Monday, November 14, 2011

Journal Club: Blocking complement prevents antibody mediated rejection in positive crossmatch living donor transplantation.

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.  

Post by 
Dr.Vinay Nair
Mt Sinai, Transplant Division
New York, USA

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