TY - JOUR
T1 - 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
AU - Delville, Marianne
AU - Lamarthée, Baptiste
AU - Pagie, Sylvain
AU - See, Sarah B
AU - Rabant, Marion
AU - Burger, Carole
AU - Gatault, Philippe
AU - Giral, Magali
AU - Thaunat, Olivier
AU - Arzouk, Nadia
AU - Hertig, Alexandre
AU - Hazzan, Marc
AU - Matignon, Marie
AU - Mariat, Christophe
AU - Caillard, Sophie
AU - Kamar, Nassim
AU - Sayegh, Johnny
AU - Westeel, Pierre-François
AU - Garrouste, Cyril
AU - Ladrière, Marc
AU - Vuiblet, Vincent
AU - Rivalan, Joseph
AU - Merville, Pierre
AU - Bertrand, Dominique
AU - Le Moine, Alain
AU - Duong Van Huyen, Jean Paul
AU - Cesbron, Anne
AU - Cagnard, Nicolas
AU - Alibeu, Olivier
AU - Satchell, Simon C
AU - Legendre, Christophe
AU - Zorn, Emmanuel
AU - Taupin, Jean-Luc
AU - Charreau, Béatrice
AU - Anglicheau, Dany
N1 - Copyright © 2019 by the American Society of Nephrology.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85063941920&partnerID=8YFLogxK
U2 - 10.1681/ASN.2018080868
DO - 10.1681/ASN.2018080868
M3 - Article (Academic Journal)
C2 - 30850439
SN - 1046-6673
VL - 30
SP - 692
EP - 709
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 4
ER -