ORGAN TRASPLANTATION

• Moderator : Dr.Basavaraj

• Presenters : Dr.Guru

Dr.Sunil Math

The History of Organ Transplant

• Prehistoric transplantation exists in mythological tales of chimeric beings

• 1903-1905: Modern transplantation began with the work of Alexis Carrel who refined vascular anastomoses as well as transplanted organs within animals

• 1914-1918: Skin grafting in WWI• 1953: HLA described by Medawar, Billingham and Brent• 1952: Dr. Hume at Peter Bent Bringham Hospital in Boston

attempted allograft kidney from unrelated donor and found that it functioned for a short period; attributed chronic uremia as suppressant of the immune function for the recipient

• 1954: Dr. Joseph E. Murray transplanted kidney from Ronald Herrick to his identical twin, Richard Herrick, to allow him to survive another 8 years despite his ESRD

• 1956: First successful BMT by Dr. Donnall Thomas, the recipient twin received whole body radiation prior to transplant

The History of Organ Transplant Continued

• 1957: Azathioprine deveoped by Drs. Hitchings and Elion• 1966: First successful pancreas transplant by Kelly and Lillehei• 1967: First successful heart transplant by Christiaan Barnard in

South Africa, recipient was 54 yo male who died 18 days after transplant from Pseudomonas pneumonia. That same yr., first successful liver transplant performed by Thomas Starzl

• 1981: First successful heart/lung transplant by Dr. Reitz at Stanford• 1983: First successful lung transplant by Dr. Joel Cooper;

cyclosporin approved• 1984: Congress passed the National Organ Transplant Act (NOTA)

which stated that it was illegal to buy/sell organs, OPTN and UNOS were created as well as the scientific registry of transplant recipients

• 1990: tacrolimus approved• 1995: mycophenolate mofetil approved• 1997: daclizumab approved• 1999: pancreatic islet cell transplant by Dr. Shapiro• 2008: face transplant

Transplantable Organs/Tissues

• Liver• Kidney• Pancreas• Heart • Lung• Intestine• Bone Marrow• Cornea• Blood

Types of Transplant

• Heterotopic or Orthotopic

different same

• Autograft: same being• Isograft/Syngenetic graft: identical twins• Allograft/homograft: same species• Xenograft/heterograft: between species

Pre-Transplantation Evaluation• Blood Type (A, B, AB, and O)

Rh factor does not matter• Human Leukocyte Antigen (HLA); antigens on

WBC; familial matching can be 100-50-or 0%• Crossmatch; if positive, then cannot receive

organ; done multiple times up to 48 hrs prior to transplant

• Serology; for HIV, CMV, hepatitis• Cardiopulmonary, cancer screening

• Although MHC antigens do not exist to prevent organ transplantation, they nonetheless can act as the targets of the immune response in organ rejection. These MHC antigens are particularly important, in part because they elicit both T- and B-cell immune responses.

Recepient Qualification

• Most cases <60 yr old

• Disqualified if:– Recent MI– Active infection– Malignancy– Substance abuse– Limited life expectancy from unrelated

disease

Determination of Brain Death

• Defined formally in 1968 by ad Hoc committee at Harvard headed by Beecher

• Defined by government in Office of the President with Uniform Determination of Death Act in 1981– Individual who has sustained either 1. irreversible

cessation of circulatory or respiratory functions or 2. irreversible cessation of all functions of the entire brain, including brainstem, is dead. A determination of death must be made in accordance with accepted medical standards.

Diagnosis of Brain Death

• Pt suffered irreversible loss of brain function (either cerebral hemisphere or brainstem)

• Establish cause that accounts for loss of function

• Exclude reversible etiology:– Intoxication

}- perform tox screen– NM blockade– Shock– Hypothermia (<90 deg F)warming blanket

When Etiology Determined and NOT Reversible

• LACK OF CEREBRAL FUNCTION

___________________

Deep coma

No response to painful stimuli

**Can have spinal cord reflexes

• LACK OF BRAINSTEM FUNCTION

_______________________

Pupillary reflexesCorneal reflexesOcculocephalic reflexes Occulovestibular reflexesGag reflexCough reflex

Brain Death

• Ancillary Testing to Include:– EEG– Nuclear scan– Angiography for absence of cerebral blood

flow

-Brain death determined after 6 hr with cessation of brain function, 12 hr without confirmatory testing

-Documentation

Transplant Regions

• Organs are first offered to patients within the area in which they were donated* before being offered to other parts of the country in order to: – reduce organ preservation time– improve organ quality and survival outcomes– reduce costs incurred by the transplant

patient – increase access to transplantation*With the exception of perfectly matched donor kidneys.

Graft Rejection

• Hyperacute rejection• Hyperacute rejection usually occurs within

minutes after restoration of the blood supply to a transplanted organ. After an initial period of normal circulation, the transplanted organ becomes swollen and discoloured by interstitial haemorrhage and then undergoes intravascular thrombosis. There is no known intervention that can do more than slightly delay this process once it is begun.

• Accelerated vascular rejection• Accelerated vascular rejection is one of

several terms for a type of rejection that generally occurs within the first week after surgery and is also quite rare in clinical practice. Other names for the process have included simply 'vascular' or 'humoral' rejection. Its three cardinal features are fibrinoid necrosis of the small arteries with evidence of intravascular thrombosis, a relatively scant cellular infiltrate, and the development of a positive cross-match due to the new generation of antidonor antibodies.

• Acute rejection• For most of the history of clinical

transplantation the most common type of rejection encountered has been during the first several weeks to months after organ transplantation and its effects have proceeded rapidly over the course of several days. The process is called acute rejection and it is mediated by T cells. Histologically, there is usually a substantial lymphocyte infiltrate when biopsies from organs undergoing acute rejection are obtained.

• Chronic rejection• Chronic rejection refers to a clinical picture

of slow deterioration in organ function over months or years. The deterioration is difficult to control by standard immunosuppression. With the decline in the frequency of acute rejection episodes, this is now probably the most frequent type of rejection encountered in clinical practice.

ImmunosuppressionType Generic Trade Name MOA SE Monitoring Use

Steroid Prednisone Solumedrol

Medrol, etc.

Inhibition of transcription factors (AP1 and NFKB)

HTN, emotions, ulcer, poor wound healing, myopathy, DLD, moon facies, DM, adrenal insufficiency

None-clinical Induction, Maintenance, Antirejection

Antiproliferative

Azathioprine

(AZA)

Imuran Inhibits synthesis and prolif of T/B lymphocytes

Mylesuppression that is dose-related

Cell Counts, drug levels not available

Combination/Maintainance therapy

Antiproliferative

Mycophenolate Mofetil (MMF)

Cellcept Inhibitor of de novo synthesis of guanine nucleotides

GI side effects

Increased risk of OI

Cyclosporine can decrease levels

More costly than AZA

Rejection prophylaxis in renal, liver and cardiac transplant-especially recurrent rejection

Immunosuppression (con’t)Calcineurin Inhibitors

Cyclosporine

(CSA)

Sandimmune

Neoral

Gengraf

Inhibit transcription of IL-2

Block calcineurin

Nephrotoxic, HTN, DLD, DM, HUS, Neuro, GI, Gingival hyperplasia

Trough levels

Prophylaxis of organ rejection in kidney, liver and heart

Calcineurin Inhibitors

Tacrolimus

(TAC)

FK 506

Prograf Inhibits calcineurin

DLD, HTN Blood levels

Maintanence immunosuppression, recurrent rejection

TOR Inhibitors Sirolimus/Rapamycin

(SIR)

Rapamune Macrolide antibiotics, inhibits kinase the Target of Rapamycin

DLD, increased LDL, thrombocytopenia, neutropenia, anemia

Whole blood levels

Prophylaxis of rejection after renal transplant, combination to prevent acute rejection

BIOETHICAL ISSUES

Transplant TourismWealthy individuals go to poorer nations and buy organs for transplantation

Organ HarvestingOrgans are taken from living or deceased individuals without their consent and sold for transplantation

The World Health Organization (WHO) has ranked the Philippines as one of the top five countries in the world for human organ trafficking

Organ donors, recruited from poor Filipino communities, neighboring provinces, and central Philippines are paid from $2,000 to $3,000 per kidney, but underground syndicates and illicit transplant surgeons make a killing on foreign patients who spend anywhere between $70,000 to $115,000 for a kidney transplant. Liver transplants go as high as $130,000!!!

Baseco, Philippines: “One Kidney Island”

http://www.dailymail.co.uk/news/article-499486/Inside-transplant-tourist-trade-The- desperate-men-One-Kidney-Island.html

Line of despair – Donors from the slums of Baseco with scars from their operations

References(in order of appearance)

1. National Institute of Allergy and Infectious Diseases. Available at: http://www3.niaid.nih.gov/topics/transplant/history. Accessed January 12, 2009.

2. Sade RM. Transplantation at 100 Years: Alexis Carrel, Pioneer Surgeon. Ann Thorac Surg. 2005;80:2415-8.

3. United Network for Organ Sharing. Available at: http://www.unos.org. Accessed January 12, 2009.

4. Lindenfeld J, Miller GG, Shakar SF, Zolty R, Lowes BD, Wolfel EE, Mestroni L, Page RL, Kobashigawa J. Drug Therapy in the Heart Transplant Recipient: Part II: Immunosuppressive Drugs. Circulation. 2004;110:3858-3865.

5. Department of Health and Human Services. Available at: http://www.organdonor.gov. Accessed January 10, 2009.

6. Ad Hoc Committee of the Harvard Medical School. A Definition of Irreversible Coma. JAMA.1968;205(6):337-40.

7. Steinbrook R. Organ Donation after Cardiac Death. NEJM. 2007;357(3):209-13.8. Pascual J, Zamora J, Pirsch JD. A Systematic Review of Kidney Transplantation

From Expanded Criteria Donors. Am J Kid Dis. 2008; 52(3):553-586.9. Siminoff LA, Gordon N, Hewlett J. Factors Influencing Families’ Consent for

Donation of Solid Organs for Transplantation. JAMA. 2001;286(1):71-77.