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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

Research output: Contribution to journalArticle

  • 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 Ladrière
  • Vincent 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
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
DateAccepted/In press - 31 Jan 2019
DateE-pub ahead of print - 8 Mar 2019
DatePublished (current) - 1 Apr 2019

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.

Additional information

Copyright © 2019 by the American Society of Nephrology.

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    Rights statement: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via JASN at https://doi.org/10.1681/ASN.2018080868 . Please refer to any applicable terms of use of the publisher.

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