reaction induced by T lymphocytes present in the graft
• Etiology: GvHD is associated with transplantation of lymphocyte-rich organ transplants
  • Transfusion of nonirradiated blood products
  • Liver transplantation
  • Allogenous hematopoietic stem cell transplantation; the inflammatory reaction triggered by grafts can be used therapeutically to target tumor cells, e.g., in leukemia (graft-versus-tumor-effect).
  • Small bowel transplantation

The skin, intestines, and liver are the most commonly affected organs in GvHD.

Infection

Post-transplant malignancy

• Incidence: 0.4% following organ transplantation
• Common malignancies
  • Non-Hodgkin lymphoma
  • Nonmelanoma skin cancer (especially squamous cell carcinoma)
  • Kaposi sarcoma
  • Hepatocellular carcinoma
  • Anal or vulval carcinoma

Pretransplant measures ^[18]

• Screen both the donor and the recipient for infections and treat any existing infections in the recipient.
  • All pretransplant patients
    • Serological screening for CMV, HSV, VZV, EBV, HIV, HBV, HC, T. pallidum
    • Tuberculin skin test or interferon-gamma release assay
    • Urinalysis and urine culture
    • Chest x-ray
    • Patients from endemic regions: serological tests for S. stercoralis, Leishmania, Coccidioides immitis, T. cruzi
  • Heart transplant recipients: T. gondii serology
  • Lung transplant recipients
    • Sputum stains and culture
    • Patients from endemic regions: H. capsulatum serology
  • In kidney transplant recipients from endemic regions: urine microscopy for Schistosoma
• Ensure that vaccinations are up-to-date.
• Perioperative antibiotic prophylaxis

Post-transplant measures ^[16]

• Monitoring
  • CMV viral loads in blood monthly for a minimum of 12 months
  • EBV viral loads in blood monthly for a minimum of 12 months
  • In kidney transplant recipients: BK virus viral loads monthly for 6 months, then at 9 and 12 months
• Universal prophylaxis
  • PCP prophylaxis with trimethoprim-sulfamethoxazole for a minimum of 6–12 months
  • CMV prophylaxis with ganciclovir or valganciclovir for 12–14 weeks
• Specific situations
  • Recipients seronegative for T. gondii who receive a heart transplant from a seropositive individual: pyrimethamine with folinic acid for 6 months
  • Hematopoietic stem cell transplantation
    • Acyclovir for prophylaxis against HSV and VZV
    • 12 months post-transplantation: tetanus, diphtheria, H. influenzae, polio, and pneumococcal pneumonia vaccination
    • 24 months post-transplantation: MMR, VZV, and possibly pertussis vaccination

Because the symptoms of CMV infections can appear similar to those of transplant rejection, differentiating between conditions can be difficult.

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