Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens

Marianne Delville, Baptiste Lamarthée, Sylvain Pagie, Sarah B See, Marion Rabant, Carole Burger, Philippe Gatault, Magali Giral, Olivier Thaunat, Nadia Arzouk, Alexandre Hertig, Marc Hazzan, Marie Matignon, Christophe Mariat, Sophie Caillard, Nassim Kamar, Johnny Sayegh, Pierre-François Westeel, Cyril Garrouste, Marc LadrièreVincent Vuiblet, Joseph Rivalan, Pierre Merville, Dominique Bertrand, Alain Le Moine, Jean Paul Duong Van Huyen, Anne Cesbron, Nicolas Cagnard, Olivier Alibeu, Simon C Satchell, Christophe Legendre, Emmanuel Zorn, Jean-Luc Taupin, Béatrice Charreau, Dany Anglicheau*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

29 Citations (Scopus)
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Abstract

BACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.

METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.

RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.

CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.

Original languageEnglish
Pages (from-to)692-709
Number of pages18
JournalJournal of the American Society of Nephrology
Volume30
Issue number4
Early online date8 Mar 2019
DOIs
Publication statusPublished - 1 Apr 2019

Bibliographical note

Copyright © 2019 by the American Society of Nephrology.

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