Medical Advances of Heart Transplant & Transplantation
Statement to the Subcommittee on
Labor, Health and Human Services, Education and Related Agencies
Committee on Appropriations, United States House of Representatives
Presented by Thomas A. Gonwa, M.D.
RE: Funding for the National Institutes
of Health
February 2, 1995
Date posted on the Web: July 25,
1996
Thank you for the invitation to
appear here. I am Thomas A. Gonwa, M.D., President of the American
Society of Transplant Physicians. I am the Director of Clinical
Research and the Associate Director of Transplantation Services,
Baylor University Medical Center, Dallas, Texas. I received
my M.D. degree at the University of Illinois.
Over the last 20 years, transplantation
of solid organs has moved from experimental to accepted therapy.
In 1975, a person receiving a renal transplant had a 50% chance
of success at one year and a 20% chance of dying. In 1995,
the same patient has an 85-90% chance of success and a 5% chance
of dying. Liver and heart transplants were clinically insignificant
in 1975. In 1995, between 400 and 500 patients a month receive
liver and heart transplants and the one year success rate for
both is 80-85%. The growth of transplantation can be seen by
examining data from the United Network for Organ Sharing (UNOS)
Scientific Registry Annual Report. The total transplants performed
in the U.S. has grown from 12,788 in 1988 to 18,168 in 1993;
a 42% increase. Unfortunately, the number of patients on lists
waiting for transplantation has grown considerably from 16,026
in 1988 to 33,352 in 1993; a 108% increase. With the growing
demand for transplant, there has sadly been an increase in
patients dying while waiting for a transplant. During 1993,
2,889 patients died while awaiting transplant, nearly 8 patients
a day.
As a clinician and a transplant
physician, I am reminded daily of the great strides which have
been made. Transplantation is a unique field in which the basic
scientist and the clinician exist in symbiosis. The basic scientist
has made tremendous progress over the last 20 years in understanding
the immune system. Much of this progress has been driven by
the clinical reality of transplantation. Conversely, the clinician
has benefited greatly from the work of the basic scientist
and the knowledge gained has spilled over into all areas of
clinical medicine, not just transplantation. Examples include
research in AIDS, cancer, immunologic disease, and many others.
Most of this work was funded by the National Institutes of
Health (NIH) and must continue.
The costs of transplant are large,
but the rewards are great. No one who has shepherded a young
woman through renal disease, dialysis, transplant, marriage,
and finally child birth would think twice of the importance
of this therapy. Thirty years ago, that same patient would
have died for lack of therapy. Regardless, we must consider
costs. The End Stage Renal Disease program in the United States
has grown dramatically. According to the 1994 annual data report
of the U.S. Renal Data System, there were 186,261 patients
being treated for ESRD and paid by Medicare at the end of 1991.
There has been a steady growth rate in ESRD patients of 8-10%
per year. Of these, 27-30% were transplant patients. Total
costs both public and private in 1991 was estimated to be more
than $8.5 billion. Studies have demonstrated that transplantation
is the most effective and economical long term therapy for
patients with ESRD. Optimizing the total number of transplants
and long term function of transplants would reduce ESRD costs.
Similar savings would be obtained from optimizing heart and
liver transplants.
Mr. Chairman, there are many barriers,
however, which prevent an increase in transplants:
- Organ availability
- Graft loss due to chronic rejection
- Graft loss due to acute rejection.
The research priorities which we
present touch on all three of these areas. First I must state
that the American Society of Transplant Physicians (ASTP) favors
Request For Proposals (RFP) on specific topics to maximize
impact on transplant related research. This funding mechanism
has been utilized successfully by the National Institute for
Allergy and Infectious Diseases. We also believe investigator
initiated research (ROI's) is a good avenue, but given limited
resources, topic driven research may provide a bigger payoff.
The A.S.T.P. would suggest the following priorities need to
be addressed to impact the above restraining forces on transplantation.
#1. CHRONIC REJECTION 1
The leading cause
of renal transplant loss is chronic rejection. Although progress
has been made
in preventing acute graft loss in the first year after transplant,
chronic rejection persists. The rate of loss after the first
year has remained constant over the last 10 years. The number
one diagnosis of patients entering the renal transplant list
is loss of transplant from chronic rejection. A similar situation
exists in heart transplantation. Little is known of the cause
of chronic rejection, thus studies on this topic remain our
highest priority. A recently released study by the National
Institutes of Health sets out the research agenda to deal with
chronic rejection of kidneys. I submit this important work
by "NIH National Kidney and Urologic Advisory Board Transplantation
Task Force" for your consideration. Studies on chronic
rejection of heart transplants are also needed.
#2. XENOTRANSPLANTATION
Xenotransplantation refers to the
use of organs from other species such as baboons or pigs for
human transplantation. This process is particularly difficult
as crossing species leads to violent rejection and destruction
of grafts, however over the last few years, great progress
has been made in understanding this process. The scientific
community is now on the brink of unraveling this problem and
making xenotransplantation a reality. This would greatly increase
the organ supply and make transplant more readily available
to the large numbers of citizens on waiting lists. However,
much work remains to be done. Not only must rejection be overcome,
but better information on possible diseases which could be
transmitted from animals to humans (zoonoses) must be obtained.
A continuation of basic research on both these topics must
be supported.
#3. ACUTE REJECTION 2
Despite recent advances, acute rejection
remains a major problem. Not only is it common in all transplants,
but it leads to increased illness and cost. Furthermore, in
renal transplantation it is the most powerful risk factor for
the development of chronic rejection. Further research is needed
on the cause of acute rejection, cellular mechanisms, drug
therapy for prevention, prediction and treatment. All of these
are complex issues which can only be solved with basic research.
These three areas
(organ availability, graft loss due to chronic rejection, and
graft loss due to
acute rejection) are our top priority for transplant related
research. Three other areas however, deserve special comment
as deserving support also. These are more "cutting edge" and
have great potential for future benefit.
- A. Graft Immunogenicity
- How does the
transplant provoke an immune response? Can it be altered
or genetically engineered
to prevent this? These are "cutting edge" questions
in demand of specific research support. A reduction of immunogenicity
(the ability to provoke response) would lead to reduction
in the use of drugs and all of their associated side effects.
B. Tolerogenic Regimens - The "Holy Grail" of
transplantation is the ability to achieve acceptance of the
transplant without drug therapy (Tolerance). Further research
and clinical trials in this area are greatly needed and would
potentially provide great benefits and cost savings.
C. New Biological Reagents - Development of new drugs which
directly target activated cells and specific receptors are
possible. Recent advances in molecular biology and immunology
can be exploited to create novel biotherapeutic agents which
could revolutionize transplantation. The opportunity awaits
funding support.
FOOTNOTES:
(1) Chronic rejection
is defined as an indolent slowly progressive loss of kidney
transplant function. It occurs at any time post-transplant,
but most commonly shows up at more than six months post-transplant.
It is characterized in a biopsy of the transplant by obliteration
of the blood vessels and gradual fibrosis of the kidney. In
heart transplant, the manifestation of chronic rejection is
hardening of the heart arteries called graft atherosclerosis.
In liver transplants, chronic rejection is manifested by obliteration
of the small bile ducts within the liver and gradual destruction
of the liver transplant.
(2) Acute transplant
rejection is defined as functional and structural deterioration
of the kidney transplant. This is due to the recipient's immune
response to the donor. It does not include nonimmunological
causes of transplant dysfunction such as injury, shock, bleeding,
and technical problems. The clinical expression of rejection
may include graft enlargement, tenderness fever, retention
of sodium and water, decreased urine output, high blood pressure,
and worsening function. The most common cause of kidney transplant
dysfunction in the post-transplant time period is acute rejection.
The highest incidence is in the first three months following
transplant, but it can occur at any time post-transplant particularly
if patients discontinue their transplant drugs. It occurs in
approximately 30-50% of cadaveric transplants and 10-15% of
living related transplants. It can lead to graft loss, and
is expensive to treat along with the associated illness if
it precipitates. the ultimate diagnosis is made on biopsy of
the transplant itself. Acute rejection in heart transplant
can lead to dysfunction of the heart itself with death. It
is characterized, again, by a functional and anatomical disruption
of cardiac function. In liver transplant, acute graft rejection
is manifested by an infiltration of cells into the bile ducts
of the transplant itself leading to marked jaundice and disruption
of graft function. Both in cardiac and liver transplantation,
acute rejection can be fatal due to the life saving nature
of these grafts.
