title: Elevated Urinary Matrix Metalloproteinase-7 Detects Underlying Renal Allograft Inflammation and Injury.
abstract: BACKGROUND
  The urinary CXC chemokine ligand (CXCL)10 detects renal transplant inflammation noninvasively, but has limited sensitivity and specificity. In this study, we performed urinary proteomic analysis to identify novel biomarkers that may improve the diagnostic performance of urinary CXCL10 for detecting alloimmune inflammation in renal transplant patients.
  
  
  METHODS
  In preliminary studies, adult renal transplant patients with normal histology (n = 5), interstitial fibrosis and tubular atrophy (n = 6), subclinical (n = 6) and clinical rejection (n = 6), underwent in-depth urine protein compositional analysis with LC-MS/MS, and matrix metalloproteinase-7 (MMP7) were identified as a potential candidate for the diagnosis of renal allograft inflammation. Urine MMP7 performance was then studied in a larger, prospective adult renal transplant population (n = 148 urines from n = 133 patients) with matched surveillance/indication biopsies. The diagnostic performance of urinary MMP7 and CXCL10 in combination was next evaluated using concordance (C-) statistics, net reclassification improvement and integrated discrimination improvement indices, to determine whether it was better than CXCL10 alone.
  
  
  RESULTS
  Urinary MMP7:creatinine (Cr) was lower in normal transplants compared to those with inflammation: glomerulonephritis (P = 0.009), viral nephropathies (P = 0.002), interstitial fibrosis and tubular atrophy and inflammation (P = 0.04), borderline (P = 0.08), subclinical (P = 0.01) and clinical rejection (P = 0.0006), and acute tubular necrosis (P < 0.0001). Urinary MMP7:Cr and CXCL10:Cr significantly distinguished noninflamed from inflamed biopsies (area under the curve, 0.74 and 0.70, respectively). The addition of urinary MMP7:Cr to CXCL10:Cr improved the diagnostic performance for subclinical and clinical inflammation/injury by integrated discrimination improvement (P = 0.002) and net reclassification improvement (P = 0.006) analyses.
  
  
  CONCLUSIONS
  Urinary MMP7:Cr improves the overall diagnostic performance of urinary CXCL10:Cr for distinguishing normal histology from subclinical and clinical inflammation/injury, but not subclinical inflammation alone.
authors.affiliation: 1 Section of Nephrology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.2 Manitoba Centre for Proteomics and Systems Biology, University of Manitoba and Health Sciences Centre, Winnipeg, Manitoba, Canada.3 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.4 Institute for Technical Biochemistry, University of Stuttgart, Stuttgart, Germany.5 University of Manitoba, Winnipeg, Manitoba, Canada.6 Cardiac Sciences Program, Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada.7 Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Ho
authors.forename: David N
authors.initials: DN
authors.lastname: Rush
authors.forename: Oleg
authors.initials: O
authors.lastname: Krokhin
authors.forename: Mihaela
authors.initials: M
authors.lastname: Antonovici
authors.forename: Ang
authors.initials: A
authors.lastname: Gao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bestland
authors.forename: Chris
authors.initials: C
authors.lastname: Wiebe
authors.forename: Brett
authors.initials: B
authors.lastname: Hiebert
authors.forename: Claudio
authors.initials: C
authors.lastname: Rigatto
authors.forename: Ian W
authors.initials: IW
authors.lastname: Gibson
authors.forename: John A
authors.initials: JA
authors.lastname: Wilkins
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nickerson
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis* / Q000652:urine; D000328:Adult; D064591:Allografts; D015415:Biomarkers / Q000652:urine; D054357:Chemokine CXCL10 / Q000652:urine; D002853:Chromatography, Liquid; D004796:Clinical Enzyme Tests / Q000379:methods*; D003404:Creatinine / Q000652:urine; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000652:urine*; D008875:Middle Aged; D009393:Nephritis / Q000175:diagnosis* / Q000652:urine; D011237:Predictive Value of Tests; D011446:Prospective Studies; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome; D015854:Up-Regulation; D016482:Urinalysis / Q000379:methods
chemical_list: D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D003404:Creatinine; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7