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A Comparison of HLA Molecular Mismatch Methods to Determine HLA Immunogenicity

Wiebe, C1,2*; Kosmoliaptsis, V3,4*; Pochinco, D2; Taylor, C5; Nickerson, P1,2,6

doi: 10.1097/TP.0000000000002117
Original Clinical Science—General: PDF Only

Background Antibody-mediated rejection is a major cause of premature graft loss in kidney transplantation. Multiple scoring systems are available to assess the HLA mismatch between donors and recipients at the molecular level, however, their correlation with the development of de novo donor-specific antibody (dnDSA) has not been compared in recipients on active immunosuppression.

Methods HLA-DRβ1/3/4/5/DQα1β1 molecular mismatch was determined using eplet analysis, amino acid mismatch, and electrostatic mismatch for 596 renal transplant recipients and correlated with HLA-DR/DQ dnDSA development. The molecular mismatch scores were evaluated in multivariate models of posttransplant dnDSA free survival.

Results Eplet mismatch correlated with amino acid mismatch and electrostatic mismatch (R2=0.85-0.96). HLA-DR dnDSA free survival correlated with HLA-DR eplet mismatch (HR 2.50 per 10 eplets mismatched, p<0.0001), amino acid mismatch (HR 1.49 per 10 amino acids mismatched, p<0.0001), and electrostatic mismatch (HR 1.23 per 10 units mismatched, p<0.0001). HLA-DQ dnDSA free survival correlated with HLA-DQ eplet mismatch (HR 1.98 per 10 eplets mismatched, p<0.0001), amino acid mismatch (HR 1.24 per 10 amino acids mismatched, p<0.0001), and electrostatic mismatch (HR 1.14 per 10 units mismatched, p<0.0001). All 3 methods were significant multivariate correlates of dnDSA development after adjustment for recipient age, baseline immunosuppression, and nonadherence.

Conclusion HLA molecular mismatch represents a precise method of alloimmune risk assessment for renal transplant patients. This report highlights that the use of one method over the other is likely to be driven by familiarity and ease of use as highly correlated results are produced by each method.

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1Department of Medicine, University of Manitoba

2Diagnostic Services of Manitoba

3Department of Surgery, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK; and the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at the University of Cambridge

4The NIHR Cambridge Biomedical Research Centre, Cambridge, UK

5Tissue Typing Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

6Department of Immunology, University of Manitoba

Received 4 December 2017. Revision received 1 January 2018.

Accepted 9 January 2018.

*Co-first authors: Contact Information for Chris Wiebe, Room 331-777 William Avenue, Winnipeg, Manitoba, R3E3R4, Ph: (204)-789-1051, Fax: (204)-789-1198, Email: cwiebe@hsc.mb.ca

Authorship: CW and VK authored the manuscript, conceived of the research idea and conducted the analysis; PW and CT collectively conceived of the research program, provided input into design, and the analysis plan. All co-authors provided review and revisions to the manuscript and ultimately approved the final version for submission and publication.

Disclosures: The authors declare no conflicts of interest.

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