title: Molecular diagnosis of antibody-mediated rejection in human kidney transplants.
abstract: Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores>0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta.|Servei de Nefrologia, Hospital de la Vall d'Hebron, Barcelona, Spain.
authors: J
authors: J
authors: Sellarés
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta.|Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors: J
authors: J
authors: Reeve
authors: Kidney Transplant Department, Necker Hospital, Paris, France.
authors: A
authors: A
authors: Loupy
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta.|Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors: M
authors: M
authors: Mengel
authors: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors: B
authors: B
authors: Sis
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta.|Department of Anatomical Pathology, Austin Hospital, Heidelberg, Victoria, Australia.
authors: A
authors: A
authors: Skene
authors: Department of Renal Medicine, Manchester Royal Infirmary, Manchester, UK.
authors: D G
authors: DG
authors: de Freitas
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta.|Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, AB, Canada.
authors: C
authors: C
authors: Kreepala
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta.|Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors: L G
authors: LG
authors: Hidalgo
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta.|Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors: K S
authors: KS
authors: Famulski
authors: Alberta Transplant Applied Genomics Centre, Edmonton, Alberta.|Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, AB, Canada.
authors: P F
authors: PF
authors: Halloran
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D015935:Complement C4b / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000175:diagnosis* / Q000276:immunology*; D006085:Graft Survival; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016030:Kidney Transplantation; D007694:Killer Cells, Natural / Q000166:cytology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000276:immunology; D011336:Probability; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012044:Regression Analysis; D055815:Young Adult
chemical_list: D000906:Antibodies; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d; D007371:Interferon-gamma