title: Evaluation of biomarkers of cell cycle arrest and inflammation in prediction of dialysis or recovery after kidney transplantation.
abstract: Early prediction of delayed graft function (DGF) after kidney transplantation would facilitate patient management. Cell cycle arrest and inflammation are implicated in the pathogenesis of DGF. We assessed the utility of two novel acute kidney injury (AKI) biomarkers, urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), and five inflammatory markers to predict DGF following deceased-donor kidney transplantation. Serial urine concentrations of TIMP-2 and IGFBP7 were measured immediately after transplantation in 56 recipients along with vascular endothelial growth factor-A (VEGF-A), macrophage migration inhibitory factor (MIF), monocyte chemotactic protein-1 (MCP-1), trefoil factor 3 (TFF3) and chemokine (C-X-C) ligand 16 (CXCL16). Delayed graft function (DGF) was defined as requirement for dialysis within 7 days. Integrated discrimination improvement analysis was used to evaluate whether these biomarkers enhanced prediction of DGF independently of a validated clinical risk prediction model. DGF occurred in 22 patients (39%). At 4 h after kidney reperfusion, the area under the receiver operator characteristic curve (AUC) for VEGF-A was good (AUC > 0.80); for TIMP-2, IGFBP7 and [TIMP-2] × [IGFBP7] fair (AUCs 0.70-0.79); and for MIF, MCP-1, TFF3 and CXCL16 poor (AUC < 0.70). Only TIMP-2 and VEGF significantly enhanced the DGF prediction at 4 and 12 h. The cell cycle arrest marker urinary TIMP-2 and the inflammatory biomarker VEGF-A are potentially useful adjuncts to clinical data for early prediction of DGF.
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.|Northern Clinical School, Melbourne Medical School, University of Melbourne, Epping, Vic, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Pianta
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Peake
authors.affiliation: Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: John W
authors.initials: JW
authors.lastname: Pickering
authors.affiliation: Department of Nephrology, Prince of Wales Hospital, Sydney, NSW, Australia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kelleher
authors.affiliation: Clinical Pharmacology, University of Sydney, Sydney, NSW, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Buckley
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.|Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Zoltan H
authors.initials: ZH
authors.lastname: Endre
mesh_terms: D015415:Biomarkers / Q000652:urine; D059447:Cell Cycle Checkpoints; D018932:Chemokine CCL2 / Q000652:urine; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000652:urine; D051799:Delayed Graft Function / Q000209:etiology* / Q000652:urine*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000652:urine*; D018969:Insulin-Like Growth Factor Binding Proteins / Q000652:urine; D019746:Intramolecular Oxidoreductases / Q000652:urine; D016030:Kidney Transplantation / Q000009:adverse effects*; D008263:Macrophage Migration-Inhibitory Factors / Q000652:urine; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000652:urine; D011237:Predictive Value of Tests; D051116:Receptors, Scavenger; D006435:Renal Dialysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000652:urine; D000071165:Trefoil Factor-3; D042461:Vascular Endothelial Growth Factor A / Q000652:urine
chemical_list: D015415:Biomarkers; C111835:CCL2 protein, human; C423727:CXCL16 protein, human; D018932:Chemokine CCL2; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D018836:Inflammation Mediators; D018969:Insulin-Like Growth Factor Binding Proteins; D008263:Macrophage Migration-Inhibitory Factors; D010455:Peptides; D051116:Receptors, Scavenger; C082495:TFF3 protein, human; C560823:TIMP2 protein, human; D000071165:Trefoil Factor-3; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C102529:insulin-like growth factor binding protein-related protein 1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: cell cycle arrest; delayed graft function; insulin-like growth factor-binding protein 7; tissue inhibitor of metalloproteinases-2; urinary biomarkers; vascular endothelial growth factor