Aleksandar Senev1,2, Maarten Coemans1,3, Evelyne Lerut4, Vicky Van Sandt2, Johan Kerkhofs2, Liesbeth Daniëls2, Marleen Vanden Driessche2, Veerle Compernolle2, Ben Sprangers1,5, Elisabet Van Loon1,5, Jasper Callemeyn1,5, Frans Claas6, Anat R Tambur7, Geert Verbeke3, Dirk Kuypers1,5, Marie-Paule Emonds1,2, Maarten Naesens8,5. 1. Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit (KU) Leuven, University of Leuven, Leuven, Belgium. 2. Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium. 3. Department of Public Health and Primary Care, Leuven Biostatistics and Statistical Bioinformatics Centre (L-BioStat), KU Leuven, University of Leuven, Leuven, Belgium. 4. Department of Imaging and Pathology, University Hospitals Leuven, Leuven, Belgium. 5. Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. 6. Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands. 7. Transplant Immunology Laboratory, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 8. Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit (KU) Leuven, University of Leuven, Leuven, Belgium maarten.naesens@uzleuven.be.
Abstract
BACKGROUND: In kidney transplantation, evaluating mismatches of HLA eplets-small patches of surface-exposed amino acids of the HLA molecule-instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes. METHODS: To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches. RESULTS: De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell- or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch. CONCLUSIONS: Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA1 and DQB1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.
BACKGROUND: In kidney transplantation, evaluating mismatches of HLA eplets-small patches of surface-exposed amino acids of the HLA molecule-instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes. METHODS: To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches. RESULTS: De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell- or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch. CONCLUSIONS: Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA1 and DQB1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.
Authors: N Lachmann; M Niemann; P Reinke; K Budde; D Schmidt; F Halleck; A Pruß; C Schönemann; E Spierings; O Staeck Journal: Am J Transplant Date: 2017-07-28 Impact factor: 8.086
Authors: Robert C Williams; Gerhard Opelz; Chelsea J McGarvey; E Jennifer Weil; Harini A Chakkera Journal: Transplantation Date: 2016-05 Impact factor: 4.939
Authors: A Hart; J M Smith; M A Skeans; S K Gustafson; A R Wilk; A Robinson; J L Wainright; C R Haynes; J J Snyder; B L Kasiske; A K Israni Journal: Am J Transplant Date: 2018-01 Impact factor: 8.086
Authors: Anat R Tambur; Hannah McDowell; Reut Hod-Dvorai; Maria A C Abundis; David F Pinelli Journal: Am J Transplant Date: 2019-07-08 Impact factor: 8.086
Authors: Renaud Snanoudj; Nassim Kamar; Elisabeth Cassuto; Sophie Caillard; Marie Metzger; Pierre Merville; Antoine Thierry; Isabelle Jollet; Philippe Grimbert; Dany Anglicheau; Marc Hazzan; Gabriel Choukroun; Bruno Hurault De Ligny; Bénedicte Janbon; Vincent Vuiblet; Anne Devys; Yann Le Meur; Michel Delahousse; Emmanuel Morelon; Elodie Bailly; Sophie Girerd; Kahina Amokrane; Christophe Legendre; Alexandre Hertig; Eric Rondeau; Jean-Luc Taupin Journal: Kidney Int Date: 2019-03-05 Impact factor: 10.612
Authors: Wai H Lim; Jeremy R Chapman; Patrick T Coates; Joshua R Lewis; Graeme R Russ; Narelle Watson; Rhonda Holdsworth; Germaine Wong Journal: Clin J Am Soc Nephrol Date: 2016-03-31 Impact factor: 8.237
Authors: C Wiebe; D Pochinco; T D Blydt-Hansen; J Ho; P E Birk; M Karpinski; A Goldberg; L J Storsley; I W Gibson; D N Rush; P W Nickerson Journal: Am J Transplant Date: 2013-10-25 Impact factor: 8.086
Authors: Mohsen Yaghoubi; Sonya Cressman; Louisa Edwards; Steven Shechter; Mary M Doyle-Waters; Paul Keown; Ruth Sapir-Pichhadze; Stirling Bryan Journal: Appl Health Econ Health Policy Date: 2022-08-09 Impact factor: 3.686
Authors: Maria Meneghini; Elena Crespo; Matthias Niemann; Alba Torija; Nuria Lloberas; Vincent Pernin; Pere Fontova; Edoardo Melilli; Alexandre Favà; Nuria Montero; Anna Manonelles; Josep Maria Cruzado; Eduard Palou; Jaume Martorell; Josep Maria Grinyó; Oriol Bestard Journal: Front Immunol Date: 2021-03-10 Impact factor: 7.561