title: A molecular classifier for predicting future graft loss in late kidney transplant biopsies.
abstract: Kidney transplant recipients that develop signs of renal dysfunction or proteinuria one or more years after transplantation are at considerable risk for progression to renal failure. To assess the kidney at this time, a "for-cause" biopsy is performed, but this provides little indication as to which recipients will go on to organ failure. In an attempt to identify molecules that could provide this information, we used microarrays to analyze gene expression in 105 for-cause biopsies taken between 1 and 31 years after transplantation. Using supervised principal components analysis, we derived a molecular classifier to predict graft loss. The genes associated with graft failure were related to tissue injury, epithelial dedifferentiation, matrix remodeling, and TGF-beta effects and showed little overlap with rejection-associated genes. We assigned a prognostic molecular risk score to each patient, identifying those at high or low risk for graft loss. The molecular risk score was correlated with interstitial fibrosis, tubular atrophy, tubulitis, interstitial inflammation, proteinuria, and glomerular filtration rate. In multivariate analysis, molecular risk score, peritubular capillary basement membrane multilayering, arteriolar hyalinosis, and proteinuria were independent predictors of graft loss. In an independent validation set, the molecular risk score was the only predictor of graft loss. Thus, the molecular risk score reflects active injury and is superior to either scarring or function in predicting graft failure.
authors.affiliation: Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Einecke
authors.forename: Jeff
authors.initials: J
authors.lastname: Reeve
authors.forename: Banu
authors.initials: B
authors.lastname: Sis
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.forename: Luis
authors.initials: L
authors.lastname: Hidalgo
authors.forename: Konrad S
authors.initials: KS
authors.lastname: Famulski
authors.forename: Arthur
authors.initials: A
authors.lastname: Matas
authors.forename: Bert
authors.initials: B
authors.lastname: Kasiske
authors.forename: Bruce
authors.initials: B
authors.lastname: Kaplan
authors.forename: Philip F
authors.initials: PF
authors.lastname: Halloran
mesh_terms: D001706:Biopsy; D002196:Capillaries / Q000473:pathology; D018450:Disease Progression; D005544:Forecasting; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000175:diagnosis* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation / Q000473:pathology*; D011507:Proteinuria / Q000473:pathology; D051437:Renal Insufficiency / Q000473:pathology*; D016212:Transforming Growth Factor beta
chemical_list: D016212:Transforming Growth Factor beta