- Clinical science
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.
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
Major histocompatibility complex (MHC) and (HLA)
- MHC: a gene cluster on chromosome 6 that codes for (HLA) molecules.
- HLA: 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
- Expression of MHC genes is codominant. i.e., genes on both the paternally and maternally derived chromosomes are expressed → An individual may therefore express 6–12 different loci (depending on the degree of homozygosity at the different loci).
- See “” for more details
- 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.
Types of HLA
- Class I HLA
- Class II HLA
- 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.
- 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 lymphocyte, 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
Recipient serum is examined for preformed antibodies against donor T and B lymphocytes; or an HLA-typed panel representing the broad range of HLA types within the population.
- A positive cross match against donor T and B lymphocytes indicates a high risk of hyperacute rejection → The transplantation must not be performed. A positive cross-match against donor T and B lymphocytes indicates a high risk of
- A negative cross-match against T cells but a positive cross-match against B cells → Transplantation may be performed but there is a higher risk of acute rejection.
- A negative cross-match against T and B cells → lower risk of rejection reactions
- Recipient serum is examined for preformed antibodies against donor T and B lymphocytes; or an HLA-typed panel representing the broad range of HLA types within the population.
- ABO compatibility
- MHC matching at the HLA-DR, HLA-A, and HLA-B loci
- The degree of mismatch for each locus (HLA-DR, HLA-A, and HLA-B) is coded as 0, 1, or 2
- Odds of histocompatibility
- Relative size of the donor and recipient
|Types of grafts based on histocompatibility between donor and recipient|
|Xenograft|| || |
autograft transplantation! is not required for
- 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
- Contraindications for organ donation
- The following conditions are NOT contraindications to organ donation:
- 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.
- Disadvantages: increased morbidity and mortality in the donor
- 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
Site of organ transplantation
|Paratopic|| || |
- Induction therapy using anti-T-lymphocyte antibodies
- Maintenance therapy: commonly via a triple-drug regimen
immunosuppression, and the risk of infection increases. Too little, and the risk of rejection increases! is a balancing act: Too much
- Number of procedures: ∼ 19,000 cases in 2016
- Indication: patients with end-stage kidney disease (CKD 5)
- Unsuitable vascular anatomy
- 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)
- Age < 1 year or > 75 years
- Diseases of the lower urinary tract
- Age < 1 year or > 75 years
- Specific contraindications for living donors
Two healthy, fully functioning kidneys are an essential requirement for kidney donation by a living donor!
- Technique: heterotopic implantation in the iliac fossa connecting donor ureter to recipient bladder
- Serial monitoring of renal function tests
- Diagnostic algorithm in the case of renal dysfunction following renal transplantation
- Consider pre-renal causes of acute renal failure.
- Measure urine protein and perform a dipstick urine test for hematuria.
- Hematuria or proteinuria are present: Perform a renal biopsy directly.
Hematuria and proteinuria are not present:
- If the patient is not on anticalcineurins → perform a renal biopsy
- If the patient is on anticalcineurins → measure serum anticalcineurin levels
- ↑ Anticalcineurin levels: reduce anticalcineurin levels and remeasure creatinine
↔︎ Anticalcineurin levels (i.e., within the target range): perform renal and bladder ultrasound to rule out obstruction
- If evidence of obstruction is present: perform renal scintigraphy
- ↓ Anticalcineurin levels: perform a renal biopsy
- Prognosis: graft functions for approx. 14 years, longer if received from a living donor
|1-year survival rate||2-year survival rate||5-year survival rate|
|Graft from living donor||94%||93%||84%|
- Number of procedures: ∼ 7800 cases in 2016
- Fulminant hepatic failure
- Decompensated cirrhosis with a MELD score ≥ 15
- Hepatocellular carcinoma without metastatic disease, and with one lesion ≤ 5 cm, or three lesions each ≤ 3 cm (Milan's criteria)
- Severe metabolic dysfunction due to liver-related diseases with systemic manifestations (e.g., Crigler-Najjar syndrome type I, glycogen storage diseases types I, III, IV)
- MELD score < 15
- Ongoing alcohol or drug abuse
- Hepatocellular carcinoma with metastatic spread
- Intrahepatic cholangiosarcoma
- Severe cardiac or pulmonary disease
- Extrahepatic malignancy
- Ongoing alcohol or illicit substance abuse
- Uncontrolled sepsis
- Fulminant hepatic failure with a sustained ICP > 50 mm Hg, or CPP < 40 mm Hg
- Lack of adequate social support
Types of liver grafts
- Transfer of the entire organ from a brain-dead donor
- Split-liver transplantation from a living or brain-dead donor
- Technique: orthotopic transplantation
- Vascular complications (8–12% of patients)
Biliary complications (10–35%)
- Biliary leak
- 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
- If there is no evidence of biliary dilation or vascular pathology: liver biopsy
- If evidence of biliary dilation is present: ERCP or percutaneous transhepatic cholangiography
- > 6 months post-transplant: liver biopsy
- < 6 months post-transplant; : duplex ultrasonography to identify biliary or vascular pathology
- Post-transplant care
- Number of procedures: ∼ 3200 cases in 2016
- End-stage heart failure (NYHA class IV) and an ejection fraction < 20%, with no other viable treatment option
- Intractable, life-threatening ventricular arrhythmias, that cannot be treated with pharmacological or surgical therapy
- As a first-line treatment for certain congenital heart defects
- AIDS with recurrent opportunistic infections
- Malignancy within the past 5 years
- Obstructive lung disease with an FEV1< 1 L/min
- Pulmonary hypertension with a pulmonary artery systolic pressure > 60 mm Hg, mean transpulmonary gradient > 15 mm Hg, and/or a pulmonary vascular resistance > 6 Woods units
- Active SLE, sarcoidosis, or amyloidosis with multisystem involvement
- ESRD or irreversible hepatic failure if only cardiac transplantation is considered
- 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
- Absolute contraindications
Technique: A graft from a deceased donor is transplanted orthotopically.
- Midline sternotomy
- Systemic anticoagulation and cardiopulmonary bypass with therapeutic hypothermia
- 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.
- Creation of an atrial cuff in the donor heart
- Anastomosis of the atrial cuff with first the remnant of the recipient's left atrium, then the right atrium.
- Anastomosis of the pulmonary artery and aorta
- Closure of the midline sternotomy, rewarming the patient, and weaning off of cardiopulmonary bypass
- Surveillance endomyocardial biopsies to identify rejection reactions
|Survival rates||1-year survival rate||3-year survival rate||5-year survival rate|
|Hematopoietic stem cell graft||Source||Risk of||Engraftment|
|Bone marrow transplant|| || || |
|Peripheral blood stem cell transplant|| || |
|Umbilical cord blood transplant|| || |
Types of HSCT
- Number of procedures: ∼ 20,000 cases in 2015
|Autologous stem cell transplantation||Allogenous stem cell transplantation|
|Preferred source for graft|
|Disadvantages|| || |
- Preparation of a hematopoietic stem cell graft from the donor using bone marrow aspirate, peripheral blood, or umbilical cord blood
- Transplant preparative regimen: recipient preparation using high-dose chemotherapy and/or total body irradiation
- Severe combined immunodeficiency: No recipient preparation is required.
- Aplastic anemia: antithymocyte globulin + high-dose cyclophosphamide
- Thalassemia, sickle cell anemia: antithymocyte globulin + high-dose cyclophosphamide + busulfan
- Malignancies: various combinations of total body irradiation, antithymocyte globulin, cyclophosphamide, busulfan, melphalan, thiotepa, carmustine, and etoposide
- Intravenous injection of the harvested hematopoietic stem cells
Stem cell engraftment
- Definition: anatomical and functional incorporation of transfused hematopoietic stem cells in the recipient's bone marrow
- Factors that affect the rate of engraftment
- Earlier engraftment
- Delayed engraftment
- In allogenous stem cell transplantation: regimen to prevent graft-vs-host disease (see “Prevention” in )
When considering a regimen to prevent graft-versus-host disease following for hematological malignancies, the risk of should always be weighed against the loss of a beneficial graft-vs-tumor effect, and the risk of graft failure due to drug toxicity!
- Graft failure
Related to transplant preparative regimen
- Direct chemoradiotoxicity
- Nausea, vomiting
- Mucocutaneous manifestations: severe oral mucositis , skin erythema, hair loss
- Sinusoidal obstruction syndrome (3–10% of cases): intrahepatic portal hypertension with a high mortality (30%)
- Noninfectious diffuse interstitial pneumonia (5% of cases)
- With regimens that include cyclophosphamide: acute hemorrhagic cystitis, acute hemorrhagic carditis
- Direct chemoradiotoxicity
- 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|| || || |
|Clinical findings|| || |
|Prevention|| || || |
|Treatment|| || || |
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!
- Definition: damage to the host as a result of a systemic inflammatory reaction induced by T lymphocytes present in the graft
- Types of graft-versus-host disease
|Acute graft-versus-host disease||Chronic graft-versus-host disease|
|Epidemiology|| || |
|Onset|| || |
|Pathophysiology|| || |
|Clinical presentation|| || |
|Affected organ||Severity of acute graft-versus-host disease|
|Major clinical finding||Stage I||Stage II||Stage III||Stage IV|
| || || || || |
| || || || |
| || || || |
|Classification according to the Glucksberg criteria. A score indicating the severity of GvHD can be calculated based on clinical findings.|
(< 1 month after transplantation)
|> 12 months|
Screen both the donor and the recipient for infections and treat any existing infections in the recipient.
- In all pretransplant patients:
- Additional testing depending on the transplanted organ
- Ensure that vaccinations are up-to-date.
- Screen both the donor and the recipient for infections and treat any existing infections in the recipient.
- Monitoring for the following infections
- CMV viral loads in blood monthly for a minimum 12 months if either the donor or the recipient is seropositive prior to transplantation
- EBV viral loads in blood for a minimum of 12 months in EBV D+/R-, and pediatric EBV-negative recipients
- In kidney transplant recipients: BK virus viral loads monthly for 6 months, then at 9 and 12 months
- Universal prophylaxis
- 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
- Post-transplant revaccination to retrain the immune system
- Monitoring for the following infections
- Incidence: 0.4% following organ transplantation
- Common malignancies
We list the most important complications. The selection is not exhaustive.