`TRANSPLANT SURGERYfrom Immunology to Surgery

Department of Surgery

Faculty of Medicine and Surgery

University of Santo Tomas

Renato M. Reyes MD

Landmarks on Transplantation in the

PHILIPPINES The first successful Renal Transplant was done at UST

Hospital in1968 by Dr. Domingo Antonio and Renal Transplant Team). A small series of patients were done and later the program was abandoned.

Establishment of a National Health Center: National Kidney & Transplant Institute being the main training program in the country

General Surgeons & Urologist and Fellowship Program overseas contributed to the Training Program of local Transplant Surgeons

Renal Transplantation was the mainstay. Small series of Liver, Pancreas and Heart Transplants were done.

Transplant Immunobiology

unlike surgery in general which was born out of the discovery of knife, needle and

thread TRANSPLANT SURGERY evolved from understanding of the complex process of self none self Immunobiology and the ability to trick this process with elegant

Pharmacological Intervention

Transplant Immunobiology

Major Histocompatibility Complex (MHC) & Minor Histocompatibility Antigens: Class I, II & IIIAntigens on Human Chromosome 6 expressed as HLAMolecules (A,B,C,DP,DQ,DR,DZ etc.)

Recognition of ALLOANTIGEN: T Cell Recognition of MHC (HLA) or Antigen Presenting Cell (APC)

Transplant Immunobiology Activation of T and B Cells: T cells recognize alloantigen

thru the T Cell Receptor (TCR) either as intact molecules (Direct Recognition) or processed allopeptides(Indirect Recognition). Resting B cells bind antigen by

immunoglobulin (Ig) that serves as B Cell Receptor (BCR)

Adhesion Molecules: The central event of rejection process is increased expression of Adhesion Molecules on both Endothelial Cells and Leucocytes: Selectins, Integrins, ICAM (immunoglobulin cell), VCAM (vascular cell) etc.

Transplant Immunobiology

Cytokine Networks: Autocrine and Paracrinemediators of Rejection Inflammatory Response and Transplantation Tolerance. Based on their origin (macrophages, T and B lymphocytes, fibroblast) and location

on chromosomes they are divided into IL, interferons, TNF, CSF and TFGF.

Transplantation Tolerance: Deletion, Anergy, Suppression and Ignorance

Tissue Typing & Cross Matching

Microlymphocytotoxicity Test: Human Lymphocyte & Identified Typing Sera

MHC Transplant Antigens: Class I (HLA A and B) and Class II (HLA DR)

HLA (Human Leukocyte Antigen) exhibits great degree of

polymorphism and co dominant allelic expression

Tissue Typing & Cross Matching

Two Surface Antigens are expressed for each of the MHC

HLA-A, HLA-B and HLA-DR

6 Antigen Match for HLA-A, HLA-B and HLA-DR is a Full House Match or 0 Antigen MisMatch

As a rule, the siblings will inherit 1 Haplotype from each of the Parents. Siblings therefore are 1 Haplotype, 3 Antigen Match & 3 Antigen Mismatch to their Parents

Tissue Typing & Cross Matching

HLA-DR Antigens are the strongest transplantation antigens followed by HLA-B and HLA-A

Tissue Cross Matching: Recipient Current Serum to Donors Peripheral Lymphocyte. A positive cross match is an Absolute Contraindication to Transplantation.

A poor HLA Match is NOT a contraindication to Transplantation

Steps in the Clinical Diagnosis of

BRAINSTEM DEATH:

Ascertain that certain PRECONDITIONS has been met: COMATOSE and VENTILATOR DEPENDENT

EXCLUDE reversible causes of non functioning Brainstem: HYPOTHERMIA, DRUG INTOXICATION andSEVERE METABOLIC DISTURBANCE

Establish that comatose patient is APNEIC and that BRAINSTEM REFLEXES are absent: NO PUPILLARY, CORNEAL, VESTIBULO-OCULAR, MOTOR RESPONSE,GAG REFLEX, RESPONSE TO TRACHEOBRONCHIAL CATHETER STIMULATION

Recommended Criteria for Screening Potential Cadaver Donors

Maximum Age: 65 years with Compatible Blood Type

No History of: HPN, DM, Malignancy and Drug Abuse

No Evidence of: Renal Disease and Generalized Viral or Bacterial Infection

Acceptable Urinalysis

Preterminal Urine Output above .5mL per/Kg/Hr

Normal BUN, Creatinine and Liver Function Tests

Warm Ischemia Time < 60 Minutes

Negative Serology: HIV, HBV & HCV

Cadaveric Organ Donation

Republic Act No. 7170: Organ Donation Act of 1991 and subsequent DOH pronouncements on the conduct of transplantation.

Brainstem Dead Donors

Heart Beating Cadaveric Donors

Excluded are History of Cardiac Arrest or Witnessed Cardiopulmonary Arrest (optional)

Surgical Explantation will result in Exsanguinationand Cessation of Cardiac Activity

Living Organ Donor

Living Related and Living Non Related Donation

Living Emotionally Related Donation

Living Liver Donor: Segmental Organ Donation

Legal and Illegal, Moral and Immoral

Commercial Donation and Rewarded Gifting

Routine Evaluation of a Potential Living Related Donor

Blood Typing, HLA Typing & Cross Matching

CBC, Serum Electrolytes, Coagulation Studies

Hepatitis Profile, HIV and CMV Studies

Liver Function Test, Cholesterol & Triglycerides

Urinalysis, Creatinine Clearance, Uric Acid

VDRL, Pregnancy Test

Glucose Tolerance Test

CP and Medical Clearance

Routine Evaluation of a Pretransplant Patient

Blood Typing and Tissue Typing

Hepatitis Profile: HBV and HCV

Viral Titers: EBV and CMV

CBC, Electrolytes, Coagulation Profile

Liver Function Tests, Cholesterol, Triglycerides, FBS, Renal Function Tests

HIV and VDRL

CP and Medical Clearance

Organ Retrieval and Preservation

Living Donor Harvesting:

Systematic Vascular & Ductal / Drainage Isolation, Transection & Ex Vivo Cooling and Perfusion

Cadaveric Organ Harvesting:

Arterial and Venous Cannulation

In Situ Arterial Perfusion and Core / Topical and Venous Exsanguination

Sequential Organ Evisceration and Bench Surgery Preparation

Organ Retrieval and Preservation

Hypothermic Preservation ( approx. 4 degrees Centigrade ) by In Situ or Ex Vivo Perfusion & Core and Topical Cooling

Perfusion w/ Chilled LRS, Collins, euroCollins or UW (University of Wisconsin ), Custodiol HTK Soln. (HistidineTryptophan Ketoglutarate) Preservative Solution

Injury During Preservation due to Mitochondrial Damage(loss of ATP precursors), Oxygen Free Radicals, Activation of Catabolic Enzymes from the Lysozomes(phospholipases & proteases) and Cytotoxic Products(thromboxane & leukotrienes)

Immunosuppressive Agents

STEROID: blocks Ca ionophore induced lymphocyte proliferation

Lymphokine Synthesis Inhibitors: CYCLOSPORINEand TACROLIMUS (FK506)

Nucleoside Synthesis Inhibitor: AZATHIOPRINE &MYCOPHENOLATE MOFETIL (RS61443)

Cytokine Signal Transduction Inhibitors: SIROLIMUS & LEFLUNOMIDE

MONOCLONAL & POLYCLONAL ANTIBODIES: for induction and reversal or rescue of acute rejection episode

The Clinical Immunosuppressive Matrix

Prevention and Prophylaxis of Acute Rejection Episode: Positive cross match is absolute contraindication. Identification of immunologically reactive recipients with PRA (panel of reactive antibodies)

Induction Immunosuppression: Two (2) weeks after transplant using sequential or standard immunosupression

Short Term Maintenance Immunosuppression: First 90 days after transplant characterized by delicate balancing of CyA or Tacrolimus, Mofetil and Steroids

The Clinical Immunosuppressive Matrix

Anti Rejection Immunosuppression: Period of Acute Rejection Episode within the first year of transplant. Treated with pulse steroid therapy (IV methylprednisolone) for 3 to 5 days. Steroid resistant episode is treated with OKT3 or with polyclonal antibodies

Long Term Maintenance Immunosuppression: Progressive reduction of immunosuppressive drugs.

The Risks of Immunosuppression

NEOPLASIA

The Risk for Cancer is 1% to 16%

Most Common are Non Melanotic Skin & Lip Cancer, Lymphoproliferative Diseases (LPD) and Cervical Carcinoma

OKT3 Treatment Poses a Particular Risk for LPD

Therapy is Based on Surgical Extirpation with Reduction of Immunosuppressive Therapy

The Risk of Immunosuppression

INFECTIONS

80% Develop at Least One Infection After Transplantation

40% of Death are Due to Infectious Complications

55% are Bacterial, 30% Viral and 15% Fungal

Most Infection Arise in the Urinary Tract, Plastic Venous Catheters, Surgical Wound and IntraAbdominal Site

The Risk of Immunosuppression

INFECTION Bacterial Infections are Polymicrobial

Most Common Viral Infection are DNA Viruses of the Herpes Virus Family (CMV, EBV, HSV & VZV)

Use of Polyclonal Antibodies and Monoclonal Antibodies for Acute Rejection Episodes are Associated with Increased Risk for Viral Infections

Candida Albicans and Pneumocystic Carinii are Most Common Fungal and Protozoal Agents Respectively

Solid Organ TRANSPLANTATION:An Overview

Renal Transplantation: ESRF

Liver Transplantation: Cirrhosis, Biliary Atresia, Acute Liver Failure & Inborn Errors of Metabolism

Heart Transplantation: Ischemic Disease, Cardiomyopathy, Valvular Disease, Congenital Disease, Drug Induced Myocardial Destruction

Pancreas Transplantation: Insulin Dependent Diabetes Mellitus

Small Bowel Transplantation: Short Bowel from vascular and congenital conditions

dont bring your ORGANS to Heaven, God Knows We Need Them Here

TRANSPLANTis Good,

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