Chapter 11: Principles of Organ Transplantation lflllllll

CHAPTER 11
PRINCIPLES OF ORGAN TRANSPLANTATION

General principles CHAPTER CONTENTS

• The immune system discriminates between self and non- • General principles
self and destroys the latter, be it a microbe, altered cells a • Renal transplantation
tumour cell or a transplant. • Liver transplantation
• Pancreatic transplantation
• The genetic identity of individuals is determined by certain • Heart and lung
glycoprotein molecules on the surface of cells named transplantation
Human Leucocytes Antigens (HLA) because they were • Bone marrow
transplantation
first detected on the surface of leucocytes. • Intestinal transplantation
• There are 2 important types of HLA regarding
transplantation
o Class I - HLA (A, B, C), present on the surface of all nucleated cells and platelets.
o Class II - HLA (OR, the most important for transplantation), present only in
antigen presenting cells (APC), e.g., macrophages and dendritic cells.
• HLA are genetically controlled by loci on the short arm of chromosome 6, this area of
the chromosome is termed Major Histocompatibility Complex (MHC).
• Foreign class I and class II antigens are capable of stimulating the recipient immune
mechanism and triggering lymphocytes sensitization starting rejection of the
transplanted organ.
• Acquired immunity comprises two types, cellular and humeral.
o Cellular immunity depends upon T-lymphocytes which develop in the bone
marrow and mature in the thymus. Two types of T-lymphocytes are important.
• T-helper (CD4) lymphocytes help other cells of the immune system.
• T-cytotoxic lymphocytes (CD8) which attack and destroy the foreign antigen.
o Humoral immunity depends upon 8-lymphocytes which develop and mature in the
bone marrow. 8-lymphocytes after being stimulated secrete immunoglobulins which
help in cytotoxicity and complement activation to lyse cells.
HLA-I leads to stimulation of cytotoxic lymphocytes while HLA-II leads to stimulation of
helper T-cells.

Steps of the rejection process (Fig. 11.1)

• HLA in the graft are processed by the antigen presenting cells (APC) of the recipient.
The processed antigens are presented to the recipient T-cells which have special
receptors for antigens known as T-cell receptors (TCR).
..:PJi Chapter 11: Principles of Organ Transplantation

The binding of the antigen to TCR HLA-1

leads to the liberation of cytokines
mainly IL-2 which stimulates the
entire cascade of T-cells. This
leads to
o Activation of cytotoxic (CD8)
cells which destroy the graft.
o Activation of 8-cells which
differentiate into plasma cells
which secrete allo-antibodies
that attack antigens or graft
cells.
o Activation of macrophages.

Types of solid organ

rejection Four types are known
lmmuno•
1. Hyperacute rejection globulins

• It leads to irreversible damage

to the graft within minutes to Fig. 11.1. Steps of the rejection process.
hours after reperfusion of the
transplanted organ.
• It is due to the presence of preformed antibodies against donor HLA or ABO blood
group antigens. These antibodies are present in the recipient due to sensitization
from previous transfusion, pregnancy or transplantation.
• This leads to damage of the endothelium with platelet activation, thrombosis and
ischemic damage.
• If hyperacute rejection occurs, the graft has to be removed. Hyperacute rejection
can be prevented by' pre-transplant blood group matching and tissue typing cross-
matching.
2. Accelerated acute rejection
• This type of rejection is seen within the first few days after a transplant. It involves
both cellular and antibody mediated injury.
• It is likely when a recipient has been sensitized by previous exposure to antigens
present in the donor, resulting in an immunologic memory response.
3. Acute rejection
• This is the most common type. It can occur at any time, usually within the first six
months post-transplant, but up to many years later when doses of
immunosuppressive drugs are reduced. It is usually T-cell mediated; graft biopsies
show intense lymphocyte and macrophage infiltration.
• Clinically the manifestations are non-specific with fever, lethargy and pain and
tenderness over the graft. Laboratory tests reveal deterioration of the graft function.
A sure diagnosis depends upon biopsy of the graft.
 Chapter 11: Principles of Organ Transplantation IIE:IIIIII
• Treatment depends on the severity of rejection and the type of transplant. Agents
commonly used include corticosteroids, probably with a monoclonal or polyclonal
antibody.
4. Chronic rejection
• Develops slowly after months or, more commonly, years after transplantation. There
is gradual decline of graft function and, eventually, organ failure.
• Biopsies show intimal hyperplasia of small and medium-sized arteries, interstitial
fibrosis, and atrophy.
• The cause is not clearly understood. Immune and non-immune factors may be
involved. There is no treatment that saves the graft. A new one will be needed.

Minimizing risk of rejection

Histocompatibility testing
Compatibility between donor and recipient immune systems is assessed before
transplantation.
• ABO blood group matching. Incompatibility leads to hyperacute rejection.
• HLA tissue typing. Recipient lymphocytes are tested to find out which HLA class-I and
II molecules are expressed. Six alleles, HLA-A, HLA-B, and HLA-DR (three from each
parent) are most important. HLA-DR matching is the most important, since a high
incidence of rejection is associated with a mismatch at this locus.
• HLA-antibody screening. Recipient serum is tested for antibodies targeted at non-self
HLA molecules, e.g., by mixing it with lymphocytes from a panel of HLA-typed donors.
Lysis of lymphocytes indicates a positive cross-match with this particular HLA type.
• Tissue typing cross-match. this is the final pre-transplant test when the above tests
have identified potentially compatible recipients and donors. Recipient serum is
incubated with donor lymphocytes to determine if anti-donor HLA antibodies are
present in the recipient.

lmmunosuppressive drugs
lmmunosuppressive drugs are used to prevent acute rejection and to reverse it when it
happens (Table 11.1 ). lmmunosuppressive therapy is divided into induction;
maintenance and withdrawal phases.
• Induction: starts during the transplantation procedure, before the vascular clamps are
removed to allow reperfusion of the allograft. Intravenous steroids, (methyl-
prednisolone}, often combined with a biological antibody as anti-thymocytic globulin
(ATG} or OKT3 are given and continued for several days to a few weeks.
• Maintenance therapy starts after graft implantation. In most cases, this consists of
triple oral therapy combining a calcineurin inhibitor (e.g., tacrolimus), anti-proliferative
(e.g., mycophenolate mofetil}, and corticosteroids to produce a balanced immune-
deficient state which aims to prevent rejection while minimizing the risk of infection and
drug toxicity.
• In withdrawal phase, all drug doses are gradually reduced as the risk of acute
rejection diminishes.
IIIIIIIEI Chapter 11: Principles of Organ Transplantation

Table 11.1. lmmunosuppressive drugs

- - - - - - - - - - - - - - - -

Drug Mode of action Specific side effects

Steroids -Depletion of circulating Hypertension, D.M, GIT

lymphocytes bleeding, & osteoporosis
-Inhibition of IL-2 synthesis

- Polyclonal antibodies T-cells are either lysed, inactivated Leucopenia, thrombocytopenia

- Antithymocytic globulin or cleared from the circulation. & cytokine release syndrome
- Antilymphocytic globulin (hypotension - flushing)

Monoclonal antibody (OK3) Inactivation of T-cell receptors, Cytokine release syndrome

leading to their clearance from the
circulation.

Calcineurin inhibitors Inhibits IL2 gene transcription ..... Nephrotoxicity, hypertension,

Tacrolimus (FK506), prevents T-cell proliferation D.M, hirsutism & gum
Cyclosporine hypertrophy (cyclosporine)

Mycophenolate mofetil Inhibits lymphocyte proliferation Nausea, vomiting, diarrhea &

(cellcept) bone marrow depression

Azathioprine (lmuran) AS mycophenolate Bone marrow depression

General side effects. In addition to individual drug toxicity, the immunosuppressed

recipients are susceptible to:
• Opportunistic infections
o Bacterial (e.g. T.B), viral (e.g. CMV), fungal (e.g. candidiasis), or parasitic (e.g.
toxoplasmosis ).
o The risk of infection is highest during the first 6-12 months; therefore
chemoprophylaxis is important.
• Neoplasia: Non-melanoma skin cancers (100-fold increase), lympho-proliferative
malignancies, and solid tumors associated with viral infection, e.g., Kaposi sarcoma,
and canc~r of the cervix.

Sources of organs for transplantation

Organs for transplantation may come either from live, or deceased (cadaver) donors.
Live donors
• They are the exclusive source of organs in some countries (e.g. Egypt), because of
legal and cultural issues related to organ procurement from deceased donors.
• Organs commonly obtained from live donors are a kidney and a liver lobe.
• Advantages:
o Better preoperative preparation of recipients as transplantation is planned.
o Shorter ischemia time as donor and recipient operations are simultaneous and
synchronized so that the removed organ is immediately prepared and implanted.
o The immunologic advantage of a closely matched related donor.
• Disadvantage. Small but significant mortality and morbidity risks to the healthy donor.
 Chapter 11: Principles of Organ Transplantation lfDIIII
Cadaver donors
• Advantages
o This method avoids the risk of complications, which may occur to the living donors.
o Multiple organs can be taken from one cadaver and transplanted to many patients.
• The organ is removed from a patient with proved brain death. Victims of intracranial
hemorrhage or head injury are the main source of donor organs.

• Diagnosis of brain stem death

o Flat EEG.
o The patient must be in apnoeic coma: unresponsive and dependent on mechanical
ventilation.
o No pupillary response to light, direct or consensual.
o No corneal reflex.
o Absent cough reflex via bronchial stimulation by a catheter in the endotracheal tube.
o Absent vestibule-ocular reflex; no eye movement upon injection of 50 ml of ice-cold
water into each external auditory meatus.
o Exclusions
' ■ Drug effects as sedatives, hypnotics or muscle relaxants.
■ Hypothermia, core body temperature must be above 35 degrees. Low body
temperature can induce deep coma.
• Metabolic abnormalities, e.g., hypo or hyperglycemia, hypo or hypernatraemia,
uraemia or hepatic encephalopathy.
• Intoxication by alcohol or other drugs.
o All the previous tests should be repeated after 24 hours and should be done by a
separate physician, not involved in the transplant procedure. The patient's heart will
continue beating to perfuse the tissues by the use of adequate artificial ventilation,
fluids, plasma, vasopressors and diuretics until the needed organs are surgically
removed.

• Organ preservation
o The retrieved organ is flushed with cold preservative solution, (e.g. University of
Wisconsin solution), and implanted directly if from a live donor, or placed in a
sealed bag, immersed in preservative solution and then packed in ice if from a
decreased donor.
o The operation should be performed within 6 hours from procurement for cardiac
transplantation, within 12 hours for hepatic transplantation and up to 40 hours for
renal transplantation.
Donor suitability
Not all potential donors are acceptable. Contraindications include:
• Active infection, T.B, or HIV.
• Active cancer, except CNS tumors.
• Cancer-treated donors may be accepted after a cancer-free waiting period of 2-5 years
depending on tumor type.
- Chapter 11: Principles of Organ Transplantation

Renal transplantation
Kidney transplantation is the longest established and most successful of organ
transplantations.

Indications
All cases of "end-stage renal disease", which may be due to different conditions.
Diabetes mellitus Chronic glomerulonephritis
Hypertension Chronic pyelonephritis
Lupus nephritis Polycystic kidney disease
Obstructive uropathy Bilateral Wilm's tumour

If a related living donor is available and willing, then early transplantation is indicated even
before the start of hemodialysis. If the living related donor is not available, the patient is
immediately placed on a cadaver donor list.

Technique (Fig. 11.2)

• The grafted kidney is placed in an extra-
peritoneal position in the iliac fossa (preferably
the right one).
• The arterial anastomosis is performed between
the renal artery and the external iliac artery (end
to side anastomosis), or between the renal
artery and internal iliac artery (end to end
anastomosis).
• The venous anastomosis is performed between
the renal vein and the external iliac vein (end to
side anastomosis). Fig. 11.2. Renal transplantation.
• The ureter of the graft is anastomosed to the patient's urinary bladder using the
submucosal tunnel technique as an anti-reflux procedure.

Complications (Apart from rejection)

• Renal allograft non-function. Early poor function is usually due to reversible acute
tubular necrosis secondary to reperfusion injury.
• Lymphocele from lymphatic leak in the retroperitoneum.
• Graft vessel thrombosis result in sudden cessation of urine output, rising serum
creatinine. Diagnosis is confirmed by Doppler ultrasound or 99mTc renal scan. If not
immediately corrected, the graft will be lost and nephrectomy would be performed.
• Urine leak: presents with pain, rising creatinine, and possibly urine discharge from the
wound. The cause is usually a leaking uretero-vesical anastomosis. Treatment is by re-
anastomosis.
 Chapter 11: Principles of Organ Transplantation 16'111111
Results of renal transplantation
• Cadaver donor 95% graft survival at 1 year
60% graft survival at 5 years
• Living donor 98% graft survival at 1 year
90% graft survival at 5 years

Liver transplantation

Indications
"End-stage liver failure" due to
• Various types of cirrhosis (alcoholic, post-viral, biliary, haemochromatosis, Wilson's
disease).
• Biliary atresia is the leading indication in children.
• Chronic viral hepatitis.
• Fulminant acute hepatitis.
• Sclerosing cholangitis.
• Budd Chiari syndrome.
• Advanced primary liver malignancies.

Evaluation
Evaluation of the risk of transplantation to the recipients is based on MELD' score (Model
of End Stage Liver Disease) which is based on international normalized ratio (INR), serum
creatinine and serum bilirubin.

Technique
Cadaveric liver-transplantation (Fig. 11.3)
• The whole liver of the cadaver is removed (donor hepatectomy), including the segment
of inferior vena cava (IVC) embedded in the liver.
• The recipient liver is removed (recipient
hepatectomy}.
• The new liver graft is placed in the same position of
the original liver (orthotopic transplantation} and the
following anastomoses are performed in order
o Supra-hepatic followed by infra-hepatic IVC
anastomosis.
o Portal vein of recipient to donor.
o Hepatic artery of recipient to donor. Fig. 11.3. Liver transplantation.

o Common bile duct of recipient to donor.

• Alternatively, cadaveric liver is split into two parts ex-vivo which are transplanted into
two recipients (split liver transplantation).
11111m Chapter 11: Principles of Organ Transplantation

Living donor liver transplantation

• The left lateral segment is transplanted in children whereas the right or left lobes are
transplanted in adults after removal of the recipient liver.
• Donor safety is extremely important. Detailed anatomical studies of the biliary tract by
MRCP and the liver vasculature by triphasic CT are essential.
• The recipient should have a liver graft weighing 1% of his body weight.
• The graft size can be estimated preoperatively using donor CT volumetry.

Complications
• Primary non-function (1%). The graft fails to function in the presence of patent
vascular anastomoses on Doppler ultrasonography. Death is inevitable without re-
transplantation.
• Hepatic artery thrombosis (3% in adults, up to 12% in children) leads to rapid
deterioration with fever, elevated transaminases and possibly bile leak. Urgent
thrombectomy seldom succeeds. Re-transplantation is necessary.
• Portal vein stenosis or thrombosis (rare). Rapid deterioration, massive ascites, renal
failure and hemodynamic instability ensue. If surgical thrombectomy fails, re-
transplantation becomes necessary.
• Biliary stricture. A short stricture on cholangiography may respond to balloon
dilatation; otherwise, surgical revision of the biliary anastomosis is required.

Results
• 1-year graft survival is 85%
• 5-years graft survival is 50%

Pancreatic transplantation
• Successful pancreatic transplantation cures insulin-treated diabetes and stops its
complications; restoring glucose homeostasis without risk of hypoglycemia.
• Pancreas transplantation occurs in four contexts
1. Simultaneous pancreas and kidney transplant (SPK), in patients who are both
diabetic and uremic {~80% of cases).
2. Pancreas after kidney transplant (PAK) in patients with a kidney transplant with
problems of diabetic control or risk of losing the kidney from diabetic nephropathy
{~15%).
3. Pancreas transplant alone {PTA), with brittle diabetes and adequate kidney
function.
4. Pancreatic islet cell transplantation, which not widely applicable. Isolated pancreatic
islet cells are injected by an interventional radiologist into the portal vein for
implantation in the liver. Obtaining enough islet cells to achieve glucose
homeostasis and long-term insulin independence is its main problem.
 Chapter 11: Principles of Organ Transplantation IEJIII
Technical considerations of vascularized pancreatic transplantation
Whole or segmental pancreatic transplantation is performed with the venous anastomosis
anchored to either the portal or the systemic venous circulation. The exocrine secretions
are drained either to the jejunum (Roux-en- Y loop) or to the urinary bladder lumen.

Complications
• Technical complications as arterial or venous occlusion; and duct leakage.
• Rejection.
• Pancreatitis
• Complications of immunosuppression.

Results One-year graft survival is 45%.

Heart and lung transplantation

Indications
• Indications for heart transplantation
o lschemic cardiomyopathy beyond revascularization (45%).
o Idiopathic cardiomyopathy (55%).
Several factors are individualized for each patient, e.g., poor quality of life, short life
expectancy and poor cardiac function (e.g. ejection fraction <20%).
• Combined heart and lung transplantation may be done if both organs are damaged as
in cystic fibrosis or patients with primary pulmonary hypertension with severe left
ventricular dysfunction.
• Single lung transplantation may be done for emphysema or pulmonary fibrosis.

Complications:

• Complications of immunosuppression, especially infection with cytomegalovirus.

• Graft rejection.
• Graft atherosclerosis.

Bone marrow transplantation

Indications
• Severe aplastic anaemia.
• Some types of leukaemia.
• To strengthen the depleted bone marrow of a patient weakened by high, potentially
curative doses of radiation or chemotherapies.