Organ Transplantation

1. Organ Transplantation Anne Huml, M.D. January 21 & 23, 2009

3. 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

4. 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 Standford 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

6. Transplantable Organs/Tissues Liver Kidney Pancreas Heart Lung Intestine Face Bone Marrow Cornea Blood

7. Types of Transplant Heterotopic or Orthotopic different same Autograft: same being Isograft/Syngenetic graft: identical twins Allograft/homograft: same species Xenograft/heterograft: between species

8. Transplantation Regions

9. Statistics

10. 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.

11. 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

12. Details of HLA HLA=Human Leukocyte Antigens which are found on the surface of WBC Function of HLA is to help identify and in turn, fight “foreign stuff” 2 types of HLA?some for MHC I and MHC II (MHC genes are on chromosome 6) Most important HLA are types A, B (MHC I) and DR (MHC II) Remember MHC I present antigens to cytotoxic T cells and MHC II use antigen-presenting cells for helper T cells For this reason, it is important to have closely matched HLA between donor and recipient to avoid rejection—ie. To avoid donor cells being presented to recipient immune system by MHC for destruction

13. Recepient Qualification Most cases <60 yr old Disqualified if: Recent MI Active infection Malignancy Substance abuse Limited life expectancy from unrelated disease

14. Tools Used to Stratify Transplant Recipients MELD/PELD= model for end stage liver disease and pediatric end stage liver disease MELD developed in 2002 to account for objective findings rather than subjective findings; range is 6-40 Exception is Status 1=<1% of waitlist MELD:>12y.o Cr, Bili, and INR PELD:<12 y.o. Alb, BIli, INR, growth failure and age

15. Tools Used to Stratify Transplant Recipients LAS= Lung Allocation Score, range 0-100 Developed in May, 2005 to reflect medical status of recipient as well as likelihood of successful transplant Age>12

16. Tools Used to Stratify Transplant Recipients CPRA=calculated Panel Reactive Antibody Used in allocation of kidney, pancreas, and kid/pancr Developed in 2004 Measure of antibody sensitization; reflects % of donors not compatible with candidate secondary to candidate’s unacceptable antigens If>80%, get 4 extra points

17. Tools Used to Stratify Transplant Recipients Cardiac transplant uses Candidate Status as follows: 1A: admitted to the transplant center with one of the following: Mechanical ventricular assist device x 30 days with clinical stability Total artificial heart IABP ECMO

18. Mechanical circulatory support with evidence of device related complication Continuous mechanical ventilation Continuous infusion of high dose single inotrope or multiple IV inotropes in addition to continuous hemodynamic monitoring of LV filling pressures 1B: L/R VAD with continuous infusion of inotropes 2: does not fulfill criteria of 1A/B 7: currently unsuitable for transplant

19. Immunosuppression

20. Immunosuppression (con’t)

22. “The Waiting Game” As of 1/20/09; there are 100,568 patients waiting for organ transplantation Average waiting time (as of 2003) -heart 230 days -lung 1068 days -liver 796 days -kidney 1121 days -pancreas 501 days

23. 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.

24. 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

25. 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 reflexes Corneal reflexes Occulocephalic reflexes Occulovestibular reflexes Gag reflex Cough reflex

26. Apnea Testing

27. 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

28. Making-up the Difference

29. Organ Donation after Cardiac Death Death declared on basis of cardiopulmonary criteria—irreversible cessation of circulatory and respiratory function. In 2005, IOM declared that donation after cardiac death was “an ethically acceptable practice in end-of-life care” and in March, 2007 UNOS/OPTN developed rules for it which became effective on July 1, 2007. Outcomes similar to those for organs transplanted after brain death.

31. Key Elements in the Process of Donation after Cardiac Death Withdrawal of life sustaining measures Pronouncement of death from time of onset of asystole (usually btwn 2-5 minutes); 60 sec is longest reported time of autoresuscitation To avoid conflicts of interest transplantation team physicians are not a member of the end-of-life care or declaration of death Liver within 30 min and kidney within 60 min If time to asystole exceeds 5 min, then recovery of organs is canceled

32. Drawbacks to Transplantation after Cardiac Death Healthcare workers may be uncomfortable recommending withdrawal of care for one pt to obtain organ for a second Interval between withdrawal of care and death may be shortened and family relationship may be altered Conflict of interest Use of heart in cardiac transplantation

33. Other Types of Donation Extended Criteria Donation (ECD) Defined as brain dead donor who is >60 yrs of age, or donor >50 yrs of age with 2 of the following: HTN, terminal SCr >1.5 mg/dl, or death resulting from CVA Living Donation With liver and kidney

35. Factors Contributing to Family Consent for Donation JAMA article published in 2001 about a study conducted over 5 yrs at 9 trauma centers in PA and OH Chart audit, then interview of healthcare practitioners (HCP) and organ procurement organization (OPO) staff as well as family for donor-eligible families Consent for donation mostly from young, white males with death associated with trauma Families reported + beliefs with organ donation, had prior knowledge of patient’s wishes (through donor card or discussion) Best process was that HCP approached possibility of donation followed by OPO HCP were poor judges of who would donate Family appreciated open discussions about cost, impact on funeral arrangements and organ selection for donation

36. Other Considerations Cost 1st year billed charges ($250,000-$1 mil) Religion

37. References(in order of appearance) National Institute of Allergy and Infectious Diseases. Available at: http://www3.niaid.nih.gov/topics/transplant/history. Accessed January 12, 2009. Sade RM. Transplantation at 100 Years: Alexis Carrel, Pioneer Surgeon. Ann Thorac Surg. 2005;80:2415-8. United Network for Organ Sharing. Available at: http://www.unos.org. Accessed January 12, 2009. 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. Department of Health and Human Services. Available at: http://www.organdonor.gov. Accessed January 10, 2009. Ad Hoc Committee of the Harvard Medical School. A Definition of Irreversible Coma. JAMA.1968;205(6):337-40. Steinbrook R. Organ Donation after Cardiac Death. NEJM. 2007;357(3):209-13. 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. Siminoff LA, Gordon N, Hewlett J. Factors Influencing Families’ Consent for Donation of Solid Organs for Transplantation. JAMA. 2001;286(1):71-77.