Principles of transplantation by DJ

Presented by:

Dr. Dharmendra Joshi

BSMMU

PRINCIPLES OF TRANSPLANTATION

INTRODUCTION

Definition of terms

Transplant immunology

Graft rejection

PRINCIPLES

Pre-operative

Intra-operative

Post-operative

ETHICAL CONSIDERATIONS

CONCLUSION

OUTLINE

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

ORGANS THAT CAN BE TRANSPLANTED

Heart Kidneys Liver Thymus

Pancreas Lungs Intestine

TISSUE THAT CAN BE TRANSPLANTED

Bones Tendons Cornea

Vein Heart valves Skin of leg

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

• 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…)

Cell-mediated immune response

Defend against intracellular pathogens/rejection

ActiveCytotoxic T cells

MemoryCytotoxic T cells

MemoryHelper 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

Key

Stimulates

Gives rise to

+

MemoryHelper T cells

Antigen-presenting cell

Helper T cell

Engulfed by

Antigen (1st exposure)

+

+

+

+ +

+

Defend against extracellular pathogens/Transplant rejection

MemoryB cells

Antigen (2nd exposure)

Plasma cells

B cell

Secretedantibodies

Humoral (antibody-mediated) immune response

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

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.

o Incompatibility leads to hyperacute rejection

Rejection of transplanted organs is a biggerchallenge than the technical expertise required toperform the surgery. It results mainly from HLA andABO incompatibility.

• Hyperacute

• Acute

• Chronic

GRAFT REJECTION

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…)

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)


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


PRE-OPERATIVE

Patient selection and Evaluation

Counseling

Informed written consent

Optimization

PRINCIPLES

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)

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)

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


Contra-indications for living donor

oMental disease

oDiseased organ

oMorbidity and mortality risk

oABO incompatibility

oCross matching incompatibility

oTransmissible disease


• 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.

o Infection and malignant screening

oCT-Angiogram, Intravenous urography.

oHLA typing.


• 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.


• 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.


ORGAN FUNCTION AFTER TRANSPLANT

2. PROCUREMENT-RELATED FACTORS

3. RECIPIENT-RELATED

FACTORS

1. DONOR CHARACTERISTICS

• 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

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

• 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

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

• 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…)

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…)

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

• 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

After removal, the organ is

flushed with chilled organ

preservation solution e.g.

• University of Wisconsin(UW),

• Eurocolins,

• Celsior,

• Custodiol,

• Citrate/Marshall solutions

PRESERVATION

ORGAN PACKAGING

• Initiation of preservation in situ- for DCDdonors- donation after circulatory death donors

*** DCD – Donor after Cardiac Death

DCD DONOR

• 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

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

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

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

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

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

• Immunosuppressive agents are given as

Induction: early post-op period

Maintenance: given for life

Rescue agents: to reverse acute rejection

REGIMENS

• INTERNATIONAL PERSPECTIVES ON THE ETHICS AND

REGULATION OF HUMAN CELL AND 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

Genetic engineering – Cloning

Newer specific Immuno-suppressive therapy

FUTURE TREND

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

• 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

Principles of transplantation by DJ

Health & Medicine

Transcript of Principles of transplantation by DJ