Elevated Urinary Matrix Metalloproteinase-7 Detects Underlying Renal Allograft Inflammation and Injury
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Date
2016-03
Authors
Ho, Julie
Rush, David
Krokhin, Oleg
Antonovici, Mihaela
Gao, Ang
Bestland, Jennifer
Wiebe, Chris
Hiebert, Brett
Rigatto, Claudio
Gibson, Ian
Journal Title
Journal ISSN
Volume Title
Publisher
Wolters Kluwer Health
Abstract
Background. The urinary chemokine CXCL10 detects renal transplant inflammation non-invasively, 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 (IFTA, 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) was 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 (NRI) and integrated discrimination improvement (IDI) indices, to determine whether it was better than CXCL10 alone.
Results. Urinary MMP7:Cr was lower in normal transplants compared to those with inflammation: glomerulonephritis (p=0.009), viral nephropathies (p=0.002), IFTA and inflammation (p=0.04), borderline (p=0.08), subclinical (p=0.01) and clinical rejection (p=0.0006), and ATN (p<0.0001). Urinary MMP7:Cr and CXCL10:Cr significantly distinguished non-inflamed from inflamed biopsies (AUC 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 IDI (p=0.002) and NRI (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.
Description
Keywords
Proteomics, mass spectrometry, urinary biomarker, CXCL10
Citation
Transplantation 100(3): 648-654, 2016