For surgical residents presentation

1. Principle of Organ
Transplantation
By
Dr Olofin
03/08/2021

2. Outline:
• Introduction
• Definition
• Epidemiology
• Historical background
• Transplant immunology
• Types of allograft rejection
• Perioperative considerations
• Pre op
• Intra op
• Post op
• Complications
• Future trends
• Conclusion
• Reference

3. Introduction:
Definitions:
• Transplantation: is the process of transferring an organ, tissue, or cell
from one place to another.
• Organ transplant: is a surgical procedure in which a failing organ is
replaced by a functioning one.

4. Introduction:
• Autograft the transfer of organ from one part to another in the same
individual
• Allograft from one individual to another of the same specie
• Isograft transfer of organ from one individual to his or her identical
twin
• Xenograft the transfer of organ from one individual to another of
different specie
• Orthotopic graft a graft placed in its normal anatomical position
• Heterotopic graft a graft placed at a site different from where the
organ is normally located.

5. Epidemiology:
• In 2017 alone, according to the United Network for Organ Sharing
(UNOS), about 115,000 patients in the United States were awaiting a
transplant, yet the number of transplants performed approached only
about 35,000.
• Advances in surgical technique and a better understanding of
immunology are the two main reasons that transplants have evolved.
• Lack of resources, cadaveric programs and technical facilities coupled
with late presentation continue to hamper transplant programs in
Africa

6. Historical background:
• 1954 – The first successful live donor human kidney transplant,
between identical twin brothers. The transplanted kidney functioned
for 8 years
• 1958 – The first kidney transplant in humans using
immunosuppression
• 1961 – The first successful kidney transplant between non-siblings
• 1962 – The first successful kidney transplanted from a deceased
donor occurred in Boston - the kidney functioned for 21 months. This
was the first use of the new immunosuppressive drug azathioprine

7. Historical background:
• 1963 – The first liver transplant by Thomas Starzl in Denver, Colorado.
• 1963 – The first lung transplant was performed by James Hardy in
Jackson, Mississippi.
• 1966 – The first pancreas transplant was performed by William Kelly
and Richard Lillehei in Minneapolis, Minnesota.
• 1967 – The first successful heart transplant was performed by
Christiaan Barnard in Cape Town, South Africa.

8. Transplant Immunology:
• Human leukocyte antigens (HLA): are a group of highly polymorphic
cell surface molecules that function as antigen recognition units that
display antigens for recognition by T- lymphocytes.
• HLA -A, -B, -C, -DR, -DP, and -DQ
• Class I antigens are present on all nucleated cells
• Class II antigens are expressed on antigen-presenting cells (APC) like
dendritic cells, macrophages and B lymphocytes.
• Major histocompatibility complex (MHC): genes that encode HLA.
• ABO compatibility

9. Transplant Immunology:
• The immune system recognizes graft from someone else as foreign
and triggers immune response
• Innate or acquired immune response
• Donor HLA class I and class II antigens recognize CD8 & CD4 T cells
respectively
• Activation of CD8 T cells cause target cell death via release of lytic
molecules like perforin and granzyme

10. Transplant Immunology:
• Expression of HLA class II by graft cells stimulate proliferation and
activation of CD4 T cells in response to IL-2.
• Activated CD4 T cells mediate direct target cell damage, release of
proinflammatory cytokines like Interferon 𝞬 (INF-𝞬) which recruit and
activate macrophages
• CD4 T cells also help in producing alloantibodies which bind to graft
antigen and induce target cell injury.

12. Types of allograft rejection:
Hyperacute rejection:
• Immediate graft destruction due to ABO or preformed anti-HLA
antibodies
• Characterised by intravascular thrombosis and interstitial
haemorrhage
• Kidney transplants are particularly vulnerable to hyperacute graft
rejection, whereas heart and liver transplants are relatively resistant.

13. Types of allograft rejection:
Acute rejection:
• Usually occurs during first 6 months
• T-lymphocyte mediated but alloantibodies also play a role
• Characterised by mononuclear cell infiltration of the graft
• All types of organ allograft are susceptible to acute rejection (20-30%)

14. Types of allograft rejection:
Chronic rejection:
• Occurs after first 6 months
• Most common cause of graft failure
• Antibodies play an important role
• Non-immune factors contribute to pathogenesis
• Characterised by myointimal proliferation in graft arteries leading to
ischaemia and fibrosis
• Most important risk factor for chronic rejection after kidney
transplantation is acute rejection (with vascular inflammation) and
recurrent episodes of acute rejection.

15. Graft-versus-host-disease (GVHD):
• Occasionally seen after certain types of organ transplantation.
• Some donor organs contain large numbers of lymphocytes, and these
may react against HLAs expressed by recipient tissues, leading to
GVHD.
• Characteristic rash on the palms and soles.

16. Perioperative considerations:
Pre Op:
• Patient selection and Evaluation
• Counseling
• Informed consent
• Optimization

17. Perioperative considerations:
Intra Op:
• Organ procurement and preservation

18. Organ donation and procurement:
• Deceases donors: brain-stem-dead, donation after brain death (DBD) or donation
after circulatory death (DCD)
• Living donors
Brain death: irreversible cessation of function of the circulatory, respiratory and
entire brain, including medulla.
• Ruling out barbiturate coma, hypothermia, drug overdoses, intoxication
• Test for all the reflexes of cerebral function.

19. Organ donation and procurement:
Brain death protocol:
• 2 senior physicians independently & not associated with the teams needing the organs.
• Motor response to painful stimulation
• Pupillary response to light
• Corneal reflex testing
• Oculocephalogyric reflex (doll’s eye )
• Vestibuloocular (caloric) reflex
• Upper & Lower airway (pharyngeal & ETT suction) reflexes
• Gag reflex
• All the above × 2
• Apnea test: Stop ventilation until Pa CO2 = 60mmHg without respiration.
• EEG (in US, not Europe) should be flat.
• Cerebral angiography confirms surely.

20. Organ donation and procurement:
For DBD donors:
• Careful monitoring and management of fluid balance is essential.
• Vasopressin is often given to allow reduction or cessation of
catecholamine pressors.
• Donors are also usually given methylprednisolone to aid fluid and
metabolic management
• Triiodothyronine (T3) to help cardiovascular stability.

21. Organ donation and procurement:
DCD donors are grouped using the Maastricht classification
• Category 1: Dead on arrival
• Category 2: Unsuccessful resuscitation in hospital
• Category 3: Awaiting cardiac arrest after withdrawal of support
• Category 4: Cardiac arrest while brainstem-dead
• Warm ischaemic time for categories 1,2, and 5 is usually longer and
less predictable

22. Organ donation and procurement:
Living donors:
• Age 0 – 75yrs
• Willing & not financially induced or coerced.
• Satisfactory function of vital organs
• Serology
• Malignant disease
• ABO compatible

23. Organ donation and procurement :
• After removal, the organ is flushed with chilled organ preservation
solution e.g University of Wisconsin(UW), Euro-collins, Celsior,
Custodiol, citrate/Marshall solutions
• Cooled to 4-6o by isolated perfusion pre harvest or table lavage
• Warm ischaemic time
• Cold ischaemic time
• Storage time for organs vary

24. Perioperative considerations:
Organ Optimal time Safe maximum
Kidney <24 48
Liver <12 24
Pancreas <10 24
Small intestine <4 8
Heart <3 6
Lung <3 8

25. Perioperative considerations:
Post op:
• Clinical and laboratory parameters
• Look out for features of hyperacute rejection

26. Immunosuppression:
• Aim is to maximize graft protection and minimize side effect.
• Act predominantly on T cells
• Need for immunosuppression is highest in the first 3 months
• Immunosuppressive protocols for different types of organ transplant
vary between centres, but almost all use a combination of
immunosuppressive agents acting at different points in the pathway
of lymphocyte activation.

27. Immunosuppressants:
• Induction
• Maintenance
• Rescue agents
Corticosteroids: e.g. prednisolone
• Used in combination with other agents
• Increase graft survival
• Anti inflammatory effects
• Side effects: Hypertension, dyslipidaemia, diabetes, osteoporosis,
avascular necrosis, cushingoid appearance

28. Immunosuppressants:
Calcineurin inhibitors: ciclosporin and tacrolimus
• Blocks the activity of calcineurin within the cytoplasm of the T cell.
• Calcineurin plays a critical role in facilitating the transcription of IL-2.
• Their immunosuppressive action, as well as their side effects, is
dependent on their blood concentration, and monitoring of whole-
blood drug levels
• Side effects: Nephrotoxicity, hypertension, dyslipidaemia.

29. Immunosuppressants:
Anti Proliferative Agents: Azathioprine and mycophenolic acid
preparations
• Part of maintenance therapy
• Inhibits purine metabolism
• Prevents proliferation of lymphocytes
• Side effects: leukopenia, thrombocytopenia, hepatotoxicity,
gastrointestinal symptoms

30. Immunosuppressants:
Antibody therapy:
• Monoclonal antibodies against IL-2 receptor on T lymphocytes (CD25)
• Anti-CD20 antibody - rituximab
• Others are alemtuzumab (anti-CD52 expressed on T cells and
dendritic cells )
• Polyclonal antibody - anti- thymocyte globulin (ATG)
• May be used to treat acute rejection episodes that fail to respond to
steroid therapy.
• Side effects: Infusion reaction, autoimmune disease and pulmonary
toxicity

31. Immunosuppressants:
Mammalian target of rapamycin (mTOR) inhibitors: sirolimus and
everolimus
• Interfere with intracellular signalling from the IL-2 receptor, arresting
T-cell division in the G1 phase
• Side effects: Thrombocytopenia, dyslipidaemia, pneumonitis,
impaired wound healing

32. Immunosuppressants:
T-cell co-stimulatory blockers: belatocept
• Binds to the co-stimulatory ligands CD80 and CD86 expressed on
antigen-presenting cells and prevents them from delivering the
costimulatory signals for full T-cell activation.
• May be associated with an increased risk of post-transplant
lymphoproliferative disease (PTLD).

33. Immunosuppressants:
Biologic/ non-biologic:
• Corticosteroids: Prednisolone
• Antimetabolites: Azathioprine, mycophenolate mofetil (MMF),
leflunomide
• T-cell directed drugs: Cyclosporine, Tacrolimus, Sirolimus
• Polyclonic antibodies: Antithymocyte globulin, thymoglobulin
• Monoclonic antibodies: OKT3 (anti-CD3), basiliximab, daclizumab
(anti-IL-2R), alemtuzumab (anti B-52R), anti CD20 (Rituximab)

34. Complications:
Infection: greatest risk in the first 6 months
• Viral: CMV , HSV, Herpes zoster
• Bacterial
• Fungal: Pneumocystis jiroveci
• Malignancy: especially skin cancers and PTLD

35. Future trends:
• Stem cell biology and tissue engineering:
• Totipotent stem cell- can give rise to whole organism
• Pluripotent stem cell can give rise to cells derived from three germ
layers
• Multipotent (organ specific) stem cell

36. Conclusion:
• Organ transplantation continues to play a vital role in the treatment
of many end stage organ diseases
• This has been made possible because of advances in immunology and
pharmacology.
• Advances in transplantation come with the ethical problems of organ
procurement and allocation
• In sub-Saharan Africa, transplant surgery is not widely practiced and
considered a difficult task

37. References:
• Bailey and Love’s “Short Practice of Surgery” 27th edition CRC press
Taylor and Francis group. 2013
• E.A Badoe et al, “Principles and Practice of surgery including
pathology in the tropics” 5th edition
• M.A.R Al-Fallouji; “Postgraduate Surgery the candidate guide”. 2nd
Edition. Rced Educational and Professional Pub. Ltd 1998
• Sabiston textbook of surgery. 18th edition.2007
• Schwartz’s Principle of Surgery. 11th edition. New York: McGraw
Hill;2019. 355-367p
• Principles involved in Organ transplant by Dr Bashir Yunus; 2015

38. Thank you for listening