Clinical Use Of XM-ONE® Discussed in a symposium at the ATC meeting.

Improving outcomes in kidney transplantation: Non-HLA antibodies and Enhanced Clinical Risk Assessment

On May 2 AbSorber sponsored a symposium at the American Transplant Congress held in Philadelphia, PA. The symposium focused on the clinical experience of using XM-ONE in pre transplant risk assessment in kidney transplantation and was co-chaired by Professors Kathryn Wood, Oxford, UK and Robert Montgomery, Baltimore, MD.

XM-ONE has previously been shown to identify patients at risk for early rejections in a well known multicenter study published in Transplantation in 2009 (Breimer, M et al, http://www.ncbi.nlm.nih.gov/pubmed/19307793) and in the last issue of the same paper these data was confirmed in a study performed at Johns Hopkins School of Medicine, Baltimore, MD (Jackson, AM et al, http://www.ncbi.nlm.nih.gov/pubmed/21516064).

Professor Wood started the symposium with the message that “transplant specialists have always tried to bring new tools into our armamentarium to assess risk between individual donors and recipients”. She presented data from retrospective studies that pre-assessment of new transplant patients can enhance the current standard of risk assessment. “The more tools we have, the more complex it gets, but understanding how to best use the immunosuppression we have available for each patient will have a huge impact on outcomes, particularly long-term outcomes,” said Prof. Wood. Although clinical teams test for HLA antibody reactivity before a transplant, Prof. Wood said antibody-mediated rejection (AMR) still shows up in a subset of recipients with negative cross matches.

How do we utilize the pre transplant risk assessment in organ transplantation?

This question was asked by Dr Phillip Ruiz, Professor of pathology and transplant surgery at the University of Miami, FL. As Dr Ruiz discussed there are a number of “risks” to assess, not only immunological risks but also risks such as nutritional and metabolic status, native disease and general health status of the patient. However, when focusing on the immunological testing in a donor workup a number of tests are performed (ABO typing, HLA typing, PRA (cPRA) – If live donor present, CDC, flow X-match, and DSA testing). There is also the post transplant monitoring of the immune status and response to consider. “This is however only the tip of the iceberg” Dr Ruiz stated. The challenge is to Identifying and managing hidden or unknown forces that will negatively impact on the allograft, he continued.

The purpose of a cross match is to detect the presence of antibodies in the recipient that are specific and potentially deleterious to the donated organ.

The target cell until recently was exclusively lymphocytes and the type of Ab identified are anti-HLA antibodies. With the introduction of XM-ONE, Endothelial cells can now serve as a target population in the cross match.

In the correct setting (neg. lymphocyte B/T cross match), this assay may identify anti-endothelial Abs. Endothelial cells are a prime target in allografts.

• Express both HLA and lineage specific membrane molecules

• Allow extravasation of inflammatory cells into the graft

• Respond to numerous cytokines and other mediators

• Act as APCs

Dr Ruiz concluded his talk by stating that Abs specific for non-HLA are clinically significant. Both HLA and non-HLA antibodies are associated with impaired graft half-life and by testing for these antibodies we identify patients at increased risk of rejections and reduced kidney function.

Dr John Friedewald from Northwestern University in Chicago, IL discussed their ongoing single center study. The study inclusion closed December 2010 and the follow up period is set to one year. Data reported at this time is still very preliminary. Study endpoint are acute rejections and renal function. At Northwestern protocol biopsies are performed at 1 year post transplantation and, obviously, very few patients in the study has reached that time point. In total 152 patients were included and the frequency of XM-ONE positivity was 18%. Campath was used as induction therapy in all patients and TAC/MPA was used as maintenance treatment. Dr Friedewald stated that it is still much too early to comment on the clinical outcome of the study. Their current approach is to focus on findings in the protocol biopsies, especially the chronic vascular score (Banff), proteinuria and other components related to renal function.

Intervening on the XM-ONE result

A frequent question asked by clinicians after discussing XM-ONE is what one should do if a patient is positive in the test. Professor Jan Holgersson from Sahlgrenska University Hospital in Gothenburg, Sweden, tried to bring light to this by presenting data from 99 patients transplanted with a living donor kidney at Karolinska University Hospital in Stockholm, Sweden. These 99 patients were evaluated with XM-ONE during donor evaluation (months pre transplant) and at transplantation. IgG+ and IgG+/IgM+ patients were to a large extent pre-treated with rituximab, plasmapheresis and/or immuno-adsorption, while the majority of the XM-ONE IgM+ patients received no pre-treatment. 26/99 patients (26%) were EPCXM+ during the evaluation phase. 16/26 (62%) received pre-treatment and 10/26 did not. Of the EPCXM+ and pre-treated patients, 31% had HLA DSA, 38% were re-transplanted and 62% received an ABOi graft. The rejection frequency in the EPCXM+ and pre-treated patients was 19% (3/16), while it was 21% (14/68) in the group of patients that were EPCXM- at all times. Further prospective studies with appropriate control groups are needed in order to establish whether pre-treatments aiming at removing AECA pre-transplant has a beneficial effect on graft survival.

Data from Johns Hopkins support findings from published multicenter study

Professor Robert Montgomery from Johns Hopkins presented long term data on 60 kidney transplant patients. Data from these patients was comparable with the Multicenter Study patients, and in total Dr Montgomery presented a rejection frequency of 36% among the XM-ONE® positive patients compared to 17% in the negative group. All rejections in the XM-ONE® positive group were classified as cellular rejection based on the Banff ’97 criteria. These criteria were chosen since they were previously used in evaluating patients in the Multicenter Study. Dr Montgomery concluded by saying that transplantation across a positive endothelial XM appears to associated with an increase in early dysfunction and rejections (vascular type) but not the characteristic histologic and immunohistologic features of AMR associated with HLA antibodies However, Dr Montgomery started his presentation by discussing two different cases which he found was representative for showing the clinical significance of using XM-ONE in pre transplant assessment of risk in kidney transplant recipients. These two cases where both living donor transplants with two previous transplants that had failed. In the work up of these two patients the patients had no HLA DSA against the chosen donor. However, in both cases there was a history of anti-endothelial cell antibodies detected by XM-ONE. These cases had significantly different outcome, in the first case the kidney was lost shortly after transplantation but in case two the patient had an excellent function and is currently doing fine. Dr Montgomery showed that in patient number one the XM-ONE test had become positive shortly before transplantation while in case two the patient had received multiple plasmapheresis sessions ensuring that the antibodies would not reappear. Dr Montgomery’s take home message was that Plasmapheresis/IVIg appears to deplete anti-endothelial antibodies and that desensitization may play a role in preventing early injury.

The study from Johns Hopkins has recently been published in Transplantation and is available at PubMed; http://www.ncbi.nlm.nih.gov/pubmed/21516064

New insights into the significance of non-HLA antibodies

Professor Wood summarized the meeting by concluding that understanding of the role that non-HLA antibodies play in transplantation, both pre and post-transplant, is still evolving. The case reports and ongoing clinical studies presented during the symposium provided new insights into the significance of non-HLA antibodies and highlighted the value that having information about pre-existing non-HLA antibodies can bring to pre-transplant risk assessment.

“AbSorber is excited about the very positive interest that XM-ONE® has received in the transplant community around the world. The data presented and discussed at this Clinical Advisory Board Meeting further supports the role and utility of XM-ONE® in organ transplantation” , according to Anders Karlsson, CEO of AbSorber.

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