Aleksandar Senev1,2, Evelyne Lerut3, Maarten Coemans1, Jasper Callemeyn1, Hannah Charlotte Copley4,5,6, Frans Claas7, Priyanka Koshy3, Vasilis Kosmoliaptsis4,5,6, Dirk Kuypers1,8, Ben Sprangers1,8, Amaryllis Van Craenenbroeck1,8, Elisabet Van Loon1, Vicky Van Sandt2, Marie-Paule Emonds1,2, Maarten Naesens9,8. 1. KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium. 2. Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross Flanders, Mechelen, Belgium. 3. Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium. 4. Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. 5. National Institute for Health and Care Research Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge, United Kingdom. 6. National Institute for Health and Care Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom. 7. Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands. 8. Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. 9. KU Leuven Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium maarten.naesens@kuleuven.be.
Abstract
BACKGROUND AND OBJECTIVES: The histology of antibody-mediated rejection after kidney transplantation is observed frequently in the absence of detectable donor-specific anti-HLA antibodies. Although there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To study this, we used the tools HLAMatchmaker, three-dimensional electrostatic mismatch score, HLA solvent accessible amino acid mismatches, and mismatched donor HLA-derived T cell epitope targets to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy. RESULTS: In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T cell-mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. This association was dependent neither on the presence of missing self (potentially related to natural killer cell activation) nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies. CONCLUSIONS: The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch.
BACKGROUND AND OBJECTIVES: The histology of antibody-mediated rejection after kidney transplantation is observed frequently in the absence of detectable donor-specific anti-HLA antibodies. Although there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To study this, we used the tools HLAMatchmaker, three-dimensional electrostatic mismatch score, HLA solvent accessible amino acid mismatches, and mismatched donor HLA-derived T cell epitope targets to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy. RESULTS: In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T cell-mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. This association was dependent neither on the presence of missing self (potentially related to natural killer cell activation) nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies. CONCLUSIONS: The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch.
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Authors: Chris Wiebe; Vasilis Kosmoliaptsis; Denise Pochinco; Ian W Gibson; Julie Ho; Patricia E Birk; Aviva Goldberg; Martin Karpinski; Jamie Shaw; David N Rush; Peter W Nickerson Journal: Am J Transplant Date: 2018-12-15 Impact factor: 8.086
Authors: Cynthia S M Kramer; Johan Koster; Geert W Haasnoot; Dave L Roelen; Frans H J Claas; Sebastiaan Heidt Journal: HLA Date: 2020-04-13 Impact factor: 4.513
Authors: Chris Wiebe; David N Rush; Ian W Gibson; Denise Pochinco; Patricia E Birk; Aviva Goldberg; Tom Blydt-Hansen; Martin Karpinski; Jamie Shaw; Julie Ho; Peter W Nickerson Journal: Am J Transplant Date: 2020-04-09 Impact factor: 8.086