Good article on advances on positive -crossmatch transplants

I copied and pasted the article so it will last even if the link goes dead. Thanks Jill!
okarol/admin

G I F T O F L I F E T R A N S P L A N T H O U S E VOLUME 9 | NO 3 | FA L L 2 0 0 9

Innovative Therapeutic Options for
Sensitized Renal Transplant Candidates

Mark D. Stegall, M.D., Professor of Surgery

Antibodies are an important part of the body’s normal immune protection
against infection. However, a blood transfusion or a prior transplant
can stimulate the body to make antibodies against other people’s “tissue
types” (the scientific term is Human Leukocyte Antigens or HLA).
Antibodies against HLA can be a major problem for people who need a
kidney transplant. When these antibodies are present in the bloodstream
at high levels, they can attack and damage a new kidney early
after transplant leading to early or late graft loss. Patients with these
anti-HLA antibodies are termed “sensitized” and the problem is becoming
more common—especially in people who require a second transplant
after a long-functioning transplant fails.
Historically, the risk of graft failure in patients who have antibodies
against their donor’s tissue types has been so high that most transplant
programs have considered this situation an absolute contraindication to
kidney transplantation. Patients with this condition were left with few
options. Most were placed on the deceased donor waiting list, but few
ever received a donor against whom they did not have antibodies.
Our group here at Mayo Clinic, Rochester, has become one of the
world leaders in overcoming antibody barriers to kidney transplantation.
Over the past decade, we have transplanted more than 200 kidneys into
recipients with antibodies against donor HLA. Our main approach has
been to remove the antibodies using a dialysis-like procedure called
plasmaphersis. While this technique has resulted in successful kidney
transplants in many sensitized patients, it is still complicated by high
rates of antibody-mediated damage. In addition, we have found that
some patients have antibody levels that are just too high for a successful
transplant even with plasmapheresis. This situation stimulated our group
to search for new therapeutic approaches to control anti-HLA antibody
and to ameliorate its effects on the transplanted kidney. Fortunately,
over the past year, two new studies that are testing new medicines are
beginning to show promising results. Both are approved by the Mayo
Institutional Review Board and both are still ongoing.
The first study is intended to improve the outcomes of our existing
plasmapheresis-based protocols. The rationale for using this new drug is
based on the role of specialized serum proteins, called complement, in
antibody-mediated damage. We have shown that when antibody binds to
the kidney transplant, it activates complement. Early after transplant, it
appears that antibody-activated complement actually does most of the
damage to the kidney and not the antibody by itself. Thus, we hypothesized
that blocking the body’s complement system might prevent antibody-
mediated damage of the kidney. A novel drug called Eculizumab
has been shown to block the activation of some types of complement.
The drug is approved by the FDA for a rare condition involving abnormal
complement activation (called Paroxysmal Nocturnal Hemoglobinuria).
Thus much experience exists with the drug and its safety profile is wellestablished.
In this study, patients with anti-HLA antibody against their
living donor undergo our usual plasmapheresis
treatment. In addition, they receive eculizumab
at the time of transplant and weekly for at least
the first month after transplant. Compared to
plasmapheresis alone in which antibody-mediated
rejection occurred in almost 40% of patients
in the first month after transplantation, none of
the first 10 patients treated with eculizumab
have developed rejection. All of the kidneys in
eculizumab-treated recipients are functioning
well and biopsies of the kidneys are normal.
Most patients have been able to stop eculizumab
within 3 months of transplant when anti-HLA
antibody levels have decreased to safe levels.
However, two patients have required longer
treatment.
The second study is aimed to help those patients with very high levels of
antibody—too high for our existing plasmapheresis protocols to be successful.
The medicine in this study is called Velcade and it is approved
by the Food and Drug Administration for the treatment of multiple
myeloma. Again, there is a large amount of clinical experience with this
drug and its safety profile is well-known. In preliminary studies in my
laboratory, we found that Velcade attacks normal antibody-producing
cells and thus might decrease antibody production. Since the drug
affects antibody secreting cells, the outcome that we are interested in
monitoring is the number and function of anti-HLA antibody producing
cells. These cells primarily live in the bone marrow, thus we need to take
a bone marrow sample before and after Velcade treatment to measure its
effect. If we detect a significant decrease in the cells making antibodies
against HLA, then we start our usual plasmapheresis protocol to see if
we can reduce serum antibody levels to a safe, transplantable level. The
first iteration of this protocol involved a relatively short treatment
schedule. Three of the first 4 patients treated responded. Of these 3, 2
have undergone transplant successfully and a third is scheduled. As we
gain more experience with the drug in transplant patients, we are finding
that longer treatments may be needed in patients with very high
antibody levels. Currently, we are testing this longer treatment in 5
more patients and the results appear to be better than the shorter treatment
regiment. We are hopeful that these patients will be transplanted
as they complete the protocol. Importantly, the treatment and the bone
marrow aspirations have been tolerated quite well.
We are optimistic that these new treatment options will improve the
outcome of kidney transplantation in sensitized patients. Without these
innovative protocols, many patients may never receive a kidney transplant.
Finally, our group also continues to explore other options for sensitized
patients such as participation in a national paired donor program
as they become available.