Jasper Callemeyn1,2, Evelyne Lerut3, Henriette de Loor1, Ingrid Arijs4,5, Olivier Thaunat6,7,8, Alice Koenig6,7,8, Vannary Meas-Yedid9, Jean-Christophe Olivo-Marin9, Philip Halloran10, Jessica Chang10, Lieven Thorrez11, Dirk Kuypers1,2, Ben Sprangers2,12, Leentje Van Lommel13, Frans Schuit13, Marie Essig14, Wilfried Gwinner15, Dany Anglicheau16,17,18, Pierre Marquet19,20, Maarten Naesens21,2. 1. Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium. 2. Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. 3. Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium. 4. Department of Human Genetics, Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium. 5. Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium. 6. Center for Research in Infectious Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM) U1111, Claude Bernard University Lyon I, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France. 7. Lyon-Est Medical Faculty, Claude Bernard University Lyon I, Lyon, France. 8. Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France. 9. Biological Image Analysis Unit, Pasteur Institute, CNRS Unité de Recherche Associée (URA) 2582, Paris, France. 10. Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 11. Department of Development and Regeneration, KU Leuven, Kortrijk, Belgium. 12. Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology, Rega Institute, KU Leuven, Leuven, Belgium. 13. Department of Cellular and Molecular Medicine, Gene Expression Unit, KU Leuven, Leuven, Belgium. 14. Department of Nephrology, Dialysis and Transplantation, University of Limoges, Limoges, France. 15. Department of Nephrology and Internal Medicine, Hannover Medical School, Hannover, Germany. 16. Paris Descartes University, Sorbonne Paris Cité University, Paris, France. 17. INSERM U1151, Paris, France. 18. Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique--Hôpitaux de Paris, Paris, France. 19. INSERM U1248, Limoges, France. 20. Department of Pharmacology and Toxicology, University Hospitals Limoges, Limoges, France. 21. Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium maarten.naesens@kuleuven.be.
Abstract
BACKGROUND: Circulating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype. METHODS: In this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status. RESULTS: Of 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFNγ-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA-positive and HLA-DSA-negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell-mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences. CONCLUSIONS: ABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.
BACKGROUND: Circulating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype. METHODS: In this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status. RESULTS: Of 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFNγ-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA-positive and HLA-DSA-negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell-mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences. CONCLUSIONS: ABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.
Authors: J Sellarés; D G de Freitas; M Mengel; J Reeve; G Einecke; B Sis; L G Hidalgo; K Famulski; A Matas; P F Halloran Journal: Am J Transplant Date: 2011-11-14 Impact factor: 8.086
Authors: P F Halloran; A B Pereira; J Chang; A Matas; M Picton; D De Freitas; J Bromberg; D Serón; J Sellarés; G Einecke; J Reeve Journal: Am J Transplant Date: 2013-10-03 Impact factor: 8.086
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Authors: Nicholas J Steers; Yifu Li; Zahida Drace; Justin A D'Addario; Clara Fischman; Lili Liu; Katherine Xu; Young-Ji Na; Y Dana Neugut; Jun Y Zhang; Roel Sterken; Olivia Balderes; Drew Bradbury; Nilgun Ozturk; Fatih Ozay; Sanya Goswami; Karla Mehl; Jaclyn Wold; Fatima Z Jelloul; Mersedeh Rohanizadegan; Christopher E Gillies; Elena-Rodica M Vasilescu; George Vlad; Yi-An Ko; Sumit Mohan; Jai Radhakrishnan; David J Cohen; Lloyd E Ratner; Francesco Scolari; Katalin Susztak; Matthew G Sampson; Silvia Deaglio; Yasar Caliskan; Jonathan Barasch; Aisling E Courtney; Alexander P Maxwell; Amy J McKnight; Iuliana Ionita-Laza; Stephan J L Bakker; Harold Snieder; Martin H de Borst; Vivette D'Agati; Antonio Amoroso; Ali G Gharavi; Krzysztof Kiryluk Journal: N Engl J Med Date: 2019-05-16 Impact factor: 91.245
Authors: Imran J Anwar; Isabel F DeLaura; Qimeng Gao; Joseph Ladowski; Annette M Jackson; Jean Kwun; Stuart J Knechtle Journal: Front Immunol Date: 2022-06-09 Impact factor: 8.786
Authors: Katelynn S Madill-Thomsen; Georg A Böhmig; Jonathan Bromberg; Gunilla Einecke; Farsad Eskandary; Gaurav Gupta; Luis G Hidalgo; Marek Myslak; Ondrej Viklicky; Agnieszka Perkowska-Ptasinska; Philip F Halloran Journal: J Am Soc Nephrol Date: 2021-07-12 Impact factor: 10.121
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