In an exciting pilot study published this month in AJT, Stegall et al. used Eculizumab, a C5 inhibitor, to prevent antibody mediated
rejection (AMR) in positive crossmatch living donor transplantation.
High titers of donor
specific antibody bind to the cell surface and activate complement through the
classical pathway. Cleavage of C5
precedes the formation of the MAC complex; therefore blocking C5 should inhibit
complement mediated cell lysis.
Eculizumab is a monoclonal antibody FDA approved for paroxysmal
nocturnal hemoglobinuria with a high affinity for C5.
The authors evaluated patients with donor specific antibody
(DSA) described as a B flow cytometry crossmatch with channel shift (semi
quantitative measure of antibody strength) between 200 and 450 which was
confirmed by Luminex antibody analysis, against their prospective donors. These patients were either treated with
eculizumab (n=26) or a historical control from 2008 - 2010 treated with plasma
exchange (n=51). Both groups received pre-transplant
plasma exchange until the channel shift was under 300. All control patients received post transplant
plasmapheresis while only 3 patients in the Eculizumab group received post
transplant plasma exchange. Patients
were induced with thymoglobulin.
Protocol biopsies were performed on POD# 7, 14, 28, 90 and 365.
Eculizumab was dosed as 1200mgs prior to transplantation
then 600mgs on POD 1, then weekly for 4 weeks.
At week 4 and 8 weeks crossmatch was repeated and eculizumab was stopped
if B cell crossmatch channel shift was below 200. The primary endpoint of the study was the
incidence of antibody mediated rejection in the first 3 months after living
donor transplantation.
Baseline characteristics in both groups including DSA titer
were similar. The incidence of AMR in
the first 3 months was 7.7% in the eculizumab group versus 41.2% in the control
group, with all cases occurring in the first month. Graft survival was 100% and 96%
respectively. A similar percentage of patients
developed high DSA in both groups during the first 3 months. All patients in the Eculizumab group had
positive C4D staining on protocol biopsy compared to 91% of control
patients. Mean serum creatinine was
similar in both groups however, at 1 year 6.7% patients in the eculizumab group
had transplant glomerulopathy compared to 36% of control patients. One patient in the eculizumab group with
transplant glomerulopathy was on eculizumab for a full year and lost his graft
in 2 years. One patient has subclinical
ACR and one patient developed Burketts lymphoma 2.5 years post transplant.
This study is a truly novel approach to positive crossmatch transplantation,
and extends previous reports suggesting efficacy in treating AMR. While most therapies aim at lowering DSA (plasmapheresis,
IVIg, rituximab, velcade), eculizumab simply inhibits the effector pathway of
complement. As the authors point out the
study does suffer from limitations. They
included a historical control rather than to perform a randomized trial, and the
authors did not evaluate efficacy in donor recipient pairs with a CDC positive T
cell crossmatch. It is also true that despite
complement blockade there were patients who still when on to develop AMR and
transplant glomerulopathy. The other
obvious question is what will happen 2 or 3 years down the line after
eculizumab was stopped? In addition to
therapeutic limitations, the approximate cost of a single dose of eculizumab is
about $6,000 dollars making it an extremely expensive therapy. Regardless of these limitations, this is an
exciting study that will hopefully open new doors in treating antibody mediated
rejection and facilitate transplantation of highly sensitized individuals.
Ref:
Post by
Dr.Vinay Nair
Mt Sinai, Transplant Division
New York, USA
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