Principles of organ transplant
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PRINCIPLES INVOLVED IN ORGAN TRANSPLANT DR BASHIR YUNUS SURGERY DEPT. AKTH 19/1/15 1/19/2015 [email protected] 1
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Transcript of Principles of organ transplant
PRINCIPLES INVOLVED IN ORGAN
TRANSPLANTDR BASHIR YUNUS
SURGERY DEPT.
AKTH
19/1/15
1/19/[email protected] 1
OUTLINE
O INTRODUCTIONO Definition of terms
O Transplant immunology
O Graft rejection
O PRINCIPLESO Pre-operatives
O Intra-operatives
O Post-operative
O COMPLICATIONS
O RENAL TRANSPLATATION
O ETHICAL CONSIDERATIONS
O CONCLUSION
O REFERENCES
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INTRODUCTION
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
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INTRODUCTION
• TRANSPLANT IMMUNOLOGY
The immune system recognizes graft from someone else as foreign and triggers response via immune cells or substances they produce -cytokines and antibodies
• Responses are via; recognition, amplification and memory
• CELL; • Lymphocytes; T-lymphocyte, B-lymphocyte, N-killer cells
• Antigen presenting cells(APC); macrophages, dendritic cells
• The Effector Cells; Neutrophils , macrophages and T-lymphocytes
• T-LYMPHOCYTES
• Mediator of cell mediated immunity
• They recognizes MHC antigen on transplant tissues
• Cytotoxic T-cells produces cytotoxic factors (perforins, granzymes) implicated in transplant rejection
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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
+
+
+
+
+ +
+
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Cytotoxic T cell
Perforin
Granzymes
TCRCD8
Class I MHCmolecule
Targetcell
Peptideantigen
Pore
Released cytotoxic T cell
Dying target cell
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B-LYMPHOCYTES
• Mediators of humeral immunity by antibody production.
• There activation is aided by cytokine and the T-helper cells
• Clonal selection generates plasma secreting antibodies.
• There are 5 major classes of antibodies or immunoglobulin; IgG, IgM, IgA, IgE and IgD the 1st 3 are involve in graft rejection
N-KILLER CELLS
• Cells of innate immunity, capable of killing foreign targets without prior sensitisation
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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
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• ANTIGEN PRESENTING CELLS(APC)
• They capture antigens and display to lymphocytes e.g. Macrophages, dendritic cells and follicular dendritic cells.
• Dendritic cells; initiate T-cells response
• Macrophages; Initiate effector phase of cell mediated immunity
• Follicular dendritic cells; display antigens to B-lymphocytes in humeral response.
• EFFECTOR CELLS
• They eliminate antigens by phagocytosis
• E.g neutrophils, macrophage and T-lymphocytes
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APC
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TRANSPLANT ANTIGENS
Human leucocytes antigen(HLA);
O a group of highly polymorphic cell surface molecules
O They act as antigen recognition unit on T-lymphocytes and are the major trigger for graft rejection
O Types; class1 –A,B,C present in all nucleated cells, class2 – HLA-DR,DP,DQ present only on APC
O Class 2- HLA-DR are most important in rejection
O CD8+ and CD4+ recognize class 1 and 2 receptors respectively
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MHC;
O Major histocompatibility complex. They 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
O These blood group antigen are expressed not only on red blood cells but by most cell types as well.
O Incompatibility leads to hyperacute rejection
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GRAFT REJECTION;
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.
O Hyperacute
O Acute
O Chronic
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Hyperacute rejection
O Immediate graft destruction due to ABO
or preformed anti- HLA antibodies.
O Characterized by intravenous
thrombosis and interstitial hemorrhage.
O Risk factors are previous failed transplant
and blood transfusions
O Kidney transplant is vulnerable to
hyperacute rejection
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Acute rejection
O Usually occurs during the first 6month
O May be cell mediated (T-cell), antibody
mediated or both
O Characterized by cellular infiltration of
the graft(cytotoxic, B- cells, NK cells and
macrophages )
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CHRONIC REJECTION
O it occurs after 6month
O Most common cause of graft failure
O Antibodies play important role
O Non- immunological factors contribute to
the pathogenesis
O Characterized by myointimal
proliferation in graft arteries leading to
ischemia and fibrosis
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PRINCIPLES
1. PRE-OPERATIVE
O Patient selection and Evaluation
O Counseling
O Informed consent
O optimization
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PATIENT SELECTION AND EVALUATION
RECIPIENT
O Patient who met the indication for transplant –ORGAN FAILURE
O Clinical evaluation; history and physical examination to rule out other diseases and co-morbidities
O Immunological evaluationO Serology; HIV, Hepatitis, CMV, VDRL
O Tissue typing & cross matching
O Blood group
O Infection screening – septic work-up, mantoux
O Others ; FBC, clotting profile, FBS, ECG, U/Ecr, tumour markers, stool microscopy
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Patient selection
O DONOR
a) Cadaveric
O Individuals with severe brain injury
resulting in brain death-Brain death is
defined as “complete irreversible
cessation of all brain functions”.
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Other criteria;
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.
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b. Living donor;
a living donor should be healthy
Living unrelated donor or
Living related donor.
O Improved graft survival
O Less recipient morbidity
O Early function and easier to manage
O Avoidance long waiting time for transplant
O Less aggressive immunosuppressive regimen
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O Contra-indications for living donor ;
O Mental disease
O Disease organ
O Morbidity and mortality risk
O ABO incompatibility
O Crossmatching incompatibility
O Transmissible disease
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Evaluation; to assess for suitability
O CLINCAL; history of risk factors for infection, malignancy in the past 5 years. Presence of co-morbidities
O ABO typing.
O Serology tests.
O Infection and malignant screening
O CT-Angiogram;
O Intravenous urography.
O HLA typing.
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FACTORS DETERMING ORGAN FUNCTION AFTER TRANSPLANT
DONOR CHARACTERISTICS
O ■ Extremes of age
O ■ Presence of pre-existing disease in the transplanted organ
O ■ Haemodynamic and metabolic instability
PROCUREMENT-RELATED FACTORS
O ■ Warm ischaemic time
O ■ Type of preservation solution
O ■ Cold ischaemic time
RECIPIENT-RELATED FACTORS
O ■ Technical factors relating to implantation
O ■ Haemodynamic and metabolic stability
O ■ Immunological factors
O ■ Presence of drugs that impair transplant function
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Tissue typing
O The tissue typing laboratory carries out 3 tasks
O To determine the HLA type of blood for both donor and recipient by PCR.
O Lymphocyte crosshatching to exclude circulating antibodies in recipient against HLA expressed by donor.
O HLA antibody screening and specificityin recipient before and after transplant to guide immunosuppressive therapy
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O Positive cross matching;
O Recipient antibodies attacks donor’s.
O Not suitable for transplant
O Negative cross matching;
O Recipient antibodies donot attack donor
O Suitable for transplant
O Methods;
O Microcytotoxic assay, mixed lymphocytes, flow cytometory, DNA analysis.
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PRE-OPERATIVE
O Patient selection and Evaluation
O Counseling
O Informed consent
O optimization
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COUNSELING
O May involve professional counselors/ psychotherapist
O Aimed at preventing / minimizing possible complication
O Need for adherance to post-op maintenance medications
O Regular follow-up thorough evaluation
O life style modification; smoking, alcohol, sedentary life style, junks, excessive salt ingestion.
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INFORMED CONSENT
O Living Donor ;
O Education
O Willingly not for any financial reason or
under duress
O Most undergo extensive screening –
medical phycological
O Involve family
O Surgery and anaesthetic complications
complications outline to patients
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O DECEASE DONOR
O Some Factors influencing refusal to consent by relatives;
O non-acceptance of brain death.
O Superstitions relating to being reborn with a missing organ
O A delay in funeral
O Lack of consensus within family members
O Fear of social criticism
O Dissatisfaction with the hospital staff
O Religious believes
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INFORMED CONSENT
O RECIPIENT
O Nature of disease and the need for
transplant
O Outcome and complications
O Need for compliance to
immunosuppressive therapy
O Other available options
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OPTIMIZATION OF RECIPIENT
Correction of derangements, getting patient ready for surgery
O Correction of anaemia
O Uremia
O Dehydration
O Treatment of infection
O Treatment of malaria
O Deworming of patient
O Central line
O Urethral catheter
O Loading dose immunosuppression 12hr pre-op
O Prophylactic antibiotics
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PRINCIPLES
INTRA-OPERATIVE
Organ procurement and preservation
Living donors
a. Strict asepsis and hemostasis
b. Adequate exposure
c. Control of the vessels above and below
the organs to be removed is done- cross
clamping
d. Removal of the organ
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NONHEART-BEATING KIDNEY DONATION
Initiation of preservation in situ- for
DCD donors- donation after circulatory
death donors
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h. Transplantation/vascular reconstruction
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
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Maximum and optimal cold storage times (approximate)a
O Organ Optimal (hours ) Safe maximum(hours)
O Kidney < 24 48
O Liver < 12 24
O Pancreas < 10 24
O Small intestine < 4 8
O Heart < 3 6
O Lung < 3 8
Assuming zero warm ischaemic time and organs obtained from a non-marginal
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PRINCIPLES
O Post-operativeO Post-operative assessment
O Clinical –vital signs; fever, tarchychadia, hypertension, pain at site of transplant, pedal oedema (compession of external iliac vein), decrease urine volume- features of hyperacute rejection
O Investigations ; U/Ecr
USS- increase in size, pelvicalyceal dilation
Biopsy; mononuclear infiltrates, fibrinoid necrosis, interstitial haemorrhage.
Others
O Maintenance immunosuppression
O DVT prophylaxis
O Treatment of infection
O Regular follow up
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IMMUNOSUPPRESSION
O The principles are the same for type of organ transplant; maximize graft protection and minimize side effect.
O The agents used to prevent rejection act predominantly on T cells.
O The need for immunosuppression is highest in the first 3 month but indefinite treatment is needed
O It increase the risk of infection and malignancy.
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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
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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
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REGIMENS
O Immunosuppressive agents are given as O Induction; early post-op period
O Maintanance ; given for life
O Rescue agents ; to reverse acute rejection
O Induction regimen (most currently used ) CNI + anti CD 25 monoclonal antibody
Triple therapy ; CNI, antiproliferative agent (MMF) and steroids
Dual therapy ; CNI + MMF or steroids
Polyclonal antibody (ALG/ALS)
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O Maintenance ;
O mTOR- inhibitors (esp in kidney transplant
because they provide a noo-nephrotoxic
alternative to CNI)
O Multidrug therapy ; steroids, antiproliferatives,
CNIs, lymphocytes sequestration –FTY720
O Acute rejection;
O Polyclonal antibody combine with induction
regimen- quadruple therapy.
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COMPLICATIONS OF IMMUNOSUPPRESSION
O INFECTIONS; high risk of opportunistic infections
O Bacterial; common during first month after transplantation / before recovery from surgery
Community acquired infections
Wound infection
UTI (catheter related)
Tuberculosis
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O Viral ; highest in the first six month
CMV infection; may presents as pnuemonia, gastrointestinal disease, hepatitis, retinitis, encephalitis
Herpes simplex virus (HSV) ; mucocuteneous lesions sometimes around the genitalia
BK-virus; graft dysfunction
Herpes zoster infection; chicken pox
O Fungal ; pneumocystic jiroveci(carinii), candidiasis, aspergillosis
O Parasitic; strongiloides, leimaniasis, toxoplasmosis
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O MALIGNANCY
Post transplant lymphoprolipherative
disease (PTLPD); seen 1-3% of kidney
transplant with 50% mortality
Squamous cell ca of the skin
Basal cell ca and malignant melanoma are
higher in transplant patient than the genral
population
50% of transplant patient would develop skin
malignancy in 20years
Kaposi sarcoma; 300 fold increased risk1/19/[email protected] 48
KIDNEY TRANSPLANTO Indications
O End-stage renal disease
Causes
O glomerulonephritis;
O diabetic nephropathy;
O hypertensive nephrosclerosis;
O renal vascular disease;
O polycystic disease;
O pyelonephritis;
O obstructive uropathy;
O systemic lupus erythematosus;
O analgesic nephropathy;
O metabolic disease (oxalosis, amyloid).
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O Donor Nephrectomy
O Open or laparoscopic
O Open donor nephrectomy is the gold standard
O Open donor nephrectomy is via the 12th rib
incision, and in fat patient 10th rib or
hypogastrium
O Extraperitoneal : avoid devascularizing ureter,
sharp dissection, avoid diathermy near vessels
O Renal vasculature dissect flush to IVC/Aorta
O Ligate lumbar veins posteriorly ± gonadal vein
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Donor Kidney Bench Surgery
O The kidney is perfused with ice-cold
preservative
O Iced saline is mashed into a slush and
kidney immersed
O Extra veins ligated, accessory artery(ies)
anastamosed together
O Kidney now ready for transplanting
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THE TRANSPLANT
O Right donor kidney to left recipient site and vice versa
O Gibson’s incision; Curvilinear incision 2 cm above the inguinal ligament, from midline to just above the anterior Sup. Iliac Spine
O End to side venous anastamosis 5/0 prolene
O End to end arterial anastamosis 5/0 prolene
O Implant ureter to bladder 1/19/[email protected] 55
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COMPLICATIONS
O TECHNICAL O Vascular hemorrhage; Vascular thrombosis 10-
20%, within 2-3 days→ technical, 2/12→rejection, most are lost: ↓urine output, ↑creat
O Urological ; infection, fistula, obstruction
O Wound infection
O RENAL O Acute tubula necrosis
O Cortical necrosis
O Lymphocele
O Graft rupture
O Recurrent glomerulo-nephritis
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Outcome
O Patient survival after deceased donor renal transplantation is >90% at 1 year and > 80% at 5 years.
O Graft survival is around90% at 1 year and 75% at 5 years. Graft survival after a second transplant is only marginally worse than after a first graft.
O After living-related kidney transplantation, overall graft survival is around 95% at 1 year and 85% at 5 years.
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ETHICAL CONSIDERATION
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 donationO Fair procurement of cells and tissues O Stewardship for donated cells and tissuesO Quality and safety of HC/HT procurement and
processingO Fair distribution of processed cells and tissuesO Consent for HC/HT transplantation 1/19/[email protected] 59
Future trend
O Genetic engineering –cloning
O Newer specific immuno-suppresive
therapy
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CONCLUSION
O 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 .
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REFERENCES
O Bailey and Love’s “Short Practice of Surgery” 26th edition CRC press Taylor and Francis group. 2013
O E.A Badoe et al, “Principles and Practice of surgery including pathology in the tropics” 4th
edition, Assembly of God Literature Center ltd, 2009
O M.A.R Al-Fallouji; “Postgraduate Surgery the candidate guide”. 2nd Edition. Rced Educational and Professional Pub. Ltd 1998
O Sabiston texbook of surgery. 18th edition.2007
O Andrew C et al “Operative urology at the clevelandclinic” 2nd edition. 2006.
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