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J Am Soc Nephrol. 2018 Feb;29(2):620-635. doi: 10.1681/ASN.2017050589. Epub 2017 Oct 17.

Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment.

Author information

1
Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France; carmen.lefaucheur@wanadoo.fr alexandreloupy@gmail.com.
2
Kidney Transplant Department, Saint-Louis Hospital.
3
Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France.
4
Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York.
5
Department of Surgery, University of California, San Francisco School of Medicine, San Francisco, California.
6
Kidney Transplant Department, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain.
7
Kidney Pancreas Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy.
8
Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
9
Department of Nephrology and Organ Transplantation, Centre Hospitalier Universitaire Rangueil, Toulouse, Institut National de la Santé et de la Recherche Médicale U1043, Structure Fédérative de Recherche Bio-Médicale de Toulouse, Centre Hospitalier Universitaire Purpan, Toulouse, Université Paul Sabatier, Toulouse, France​.
10
Department of Nephrology, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
11
Pathology Department, Necker Hospital.
12
Pathology Department, European Georges Pompidou Hospital, and.
13
Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
14
Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
15
Alberta Transplant Applied Genomics Center, University of Alberta, Edmonton, Alberta, Canada.
16
Department of Surgery, Division of Transplantation, Columbia University Medical Center, New York, New York.
17
Departments of Pathology and.
18
Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.
19
Department of Surgery, New York University Langone Medical Center, New York, New York; and.
20
Department of Transplantation Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Abstract

Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using in vitro human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes (CXCL11, CCL4, MS4A7, MS4A6A, and FCGR3A) indicative of endothelial activation, IFNγ response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval [95% CI], 38% to 74% versus 19%; 95% CI, 8% to 35%; P=0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; P=0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.

KEYWORDS:

complement; kidney transplantation; rejection; transcriptional profiling

PMID:
29042454
PMCID:
PMC5791056
DOI:
10.1681/ASN.2017050589
[Indexed for MEDLINE]
Free PMC Article

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