Principles of organ transplantation

PRINCIPLES OF ORGAN
TRANSPLANTATION
BABALOLA RERELOLUWA N
REGISTRAR, SURGERY

OUTLINE
• INTRODUCTION
• DEFINITIONS
• HISTORY
• BASIC IMMUNOLOGY OF TRANSPLANTATION
• ALLOGRAFT REJECTION
• CLINICAL IMMUNOSUPPRESSION
• ORGAN PROCUREMENT/HARVEST
• SPECIFIC ORGANS
• CURRENT/FUTURE TRENDS
• CONCLUSION

Introduction
• Although references to transplantation have existed in the scientific
literature for centuries, the field of modern transplantation did not
come into being until the latter half of the twentieth century.
• From an experimental procedure just 50 years ago, transplantation
has evolved to become the treatment of choice for end-stage organ
failure resulting from almost any of a wide variety of causes.
• A surgeon trained in a country like ours must thus arm himself with
the principles underlying transplantation as it is a promising field of
surgical practice in Sub-Saharan Africa

Definitions
• Transplantation is the act of transferring an organ, tissue, or cell from one
place to another.
• Autotransplants involve the transfer of tissue or organs from one part of
an individual to another part of the same individual. e.g vein grafts for
bypasses, bone and cartilage transplants, and nerve transplants.
• They are the most common type of transplants
• Because the donor and the recipient are the same person and no immunologic
disparity exists, no immunosuppression is required.
• Allotransplants involve transfer from one individual to a different
individual of the same species—the most common scenario for most solid
organ transplants performed today. Immunosuppression is required for
allograft recipients to prevent rejection.

Definitions
• Xenotransplants involve transfer across species barriers.
• Currently, xenotransplants are largely relegated to the laboratory, given the
complex, potent immunologic barriers to success.
• Isograft: This is a piece of tissue or organ taken from an individual and
transferred to his or her identical twin.
• Orthotopic graft: a graft placed in its normal anatomical site
• Heterotopic graft: a graft placed in a site different from that where
the organ is normally located

History
• One of the most widely cited early examples is that of the Christian Arab Saints Cosmas
and Damian. Around AD 300, they were reputed to have successfully replaced the
diseased leg of a patient with that from another man who had died several days earlier
• 1954 - Joe Murray performed successful kidney transplants between identical twins
(Boston, MA, USA)
• 1962 - Roy Calne demonstrated the efficacy of azathioprine in preventing rejection of
kidney allografts (Boston, MA, USA)
• 1963 - Tom Starzl performed the first human liver transplant (Denver, CO, USA)
• 1966 - Richard Lillehei and William Kelly performed first human whole organ pancreas
transplant (along with a kidney transplant) (Minneapolis, MN, USA)
• 1967 - Christian Barnard performed the first human heart transplant (Cape Town, South
Africa)
• 1968 - Fritz Derom performed the first human lung transplant (Ghent, Belgium)
• 1969 - Geoff Collins developed Collins solution – a new kidney preservation solution

HISTORY
• 1974 - David Sutherland and John Najarin performed the first human pancreatic
islet transplant (Minneapolis, MN, USA)
• 1978 - Roy Calne introduced ciclosporin into clinical practice (Cambridge, UK)
• 1981 - Bruce Reitz and Norman Shumway performed the first successful human
heart-lung transplant (Stanford, CA, USA)
• 1987 - Fokert Belzer and colleagues developed University of Wisconsin (UW)
solution – a new liver and pancreas preservation solution (Wisconsin, USA)
• Kidney transplant was first undertaken in Nigeria in March 2000 in a private
hospital in Lagos (St Nicholas Hospital), with another two units (in Ile-Ife and
Kano) starting 2 years later*
• The feat of the first Renal Transplantation to be undertaken by a team of
indigenous surgeons in any public Institution in Nigeria was successfully carried
out in the Department of Surgery of the Obafemi Awolowo University Teaching
Hospital in May 2002**

BASIC IMMUNOLOGY OF TRANSPLANTATION
• The success of transplants today is due in large part to control of the
rejection process, thanks to an ever-deepening understanding of the
immune process triggered by a transplant.
• The immune system is important not only in graft rejection, but also
in the body's defense system against viral, bacterial, fungal, and other
pathogens. It also helps prevent tumor growth and helps the body
respond to shock and trauma.
• As with the body's reaction to an infection, graft rejection is triggered
when specific cells of the transplant recipient, namely T and B
lymphocytes, recognize foreign antigens.

BASIC IMMUNOLOGY OF TRANSPLANTATION
• Allografts trigger a graft rejection response because of allelic differences at
polymorphic genes that give rise to histocompatibility antigens (transplant
antigens) of which ABO blood group antigens and human leukocyte
antigens (HLA) are important, the latter being far more important.
ABO blood group antigens
• The ABO blood group antigens are expressed not only by red blood cells,
but by most other cell types as well.
• It is vitally important, for all types of organ allograft, to ensure that
recipients do not unintentionally receive a graft that is ABO blood group
incompatible otherwise naturally occurring anti-A or anti-B antibodies will
likely cause hyperacute graft rejection.

HUMAN LEUKOCYTE ANTIGEN
• Allograft rejection (in blood group-compatible grafts) is directed
predominantly against HLA – a group of highly polymorphic cell-surface
molecules.
• Are the most common cause of graft rejection.
• Their physiological function is to act as antigen recognition units
• Are highly polymorphic (amino acid sequence differs widely between
individuals
• There are two types of HLA molecules: HLA class I and HLA class II
• It comprises a series of genes located on short arm of chromosome 6
• Expression of MHC genes is co-dominant, i.e. the genes on both the
maternally derived and the paternally derived chromosomes are expressed

• HLA class I antigens are present on all nucleated cells, whereas HLA
class II antigens have a more restricted distribution and are expressed
most strongly on antigen-presenting cells, such as dendritic cells,
macrophages and B lymphocytes
• Class I MHC molecules are encoded by three closely linked loci,
designated HLA-A, HLA-B, and HLA-C.
• In general, class I MHC molecules bind to peptides derived from
proteins synthesized within the cell (e.g., viral antigens).
• Because class I MHC molecules are present on all nucleated cells, all
virus-infected cells can be detected and eliminated by CTLs.

• Class II MHC molecules are encoded by genes in the HLA-D region,
which contains at least three sub-regions: DP, DQ, and DR.
• Unlike in class I, the tissue distribution of class II MHC-expressing cells
is quite restricted; they are constitutively expressed mainly on APCs,
notably dendritic cells, macrophages, and B cells.
• In general, class II MHC molecules bind to peptides derived from
proteins synthesized outside the cell (e.g., those derived from
extracellular bacteria).
• This allows CD4+ T cells to recognize the presence of extracellular
pathogens and to orchestrate a protective response.

Effector mechanisms of rejection
• HLA antigens expressed by graft cells activate T cells and stimulate them to proliferate in
response to interleukin-2 (IL- 2) and other T-cell growth factors.
• Activated CD4 T cells, through release of cytokines, play a central role in orchestrating
the various effector mechanisms responsible for graft rejection.
• The cellular effectors of graft rejection include cytotoxic CD8 T cells, that recognise donor
HLA class I antigens expressed by the graft and cause target cell death by releasing lytic
molecules such as perforin and granzyme.
• Graft infiltrating CD4 T cells, which recognise donor HLA class II antigens, mediate direct
target cell damage and are also able, by releasing pro-inflammatory cytokines such as
interferon-ɣ, to recruit and activate macrophages that act as non-specific effector cells.
• Finally, CD4 T cells provide essential T-cell help for B lymphocytes that differentiate into
plasma cells and produce allo-antibodies that bind to graft antigen and induce target cell
injury directly or through antibody-dependent, cell-mediated cytotoxicity.

ALLO-GRAFT REJECTION
• Hyper-acute rejection (occurs immediately);
• Accelerated acute (within the first few days);
• Acute rejection (usually occurs in the first six months);
• Chronic rejection (occurs months and years after transplantation).
Hyperacute rejection
• This is due to the presence in the recipient of preformed antibodies against
HLA class I antigens expressed by the donor. These arise from a previous
blood transfusion, a failed transplant and pregnancy.
• This type of rejection also occurs if an ABO blood group-incompatible
organ graft is performed inadvertently.
• This type of rejection generally is not reversible, so prevention is key.

ALLO-GRAFT REJECTION
Accelerated Acute
• This type of rejection, seen within the first few days post-transplant, involves both cellular and antibody-
mediated injury.
• It is more common when a recipient has been sensitized by previous exposure to antigens present in the
donor, resulting in an immunologic memory response
Acute rejection
• This usually occurs during the first six months of transplantation but may occur later.
• It is mediated predominantly by T lymphocytes, but alloantibodies may also play an important role.
• Acute rejection is characterized by mononuclear cell infiltration of the graft and includes cytotoxic T cells, B
cells, NK cells and activated macrophages.
• The process may be associated with systemic symptoms such as fever, chills, malaise, and arthralgias.
• However, with current immunosuppressive drugs, most acute rejection episodes are generally
asymptomatic. It can also be reversed with optimal immune-suppressive therapy
• They usually manifest with abnormal laboratory values (e.g., elevated creatinine in kidney transplant
recipients, and elevated transaminase levels in liver transplant recipients).

CHRONIC REJECTION
• This usually occurs after the first six months.
• The underlying mechanisms are immunological, and alloantibodies, as well as antigen-independent factors
are thought to be a major cause although cellular effector mechanisms may also contribute.
• The histological picture of chronic rejection after organ transplantation is dominated by vascular changes,
with the development of myointimal proliferation in arteries, which results in ischaemia and fibrosis.
Organ specific histological changes include:
• kidney: glomerular sclerosis and tubular atrophy;
• pancreas: acinar loss and islet destruction;
• heart: accelerated coronary artery disease (cardiac allograft vasculopathy);
• liver: vanishing bile duct syndrome;
• lungs: obliterative bronchiolitis.
• Unfortunately, currently available immunosuppressive therapy has had little effect in preventing chronic
rejection

GRAFT-VERSUS-HOST DISEASE
• Although the main immunological problem after transplantation is
graft rejection, the reciprocal problem of graft-versus host reaction is
occasionally seen following certain types of organ transplantation.
• Some donor organs (particularly liver and small bowel) contain large
numbers of lymphocytes, and these may react against HLA antigens
expressed by recipient tissues, leading to graft-versus-host disease
(GVHD).
• GVHD frequently involves the skin, causing a characteristic rash on
the palms and soles. It may also involve the liver (after small bowel
transplantation) and the gastrointestinal tract (after liver
transplantation)

TISSUE TYPING AND MATCHING
• In addition to reducing the risk of graft loss from rejection, a well-matched
kidney allograft that subsequently fails is less likely to cause sensitisation to
the HLA antigens that it expresses.
• It is particularly important in children and young adults to avoid, where
possible, grafts that are mismatched for common HLA antigens because, if
re-transplantation is required subsequently, it may be difficult to find an
organ donor who does not express the antigens to which the recipient has
become sensitized.
• In terms of organ transplantation, HLA-A, -B and -DR are the most
important antigens to take into account when matching donor and
recipient in an attempt to reduce the risk of graft rejection.
• HLA matching has a relatively small but definite beneficial effect on renal
allograft survival (HLA-DR > HLA-B > HLA-A).

TISSUE TYPING AND MATCHING
• Recipients who receive well-matched renal allografts may require less intensive
immunosuppression and also are troubled less by rejection episodes.
• It is common practice to express the degree of HLA matching between the donor
and recipient in terms of whether or not there are mismatches at each locus for
HLA-A, -B and -DR. A ‘000 mismatch’ is a ‘full-house’ or complete match, whereas
a ‘012 mismatch’ is matched at HLA-A loci, has one mismatched HLA-B antigen
and is mismatched for both DR antigens
• Allocation of organs for transplantation must also take into account the relative
size of donor and recipient.
• This is not an issue in renal transplantation, and adult kidneys can be readily used
for paediatric recipients (and vice versa).
• However, in the case of heart, lung, liver and small bowel transplantation, it is
important to consider size compatibility between the donor and recipient.

CLINICAL IMMUNOSUPPRESSION
• The success of modern transplantation is in large part due to the successful development
of effective immunosuppressive agents. Without these agents, only transplants between
genetically identical individuals would be possible.
• Immunosuppressive drugs generally are used in combination with others rather than
alone.
• Induction immunosuppression refers to the drugs administered immediately post-
transplant to induce immunosuppression.
• Maintenance immunosuppression refers to the drugs administered to maintain
immunosuppression once recipients have recovered from the operative procedure.
• Individual drugs can be categorized as either biologic or non-biologic agents.
• Biologic agents consist of antibody preparations directed at various cells or receptors
involved in the rejection process; they generally are used in induction (rather than
maintenance) protocols.
• Non-biologic agents form the mainstay of maintenance protocols.

CORTICOSTEROIDS
• Represent the first family of drugs used for clinical immunosuppression and today they
remain an integral component of most immunosuppressive protocols, and often are the
first-line agents in the treatment of acute rejection.
• Steroids have both anti-inflammatory and immunosuppressive properties as the two are
closely related.
• Primarily, they inhibit the production of T-cell lymphokines(e.g. IL-1 & TNF), which are
needed to amplify macrophage and lymphocyte responses.
• Steroids also have a number of other immunosuppressive effects that are not as specific.
For example, they cause lymphopenia secondary to the redistribution of lymphocytes
from the vascular compartment back to lymphoid tissue, inhibit migration of monocytes,
and function as anti-inflammatory agents by blocking various permeability-increasing
agents and vasodilators.
• Steroids in high doses are the first-line choice of many clinicians for the initial treatment
of acute cellular rejection. Steroids also are an integral part of most maintenance
immunosuppressive regimens.

CORTICOSTEROIDS
• High-dose IV steroids usually are administered immediately post-transplant as
induction therapy, followed by relatively high-dose oral steroids
• Adverse effects of steroid therapy are numerous and response varies markedly,
but many of the side effects are dose dependent.
• Common side effects include mild cushingoid facies and habitus, acne, increased
appetite, mood changes, hypertension, proximal muscle weakness, glucose
intolerance, and impaired wound healing.
• Less common are posterior subcapsular cataracts, glaucoma, and aseptic necrosis
of the femoral heads.
• High-dose steroid use, such as bolus therapy for treatment of acute rejection,
increases the risk of opportunistic infections, osteoporosis, and in children,
growth retardation.

CYCLOSPORIN
• A fungal polypeptide, binds with its cytoplasmic receptor protein,
cyclophilin which subsequently inhibits the activity of the kinase
calcineurin
• Calcineurin (CN) normally dephosphorylates the transcription factor NF-RT
which then enters the nucleus and activates the genes of interleukins.
• Inhibition of CN by the cyclosporine-cyclophilin complex impairs expression
of several critical T-cell activation genes, the most important being for
interleukin-2, the most important T-cell growth factor.
• As a result, T-cell activation is suppressed.
• It is nephrotoxic. Other side-effects are tremor, hirsutism,
hypercholesterolaemia, hypertension and gingival hypertrophy

TACROLIMUS
• Tacrolimus (FKS06): It is a metabolite of the soil fungus Streptomyces
tsukubaensis, found in Japan and is 2-3 times as potent as cyclosporine A.
• It acts by binding FK506-binding proteins immunophilins. The complex of
immunophilin plus the drug, like cycloporin-cyclophilin, inhibits calcineurin
with similar immunosupppressive effects
• Side effects: nephrotoxicity, neurotoxicity, impaired glucose metabolism,
hypertension, infection, and GI disturbances.
• The calcineurin inhibitors (CNIs) have a relatively small therapeutic
window. Their immunosuppressive action, as well as their side effects, is
dependent on their blood concentration, and monitoring of whole-blood
drug levels is an important guide to optimal therapy.

SIROLIMUS
• A macrolide antibiotic derived from a soil actinomycete originally found on
Easter Island (Rapa Nui)
• Previously known as rapamycin, and is structurally similar to tacrolimus
and binds to the same immunophilin (FKBP).
• Unlike tacrolimus, it does not affect calcineurin activity, and therefore does
not block the calcium-dependent activation of cytokine genes.
• Rather, the active complex binds so-called target of rapamycin proteins,
resulting in inhibition of P7056 kinase (an enzyme linked to cell division).
• The net result is to prevent progression from the G1 to the S phase of the
cell cycle, halting cell division
• Everolimus is similar in action and the two are labelled "target of
rapamycin" (TOR) inhibitors.

Azathioprine (AZA)
• An antimetabolite, AZA is a derivative of 6-mercaptopurine, the active agent.
• AZA acts late in the immune process, affecting the cell cycle by interfering with
DNA synthesis, thus suppressing proliferation of activated B and T lymphocytes.
• AZA is valuable in preventing the onset of acute rejection, but is not effective in
the treatment of rejection episodes themselves.
• The most significant side effect of AZA is bone marrow suppression.
• All three hematopoietic cell lines can be affected, leading to leukopenia,
thrombocytopenia, and anemia.
• Suppression often is dose related; it usually is reversible with dose reduction or
temporary cessation of the drug.
• Other significant side effects include hepatotoxicity, GI disturbances (nausea and
vomiting), pancreatitis, and alopecia.

Mycophenolate Mofetil (MMF)
• MMF was approved in May 1995 by the FDA for use in the prevention of acute
rejection after kidney transplants.
• A semisynthetic derivative of mycophenolate acid, it is isolated from the
mold Penicillium glaucum.
• It works by inhibiting inosine monophosphate dehydrogenase, which is a crucial,
rate-limiting enzyme in de novo synthesis of purines.
• Specifically, this enzyme catalyzes the formation of guanosine nucleotides from
inosine.
• Many cells have a salvage pathway and therefore can bypass this need for
guanosine nucleotide synthesis by the de novo pathway. Activated lymphocytes,
however, do not possess this salvage pathway and require de novo synthesis for
clonal expansion. The net result is a selective, reversible anti-proliferative effect
on T and B lymphocytes.

Mycophenolate Mofetil (MMF)
• MMF differs from cyclosporine, tacrolimus, and sirolimus in that it
does not affect cytokine production or the events immediately after
antigen recognition.
• Rather, MMF works further distally in the chain of activation events to
prevent proliferation of the stimulated T cell.
• Like AZA, it is an antimetabolite; unlike AZA, its impact is selective: It
only affects lymphocytes, not neutrophils or platelets. In several
clinical trials, it has proven to be more effective than AZA, and has
largely replaced it.

BIOLOGIC AGENTS
• POLYCLONAL AND MONOCLONAL ANTIBODIES
Polyclonal Antibodies
• Polyclonal antibodies are produced by immunizing animals such as horses or rabbits with human
lymphoid tissue, allowing for an immune response, removing the resultant immune sera, and
purifying the sera in an effort to remove unwanted antibodies.
• These lymphocyte-depleting antibodies are potent suppressors of the T-cell mediated immune
response and selectively prevent the activation of B-cells by a range of stimuli.
Antithymocyte Globulin
• Antithymocyte globulin (ATGAM) is a purified gamma globulin solution obtained by immunization
of horses with human thymocytes.
• To avoid allergic reactions, patients should be pre-medicated with methylprednisolone and
diphenhydramine hydrochloride.
• Even so, side effects may be significant because of the large amount of foreign protein. Symptoms
of cytokine release syndrome include fever, chills, arthralgia, thrombocytopenia, leukopenia, and
a serum sickness-like illness.

Monoclonal Antibodies (mAbs)
• Have emerged as a new class of immunosuppressive agents, which
appear to be effective in both the treatment and prevention of acute
rejection and are well tolerated in renal transplant recipients.
• Are produced by the hybridization of murine antibody-secreting B-
lymphocytes with a nonsecreting myeloma cell line.
• The highly specific nature of these drugs makes them less toxic than
the oral, long-term maintenance agents such as corticosteroids and
calcineurin inhibitors.

Monoclonal Antibodies (mAbs)
• Muromonab-CD3 remains a commonly used mAb but some of the
new mAbs already have confirmed their efficacy in clinical phase III
trials and are part of well-established immunosuppressive regimens.
• Others include anti-CD25 mAbs (basiliximab and daclizumab).
• Other recently developed mAbs, like humanized anti-CD52 mAb
alemtuzumab (Campath-1H), anti-CD20 (rituximab), anti–lymphocyte
function-associated antigen-1 (anti–LFA-1), anti–intercellular
adhesion molecule-1 (anti–ICAM-1) and anti–tumor necrosis factor
alpha (TNF-) (infliximab) currently are being tested and show
encouraging immunosuppressive potential.

Long term concerns with immune-
suppression
Infection and Malignancy
• Immunosuppressive therapy has played an essential role in the
success of clinical transplants. However, it is a double-edged sword,
because suppression of the immune system prevents or decreases
the risk of rejection while concomitantly predisposing the transplant
recipient to a wide variety of complications, including infections and
malignancies.
• Infections in transplant recipients may be caused by so-called
opportunistic microbes, organisms that would not be harmful to a
normal, non-immunosuppressed host, as well as more common
pathogens.

Infections
• Infections also can be classified by the primary method of treatment
into surgical or medical infections.
• Surgical infections require some surgical intervention as an integral
part of their treatment. Typical examples of surgical infections include
generalized peritonitis, intra-abdominal abscesses, and wound
infections.
• Medical infections generally do not require an invasive intervention
for treatment, but rather are primarily treated with antiviral,
antibacterial, or antifungal agents.

Infections
• Risk factors for post-transplant infections are classified into those
present in the recipient pre-transplant, those related to the donor,
those related to the recipient intra-operatively, and those that occur
post-transplant.
• Pre-transplant: Latent infections can reactivate or worsen early post-
transplant, once high-dose immunosuppression is initiated.
• Intraoperative risk factors for infections include a longer operative
procedure with significant bleeding, prolonged cold and warm
ischemia of the graft, and certain types of transplants (e.g., pancreas
and intestinal transplants are associated with a significantly higher
risk of infections vs. kidney transplants)

Infections
• Post-transplant risk factors for infection are generally related either to
the development of post-transplant complications or to the level of
immunosuppression.
• Leaks from anastomoses with spillage of contaminated fluid (e.g.,
bile, urine, and enteric contents) will lead to a localized and possibly
generalized infection.
• The level of immunosuppression is an important risk factor post-
transplant, especially for opportunistic infections. The higher the level
of immunosuppression, the greater the risk.

Infections
• Bacterial infection: It is standard practice to give a broad-spectrum antibiotic to
cover the perioperative period as prophylaxis against wound infection and
possible bacterial contamination of the donor organ.
• Viral infection: The risk of viral infection is highest during the first six months after
transplantation and the most common problem is CMV infection. Other viral
infections include Herpes, Varicella and BK virus
• Fungal infection : Pneumocystis jiroveci is one of the more important fungal
infections after transplantation.
• It occurs during the first few months and presents with respiratory symptoms.
The diagnosis is made by examination of bronchoalveolar lavage fluid or lung
biopsy material for evidence of fungal infection
• Other types of invasive fungal infections are uncommon in renal transplant
recipients but infection with Candida or Aspergillus is more common after other
types of organ transplantation.

Malignancy
Transplant recipients are at increased risk for developing certain types
of de novo malignancies, including
• Non-melanomatous skin cancers (three- to sevenfold increased risk),
• Lympho-proliferative disease (two- to threefold increased risk),
• Gynecologic and urologic cancers,
• Kaposi's sarcoma.
• The risk ranges from 1% among renal allograft recipients to
approximately 5 to 6% among recipients of small bowel and multi-
visceral transplants.***

ORGAN PROCUREMENT
Organs may be obtained from
• Living donors
• Deceased donors which may be either
• Brainstem-dead heart beating donors-donation after brain death (DBD)
donors
• Donation after circulatory death (DCD) donors.
• Living donation is limited to donation of the kidney and, to a much
lesser extent, liver or lung lobe.
• DBD donors provide a majority of organs for transplantation for all
organ types although DCD donors provide an increasing number of
kidneys, livers, pancreas glands and lungs for transplantation

Donation after brain death donors
• Brain death (BD) occurs when severe brain injury causes irreversible loss of
the capacity for consciousness combined with the irreversible loss of the
capacity for breathing.
• BD is defined as the irreversible cessation of brain stem function, but not
necessarily the physical destruction of the brain
• 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. The patient must have suffered major brain
damage of known aetiology, be deeply unconscious and require ventilatory
support.

CRITERIA AND TEST FOR DIAGNOSIS
• Necessary Pre-conditions;
• Apnoeic coma= unresponsive and requiring IPPV
• Irremediable structural brain damage caused by a disorder which
can lead to brain death (HI, SAH, Meningitis)

Necessary Exclusions;
• Absence of primary Hypothermia (core temp > 35oC)
• Absence of primary metabolic or endocrine disease (uncontrolled DM,
hyponatraemia, Addison’s disease, uraemic encephalopathy,
thyrotoxicosis e.t.c)
• Absence of acid- base Abnormality
• Absence of paralysis caused by NMB or NM disorders e.g. GBS
• Absence of drug intoxication including sedatives given in the ICU.
• Absence of abnormal posturing (decorticate or decerebrate )
• Severe hypotension
• Markedly elevated PaCO2

BRAIN DEATH
• Bailey and Love’s Short Practice of Surgery, 26th Edition

Necessary Clinical findings
• These should be performed by two doctors but not necessarily at the
same time.
• Neither should belong to the transplant team and both should have
been registered for 5 years or more
• One must be a consultant
• More than 6 hrs should have elapsed since the event that caused the
suspected BSD
• Two sets of tests should be performed at least 12 hours apart
• They may be carried out by the doctors separately or together
• Careful record should be kept

ORGAN HARVEST: DBD/DCD DONORS
• Single or multiple organs can be harvested.
• Recovery of organs requires rapid flushing with organ preservative
solutions and cooling of the organs to eliminate warm ischemia time – the
time between organ harvest and rapid cooling
• This rapid cooling reduces organ metabolism and preserves viability
• In the case of a DBD donors this is easier to achieve than DCD donors as
there will need time for a diagnosis of cardio-respiratory arrest to be made,
the transplant team to be assembled and for consent to be sought from
the relations
• Up to 45 minutes warm ischemia time is acceptable for various logistics
involved(in DCD donors)

ORGAN HARVEST
• Various organ preservative solutions are available for flushing organs
before cold storage.
• They all contain impermeants to limit cell swelling, buffers to counter
acidosis and electrolytes, the composition of which reflects that of
intracellular rather than extracellular fluid.
• Commonly used preservation solutions include University of
Wisconsin (UW) solution and Euro-Collins solution, but there are
many others.

KIDNEY TRANSPLANTATION
• Renal transplantation is the most common organ transplantation and
is the preferred treatment for many patients with end-stage renal
disease because it provides a better quality of life for them than
dialysis, releases patients from the dietary and fluid restrictions of
dialysis, the physical constraints imposed by the need to dialyse and is
also more cost-effective than dialysis and improves patient survival
• INDICATIONS – End Stage Renal Disease usually secondary to diabetic
nephropathy, hypertensive nephropathy, renal vascular disease and
chronic glomerulo-nephritis; congenital polycystic disease and chronic
pyelo-nephritis

PRE-OP EVALUATION
• Evaluation undertaken by appropriate multidisciplinary team including the
surgeon and physicians
• Determine presence of comorbid disease
• Exclude malignancy and systemic sepsis
• Evaluate against organ-specific criteria for transplantation
• Determine probable ability to cope psychologically with transplant and comply
with immunosuppression
• Evaluate need for any preparative surgery needed to facilitate transplantation
• Optimize recipient condition prior to transplantation
• Patient is tissue-typed and blood-grouped
• The left kidney is preferred as the artery is one and its vein is longer and so
simplifies the operation

ORGAN HARVEST AND TRANSPLANT
• Living donor nephrectomy could be done via either open or laparoscopic
methods
• Donors should be appropriately matched and be made to donate without
forceful coercion or financial inducement
• In deceased donors, attempt is made to harvest the organ with the
circulation intact, meaning the ventilators will be switched off in theatre
• The transplant kidney is placed in the iliac fossa, in the retroperitoneal
position, leaving the native kidneys in situ.
• The renal vein anastomosed to the external iliac vein and the artery, on a
patch of donor aorta, to the external iliac artery.

• If the donor renal artery lacks an aortic patch, as in the case of a living-donor transplant,
it may be preferable to anastomose the donor artery end-to-end to the recipient internal
iliac artery.
• While the vascular anastomoses are being undertaken, the kidney is kept cold by
application of topical ice.
• Following completion of the venous and arterial anastomoses, the vascular clamps are
removed and the kidney is allowed to reperfuse with blood.
• The ureter, which is kept reasonably short to avoid the risk of distal ischaemia, is then
anastomosed to the bladder.
• This is achieved by direct implantation of the ureter into the dome of the bladder with a
mucosa-to-mucosal anastomosis followed by closure of the muscular wall of the bladder
over the ureter to create a short tunnel, the Lich–Gregoir technique.
• A double-J ureteric stent should be left in situ, to reduce the risk of urine leak or early
obstruction, and removed after several weeks by cystoscopy.

Townsend: Sabiston Textbook of Surgery, 18th ed.
Copyright © 2007 Saunders, An Imprint of Elsevier

Early Postoperative Care
• Stabilizing the major organ systems (e.g., cardiovascular, pulmonary, and renal)
• Evaluating graft function
• Achieving adequate immunosuppression
• Monitoring and treating complications directly and indirectly related to the transplant.
• Blood pressure, heart rate, and urine output are measured. CVP monitoring may be
useful in guiding fluid replacement therapy.
• Achieving hemodynamic stability is important for the recipient's overall status, but it also
is necessary to optimize graft function; hemodynamically unstable recipients experience
poor perfusion of their kidney graft.
• Careful attention to fluid and electrolyte management is crucial. In general, recipients
should be kept euvolemic or slightly hypervolemic.
• Those with ATN and fluid overload or hyperkalemia may need fluid restriction and even
hemodialysis.

Repeated evaluation of graft function
• INTRA-OP: Signs of good kidney function include appropriate color and texture along
with evidence of urine production.
• POST-OP: Urine output is the most readily available and easily measured indicator of
graft function: pre-transplant urinary output should be borne in mind
• Serum blood urea nitrogen and creatinine levels.
• Recipients can be divided into three groups:
• (a) immediate graft function, characterized by a brisk diuresis post-transplant and rapidly falling
serum creatinine level;
• (b) slow graft function, characterized by a moderate degree of kidney dysfunction post-transplant,
with modest amounts of urine and a slowly falling creatinine level, but no need for dialysis at any
time post-transplant; and
• (c) delayed graft function, which represents the far end of the spectrum of post-transplant graft
dysfunction and is defined by the need for dialysis post-transplant
• REDUCED URINE:- Hypovolemia, blocked urinary catheter, vascular thrombosis, a urinary
leak or obstruction, early acute rejection, drug toxicity, or delayed graft function.

COMPLICATIONS
Vascular
• Renal artery thrombosis (~1%).
• Renal vein thrombosis(~ 5%) . It presents during the first week after
transplantation with sudden pain and swelling at the site of the graft.
• The diagnosis is confirmed by Doppler ultrasonography. Urgent surgical
exploration is indicated, and in most cases transplant nephrectomy is required.
• The incidence of renal vein thrombosis can be minimized by giving low-dose
heparin or aspirin prophylaxis.
• Renal artery stenosis usually presents late (often years) after transplantation with
increasing hypertension and decreasing renal function.
• It may occur in up to 10 per cent of grafts and is diagnosed by angiography. Renal
artery stenosis is best treated by angioplasty, or by open surgery and vascular
reconstruction.

Urological complications
• Incidence can be reduced markedly by leaving a temporary ureteric stent in situ.
• Urinary leaks result from technical errors at the ureteric anastomosis or because of ureteric
ischaemia.
• They present with discomfort and leakage of urine from the wound and usually require surgical
intervention and reimplantation of the ureter into the bladder or anastomosis of the transplant
ureter to the ipsilasteral native ureter.
• Obstruction of the transplant ureter may occur early or late. Causes of obstruction include
technical error, external pressure from a haematoma or lymphocoele and ischaemic stricture.
• Ureteric obstruction presents with painless deterioration in graft function and is confirmed by
demonstrating hydronephrosis and ureteric dilatation on ultrasound examination.
• Initial treatment is by percutaneous antegrade nephrostomy and insertion of a stent. Some
ureteric strictures may be amenable to treatment by balloon dilatation but most are best treated
by surgical intervention, re-implanting the donor ureter into the bladder or anastomosing it to the
native ureter

Lymphocoele
• Peri-transplant lymphocoeles(lymph collections resulting from
divided lymphatics in the recipient) are usually asymptomatic, but
occasionally they become large enough to cause ureteric or vascular
obstruction, reduced graft function or oedema of the ipsilateral leg.
• Initial treatment is usually by ultrasound-guided percutaneous
drainage.
• In the case of large or recurrent lymphocoeles, surgical intervention
may be needed to drain a persistent lymphocoele into the peritoneal
cavity, and this can often be achieved by a laparoscopic or open
approach.

Causes of allograft dysfunction
Early
• Primary non-function (irreversible ischaemic damage)
• Delayed function (reversible ischaemic injury)
• Hyperacute and acute rejection
• Arterial or venous thrombosis of the graft vessels
• Drug toxicity (e.g. CNI toxicity)
• Infection (e.g. CMV disease in graft
• Mechanical obstruction (ureter/common bile duct)
Late
• Chronic rejection
• Arterial stenosis
• Recurrence of original disease in graft (glomerulonephritis, hepatitis C)
• Mechanical obstruction (ureter, common bile duct)

Investigation of graft dysfunction
• A Doppler ultrasound examination of the graft is the single most important
investigation as it allows exclusion of vascular thrombosis and urinary obstruction
as causes of graft dysfunction.
• Renal radionucleotide scanning provides information on renal perfusion and
excretion and may be helpful but is used infrequently.
• If graft dysfunction is still present after several days, it is usual to perform an
ultrasound-guided needle biopsy of the kidney to ensure that graft rejection is
not present and then to repeat the investigation every week or so until graft
function occurs.
• CNI toxicity may cause graft dysfunction and it is important to monitor CNI blood
levels to avoid nephrotoxicity.
• Acute tubular necrosis usually resolves within the first 4 weeks of transplantation,
but a small number of grafts (<5 per cent) suffer primary non-function (i.e. never
function).

LIVER TRANSPLANTATION
• Liver transplantation was first successfully performed in 1963 by Starzl and
although it was a hazardous procedure for many years , it has now become
the standard treatment for almost all kinds of end-stage liver diseases
• INDICATIONS:
• End-stage chronic liver failure: Cirrhosis with hepato-renal syndrome, refractory
ascites, spontaneous bacterial peritonitis, portal hypertensive bleeding and hepatic
encephalopathy
• Acute fulminant hepatic failure.
• Early hepatocellular carcinoma: (HCC)- solitary HCC < 5cm or 3 tumor< 3cm each
• Hepatoblastoma in children
• Wilson's disease, biliary atresia

Types of liver transplantation
• Adult whole liver graft: The whole adult cadaver liver is used
• Reduced size liver transplantation: It is used in children. The donor
liver is reduced in size to fit the recipient space.
• Split liver transplantation – liver is split and the left lobe is used in the
child and the larger right lobe in the adult
• Living donor liver transplantation – the left lobe of a living donor is
transplanted into a child
• Right lobe living donor liver transplantation: the right lobe of the liver
is resected and transplanted into an adult

Townsend: Sabiston Textbook of Surgery, 18th ed.

• The donor liver is inserted into the same site and connected to the inferior vena cava,
portal vein, common bile duct and hepatic artery - usually with a dramatic immediate
improvement in the patient's general metabolism.
Complications
• Primary non-function
• Acute renal failure
• Acute rejection.
• Chronic rejection.
• Biliary complications: Anastomotic leakage and stricture may occur and are managed by
ERCP and stenting. Recurrent cholangitis, biliary sludge and calculi may also occur.
• Hepatic artery thrombosis:
• Sepsis

CORNEAL TRANSPLANTATION
• This was one of the earliest forms of practical clinical transplantation.
• Now used extensively throughout the world as a treatment for corneal
opacification.
• The donor eye is enucleated as soon after death as possible and stored at
household refrigerator temperature for up to 24h before use.
• The donor and recipient cornea are removed with the same trephine and
the transplanted cornea sutured into position.
• The immunological rules that apply to kidney transplantation do not seem
to apply here, presumably because the transplanted cornea is not exposed
to the normal immunological recognition processes because of its
privileged site i.e. it is not directly exposed to the circulation

HEART TRANSPLANTATION
• Much public interest was aroused when the first human heart was successfully
transplanted by Christiaan Barnard in South Africa in 1967 .
• INDICATIONS
• Dilated cardiomyopathy not responsive to conservative treatment
• Ischaemic heart disease with severe myocardial involvement
• Congenital heart disease or other cardiac diseases not amenable to surgical correction
PROCEDURE
• The donor heart is accessed through a median sternotomy. It is then removed by
transecting the aorta and pulmonary artery and cutting around the atria saving their
posterior wall in situ.
• It is absolutely essential that the donor heart is still beating when it is removed in order
to avoid any ischaemic damage.
• It is then anastomosed to the recipient great vessels after resecting the recipient heart

HEART-LUNG TRANSPLANTATION
• It is the simultaneous replacement of the heart and lungs in patients
with end-stage cardiopulmonary disease.
INDICATIONS
• Complete congenital anomalies that cannot be repaired by the usual
procedures.
• Eisenmenger syndrome i.e. atrioventricular canal defect,
transposition of the great vessels and truncus arteriosus
• Irreversible right-heart failure secondary to pulmonary hypertension.
• Cystic fibrosis of the lung and bronchietasis if cardiac function is
irreversibly impaired

HEART-LUNG TRANSPLANTATION
• The donor should be brain-dead following a sudden severe event and
should be on a ventilator
• The patient is first put on cardiopulmonary bypass . The heart and
lungs are then inspected through a median sternotomy and removed.
• Care being taken to preserve the phrenic, vagus and recurrent
laryngeal nerves. The donor heart and lungs are then inserted .
• The trachea is anastomosed first then the right atrium and aorta

LUNG TRANSPLANTATION
• The first human single-lung transplant was performed by James Hardy at the University of
Mississippi in 1963 .
• Many more have been done due to advances in immuno-suppression
Indications
• The main indication is end-stage chronic pulmonary disease without right heart failure. The usual
conditions are pulmonary fibrosis, cystic fibrosis and bronchiectasis.
• For septic lung conditions, bilateral lung transplantation is done to prevent soiling of the
remaining native lung.
Technique
• A single lung transplantation is done through a postero-lateral thoracotomy and a double one
preferably through a median sternotomy.
• First, the donor Ieft atrial cuff with the pulmonary veins is anastomosed to the recipient left
atrium, then the bronchial and pulmonary artery anastomoses.
• Postoperative care is as for cardiopulmonary transplantation.

PANCREATIC TRANSPLANTATION
• About 20% of patients with Type- I (insulin-dependent) diabetes
mellitus develop microvascular disease which may lead to
nephropathy, retinopathy, neuropathy, severe coronary disease,
impotence and leg amputation.
• Hyperglycaemia is the cause of these changes and the aim of
pancreas and islet cell transplantation is to establish the same degree
of glucose control that is provided by endogenous secretion of insulin
from a healthy native pancreas and so properly stabilize the blood
sugar and thereby arrest and ameliorate the micro-vascular and
metabolic complications in these patients.

PANCREATIC TRANSPLANTATION
• There are 3 types of pancreas transplantation.
• Simultaneous pancreas-kidney transplant (SPK-86 %): For IDDM
patients with nephropathy and renal dysfunction (creatinine
clearance < 20ml/min) or patients on dialysis or close to starting
dialysis or failure of previous kidney transplant
• Pancreas transplant alone (PTA-5%) - For patients with two or more
diabetic complications
• Pancreas transplant after kidney transplant(PAK-8%)

PANCREATIC TRANSPLANT
Schwartz's Principles of Surgery, Ninth Edition

PANCREATIC TRANSPLANT
• A segment of duodenum with the entire pancreas is anastomosed to the
bladder (urinary drainage) or preferably and more physiologically to a loop
of proximal ileum (enteric drainage)
• The donor vessels are anastomosed to the right external iliac vessels.
• With the urinary drainage the amylase in the urine can be used to monitor
rejection
• Its complications include anastomotic leaks, cystitis, urethritis, urethral
stricture, dehydration, electrolyte disturbances, acidosis and reflux
pancreatitis.
• Complications of enteral drainage include anastomotic leak and peritoneal
sepsis. The urinary amylase cannot be used to monitor rejection.

Islet Cell Transplantation
• Treatment of diabetes by transplantation of isolated islets of Langerhans is a
more attractive concept than vascularised pancreas transplantation because
major surgery and the potential complications of transplanting exocrine pancreas
are avoided.
• Until recently, human islet transplantation had been performed intermittently
and with very disappointing results. However, in 2000, Shapiro and colleagues in
Edmonton, Canada, reported success with islet transplantation in seven patients
with type I diabetes.
• Sequential islet transplantation from two or three donor pancreas glands was
required to produce insulin independence.
• Isolating islet cells from the pancreas is difficult and the yield is rather small.
• Besides, most of the cells eventually perish with the present immunosuppressive
regime. The cells are transplanted via the portal vein into the liver.

Islet Transplantation
• Advances in islet microencapsulation and xenotransplantation and
new immunosuppression incorporating 15-de-oxyspergualin, which
minimizes the macrophage-mediated attack on the transplanted
islets, will enhance improvement in islet cell long survival.
• The protective membranes are designed with a pore size that allows
insulin to pass through but prevents antibodies and leukocytes from
reaching the islets, thereby avoiding the need for immunosuppressive
therapy.
• A major attraction of this approach is that islets isolated from animals
can be used and bioartificial pancreas grafts containing xenogeneic
islets are currently under evaluation.

SMALL BOWEL TRANSPLANTATION(SBT)
• The small bowel is the most hazardous abdominal organ to transplant
because of the severe immune response to the allograft due to the
abundance of lymphocytes in it.
• This necessitates profound immunosuppression with its attendant
severe complications
INDICATIONS
• Patients with intestinal failure or "short gut syndrome" on permanent
total parenteral nutrition (TPN) are the main indication for SBT with
failure of the TPN as indicated by the following:
• Liver failure - steatosis, cholestasis or liver fibrosis

• Recurrent or life-threatening catheter-related line sepsis.
• Major vein thrombosis.
• Severe recurrent dehydration.
• In children
• Intestinal atresia
• Volvulus neonatorum,
• Necrotising enterocolitis
• Diffuse gastrointestinal aganglionosis
• In adults
• Mesenteric infarction
• Volvulus
• Trauma
• Crohn's disease
• Desmoid tumours

• Small bowel only transplantation: If there is no evidence of failure or
failing of the liver
• Liver and small bowel transplantation - This is performed when the
liver is affected .
• Multi-visceral SBT: In this, the liver, small bowel, pancreas, stomach
and duodenum together with the small bowel are transplanted. It is
indicated for diffuse gastrointestinal disorders or desmoid tumours

OUTCOMES AFTER TRANSPLANTATION
• Transplantation improves the quality and duration of life in most recipients
• Transplant outcome has improved progressively over the last two decades and continues
to improve
• Improved outcome is due to better immunosuppression, organ preservation,
chemoprophylaxis and technical advances
• Graft survival after kidney, liver and heart transplantation is >90 per cent at one year and
>80 per cent at five years
• The results of lung and small bowel transplantation are less good
• Chronic rejection is the most common cause of graft failure after all types of solid-organ
transplant
• Recurrence of the original disease necessitating transplantation may also lead to graft
failure
• Death with a functioning transplant from cardiovascular disease is relatively common

CURRENT AND FUTURE TRENDS
IMMUNO-SUPPRESSIVE AGENTS
• AEB: This is a new oral compound that effectively blocks early T-cell activation by
selective inhibition of protein kinase C. Therefore, it has a different mechanism of
action from that of calcineurin inhibitors, and early studies suggest it is not
associated with the nephrotoxicity seen with calcineurin inhibitors. This agent is
currently in phase II testing.
• ISA247: This is a novel semisynthetic analogue of cyclosporine that is structurally
similar to it except for a modification of a functional group. This agent has not
been associated with the nephrotoxicity seen with cyclosporine and currently is
in phase II testing.
• Janus kinase-3 (JAK-3) inhibitors: JAKs are cytoplasmic tyrosine kinases that
participate in the signaling of a broad range of cell surface receptors, particularly
members of the cytokine receptor superfamily. JAK-3 is found primarily on
hematopoietic cells and blocking this may provide a significant degree of
selectivity in immunosuppression. It is currently in phase II trials

NEWER TRENDS: XENOTRANSPLANTS
• Clinical xenotransplants have offered great hope for solving the
problem of the expanding waiting list, but the primary hurdle is the
formidable immunologic barrier between species.
• Other problems include the potential risk of transmission of infections
(zoonoses) and the ethical problems involved with using animals for
widespread human transplants.
• Many different options are being tested to overcome these barriers,
including the genetic engineering of pigs to express human genes, use
of agents to inhibit platelet aggregation and complement activation,
and administration of powerful immunosuppressive drugs.

ALTERNATIVES TO TRANSPLANTATION
• Xenotransplantation is not the only therapeutic approach currently
being investigated for organ replacement therapy. Other possible
approaches include cellular transplants, organogenesis, and artificial
and bio-artificial devices
• Cellular transplants involve the injection of cells that have the
potential to replace cells in an organ that has been damaged by
disease, thereby augmenting the function of that organ.
• An example of a cellular transplant would be the injection of stem
cells or isolated hepatocytes into a failing liver OR the transplantation
of stem cells or primitive muscle cells into a damaged heart

ALTERNATIVES TO TRANSPLANTATION
• Organogenesis - Involves growing organs de novo from primitive cells
or stem cells.
• Use of bioartificial and artificial mechanical devices. Considerable
investigative work has been undertaken to develop a bioreactor using
artificial elements and hepatocytes to treat liver failure as a bridge to
liver transplantation. However, consistent results have yet to be
achieved in the clinical setting. The heart model is in the most
advanced stage of development. Various implantable assist devices
are already in routine clinical use. Currently, these are usually
temporary devices that serve as a bridge to a transplant

CONCLUSION
• Transplantation often serves to offer a new hope of continued living
and improved life quality especially when other treatment methods
have failed or are unlikely to be sustainable in the long-term
• Although transplantation in our country has tremendously lagged
behind that in the more advanced Western countries, our success
stories of the transplants done give a hope of a brighter future in this
regard
• The future of transplantation is certainly exciting. Establishment of
better tissue typing facilities, organ procurement and donation
facilities with more research and multi-disciplinary action is needed

References
• Schwartz's Principles of Surgery, Ninth Edition. Copyright © 2010 by The
McGraw-Hill Companies, Inc. F. Charles Brunicardi, MD,FACS et al
• Bailey and Love’s Short Practice of Surgery, 26th Edition. CRC Press Publishers.
Edited by Norman S. Williams MS FRCS FMed Sci; Christopher J.K. Bulstrode MCh
FRCS(T&O) and P. Ronan O’Connell, MD FRCSI, FRCPS Glas.
• PRINCIPLES AND PRACTICE OF SURGERY INCLUDING PATHOLQGY IN THE
TROPICS, Fourth Edition. E. A. Badoe (Hon) MD, Ch.M (Sheffield), FRCS, DTM & H,
FWACS, FGA; E. Q. Archampong B.Sc, M.S (Lond), FRCS (Ed & Eng), FICS, FWACS,
FGA, FGCP & S, Cov And J. T. Da Rocha-afodu KSS
• *Obafemi Awolowo University- Wikipedia, the free encyclopedia.
http://en.wikipedia.org/wiki/Obafemi_Awolowo_University, accessed January 25,
2015

References
• *Sanusi AA, Arogundade FA, Badmus TA. Renal transplantation: its
evolution, problems, prospects and challenges. Nigerian J Health Sci
2008; 8: 12–15.
• *Badmus TA, Arogundade FA, Sanusi AA et al. Kidney transplantation
in a developing economy: Challenges and initial report of three cases
in a Nigerian teaching hospital. Centr Afr J Med 2005; 51: 102–106.
• ***Lutz J, Heemann U: Tumours after kidney transplantation. Curr
Opin Urol 13:105, 2003. [PMID: 12584469]
• Townsend: Sabiston Textbook of Surgery, 18th ed. Copyright ©2007
Saunders, An Imprint of Elsevier

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