Organ TransplantationOrgan Transplantation

Anne Huml, M.D.January 21 & 23, 2009

Objectives

• Provide a history of transplantation

• Review organs that are transplantable

• Define types of transplants

• Issues related to recipients

• Overview of immunosuppression

• Issues related to donors

• Other considerations

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 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

Transplantable Organs/Tissues

• Liver• Kidney• Pancreas• Heart • Lung• Intestine• Face• 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

Transplantation Regions

Statistics

All organs 7282

Kidney 5827

Liver 743

Pancreas 106

Kid/Panc 182

Heart 211

Lung 200

Heart/Lung 1

Intestine 12

All organs 2662

Kidney 1498

Liver 610

Pancreas 86

Kid/Panc 115

Heart 174

Lung 144

Heart/Lung 5

Intestine 30

On Waitlist as of 1/9/09 (reg 10) Transplanted in 2007 (reg 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.

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

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 HLAsome 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

Recepient Qualification

• Most cases <60 yr old

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

disease

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.oCr, Bili, and INR

• PELD:<12 y.o.Alb, BIli, INR, growth failure and age

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

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

POOLED HLA (100 DONORS)

Panel Reactive AntibodiesPanel Reactive Antibodies

(PRA)(PRA)

CPRA-calculated from frequency in population

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

– 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

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

“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

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

Apnea Testing

Apnea

Baseline ABGNo ventilator, just oxygenate

10 min with observation for effortOf respiration

Restart ventilator and repeat ABGApnea confirmed if PaCO2 >60

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

Making-up the Difference

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.

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

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

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

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

Other Considerations

• Cost– 1st year billed charges ($250,000-$1 mil)

• Religion

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.