Transplantation

Transplantation is the process of transferring an organ or part of an organ (known as a graft) from one donor to either themselves (autologous transplantation) or another recipient (allogeneic 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 allogeneic 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), allogeneic transplantation subsequently requires immunosuppressive therapy. Close follow-up and infection prevention measures (e.g., vaccination) are required because of the risks of posttransplant infection and graft rejection

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

Crossmatching (transplantation)

• Recipient serum is examined for preformed antibodies (donor-specific antibodies) against donor T and B lymphocytes
  • A negative crossmatch against T and B cells indicates a lower risk of rejection reactions; therefore, transplantation may be performed.
  • A negative crossmatch against T cells but a positive crossmatch against B cells indicates a higher risk of acute rejection, but transplantation may still be performed with a high level of caution.
  • A positive crossmatch 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 allogeneic 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.

Pretransplant evaluation ^[1][2]

• Consult multidisciplinary services for pretransplant evaluation and optimization.
  • Infectious diseases: chronic infection management (e.g., tuberculosis)
  • Social work: comprehensive psychosocial evaluation
  • Other specialists: based on comorbid conditions (e.g., morbid obesity, malnutrition)
• Perform a preoperative risk assessment and coordinate perioperative preparation steps (e.g., perioperative antibiotic prophylaxis).

Pretransplant infectious workup

• Screen both the donor and recipient for infections, including (at a minimum):
  • HIV, human T-cell lymphotropic virus
  • Herpes simplex virus, varicella zoster virus
  • Epstein-Barr virus, cytomegalovirus
  • Viral hepatitis panel
  • Rapid plasma reagin
  • Toxoplasma gondii antibody
  • Tuberculin skin test or interferon-γ release assay
• Consider serological screening for endemic infections, e.g., Leishmania, Trypanosoma cruzi
• Ensure immunization schedule is completed.

Posttransplant infectious workup ^[3]

• 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.

Posttransplant immunosuppressive therapy ^[4]

• 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 posttransplant infections and posttransplant malignancy.

Post solid organ transplant

• Phase 1: induction therapy using anti-T-lymphocyte antibodies
  • Nondepleting antibodies (monoclonal): basiliximab
  • Lymphocyte-depleting antibodies (polyclonal): thymoglobulin
• Phase 2: maintenance therapy. Commonly a triple-drug regimen consisting of:
  • Glucocorticoids
  • Calcineurin inhibitor (e.g., cyclosporine, tacrolimus)
  • Antiproliferative agents (e.g., azathioprine, mycophenolate mofetil, sirolimus)

Post allogeneic stem cell transplant

See “Prevention” in “Graft-versus-host disease.”

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

General principles ^[2]

• Long-term management includes monitoring of:
  • Allograft function
  • Adverse effects of immunosuppressants
  • Posttransplant infections
• Transplant centers typically guide posttransplant management for 3–12 months.
• Consider a broad differential diagnosis and consult specialists for patients with complications (e.g., graft rejection, posttransplant infections).

Living donors

• Overview
  • Nonvital organs and tissues (e.g., kidney or bone marrow) can be acquired from living donors.
  • The organ is retrieved from a living donor (usually a relative with a compatible blood type) at the time of the transplant surgery.
  • When there is no relative with blood type compatibility, a donor may engage in a swap transplantation with a nonrelated donor.
  • Prior to donation, donors must give full informed consent.
  • Donors may select the recipient of their donation.
  • Donors may not be paid for their donation, but can be reimbursed for associated costs (e.g., travel, food, lost wages).
  Advantages
  • Donor is usually healthy, which reduces the risk of complications for both donor and recipient.
  • Preoperative and perioperative immunomodulation is possible in the recipient.
  • Short cold ischemia time
  • Minimal waiting time
• Disadvantages: increased risk of morbidity and mortality in the donor

Deceased and dying donors

Organ donation can save lives, and doctors play an important role in the organ donation system. Doctors should always honor their patients' end-of-life wishes and provide the best possible care, but they should also recognize the medical and social benefits of organ donation. When treating a dying patient, it is therefore important to initiate conversations with the patient and their family about the potential for organ donation. Due to the ethical concerns associated with organ donation, there are several procedures in place to protect the interests of the patient while expanding the practice of donation.

Legal and organizational aspects

• An individual may register to become an organ donor (e.g., in a state donor registry) and can revoke this decision at any time.
• Donors may specify the solid organs they wish to donate (e.g., heart, two lungs, two kidneys, pancreas, liver).
• The organ is retrieved from a donor after brain-death (DBD) or a donor after circulatory death (DCD).
• Deceased patients who have not specifically declined to become donors (e.g., in an advance directive) may be considered if consent is obtained from the next of kin.
• Dying patients (e.g, terminally ill, in palliative care) who have not previously opted-in to the donation system may also be considered for organ donation.
• To avoid any conflict of interest, the decision to end life-sustaining care is always made by a medical team that is independent of the transplant team.
• If the individual is a donor candidate and did not explicitly decline to donate organs (e.g., in a living will) the hospital notifies the local Organ Procurement Organization (OPO).
• Factors that the OPO will consider:
  • Is there an organ donation plan?
  • If no such plan exists, did the deceased declare their intention to donate organs (e.g., by registering in the state organ donor registry)?
  • If the patient did not declare their intention to donate organs, the OPO discusses the possibility of donation with the patient's next of kin.
  • Is the patient a suitable candidate for donation?

Organ assessment and matching

• The Organ Procurement and Transplant Network (OPTN) is a national system that links all professionals involved in organ donation and transplantation (e.g., OPOs, transplant centers, histocompatibility laboratories).
• It is administered by the United Network for Organ Sharing (UNOS), a private nonprofit organization contracted by the federal government.
• The UNOS manages the national transplant waiting list and works with OPOs to match donors with recipients.
• Guidelines for matching include donor compatibility, medical utility, geography, and survival benefit of the transplant.
• The following are the expected waiting periods for new transplant candidates:
  • Kidney: 5 years
  • Liver: 11 months
  • Heart: 4 months
  • Lung: 4 months
  • Pancreas: 2 years
  • Kidney/pancreas: 1.5 years
• Contraindications for the acceptance of organs include: ^[5][6]
  • Terminal malignancies and/or malignancies with a high risk of transmission, such as melanomas and choriocarcinomas
  • Untreated fungal, bacterial, or viral sepsis
  • Transmissible spongiform encephalopathies (e.g., Creutzfeldt-Jakob disease)
  • Cardiac arrest occurring before brain death
  • Poor organ function or prolonged organ ischemia
• Circumstances under which organ transplants can be accepted include:
  • For HIV-positive recipients: donor HIV infection ^[7][8]
  • For hepatitis C-positive recipients: donor hepatitis C infection
  • For HBsAg-positive recipients or recipients with HBV immunity: donor hepatitis B infection
  • Low-grade, localized tumors without evidence of metastasis at the time of death
  • History of malignancy with a disease-free duration > 5 years
  • Hypertension
  • Diabetes
  • Advanced age (if organ function is preserved)

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 posttransplant period.

Transplantation sites

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 of renal transplantation ^[9][10]

The most important complications are listed. Timelines are estimates.

Any time post-transplant

• Posttransplant infections
• Graft rejection, e.g., acute rejection:
  • ↑ Blood pressure and kidney function lab values
  • ↓ Urine output
• Adverse effects of immunosuppressants (e.g., calcineurin-induced nephrotoxicity)
• Recurrence of primary disease ^[11]

Acute postoperative (< 1 week)

• Acute tubular necrosis
• Urinary leakage ^[12]
  • Clinical features: increased postoperative drain output, graft pain and/or swelling, fever, urinoma
  • Diagnostics: abdominal imaging , biochemical analysis of drainage fluid
• Renal vein thrombosis (rare and serious)
  • Clinical features: oliguria, hematuria, graft pain/swelling
  • Diagnostics: Doppler ultrasound
  • Treatment: urgent surgical intervention (e.g., thrombectomy, nephrectomy)

Early (1–12 weeks)

• Urinary tract obstruction (acute)
  • Etiology: extraluminal compression (e.g., hematoma), edema, thrombus, kinking of the anastomosis
  • Clinical features: renal colic, hematuria, oliguria
• Lymphocele
  • Clinical features: often asymptomatic or nonspecific symptoms
  • Diagnostics: biochemical analysis and microscopy of the fluid collection
• Renal artery thrombosis (rare and serious)

Late (> 12 weeks)

• Renal artery stenosis: most common vascular complication (onset is often ∼ 6 months post-transplant) ^[13]
  • Etiology: anastomotic failure, atheroma, immune-mediated
  • Clinical features: renal dysfunction, hypertension
  • Diagnostics: ultrasound, CT or MR angiography
• Urinary tract obstruction (subacute or chronic) ^[14]
  • Etiology: fibrosis of the ureter
  • Clinical features: hypertension; often asymptomatic
• Posttransplant malignancy (e.g., renal cell carcinoma)

Posttransplant care ^[15]

• Within 24 hours of transplant, one or more dialysis treatments may be required in patients with any of the following:
  • Delayed graft function ^[16]
  • Indications for renal replacement therapy similar to nontransplant patients (e.g., refractory hyperkalemia, pulmonary edema)
• Long-term management
  • Serial monitoring of renal function tests (e.g., serum creatinine, urine protein)
  • See “Posttransplant immunosuppressive therapy.”
  • See “Prevention of posttransplant 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 ^[17]

• 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
  • AIDS ^[17]
  • 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 brain-dead donor (BDD)
  • Split-liver transplantation from a living donor or BDD

Complications of liver transplantation ^[18][19][20]

The most important complications are listed. Timelines are estimates.

Vascular complications ^[21]

• Postoperative hemorrhage
• Hepatic artery thrombosis: most common vascular complication
  • Clinical features: elevated hepatocellular enzymes, fever, graft necrosis
  • Sequela: biliary complications, high incidence of graft failure
  • Diagnostics: Doppler ultrasound or CT abdomen
  • Treatment: thrombectomy, stenting, thrombolysis, retransplantation
• Portal vein thrombosis
• Hepatic artery stenosis: Median onset ∼ 3 months post-transplant ^[19]

Biliary complications ^[22]

• Biliary leakage: typically occurs within 6 months of transplantation
  • Etiology: vascular complications, dehiscence of anastomosis, T-tube removal
  • Clinical features: fever, signs of peritonitis
  • Diagnostics: ERCP
• Biliary stricture (anastomotic and nonanastomotic)
• Bile duct obstruction
• Biloma

Other complications

• Posttransplant infections
• Graft rejection ^[23]
  • Acute cellular rejection
    • Typically occurs within one month of transplantation
    • Incidence: 10–30% of patients who take immunosuppressive therapy
    • Laboratory studies: elevation of AST/ALT, ALP, GGT, bilirubin
    • Definitive diagnosis: graft biopsy showing eosinophil, lymphocyte, and/or neutrophil infiltration in portal tracts and inflammation of bile ducts and venous endothelium
    • Prognosis: responds well to treatment with steroids
  • Chronic rejection
    • Typically occurs months to years after transplantation
    • Diagnostics: graft biopsy showing obliterative arteriopathy and ductopenia
    • Prognosis: may result in graft loss and possibly death
• Adverse effects of immunosuppressants
• Posttransplant malignancy
• Recurrence of primary disease

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

Posttransplant care

• Serial monitoring of liver function tests, including ALP
• See “Posttransplant immunosuppressive therapy.”
• See “Prevention of posttransplant 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 ^[24][25][26]

• 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 crossclamped 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

• Posttransplant infections
• 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

Posttransplant care

• Surveillance endomyocardial biopsies to identify rejection reactions
• See “Posttransplant immunosuppressive therapy.”
• See “Prevention of posttransplant infections.”

Prognosis

Overview ^[27]

• 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 (unless the viral load is undetectable)
    • 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
    • Ongoing HBV, HCV, or TB infections
• 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 ^[28]
  • Single-lung
  • Double-lung
  • Heart-lung

Complications of lung transplantation ^[29]

The most important complications are listed. Timelines are estimates.

Any time post-transplant

Graft rejection

• Acute lung transplant rejection (ALTR) ^[30]
  • Definition: an acute complication, occurring within the first year of transplantation, in which the recipient's T-lymphocytes or antibodies attack antigens in the donated lung
  • Clinical features
    • Usually asymptomatic or nonspecific symptoms (e.g., cough, shortness of breath, tachypnea, fever, hypoxemia, crackles on auscultation)
    • Severe cases: acute respiratory distress
  • Diagnostics
    • Blood test: donor-specific antibodies (DSA) in case of antibody-mediated rejection
    • Chest x-ray: perihilar opacities, interstitial edema, pleural effusion
    • CT scan: ground-glass opacities, septal thickening, volume loss, pleural effusion
    • Spirometry: ↓ FEV₁ and/or ↓ FVC
    • Bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy
      • Bronchoscopy with BAL: to help differentiate ALTR from bronchial stenosis and infection
      • Transbronchial biopsy (gold standard): lymphocytic perivascular or peribronchial infiltrates
  • Differential diagnoses
    • Posttransplant infections
    • Bronchial stenosis
    • Tracheobronchomalacia
    • Exophytic granulation tissue
    • Chronic lung allograft dysfunction
    • Thromboembolism
    • Recurrence of primary disease
  • Treatment: plasmapheresis and/or immunosuppression
• Chronic lung allograft dysfunction (CLAD) ^[31]
  • Definition: a progressive decline in lung function more than a year after transplantation that persists for longer than 3 weeks
  • Phenotypes: bronchiolitis obliterans syndrome (most common) and restrictive allograft syndrome
  • Clinical features: asymptomatic or nonspecific symptoms (e.g., dyspnea, nonproductive cough, tachypnea, hypoxemia, crackles on auscultation)
  • Diagnostics: ≥ 20% ↓ in FEV1 or FVC from posttransplant baseline for at least 3 weeks
  • Management: azithromycin, immunosuppression, retransplantation

Other

• Posttransplant infections; (especially pneumonia)
• Adverse effects of immunosuppressants
• Recurrence of primary disease

Early (< 4 weeks)

• Primary graft dysfunction ^[32]
  • Definition: acute lung injury within 72 hours of transplantation
  • Etiology: ischemia-reperfusion injury, mechanical ventilation
• Pleural effusions: hemothorax, chylothorax, empyema
• Venous thromboembolism
• Pulmonary vascular stenosis: pulmonary artery (more common) and pulmonary vein
  • Etiology: kinking of the anastomosis, donor anatomy, thrombosis
  • Clinical features: pulmonary edema, hypoxemia
  • Diagnostics: CTA chest, transesophageal echocardiogram
• Pneumothorax
• Nerve injury
• Bronchial necrosis and dehiscence ^[33]
  • Clinical features: dyspnea, failed trial of spontaneous breathing, subcutaneous emphysema, pneumomediastinum
  • Diagnostics: bronchoscopy

Late (> 4 weeks) ^[33]

Signs of airway obstruction and post-obstructive pneumonia are common manifestations of late lung transplant complications.

• Bronchial stenosis: most common airway complication following lung transplantation ^[33]
• Exophytic granulation tissue
  • Etiology: excess inflammatory response, ischemia, trauma from therapeutic interventions (e.g., stent)
  • Diagnostics: abnormal spirometry
• Tracheobronchomalacia
• Fistulae: e.g., bronchopleural, bronchovascular, bronchomediastinal
  • Clinical features: vary based on the type of fistula
  • Diagnostics: CT chest, bronchoscopy
• Chronic lung allograft dysfunction (e.g., bronchiolitis obliterans)
• Post-transplant malignancy

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 allogeneic 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: 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 allogeneic stem cell transplantation: regimen to prevent GvHD

Complications

Hepatic venoocclusive disease (hepatic VOD) ^[35]

• Definition: a clinical syndrome characterized by obstruction of hepatic sinusoids with cellular detritus resulting from endothelial lesions in hepatic sinusoids and venules
• Etiopathogenesis: toxic injury to endothelium of sinusoids and venules (from, e.g., myeloablative high-dose chemotherapy, liver radiation, pyrrolizidine alkaloids) → initiation of coagulation cascade → embolism formation (fibrin, cellular debris) → progressive obstruction of sinusoids → intrahepatic post sinusoidal portal hypertension
• Clinical features
  • Painful hepatomegaly, right upper quadrant pain, jaundice
  • Signs of fluid retention: ascites, edema, weight gain
• Diagnostics
  • Clinical diagnosis
  • Blood tests: hyperbilirubinemia
  • Supportive diagnostics: hepatic Doppler ultrasonography, liver biopsy
• Differential diagnoses
  • Budd-Chiari syndrome, acute/chronic liver disease
  • GvHD
• Treatment: supportive (no specific treatment available)
  • Based on limited evidence from studies, defibrotide has been used successfully in the treatment of hepatic VOD.
  • Consider TIPS in severe cases of VOD in liver transplanted individuals.
• Complications: hepatic encephalopathy, multiorgan failure
• Prognosis: highly variable
• Prevention
  • Limiting hepatotoxicity by choosing less hepatotoxic treatment regimens, monitoring drug blood concentrations, and finding the least toxic route of administration.
  • Ursodeoxycholic acid and antioxidants may be beneficial.

Engraftment syndrome ^[36]

• Definition: a clinical syndrome characterized by fever, rash, diarrhea, and/or, in more severe cases, organ dysfunction
• Etiopathogenesis
  • Poorly understood; associated with HSCT
  • Thought to be mediated by the release of proinflammatory cytokines (e.g., IL-2, IL-6, TNF-α, interferon-γ), erythropoietin, and products of neutrophil degranulation and oxidative metabolism; involves systemic endothelial damage
• Clinical features: develops within the first 3–4 days of engraftment
  • Fever, skin rash, diarrhea
  • Transient encephalopathy
  • Pulmonary edema, hypoxia, weight gain
• Diagnostics: clinical diagnosis
• Differential diagnoses
  • Acute and hyperacute GvHD, preengraftment syndrome, hematopoietic graft rejection
  • Drug/radiation-induced toxicity
  • Sepsis
• Treatment: depends on severity, but mainly involves corticosteroids (e.g., methylprednisolone, prednisolone), supportive measures (e.g., antipyretics, diuretics), and cardiovascular support (e.g., intubation and mechanical ventilation)
• Complications: hepatic and renal dysfunction
• Prognosis: highly variable, ranging from spontaneous resolution to fatal outcomes
• Prevention: limited data suggest that G-CSF avoidance and use of prophylactic corticosteroids can decrease ES incidence ^[37]

Other

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

The mortality rate of allogeneic stem cell transplantation is declining but is still as high as 50%.
When considering a regimen to prevent GvHD following allogeneic 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.

Overview

• Definition: graft failure resulting from damage by the recipient's immune response

Hyperacute rejection

• Frequency: < 1% of posttransplant organ dysfunction
• Onset: < 48 hours after transplantation (usually within minutes to hours)
• Risk factors: ABO incompatibility, HLA incompatibility ^[38]
• Pathophysiology
  • Humoral rejection (type II hypersensitivity reaction): recipient's preformed cytotoxic antibodies against donor's class I HLA molecules or blood group antigens → activation of the complement system and adhesion to cells → thrombosis of vessels → graft ischemia and necrosis
  • Preformed antibodies against HLA antigens result from exposure to foreign HLA haplotypes during pregnancy, transfusion, or a previously rejected transplant.
• Clinical features: swelling of the organ as soon as perfusion is restored during transplantation
• Diagnostics: small vessel thrombosis, ischemia, and graft necrosis on biopsy
• Treatment: graft removal
• Prevention: preoperative crossmatching and ABO grouping

Acute rejection

• Frequency: ∼ 50% of posttransplant organ dysfunction
• Onset: < 6 months after transplantation (usually within weeks to months)
• Risk factors: HLA incompatibility, inadequate immunosuppression, or patient nonadherence ^[38]
• Pathophysiology
  • Allorecognition → T lymphocyte induced cell-mediated and/or humoral immunity
  • Acute cellular rejection (type IV hypersensitivity reaction)
    • Donor MHC class II antigens react with recipient CD4+ T cells, which then differentiate into Th1 helper T cells → cytokine (INF-γ) release → macrophage recruitment → parenchymal and endothelial inflammation
    • Donor MHC class I antigens react with recipient CD8+ T cells → direct cytotoxic cell damage
  • Acute humoral rejection (type II hypersensitivity reaction): recipient antibodies, formed before or after transplantation, react against donor HLA antigens
• Clinical features
  • Pain in the graft region
  • Graft edema
  • Fever and deterioration of general condition
• Diagnostics
  • Screening test: serial organ function tests to assess for a decline in organ function
  • Biopsy (confirmatory test)
    • Dense interstitial lymphocytic infiltrate with vasculitis
    • Heterogenous mononuclear aggregates with or without antibody deposition
    • Positive C4d staining indicates humoral graft rejection. ^[39]
    • Negative C4d staining indicates cellular rejection.
• Treatment: Adjust dosage or regimen of immunosuppressive therapy.
  • Acute cellular rejection
    • First-line: high-dose glucocorticoids
    • Second-line: lymphocyte-depleting antibodies or OKT3 (muromonab or anti-T-cell antibody)
  • Acute humoral rejection
    • First-line
      • Plasmapheresis
      • IVIG
      • Anti-CD20 antibodies
      • Lymphocyte depleting antibody
    • Corticosteroids may be used as an adjunct.
• Prevention
  • Preoperative crossmatching and ABO grouping
  • Preoperative HLA matching (see “Histocompatibility”)
  • Posttransplant immunosuppressive therapy

Chronic rejection

• Frequency: ∼ 50% of posttransplant organ dysfunction
• Onset: > 6 months after transplantation (usually after a few years)
• Risk factors ^[38]
  • Previous episode of acute rejection
  • Poor HLA match
  • Prolonged cold ischemia time
  • Hyperlipidemia
  • Inadequate immunosuppression or patient nonadherence
• Pathophysiology
  • Combination of humoral rejection (type II hypersensitivity reaction) and cellular rejection (type IV hypersensitivity reaction)
  • Donor MHC class II antigens react with recipient CD4+ T cells → differentiation into Th1 helper T cells → cytokine (INF-γ) release → macrophage recruitment → parenchymal and endothelial inflammation
• Clinical features: slow, progressive loss of organ function
• Diagnostics
  • Biopsy: mainly arteriosclerosis
    • Interstitial fibrosis
    • Obstruction of vessels
    • Vascular smooth muscle proliferation
    • Graft atrophy ^[3]
  • Organ-specific manifestations
    • Glomerular sclerosis (kidneys)
    • Accelerated coronary artery disease (heart)
    • Vanishing bile duct syndrome (liver)
    • Bronchiolitis obliterans (lung)
• Treatment: Graft removal
• Prevention: Irreversible process with no known prevention

Graft rejection manifests with organ failure and is very difficult to distinguish from other posttransplant complications. A biopsy is required to confirm the diagnosis.

Overview

• Definition: an immunological response that occurs when donor T lymphocytes in the graft recognize the recipient as foreign, resulting in a systemic inflammatory reaction
• Etiology
  • Graft-versus-host disease (GvHD) is common in transplantation of lymphocyte-rich organs, including:
    • Allogeneic hematopoietic stem cell transplantation
    • Transfusion of nonirradiated blood products
    • Small bowel transplantation
  • HLA mismatch (especially HLA-A, HLA-B, and HLA-DR) is associated with an increased risk of GvHD.
• Classification ^[40]
  • Acute: presence of acute GvHD clinical features (previously defined as onset ≤ 100 days after transplantation)
    • Classic acute: ≤ 100 days after transplantation
    • Persistent, recurrent, or late-onset acute GvHD: > 100 days after transplantation
  • Chronic: presence of chronic GvHD clinical features regardless of time of onset (previously defined as onset > 100 days after transplantation)
    • Classic chronic GvHD: Only chronic GvHD features are present.
    • Overlap syndrome: Both acute and chronic GvHD features are present.

Acute GvHD

• Epidemiology: Incidence with prophylaxis is 9–50%; incidence without prophylaxis is 70–100%.
• Pathophysiology: Donor T lymphocytes trigger a type IV hypersensitivity reaction in the recipient organs, leading to severe organ damage.
• Clinical features
  • Pruritic and/or painful maculopapular rash (involves the ears, nape of the neck, shoulder, soles, and palms)
  • Gastrointestinal upset
    • Nausea, vomiting, diarrhea
    • Cramping abdominal pain
  • Hepatic dysfunction: jaundice, hepatosplenomegaly
  • In rare cases: lagophthalmos, hemorrhagic conjunctivitis, conjunctival pseudomembrane formation
• Diagnostics
  • Anemia, thrombocytopenia, leukopenia
  • ↑ ALP
  • Confirmatory test: biopsy of skin, rectum, or liver shows cell apoptosis, endothelial damage, and lymphocytic infiltration
    • Skin: damaged epidermis and hair follicles
    • Liver: segmental disruption of small bile ducts
    • Intestines: disruption of crypts, mucosal ulceration
• Treatment ^[41]
  • Optimize GvHD prophylaxis (e.g., cyclosporine levels)
  • < 50% Skin involvement: topical steroids
  • Involvement of the GI tract, liver, or > 50% of skin: systemic steroids and/or topical steroids
  • Octreotide to control severe diarrhea
• Prevention
  • Irradiated blood products (for immunocompromised individuals)
  • Antithymocyte globulin
  • Cyclosporine PLUS one of the following:
    • Methotrexate
    • Mycophenolate mofetil

Chronic GvHD ^[40]

• Epidemiology: ∼ 40% of patients following allogeneic stem cell transplantation
• Pathophysiology: Mostly unknown
• Clinical features
  • Any organ can be affected.
  • Pruritic maculopapural rash
  • Sicca syndrome
  • Chronic enteritis: bloody diarrhea, abdominal pain, weight loss
  • Hepatic dysfunction: jaundice
  • Bronchiolitis obliterans: chronic cough, wheezing, dyspnea
  • Myasthenic symptoms
  • Polymyositis
  • Scleroderma-like and lichenoid skin changes
  • Fasciitis
• Diagnostics
  • Spirometry: obstructive lung disease
  • Confirmatory test: biopsy of the skin, oral cavity, liver, or lung
• Treatment ^[41]
  • First-line: corticosteroids
  • Second-line : cyclosporine and increased corticosteroid dose
• Prevention: same as for acute GvHD

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

Infection

Posttransplant 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