ESOT 2013 Report – DSA in 2013: What is it? How do we prevent it? How do we manage it?

by Maria Dalby – Donor-specific anti-human leukocyte antigen (HLA) antibodies, or DSAs, have emerged in recent years as one of the most important factors for predicting the outcome of solid organ transplantations. In the second Astellas sponsored satellite symposium at ESOT 2013, a distinguished panel of scientists and clinicians discussed current technologies and protocols and the implications of de novo DSAs in clinical practice.

Dr Sue Fuggle from Oxford opened the symposium with an overview of the detection and specification of DSAs. Advances in technology has allowed laboratory scientists to move away from cell-based assays and increasingly use highly sensitive solid phase immunoassays for detecting DSAs. Dr Fuggle’s team has carried out extensive work using the Luminex bead assay which allows very low levels of DSAs to be detected. These findings can be used for informing clinical decisions based on the risk of developing antibody-mediated rejection, and for monitoring treatment regimens.

In the next session, Dr Alexandre Loupy from the Paris Translational Research Centre for Organ Transplantation outlined the importance of preventing the development of de novo DSAs. Once DSAs appear, they represent a continuous process towards worsening endothelial injury and deteriorating graft function which will ultimately lead to graft loss [1,2]. There are curative treatments available, such as plasmapheresis, but as Dr Loupy reminded the audience, these are not always effective and it is therefore essential to have effective prevention protocols in place [3]. Prior to the transplantation, there are few risk factors for HLA sensitisation that can actually be modified – one is blood transfusions, which are known to increase the risk of developing HLA antibodies by as much as 10 times [4]. At the time of the transplantation it is important to avoid unacceptable mismatches [5,6].

In contrast, a range of modifiable risk factors will affect the outcome post-transplantation. Non-adherence with immunosuppressive therapy has been found to be a major cause of graft failure – more than half of all cases of graft failure due to antibody-mediated rejection are thought to be due to non-adherence [7]. In a survey, 68% of US transplant programmes reported deaths and graft losses due to cost-related non-adherence [8]. Other modifiable risk factors include immunosuppression minimisation and/or switch protocols, which have been shown to involve a significant risk of adverse graft outcomes [9].

The clinical implications of DSAs were discussed by Dr Peter Nickerson from the University of Manitoba in Canada. Dr Nickerson pointed out that the literature on de novo DSA development suffers from limitations, both in terms of the sensitivity of the assays used to detect the antibodies and the definition of ‘de novo’, and also in terms of the length of follow-up. Recently published data from Dr Nickerson’s own centre shows that kidney transplant recipients who develop DSA antibodies have significantly poorer 10-year graft survival compared with those who do not (57% vs 96%, p < 0.0001) [10]. Univariate analysis in this population has revealed predictors of de novo DSA that often are detectable long before the first signs of graft dysfunction, thereby providing opportunities to intervene and prevent adverse outcomes. These predictors include younger age, previous rejection episodes, and the use of non-tacrolimus-based immunosuppression [11].

In the final presentation of the symposium, Professor Robert Montgomery from Johns Hopkins University in Baltimore shared some of the experience at his centre of the practical management of desensitisation strategies for preventing DSA development in HLA-incompatible live donor transplantations, stressing the importance of taking into account all the available information and assessing each patient based on his/her individual presentation. In the concluding patient case discussion, which involved a 17-year old male with Alport’s syndrome who developed biopsy-proven rejection five years after receiving a kidney transplantation from a living related donor, the majority of delegates in the audience would consider treatment with intravenous immunoglobulin, with or without plasmapheresis  (55.6%); a smaller proportion (20%) would consider treatment with rituximab.

 

References

1. Loupy, A., G.S. Hill, and S.C. Jordan, The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol, 2012. 8(6): p. 348-57.

2.Hidalgo, L.G., et al., De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure. Am J Transplant, 2009. 9(11): p. 2532-41.

3. Bradley, J.A., et al., Antibody-mediated rejection–an ounce of prevention is worth a pound of cure. Am J Transplant, 2011. 11(6): p. 1131-9.

4. Yabu, J.M., et al., Sensitization from transfusion in patients awaiting primary kidney transplant. Nephrol Dial Transplant, 2013.

5. Lefaucheur, C., et al., Mastering the risk of HLA antibodies in kidney transplantation: an algorithm based on pretransplant single-antigen flow bead techniques. Am J Transplant, 2011. 11(8): p. 1592-8.

6. Rees, M.A., et al., A nonsimultaneous, extended, altruistic-donor chain. N Engl J Med, 2009. 360(11): p. 1096-101.

7. Sellares, J., et al., Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant, 2012. 12(2): p. 388-99.

8. Evans, R.W., et al., Cost-related immunosuppressive medication nonadherence among kidney transplant recipients. Clin J Am Soc Nephrol, 2010. 5(12): p. 2323-8.

9. Liefeldt, L., et al., Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation. Am J Transplant, 2012. 12(5): p. 1192-8.

10. Wiebe, C., et al., Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant, 2012. 12(5): p. 1157-67.

11. Wiebe, C. and P. Nickerson, Posttransplant monitoring of de novo human leukocyte antigen donor-specific antibodies in kidney transplantation. Curr Opin Organ Transplant, 2013. 18(4): p. 470-7.