Principles of transplantation Presentation by DJ as Resident Doctor

1. Presented by:
Dr. Dharmendra Joshi
BSMMU
PRINCIPLES OF TRANSPLANTATION

2. INTRODUCTION
Definition of terms
Transplant immunology
Graft rejection
PRINCIPLES
Pre-operative
Intra-operative
Post-operative
ETHICAL CONSIDERATIONS
CONCLUSION
OUTLINE

3. DEFINITION OF TERMS
An organ transplant is a surgical procedure in which a failing
organ is replaced by a functioning one from a donor with a compatible
tissue type.
• Autograft
• Allograft
• Isograft
• Xenograft
• Orthotopic graft
• Heterotopic graft
INTRODUCTION

4. ORGANS THAT CAN BE TRANSPLANTED
 Heart  Kidneys  Liver Thymus
 Pancreas Lungs  Intestine

5. TISSUE THAT CAN BE TRANSPLANTED
 Bones  Tendons  Cornea
 Vein Heart valves  Skin of leg

6. The immune system recognizes graft from
someone else as foreign body and triggers response
via immune cells and substances they produce -
cytokines and antibodies
(Responses are via; recognition, amplification and
memory)
• Immunity
TRANSPLANT IMMUNOLOGY
Humoral
(Antibody mediated) Cell mediated

7. • IMMUNE CELLS
 Lymphocytes : T-lymphocyte, B-lymphocyte, N-killer
cells
 Antigen presenting cells(APC) : macrophages, dendritic
cells
 The Effector Cells : Neutrophils , macrophages and T-
lymphocytes
TRANSPLANT IMMUNOLOGY (Contd…)

8. Cell-mediated immune response
Defend against intracellular pathogens/rejection
Active
Cytotoxic T cells
Memory
Cytotoxic T cells
Memory
Helper T cells
Antigen-
presenting cell
Antigen (2nd exposure)
Helper T cell
Engulfed by
Antigen (1st exposure)
Cytotoxic T cell
Key
Stimulates
Gives rise to
+
+
+
+
+ +
+
T-CELLS
- Helper T cells
- Cytotoxic T cells
- Memory T cells

9. Key
Stimulates
Gives rise to
+
Memory
Helper T cells
Antigen-
presenting cell
Helper T cell
Engulfed by
Antigen (1st exposure)
+
+
+
+ +
+
Defend against extracellular pathogens/Transplant rejection
Memory
B cells
Antigen (2nd exposure)
Plasma cells
B cell
Secreted
antibodies
Humoral (antibody-mediated) immune response

10. Human leucocytes antigen (HLA):
• a group of highly polymorphic cell surface molecules
• They act as antigen recognition unit on T-lymphocytes and are
the major trigger for graft rejection
• Types : class1 – HLA- A,B,C present in all nucleated cells,
• CD8+ recognizes class 1 HLA
• class2 – HLA- DR, DP, DQ present only on APC
• Class 2- HLA-DR are most important in rejection
• CD4+ recognize class 2 HLA
TRANSPLANT ANTIGENS

11. Major histocompatibility complex MHC:
oThey are clusters of genes on the short arm of
chromosome 6 expressed on the cell surface as HLA i.e.
genes that encode HLA.
ABO:
oThese blood group antigen are expressed not only on red
blood cells but by most cell types as well.
oIncompatibility leads to hyperacute rejection

12. Rejection of transplanted organs is a bigger
challenge than the technical expertise required to
perform the surgery. It results mainly from HLA and
ABO incompatibility.
• Hyperacute
• Acute
• Chronic
GRAFT REJECTION

13. Hyper acute rejection
• Immediate graft destruction due to ABO or preformed
anti- HLA antibodies.
• Characterized by intravenous thrombosis and
interstitial hemorrhage.
• Risk factors are previous failed transplant and blood
transfusions
• Kidney transplant is vulnerable to hyperacute rejection
GRAFT REJECTION (Contd…)

14. Acute rejection
• Usually occurs during the first 6 months.
• May be cell mediated (T-cell), antibody mediated or both
• Characterized by cellular infiltration of the graft(cytotoxic,
B- cells, NK cells and macrophages)
GRAFT REJECTION (Contd…)

15. Chronic Rejection:
• It occurs after 6 months.
• Most common cause of graft failure
• Antibodies play important role
• Non- immunological factors contribute to the
pathogenesis
• Characterized by myointimal proliferation in graft
arteries leading to ischemia and fibrosis
GRAFT REJECTION (Contd…)

16. PRE-OPERATIVE
Patient selection and Evaluation
Counseling
Informed written consent
Optimization
PRINCIPLES

17. 1. RECIPIENT
Clinical evaluation; history and physical examination
Immunological evaluation
Infection screening – septic work-up
Others ; CBC, clotting profile, FBS, ECG, LFT, RFT,
tumour markers.
PATIENT SELECTION & EVALUATION
(Recipient)

18. I. Living donor : Donor remains alive and donates a
renewable tissue/cell, or donates an organ or part of an
organ in which the remaining organ can regenerate or take
on the workload of the rest of the organ (single kidney
donation, partial donation of liver). A living donor should
be healthy
• Living unrelated donor (LURD)
• Living related donor. (LRD)
Patient selection & evaluation (DONOR)

19.  Advantages of living donor
Improved graft survival
Less recipient morbidity
Early function and easier to manage
Avoidance of long waiting time for transplant
Less aggressive immunosuppressive regimens
Patient selection & evaluation (DONOR)

20.  Contra-indications for living donor
oMental disease
oDiseased organ
oMorbidity and mortality risk
oABO incompatibility
oCross matching incompatibility
oTransmissible disease
Patient selection & evaluation (DONOR)

21. • Evaluation : to assess for suitability
oCLINCAL - history of risk factors for infection,
malignancy in the past 5 years. Presence of co-
morbidities
oABO typing, Serology tests.
oInfection and malignant screening
oCT-Angiogram, Intravenous urography.
oHLA typing.
Patient selection & evaluation
(DONOR)

22. • II. Deceased donor
- Brain dead donors:
o Normothermic patient.
o No respiratory effort by the patient.
o The heart is still beating.
o No depressant drugs intake should be there while evaluating the
patient.
o Individual should not have any sepsis, cancer (except brain tumour).
o Not a HIV or hepatitis individual.
Patient selection & evaluation (DONOR)

23. • II. Deceased donor
- Cardiac Death Donors (formerly non-heart beating
donors) to increase the potential pool of donors as demand
for transplants continues to grow.
These organs have inferior outcomes to organs
from a brain-dead donor.
Patient selection & evaluation (DONOR)

24. ORGAN FUNCTION AFTER TRANSPLANT
2. PROCUREMENT-
RELATED FACTORS
3. RECIPIENT-RELATED
FACTORS
1. DONOR
CHARACTERISTICS

25. • The tissue typing laboratory carries out 3 tasks :
To determine the HLA type of blood for both
donor and recipient by PCR.
Lymphocyte cross-matching.
HLA antibody screening and specificity
TISSUE TYPING

26. Positive cross matching;
o Recipient antibodies attacks donor’s.
o Not suitable for transplant
Negative cross matching;
o Recipient antibodies do not attack donor
o Suitable for transplant
Methods;
o Micro-cytotoxic assay, mixed lymphocytes, flow cytometry, DNA
analysis.
CROSS MATCHING

27. • May involve professional counselors/ psychotherapist
• Aimed at preventing / minimizing possible complication
• Need for adherence to post-op maintenance medications
• Regular follow-up thorough evaluation
• Life style modification; smoking, alcohol, sedentary life
style, excessive salt ingestion.
COUNSELING

28. Living Donor:
Education
Willingly but not for any financial reason or under stress
Most undergo extensive screening – medical,
psychological
Surgery and anesthetic complications outline to patients
INFORMED WRITTEN CONSENT

29. • DECEASED DONOR
• Some Factors influencing refusal to consent by relatives;
non-acceptance of brain death.
A delay in funeral
Lack of consensus within family members
Fear of social criticism
Dissatisfaction with the hospital staff
Various Superstitions & Religious beliefs
INFORMED WRITTEN CONSENT (Contd…)

30. RECIPIENT
Nature of disease and the need for transplant
Outcome and complications
Need for compliance to immunosuppressive therapy
Other available options
INFORMED WRITTEN CONSENT (Contd…)

31. Correction of derangements, getting patient ready for surgery
Correction of anemia
Uremia
Dehydration
Treatment of infection
Central line
Urethral catheter
Loading dose immunosuppression 12hr pre-op
Prophylactic antibiotics
OPTIMIZATION OF RECEPIENT

32. • Organ procurement and preservation
• LIVING DONORs
a. Strict asepsis and hemostasis
b. Adequate exposure
c. Removal of the organ
d. Preservation
e. Organ packaging
f. Transplantation/vascular reconstruction
INTRA-OPERATIVE PRINCIPLE

33. After removal, the organ is
flushed with chilled organ
preservation solution e.g.
• University of Wisconsin(UW),
• Eurocolins,
• Celsior,
• Custodiol,
• Citrate/Marshall solutions
PRESERVATION

34. ORGAN PACKAGING

35. • Initiation of preservation
in situ- for DCD
donors- donation after
circulatory death donors
*** DCD – Donor after Cardiac Death
DCD DONOR

36. • Warm ischemic time: time an organ remains at
body temperature between which the blood
supply is cut off before cold perfusion. (within
30min)
• Cold ischemic time: the time between the
chilling of the organ, after blood supply has been
cut off and the time it is warmed by reconnection
ISCHEMIC TIME

37. Maximum and optimal cold storage times (approximate)
• Organ Optimal (hours ) Safe maximum(hours)
• Kidney < 24 48
• Liver < 12 24
• Pancreas < 10 24
• Small intestine < 4 8
• Heart < 3 6
• Lung < 3 8
COLD STORAGE TIME

38. Post-operative assessment
• Clinical – vital signs; fever, tachychardia, hypertension, pain at
site of transplant, pedal edema (compression of external iliac
vein), decrease urine volume- features of hyperacute rejection
• Investigations: USG- increase in size, pelvicalyceal dilation,
Biopsy: mononuclear infiltrates, fibrinoid necrosis, interstitial
haemorrhage. etc.
• Maintenance immunosuppression, DVT prophylaxis, Treatment
of infection , Regular follow up
POST-OPERATIVE PRINCIPLE

39. The principles are the same for all type of organ transplant; maximize
graft protection and minimize side effect.
The agents used to prevent rejection act predominantly on T cells.
The need for immunosuppression is highest in the first 3 month but
indefinite treatment is needed
It increase the risk of infection and malignancy.
Post-operative IMMUNOSUPRESSION

40. AGENT MODE OF ACTION SIDE FFECT
CALCINEURINE
INHIBITORS
Cyclosporine
Tacrolimus
Block IL-2 gene
transcription
Nephrotoxicity,
hypertension,
dyslipidaemia, hirsutism,
gingival hyperplasia,
neurotoxicity and diabetes
AZATHIOPRINE Prevents lymphocyte
proliferation
Leucopenia,
thrombocytopenia,
hepatotoxicity,
gastrointestinal
symptoms
MYCOPHENOLIC ACID
DERIVATIVES eg MMF –
Mycofenolate mofetil
Prevents lymphocyte
proliferation
Leucopenia,
thrombocytopenia,
gastrointestinal symptoms
CORTICOSTEROIDS Widespread anti-
inflammatory
effects
Hypertension,
dyslipidaemia, diabetes,
osteoporosis, avascular
necrosis,
cushingoid appearance
mTOR-inhibitors
Sirolimus, Everolimus
Blocks IL-2 receptor signal
transduction
Thrombocytopenia,
dyslipidaemia,
pneumonitis, impaired
wound
healing

41. AGENT MODE OF ACTION SIDE EFFECT
ANTIBODY THERAPIES
a. OKT3 monoclonal
antibody
b. Anti-CD25
monoclonal antibody
c. Polyclonal antibody
[antilymphocyte
globulin (ALG) or anti-
lymphocyte serum (ALS)]
Depletion and blockade
of T
Cells
Targets activated T cells
Depletion and blockade
of
lymphocytes
a. Cytokine release
syndrome,
pulmonary oedema,
leucopenia
b. None described
c. Leucopenia,
thrombocytopenia

42. • Immunosuppressive agents are given as
Induction: early post-op period
Maintenance: given for life
Rescue agents: to reverse acute rejection
REGIMENS

43. • INTERNATIONAL PERSPECTIVES ON THE ETHICS AND
REGULATION OF HUMAN CELLAND TISSUE
TRANSPLANTATION
o Consent for removal of human cells and tissues
o Confidentiality of donor data
o Unpaid donation
o Fair procurement of cells and tissues
o Quality and safety of HC/HT procurement and processing
o Fair distribution of processed cells and tissues
o Consent for HC/HT transplantation
ETHICAL CONSIDERATION

44. Genetic engineering – Cloning
Newer specific Immuno-suppressive therapy
FUTURE TREND

45. Organ transplant is a successive therapeutic option for
treatment of end-stage organ disease. Success depends on
improved surgical technique, immunosuppression, organ
preservation and follow-up .
CONCLUSION

46. • Bailey and Love’s “Short Practice of Surgery” 26th edition CRC
press Taylor and Francis group. 2013
• E.A Badoe et al, “Principles and Practice of surgery including
pathology in the tropics” 4th edition, Assembly of God Literature
Center ltd, 2009
• M.A.R Al-Fallouji; “Postgraduate Surgery the candidate guide”. 2nd
Edition. Rced Educational and Professional Pub. Ltd 1998
• Sabiston texbook of surgery. 18th edition.2007
• Andrew C et al “Operative urology at the cleveland clinic” 2nd
edition. 2006.
• Pediatric Liver Transplantation Author: F Brian Boudi, MD, FACP;
Chief Editor: Stuart M Greenstein, Medscape.
REFERENCES