Organ Transplantation

Teodoro Antonio Umali, M.D

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 rejectionie. 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.o
Cr, 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 candidates
unacceptable antigens
If>80%, get 4 extra points
POOLED HLA (100 DONORS)
Panel Reactive Antibodies
(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(VAD) 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
Immunosuppression
Type 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
Antiproliferativ
e
Azathioprine
(AZA)
Imuran Inhibits
synthesis and
prolif of T/B
lymphocytes
Mylesuppressio
n that is dose-
related
Cell Counts,
drug levels
not available
Combination/M
aintainance
therapy
Antiproliferativ
e
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 (cont)
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
immunosupp
ression,
recurrent
rejection
TOR Inhibitors Sirolimus/Rapa
mycin
(SIR)
Rapamune Macrolide
antibiotics,
inhibits kinase
the Target of
Rapamycin
DLD, increased
LDL,
thrombocytope
nia,
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 reflexes
Corneal reflexes
Occulocephalic reflexes
Occulovestibular reflexes
Gag reflex
Cough reflex

Apnea Testing
Apnea
Baseline ABG
No ventilator, just oxygenate
10 min with observation for effort
Of respiration
Restart ventilator and repeat ABG
Apnea 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
criteriairreversible 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 patients 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
1
st
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.