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136 What is chronic rejection? What is being done about it?


This article is from the Organ Transplant FAQ, by mike_holloway@hotmail.com (Michael Holloway) with numerous contributions by others.

136 What is chronic rejection? What is being done about it?

There are three general forms of rejection: hyperacute, acute, and chronic.
"Hyperacute" rejection occurs within minutes of transplantation due to
antibodies in the organ recipients blood stream that react with the new
organ and result in organ failure within the first hours after
transplantation. The kidney and heart are most susceptible to this problem,
the liver is relatively resistant. Hyperacute rejection has not been
sufficiently studied in pancreas or lung transplantation. Cross matches are
done between a particular kidney and a potential recipient of that kidney
to decrease the likelihood that hyperacute rejection will occur. "Acute"
rejection generally occurs in the first 6 to 12 months after
transplantation. Lymphocytes from the thymus (t-cells) are blamed for
causing acute rejection. For most organs, the only way to show
unequivocally that rejection is occurring is by biopsy of that organ. For
practical reason, however, biopsies are not always done when acute
rejection is suspected. In some circumstances treatment for rejection is
begun and a biopsy is performed at a later date if the organ doesn't seem
to be improving. This strategy varies from organ to organ and transplant
center to transplant center. The diagnosis and treatment of acute rejection
can be extremely difficult at times.

Chronic rejection is less well defined than either hyperacute or acute
rejection. It is probably caused by multiple factors: antibodies as well as
lymphocytes. The definitive diagnosis of chronic rejection is again
generally made by biopsy of the organ in question. The heart is an
exception to this generalization: chronic rejection in heart grafts is felt
to be manifest by accelerated graft atherosclerosis. In other words, the
transplanted heart rapidly develops "hardening of the arteries". Kidneys
with chronic rejection have fibrosis (scarring) and damage to the
microscopic blood vessels in the substance of the kidney. Livers with
chronic rejection have a decreased number of bile ducts on biopsy. This is
referred to as the "vanishing bile duct syndrome". Transplanted lungs with
chronic rejection are said to have "bronchiolitis obilterans" a scarring
problem in the substance of the lung.

To date, most research has focused on graft survival for the first three
years. It is not that we, the physicians involved with transplantation,
don't care about long term results. The long term problem is simply tough
to tackle. Animal models exist but they do not perfectly reflect what goes
on in humans. Most studies on people that look at long term outcome are not
well "controlled", so their conclusions are nebulous. To be "controlled" a
study needs to have two groups of patients, one that received a particular
treatment and one that didn't. The best kind of controlled study is
prospective and randomized, meaning the decision as to which treatment the
patient has is decided before the treatment begins in a random fashion.
This eliminates many biases that otherwise appear. Theses studies take very
long time periods, are extremely difficult and labor intensive and require
large numbers of patients to look at long term results. More typically,
studies use "historical controls" meaning that one group, say patients
transplanted from 1987 to 1990 is compared to another group of patients
transplanted at a different time point, like 1984 to 1986. The problem with
such studies is that so many things changed between the two groups.
Techniques change: better perfusion solutions for the organs, quicker, more
accurate methods of measuring blood levels of cyclosporine ("Sandimmune").
New agents, like FK506 (tacrolimus or "Prograf") are introduced and other
agents are removed from the market. Understanding of common infections in
transplant patients improves; this improves overall results even though the
improvement wasn't exactly related to what immunosuppression they received.
The studies therefore get muddled over the years. To look at ten year
results today we have to look at transplants that were done in 1985 when
techniques were significantly different in many ways from the way we do
things now. So the bottom line is that much of what we do today is not
firmly based on actual evidence that it is the one best treatment. This
explains why different transplant centers do different things: their
particular experience has been biased by the particular patient population.

Fortunately, much work is currently being done on chronic rejection, both
in the lab and clinically. Some new agents not yet in use clinically look
to be particularly effective at combating chronic rejection. As these new
drugs appear long term graft survival will hopefully increase. In many
situations, the current standard treatment for chronic rejection is
retransplantation. This approach is not satisfactory, however, because it
makes the existing organ shortage worse, and retransplantation is more
difficult from a surgical perspective.

Jeff Punch
Transplant Surgery
University of Michigan


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