organ transplantation

1. ORGAN TRANSPLANTATION
BY:
DR. MOHAMMAD MASOOM PARWEZ
MODERATOR: DR. BHARATI PANDYA

2. DEFINITIONS
• Transplantation is the process of transferring an organ, tissue, or cell
from one place to another
• An organ transplant is a surgical procedure in which a failing organ is
replaced by a functioning one
ORTHOTOPIC: implanted in the same anatomic location in the recipient as it
was in the donor --- requires removal of the diseased organ
HETEROTOPIC: implanted at a different anatomical location --- diseased organ
is kept in place

3. Categories of transplants
 Autotransplant: transfer of cells, tissue, or an organ from one part
of the body to another part in the same person --- no
immunosuppression required
• Eg: skin and vein, bone, cartilage, nerve, and islet cell transplants
 Allotransplant: transfer of cells, tissue, or an organ from one person
to another of the same species
• recipient recognizes the donated organ as a foreign body, so
immunosuppression is required

4. Categories of transplants
 Xenotransplant: transfer of cells, tissue, or an organ from one
organism to another from a different species
• To date, animal-to-human transplants are still experimental
procedures

5. History of organ transplantation
• Miracle of Saints Cosmas and
Damian --- 15th century
• removal of the diseased leg of
Roman Justinian
• and replacement with the leg of
a recently deceased Ethiopian
man

6. History of organ transplantation
• 19th century: French surgeon Alexis
Carrel developed a method for
joining blood vessels (Nobel Prize in
Medicine, 1912)
• Peter Medawar and Frank
Macfarlane Burnet : concept of
immunologic tolerance --- definition
of “self ” was not preprogrammed
but actively developed during
embryonic development

7. Milestones

8. Graft Rejection
• Allografts provoke a powerful immune response resulting in rapid
graft rejection
• T lymphocytes play an essential role
• Rejection is due to allelic differences at polymorphic genes that give
rise to histocompatibility antigens (transplant antigens)
ABO blood group antigens
Human leukocyte antigens (HLAs)

9. ABO blood group antigens
• expressed not only by RBCs, but also by most other cell types
• Recipients must 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

10. HLA
• 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)
• HLA-A, -B, -C (class I), and -DR, -DP and -DQ (class II) are most
important in organ transplantation
• HLA class I antigens are present on all nucleated cells
• HLA class II antigens are expressed most strongly on antigen-
presenting cells, such as dendritic cells, macrophages and B
lymphocytes

11. HLA

12. Recognition of HLA by T cells
T cells recognize HLA molecules via their
T-cell receptor, but full T-cell activation
also requires the delivery of a second
signal by the interaction of co-
stimulatory molecules on the surface of
the antigen-presenting cell and T cell

13. Effector mechanisms of rejection
• Activated T cells release IL-2 and other
T cell growth factors
• Activated CD4 T cells release cytokines
and orchestrate the various
mechanisms of graft rejection
• Activated CD8 T cells recognise donor
HLA class I antigens expressed by the
graft and cause target cell death
through the release of lytic molecules
such as perforin and granzyme

14. Types of allograft rejection
1. Hyperacute rejection (occurs immediately)
2. Acute rejection (usually occurs in the first 6 months)
3. Chronic rejection (occurs months and years after transplantation)

15. Hyperacute rejection
• 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
• Also occurs if an ABO blood group-incompatible organ graft is
performed
• After revascularisation of the graft, antibodies bind immediately to
the vasculature, activate the complement system, and cause
extensive intravascular thrombosis, interstitial haemorrhage and graft
destruction within minutes and hours

16. Hyperacute rejection

17. • Kidney transplants are particularly vulnerable to hyperacute graft
rejection, whereas heart and liver transplants are relatively resistant
• can be avoided by ensuring ABO blood group compatibility and
performing a cross-match test on recipient serum to ensure that
there are no clinically relevant antibodies directed against HLAs
expressed by a prospective kidney donor

18. Acute rejection
• mediated predominantly by T lymphocytes
• characterised by mononuclear cell infiltration of the graft which
includes cytotoxic T cells, B cells, natural killer (NK) cells and activated
macrophages
• Antibody-mediated damage may also be present, as evidenced by the
deposition of the complement C4d within the graft microvasculature
• All types of organ allograft are susceptible to acute rejection (typically
occurring in around 20–30% of grafts)

19. Acute rejection

20. Acute rejection
• Most episodes of acute cellular rejection can be reversed by
additional immunosuppressive therapy
• Acute antibody-mediated rejection is more difficult to treat effectively
and may require plasmapheresis or immunoadsorption

21. Chronic rejection
• Occurs after the first 6 months
• Pathophysiology of chronic rejection is not well understood although
alloantibodies are thought to be a major cause and cellular effector
mechanisms may also contribute

22. Chronic rejection
• Risk factors for chronic rejection of a kidney transplant are:
• previous episodes of acute rejection
• poor HLA match
• long cold ischaemia time
• cytomegalovirus (CMV) infection
• raised blood lipids
• inadequate immunosuppression (including poor compliance)

23. Chronic rejection
• 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

24. Chronic rejection
Organ-specific features of chronic graft rejection are:
• 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

25. Chronic rejection

26. Graft-versus-host disease
• Some donor organs (particularly liver and small bowel) contain large
numbers of lymphocytes, and transfusion of unirradiated blood
products
• these may react against HLAs 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)
• GVHD is a serious and sometimes fatal complication

27. Graft-versus-host disease
• Acute GVHD: distinctive syndrome of dermatitis, hepatitis and
enteritis developing within 100 days of allogenic HSCT
• Chronic GVHD: more diverse syndrome developing after day 100
• Signs and symptoms:
• Pruritic and painful rash
• Anorexia, weight loss, followed by hepatic coma (rarely)
• Diarrhea, intestinal bleed, cramping abdominal pain and ileus

28. HLA MATCHING
• HLA molecules are encoded by the
major histocompatibility complex
(MHC), a cluster of genes situated
on the 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

29. HLA matching
• 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
• Recipients who receive well-matched renal allografts require less
intensive immunosuppression and are also troubled less by rejection
episodes
• HLA matching between the donor and recipient is expressed in terms
of whether or not there are mismatches at each locus for HLA-A, -B
and -DR

30. HLA matching
• 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 anti
gen and is mismatched for both -DR antigens
• Allocation of organs for transplantation must also take into account
the relative size of the donor and recipient (heart, lung, liver and
small bowel)
• In the case of liver transplants, HLA matching does not confer an
advantage and, although it is beneficial in cardiac transplantation, it is
not practicable because of the relatively small size of the recipient
pool and the short permissible cold ischaemic time

31. Organ procurement
Deceased donor:
• Donation after brain death
• Donation after cardiac death
Living donors

32. Donation after Brain Death
• Brain death is defined as the irreversible cessation of brain function,
including the brainstem
• However, conditions like drug overdose, medication side effects, severe
hypothermia, hypoglycemia, induced coma, and chronic vegetative state—
need to be excluded
• clinical diagnosis of brain death consists of four essential steps:
(a) establishment of the proximate cause of the neurologic insult
(b) clinical examinations to determine coma, absence of brainstem reflexes, and apnea
(c) utilization of ancillary tests, such as electroencephalography (EEG), cerebral
angiography, or nuclear scans, in patients who do not meet clinical criteria
(d) appropriate documentation

33. Clinical examination

34. Donation after Cardiac Death
• also known as donation by non–heart-beating donors (NHBDs)
• Currently, most NHBDs in the US meet Maastricht classification III;
that is, they have suffered a devastating injury with no chance of a
meaningful recovery but do not meet the criteria for brain death
• After consent for donation is obtained from the next of kin, the
donor’s life support is removed
• After the cessation of cardiac and respiratory function, organ
procurement commences

35. Donation after Cardiac Death
• DCD donors can be grouped according to the Maastricht classification
as follows:
• category 1: dead on arrival at hospital;
• category 2: resuscitation attempted without success;
• category 3: ‘awaiting cardiac arrest’ after withdrawal of support;
• category 4: cardiac arrest while brain dead;
• category 5: cardiac arrest and unsuccessful resuscitation in hospital

36. Living donors
• The ethical framework of living organ donation rests on three guiding
principles:
• beneficence to the recipient
• nonmaleficence to the donor, and
• the donor’s right to autonomy
• use of living donors offers numerous advantages for recipients in need
• availability of lifesaving organs for those who would otherwise succumb to the
progression of their end-stage disease
• significantly shorten the waiting time for recipients
• with the use of living donors, transplants are planned (rather than emergency)
procedures, allowing for better preoperative preparation of the recipient

37. Living donors
• The major disadvantage is the risk to living donor
• The risk of death associated with donation depends on the organ
being removed
• For a nephrectomy, the estimated mortality risk is less than 0.05%
• for a partial hepatectomy, about 0.2%
• All potential risks must be carefully explained to the potential donor,
and written informed consent must be obtained

38. Living donors
• Living donor transplants of organs other than the kidney and liver are fairly
uncommon
• Living donor pancreas transplants involve performing a distal
pancreatectomy, with the graft consisting of the body and tail of the
pancreas; vascular inflow and outflow are provided by the splenic artery
and splenic vein
• Living donor intestinal transplants usually involve removal of about 200 cm
of the donor’s ileum, with inflow and outflow provided by the ileocolic
vessels
• Living donor lung transplants involve removal of one lobe of one lung from
each of two donors; both grafts are then transplanted into the recipient

39. Evaluation of the deceased donor
• assess the donor from the point of view of transmissible infectious agents
and malignancy
• medical history should be scrutinized, evidence sought of risk factors for
human immunodeficiency virus (HIV) and hepatitis B and C virus infection,
such as intravenous drug abuse
• The presence of Creutzfeldt–Jakob disease is an absolute contraindication
to organ donation
• Organs from HIV-infected donors should not be used for transplantation,
except sometimes in recipients who are already infected by HIV. Hepatitis B
infection (in most countries) and active systemic sepsis, e.g. major
abdominal infection, are contraindications to donation

40. Evaluation of the deceased donor
• The presence of malignancy within the past 5 years is usually an
absolute contraindication to organ donation
• Exceptions: primary tumours of the CNS, non-melanotic tumours of
the skin and carcinoma in situ of the uterine cervix
• The chronological age of the donor is less important than the
physiological function of the organs under consideration for
transplantation
• The organs to be donated should generally be free from primary
disease

41. Criteria for organ donation
• Should be >18yrs old
• Potential kidney donors: reasonable urine output and relatively
normal serum urea and creatinine
• liver donors: should not have a hepatic disease
• Heart donors should have a normal electrocardiogram and, in
doubtful cases, echocardiography may be necessary
• For lung donors the chest radiograph and gas exchange should be
satisfactory, and bronchial aspirates should be free from fungal and
bacterial infection

42. Criteria for organ donation
• In the case of kidney transplantation an extended criteria donor is
defined in the USA as:
• A donor age >60 years
or
• one between the ages of 50 and 60 years with two of the following:
• hypertension,
• death from stroke
• and a terminal creatinine >132 mmol/L

43. Organ Preservation
• Hypothermia and pharmacologic inhibition are the two most frequent
methods
• Both slow—yet cannot completely shut down—the removed organ’s
metabolic activity, so both have adverse effects, such as cellular
swelling and degradation
• The most effective, preservation solution was developed at the
University of Wisconsin containing:
• lactobionate (which helps prevent cellular swelling and reperfusion injury)
• raffinose, and
• hydroxyethyl starch (which helps reduce swelling of endothelial cells, thereby
decreasing edema)

44. Organ Preservation

45. Return of organ function

46. KIDNEY TRANSPLANTATION
• Renal transplantation is the preferred treatment for many patients
with ESRD
• Transplantation is more cost-effective than dialysis and improves
patient survival
• Causes of end-stage renal disease are:
• Glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis,
polycystic disease, renal vascular disease, SLE
• No upper age limit for transplant, however older patients (>65 yrs)
are less likely to be suitable candidates because of associated
comorbid conditions

47. Kidney transplantation

49. Complications of renal transplant
• Vascular: Renal artery thrombosis(1%), Renal vein thrombosis(5%),
Renal artery stenosis (late)
• Urological: Urinary leaks, Obstruction of the transplant ureter,
lymphocoele
• Acute tubular necrosis
• Rejection of graft
• UTI

50. Pancreas transplantation
• In the USA, around a half of all patients with diabetes undergoing
kidney transplantation also receive a pancreas transplant
• The kidney and pancreas are obtained from the same donor, so-called
simultaneous pancreas and kidney (SPK) transplantation
• Pancreas transplantation is sometimes performed in patients who
have already undergone successful kidney transplantation, pancreas-
after-kidney (PAK) transplantation
• Reserved for those patients with type 1 diabetes who are relatively
young (aged <60 years) and do not have advanced coronary artery
disease or advanced peripheral vascular disease

51. Pancreas transplantation

52. Complications of pancreatic transplant
• Vascular thrombosis of the graft (5%)
• Duodenal anastomotic leaks
• Graft pancreatitis – very common, but usually mild
• Wound infection(10%)
• Specific complications of enteric drainage: intra-abdominal sepsis and
adhesive small intestinal obstruction
• Bladder drainage: cystitis, urethritis/urethral stricture; reflux pancreatitis;
urinary tract infection; haematuria; metabolic acidosis
Urinary drainage of the pancreas has the advantage that urinary amylase levels can be
used to monitor for graft rejection.

53. Transplantation of isolated pancreatic islets
• Pancreatic islets for transplantation are obtained by mechanically
disrupting the pancreas after injection of collagenase into the pancreatic
duct
• Islets are then purified by density-gradient centrifugation and can be
delivered into the recipient liver (the preferred site for transplantation) by
injection into the portal vein
• To prevent islet rejection through immunosuppressive therapy, attempts
have been made to protect isolated islet cells from rejection by
encapsulating them inside semipermeable membranes
• Membranes allows insulin to pass through but prevents antibodies and
leukocytes from reaching the islets, thereby avoiding the need for
immunosuppressive therapy

54. Liver transplantation
• Indications for liver transplantation are:
• cirrhosis
• acute fulminant liver failure
• metabolic liver disease
• primary hepatic malignancy
• Most common indication for transplantation is chronic liver failure
• In children, biliary atresia is the most common indication
• Cholangiocarcinoma has a high recurrence rate and is seldom an
indication for liver transplantation

55. Liver transplantation

56. Complications of liver transplantation
• Haemorrhage
• Vascular: Hepatic artery thrombosis (spontaneous/acute rejection),
Portal vein thrombosis (rare/ features of portal HTN)
• Biliary complications: biliary stenosis

57. Small Bowel transplantation
• Intestinal transplants stimulate a particularly strong graft rejection because
of very large amounts of lymphoid tissue
• Small bowel transplantation is a treatment option for patients with
intestinal failure requiring long-term parenteral nutrition like:
• short bowel syndrome after resection of the intestine or from intestinal dysfunction;
• intestinal atresia;
• necrotising enterocolitis;
• volvulus;
• disorders of motility;
• mesenteric infarction;
• Crohn’s disease;
• trauma

58. Small Bowel transplantation
• A small bowel transplant from a deceased donor comprises the entire
small bowel, and may include the ascending colon in the graft
• Anastomoses: SMA to aorta, SMV to IVC, proximal end to
duodenum/jejunum, distal end to side of colon with a loop/end
ileostomy
• Gastrostomy tube and FJ tube is inserted
• Most of the mortality after small bowel transplantation is due to
sepsis and multiorgan failure

59. Heart Transplantation
• Effective treatment for selected patients with end-stage cardiac
failure
• Common indications for heart transplantation are ischaemic heart
disease and idiopathic cardiomyopathy, but other indications include
valvular heart disease, myocarditis and congenital heart disease
• Considered only in patients with end stage heart disease that has
failed to respond to all other conventional therapy and when
predicted survival without transplantation is only 6–12 months
• limited to patients under the age of 65 years who do not have
irreversible damage to other organ systems

60. Heart–lung, single-lung and double lung
transplantations
• Combined heart lung transplants are done in patients with pulmonary
vascular disease in whom there is cardiac dysfunction due to
congenital (e.g. Eisenmenger’s syndrome) or acquired cardiac
dysfunction
• For most patients with end-stage pulmonary disease, however, single
or double-lung transplantation has now replaced heart–lung
transplantation
• Single-lung transplantation is performed through a posterolateral
thoracotomy and double lung transplantation through a bilateral
thoracotomy or median sternotomy

61. Xenotransplants
• Potential to solve the critical shortage of available
grafts
• Hurdles:
• immunologic barrier between species
• potential risk of transmitting infections (zoonoses)
[porcine endogenous retrovirus (PERV)]
• Pigs are generally accepted as the most likely donor
species for xenotransplants into human beings
• The immunological barrier between pigs and
human is highly complex

62. Xenotransplants
• Many different options are being tested to overcome this
immunologic barrier:
• genetic engineering of pigs,
• the use of agents to inhibit platelet aggregation and complement
activation, and the administration of powerful immunosuppressive
drugs
• Cellular xenotransplants have made great strides and encapsulated
porcine islet xenotransplants are the most advanced form

63. Immunosuppressants

65. Complications of Immunosuppression
Infections
Early: infections occurring within 1 month post transplant (bacterial,
viral, and fungal)
Surgical infections are the most common and require surgical
intervention
• Typical examples include generalized peritonitis, intra-abdominal abscesses,
and wound infections
Medical infections include respiratory, urinary tract, and bloodstream
infections

66. Complications of Immunosuppression
Late: due to chronic immunosuppression, specifically the depression
of cell-mediated immunity
• Herpes simplex virus (HSV), CMV, and EBV being the most prominent
• CMV is a latent infection; usually occur 3 to 6 months posttransplant
or during treatment for rejection
• 12-week acyclovir prophylaxis – decreases incidence
• Symptomatic infections should be treated with intravenous (IV)
ganciclovir

67. Complications of Immunosuppression
• After 6 months posttransplant, the risk of invasive fungal infections
increases. Eg: Blastomyces dermatitidis, Coccidioides immitis,
Histoplasma capsulatum, Candida or Aspergillus infections and
Pneumocystis jiroveci

68. Complications of Immunosuppression
Malignancies:
• a cohort study involving more than 175,000 solid organ transplant
recipients, showed that 10,656 of them developed malignancies
• incidence ratio was 2.10 (as compared with the general population)
• fivefold increase (as compared with the general population) in these types
of malignancies:
• Kaposi’s sarcoma,
• Nonmelanoma skin cancer,
• Non-Hodgkin’s lymphoma, and
• cancer of the liver, anus, vulva, and lip

69. Recent Advances in organ transplantation
• Biomaterials for 3D printing and tissue engineering
• Human hepatocyte transplantation for liver disease
• Face transplantation
• Uterus transplantation
• Stem cell treatment of type 1 diabetes

70. 3D bioprinting & tissue engineering
• It has already been used for the generation and transplantation of
several tissues, including multilayered skin, bone, vascular grafts,
tracheal splints, heart tissue and cartilaginous structures
• layer-by-layer precise positioning of biological materials, biochemicals
and living cells, with spatial control of the placement of functional
components, is used to fabricate 3D structures

71. 3D bioprinting & tissue engineering

72. Types of 3D bioprinting techniques

74. Face transplants

75. First uterus transplant in india

76. Thank you