Lecture:

Principles of organ Transplantation

Professor Abubakar A. Bakari MBBS, FWACS, FICS

Chief Consultant General, Vascular &Transplant
Surgery
Department of Surgery, College of Medical •
Sciences
University of Maiduguri •
 Introduction
 Organ transplantation has become a rapidly
expanding and important surgical specialty in the
last 4 decades.
 It is a specialty that requires the close
cooperation of several disciplines – Surgeons,
anaesthetists, immunologists and physicians.
 Transplantation of solid organs has become the
treatment of choice for end stage renal, hepatic,
cardiac and pulmonary disease.
 In the early 1900s clinical organ transplantation
was made more feasible to the surgeons;
 After the development of safer and more effective
immunosuppressive agents
Carrel description of a more reliable technique for
vascular anastomoses
 Allograft - an organ or tissue transplanted from
one individual to another.

Syngeneic(Isograft) – a transplant between two

identical twins.

Orthotopic graft - a graft placed in its normal

anatomical position.
Definitions
Heterotopic graft – a graft placed a site different
from that where the organ is normally located.

Xenograft – a graft performed between different

species.
 Graft rejection

 Allograft provoke powerful immune response

that results in rapid graft rejection unless
immunosuppressive therapy is given.

 It was established by Medawar in 1940s and

1950s that allograft rejection was due to an
immune response rather than non – specific
inflammatory response.
 Later studies demonstrated that T – lymphocytes
play an essential role in causing graft rejection
response.
 There are no unique immunological mechanism
causing graft rejection.
 It is the immunological mechanism evolved to
provide protection against pathogens that are
responsible for graft rejection.
 The T – lymphocytes and antigen presenting cells –
cytotoxic T – Cells, delayed type hypersensitivity
and antibody – dependent effector mechanisms are
the key cells involved.
 Successful organ transplantation(cornea) requires
the manipulation of the immunological defenses of
the recipient so as to overcome rejection.
 Auto – and Isografts do not elicit an immune
response, rather it is the genetic differences
between the donor and recipient that are the
major importance in the process of
manipulation.
 These differences are expressed as tissue or
histocompatibility antigens.
 Three categories of histocompatibility antigens
give rise to rejection.
In order of importance they are:
- ABO blood group antigens
- Human Leucocyte Antigens(HLA)(MHC)
- minor Histocompatibility Antigens(mHC)
 ABO antigens are very important in
transplantation because they are expressed by
red blood cells and most other cell types in the
body.

 It is vitally important for all types of organ

allografts to ensure that the recipient is ABO
blood group compatible with the donor.
 Individuals who do not express particular ABO
blood group antigens have naturally occurring
circulating antibodies to those antigens.

 There is no need to take account of Rhesus

antigens compatibility in organ transplantation.
 Permissible transplants
Blood group Donor Blood group Recipient

O O, A, B, AB

A A, AB

B B, AB

AB AB
 Human Leucocyte Antigens(HLA)
 Allograft rejection in blood group compatible graft
is directed predominantly against a group of highly
polymorphic cell – surface molecules called HLA.

 HLA play a great role in the immune recognition

process.
 They display antigenic peptides derived from
foreign pathogens so that they can be
recognized by T – lymphocytes.
 This property confers on them the ability to
stimulate a powerful graft rejection response.
 There are two types of HLA molecules:
- HLA Class 1
- HLA Class 11
 In both classes of HLA molecules the extracellular
domains form a cleft, the purpose of which is to
bind and display foreign peptides for surveillance
by T – lymphocytes.
 Each individual HLA molecule only binds one
peptide at a time but can bind wide range of
different peptides.
 HLA class 1 molecules present antigenic peptides
derived from within the cell.
 HLA class 11 molecules present peptides derived
from the extracellular environment.
 HLA class 1 molecules are present on all
nucleated cells.
 HLA class 11 molecules are expressed strongly
on antigen – presenting cells such as
macrophages, dendritic cells and B –
lymphocytes.
 HLA class 11 antigens expression is readily
inducible on all cell types by cytokines such as
interferon - Gamma.
 HLA molecules expressed donor tissues trigger a
strong graft rejection response in the recipient by
virtue of their special role in T – cell recognition and
the fact that they are so polymorphic.
 It is rare for two unrelated individuals to have a
completely identical set of HLA molecules.
 In the context of organ transplantation allogeneic
HLA molecules are exceptionally strong antigen
because they are able to stimulate T – cells directly
without the need to be broken down in to short
peptides and presented in the cleft of an HLA
molecule – this unique pathway is called Direct
allorecognition.
 Allogeneic molecules can also be processed like
other types of antigen and displayed as
antigeneic peptides associating with HLA
molecules on recipient antigen presenting cells.
This process is called indirect allorecognition.
 Minor Histocompatibility Antigens are
polymorphic proteins which after
transplantation are processed and presented
as antigeneic peptides by recipient antigen –
presenting cells(indirect allorecognition) and
are able to stimulate graft rejection response.
 Hence, even when grafts are matched for all
HLA antigens immunosuppression may still be
required to prevent rejection.
 Effector Mechanisms of Rejection
 Activated T – cells by alloantigen undergo a period
of clonal expression that is dependent on
interleukin 2(IL – 2) and other T – cell growth
factors.
 CD4 T – cells activate various effector mechanisms
through release of cytokines leading to graft
rejection.
 Cytotoxic CD8 T – cells recognizes donor HLA
class 1 antigens expressed by the graft and
target cell death by releasing lytic enzymes
viz– perforin and granzyme.
 Graft – infiltrating CD4 T – cells which recognizes
donor HLA class 11 antigens mediate direct cell
death by activating macrophages through release
of cytokines such as interferon – Gamma(non –
specific effector rejection).
 CD4 T – cells provide essential T – help for B –
lymphocytes that differentiate in to plasma
cells and produce alloantibodies that bind to
graft antigen and induce target cell injury
directly or through antibody – dependent cell
– mediated cytotoxicity.
 Types of allograft rejection
 Allograft rejection manifests itself as functional
failure of the transplant.
There three distinct types:
 Hyper acute rejection(occurs immediately)
o it is avoidable
o It is due to the presence in the recipient of
preformed cytotoxic antibodies against HLA
class 1 antigens expressed by the donor.
o It may arise as a result of previous blood
transfusion, previous failed transplant etc.
 Acute rejection
o Usually occurs during the first 6 months of
transplantation. It may occur later.
o It is predominantly by T- Lymphocytes
o Alloantibodies may also play an important role.
o It occurs in 20 – 50% of cases.
o It can be reversed by immunosuppressive therapy.
 Chronic rejection
o it occurs after the first 6 months
o it is major cause of allograft failure in all types
of transplants.
o The major causes of chronic graft failure are:
 Previous episodes of acute rejection
 poor HLA match
 Cytomegalovirus(CMV) infection
 raised blood lipids
 Inadequate immunosuppression
 Histocompatibility Testing and Screening for pre-
sensitization to HLA.

HLA are encoded by MHC which is a cluster of genes

situated on the short arm of chromosome 6.

 HLA class 1 antigens comprise HLA-A, -B, and –C.

 HLA class 11 antigens comprises HLA-DR,-DP &-DQ.
 Expression of MHC gene is co-dominant,
hence each individual may express between 6
and 12 different HLA antigens.

 HLA haplotype inherited from each parent is

usually inherited as a complete haplotype.
 HLA or tissue typing of an individual is done T and B
lymphocytes by serological methods, using a panel
of antisera directed against the different HLA
specificities in a microcytotoxicity assay.
 DNA – typing are newer techniques to determine
tissue type. These include polymerase chain
reaction(PCR) analysis using HLA sequence –
specific primers.
 In terms of organ transplantation HLA-A,-B and –DR
are the most important antigens to take in to
account when matching donor and recipient in an
attempt to reduce the risk of graft rejection.
 HLA has a small but definite beneficial effect on
renal allograft survival(HLA-DR HLA-B HLA-A).
 Recipients who receive well – matched
allografts may require less intensive
immunosuppression and less risk of graft
rejection.
 The HLA matching between donor and
recipient is expressed as whether or not there
are mismatches at each locus of HLA-A,-B and
–DR. e.g. complete match is ‘000’, mismatch is
‘012’.
 Immunosuppressive Therapy

When considering immunosuppression, the

transplant surgeon is faced with many different
agents to choose from.
Most immunosuppression protocols use a
combination of immunosuppressive agents:
Calcineurin blockers:
 Cyclosporin
 Tacrolimus
 Antiproliferative agents
 Azathioprine
 mycophenolate
 Steroids
 Glucocorticoids
 Antibody therapies
 Antilymphocyteglobulin(ALG)
 OKT3
 Rapamycin(sirolimus)
 Immunosuppressive regimens

 Triple therapy
 Dual therapy
 Monotherapy
  Complications of immunosuppression

 Infection
 Bacterial infection
 Viral infection
 Protozoal infection
 Fungal infection
 Malignancy
 Organ Donation
 Most of the organs used for transplantation are
obtained from brainstem – dead, heart – beating
cadaveric donors.
 Multiple organs are procured.
 The number of organs required to satisfy the needs
of transplantation far exceeds the number of
cadaveric organs available.
 There is increased trend towards increased living –
donor transplantation.
Determination of brainstem death
 Brain death occurs when severe brain injury causes
irreversible loss of the capacity for consciousness
combined with the irreversible loss of the capacity
for breathing.
 In most countries, it is accepted that the condition
brain death equates in Medical, legal and religious
terms with death of the patient.
 Acceptance of the concept of brain death had
major implications for organ transplantation as it
allowed the possibility for removal of viable organs
from brain – dead patients before their circulation
failed.
 A diagnosis of brainstem death should be
considered only when certain preconditions have
been met.
  These preconditions are:

 The patient must have suffered major brain

damage of known aetiology, be deeply unconscious
and require artificial ventilation.

 Particular care must be taken to ensure that muscle

relaxants and drugs with known CNS depressant
effects are not contributing to the clinical picture.
 Hypothermia, profound hypotension and
metabolic or hormonal conditions that may
contribute to CNS depression and confound
the diagnosis of brain death must also be
excluded.
 Clinical testing for brainstem death

 Absence of cranial reflexes

 Absence of motor response
 Absence of spontaneous respiration
 Organ retrieval

 The general suitability of the potential organ donor

must be carefully assessed.
 Particular care must be taken to assess the donor
from the point of view of transmissible infectious
agents and malignancy.
 organs are retrieved while the heart continues to
beat and the donor receives ventilatory and other
support.
 There has been a progressive relaxation in the
organ – specific selection criteria due to high
demand for cadaveric organs for transplantation
which far exceeds the supply.
 The chronological age of the donor is less
important than the physiological function of the
organs under consideration for transplantation.
 Age range for donors

Kidney 2yrs to no upper age limit

Liver No age limits

Heart 0 to 65 yrs.

Lung 0 to 60 yrs.

Pancreas 10 to 50 yrs.
 Organ procurement
 Management of the donor is aimed at preserving
the functional integrity of the organs to be
procured.
 Careful monitoring and management of fluid
balance is essential.
 Inotropic support is given and there may be a role
of tri – iodothyronine and argipressin.
 Retrieval of organs after cardiac arrest can be
usable provided rapid organ perfusion with cold
preservation solution can be done immediately.
 Retrieval of multiple organs from a cadaveric donor
requires cooperation between the thoracic and
abdominal surgical teams.
 A midline abdominal incision and median
sternotomy is used to obtain access.
 After dissection of the organs to be retrieved, they
are perfused in situ.
 This produces rapid cooling of the organs, reduces
their metabolic activity and preserves their viability.
 After removal the organs may undergo a further
flush with chilled preservation solution and then
placed in two plastic bags and stored at 0 – 4oC.
 Samples of donor spleen and mesenteric lymph
nodes are obtained for determination of tissue type
and use in the cross – match test.
 Various organ preservation solutions are available
for flushing organs before simple cold storage.
 These solutions contain impermeants to limit cell
swelling, buffers to counter acidosis and
electrolytes. Eg. University of Wisconsin(UW)
Solution, Euro-Collins Solution.
 The length of time for which an organ can be stored
before transplantation varies with the type of
organ.
 Kidney Transplantation
 Kidney transplantation is the preferred treatment
for many patients with end – stage renal disease.
 It provides a better quality of life
 It releases patients from the dietary and fluid
restrictions of dialysis.
 It is more cost – effective than dialysis.
With increasing success, the number of allografts
transplanted increased every year.
More and more patients are being admitted into
dialysis programmes and this subsequently
increased the list of patients awaiting for a suitable
allograft.
 Due to shortage of cadaveric allografts , living
donor transplantation becomes a viable option.
  Organ – donor

 Most living – donor renal transplants are between

genetically related individuals.
 Living – donor transplantation between genetically
unrelated individual give better results than well -
matched cadaveric allografts.
 In all cases of living – organ donation, it essential to
ensure the prospective donor is fully informed and
is free from coercion to donate and no risk to the
donor.
 In the UK, around 80 – 100/million population
develop end – stage renal disease.
 The incidence increases with age.
 The causes of end – stage renal disease are
numerous.
 Frequently the primary cause of end – stage renal
disease is uncertain.
 The prospective donor has to undergo rigorous
assessment to ensure that they are suitable.
 Donor nephrectomy is traditionally undertaken
either by open or laparoscopic surgery.
 Major complication rate 2%.
 Mortality rate 0.05%.
 Organ recipient
 Careful patient selection is important.
 Transplant surgeon and nephrologist should
formally assess all patients.
 The nature of the primary renal disease does not
generally affect the decision to proceed to
transplantation.
 There is no absolute upper age limit to renal
transplantation.
 Careful assessment of comorbid disease that might
affect successful outcome after transplantation is
essential.
 Operation

 The transplant is heterotopic

 The ureter is joined to the bladder to make a
new uretero – vesical junction.
 A double – J ureteric stent is often left in situ.
 The recipient’s own kidneys are left in situ.
 Technical complications
 Vascular complications; quite low
- Renal artery thrombosis - 1%
- Renal vein thrombosis – 5%
- Renal artery stenosis – 10%
 Urological complications – 10%
- Urinary leakages.
- Urinary obstruction.
 Lymphocele
- ureteric obstruction.
- Oedema of the leg.
 Causes of graft dysfunction

 Early post – op period:

- acute tubular necrosis
- arterial/venous thrombosis
- urinary leak/obstruction
- calcineurin toxicity
- hyperacute/accelerated acute rejection.
 Late post – op period( more than 1 month):
- acute/chronic rejection
- drug toxicity
- ureteric obstruction(lymphocele, u. stricture).
- recurrent disease.
- infection.
  Outcome after transplantation

 Patient survival after:

- cadaveric graft : more than 90% @ 1yr.
80% @ 5yrs.
- Living – related graft: more than 90% @ 1 yr.
more than 80% @ 5yrs.
 If a kidney transplant fails late after transplantation
and causing symptoms, transplant nephrectomy is
carried out.
 Liver Transplantation
 Starzl first attempted liver transplantation in 1963
and by 1967 had achieved prolonged survival.
Throughout the 1970s liver transplantation
remained a hazardous procedure that frequently
fails.
 However, careful patient selection, improved
immunosuppression and chemoprophylaxis, better
organ preservation, refinements in surgical
techniques and advances in perioperative care, liver
transplantation is now a routine procedure.
 Indication for liver transplantation
- Cirrhosis.
- Acute fulminant liver failure.
- Metabolic liver diseases.
- primary hepatic malignancy.
 operation

 It is ultra – major procedure because the diseased

liver may be quite difficult to remove and there are
a number of vascular anastomoses to be made
during which venous return to the heart must be
maintained by bypass.
Technique of liver transplantation
 Technical complications
 Haemorrhage
- meticulous homeostasis is important.
- Haematoma must be evacuated.
 Vascular complications
- hepatic thrombosis
- portal vein thrombosis
 Biliary complications
- Biliary leak
- Biliary stenosis
 Pancreas Transplantation
 Restores the normal control of glucose metabolism
and obviates the need for insulin therapy in diabetic
patients.
 Thus reduces the risk of secondary complication
from diabetes mellitus.
 Careful patient selection is essential to avoid
excessive mortality and morbidity.
 It is usually reserved for patients with type 1
diabetes who are relatively young( less than 50yrs.)
 Surgical technique

 Whole pancreas and duodenum – Lillehei - 1966.

 Segmental pancreas Transplantation.
 The pancreas graft is placed intra - peritoneally in
the pelvis usually on the right.
 Donor vessels anastomosed to recipient iliac
vessels.
 The graft duodenum is anastomosed either to the
urinary bladder or to the small intestine to dealt
with the exocrine secretions.
 Post – operative complications

 Technical complications – occur early.

- Vascular thrombosis – 5 – 10%
- Anastomotic leak
- Wound infection – 10%(intrabdominal)
 Specific complications
- Enteric drainage
- Bladder drainage
 Results of pancreas transplantation

 SPKT patient survival: 90%@ 1 year.

 Most death are due to cardiovascular and
overwhelming sepsis.
 Small intestine Transplantation
 Presents particular difficulties because:
- the graft contains a large volume of lymphoid
tissue
- MHC class 11 antigens are constitutively
expressed by the bowel epithelium.
- The graft is colonized with micro – organism.
 Indication
 Adults:
- Superior mesenteric artery or vein thrombosis.
- Volvulus
- Desmoid tumour in the mesentery
- Crohn’s disease
 Children:
- Intestinal atresia
- pseudo – obstruction – neurogenic failure.
- Gastroschisis, NEC.
 Surgical technique

 Proximal anastomosis of the graft is to the

recipient’s jejunum.
 the new gut is brought out distally as an end
ileostomy.
 Results

 Results encouraging with the use of FK 506

immunotherapy.
 In USA survivals are 65% @ 1 year and 43% @
2 years.
 Thoracic Organ Transplantation
 Heart transplantation:
 Dr. Barnard performed the first heart transplant in
Cape town, South Africa in 1967.
 It is considered as an effective treatment for
selected patients with end – stage cardiac failure.
 Suitable candidates are those New York Heart
Association(NYHA) class 1(symptoms on mild
exertion) or class1V(unable to perform any physical
activity without discomfort, which may occur at
rest)
 It is limited to patient under the age of 65yrs
without irreversible damage to other organ
systems.
 The pre – operative assessment is rigorous
 Pre – operative measurement of pulmonary
vascular resistance is necessary.
 Technique of heart transplantation
 Median sternotomy is performed.
 The patient is given systemic heparin and is placed
on cardiopulmonary bypass and cooled to 26oC.
 The recipient heart is excised at the mid – atrial
level after cross – clamping the aorta.
 The donor heart left atrium is opened by making
incisions in the posterior wall between the orifices
of the pulmonary veins to create an atrial cuff.
 The left and then right atrial anastomoses are
performed and the aortic and pulmonary
 Total orthotopic cardiac transplantation is an
alternative but rarely done.
 Heart – Lung, single – lung and double - lung
transplantations:
 Dr. Bruce Reitz performed the first successful
combined heart – lung transplant in 1981.
 Usually done for patients with congenital or
acquired cardiac dysfunction.
 Single – and double – lung transplantation are
effective therapies for selected patients with end –
stage chronic lung disease in which declining lung
function limits life expectancy.
 Outcome after thoracic organ transplantation

 Graft survival rates at 1 – and 5 – year after

heart transplantation are 85% and 70%
respectively.
 Heart – lung graft 75% and 40% respectively.
 Future Prospects
 Novel immunosuppressive agents.
 Strategies for inducing donor – specific
immunological tolerance.
 Xenotransplantation
 Stem cell medicine and tissue engineering.