title: Detecting Renal Allograft Inflammation Using Quantitative Urine Metabolomics and CXCL10.
abstract: BACKGROUND
  The goal of this study was to characterize urinary metabolomics for the noninvasive detection of cellular inflammation and to determine if adding urinary chemokine ligand 10 (CXCL10) improves the overall diagnostic discrimination.
  
  
  METHODS
  Urines (n = 137) were obtained before biopsy in 113 patients with no (n = 66), mild (borderline or subclinical; n = 58), or severe (clinical; n = 13) rejection from a prospective cohort of adult renal transplant patients (n = 113). Targeted, quantitative metabolomics was performed with direct flow injection tandem mass spectrometry using multiple reaction monitoring (ABI 4000 Q-Trap). Urine CXCL10 was measured by enzyme-linked immunosorbent assay. A projection on latent structures discriminant analysis was performed and validated using leave-one-out cross-validation, and an optimal 2-component model developed. Chemokine ligand 10 area under the curve (AUC) was determined and net reclassification index and integrated discrimination index analyses were performed.
  
  
  RESULTS
  PLS2 demonstrated that urinary metabolites moderately discriminated the 3 groups (Cohen κ, 0.601; 95% confidence interval [95% CI], 0.46-0.74; P < 0.001). Using binary classifiers, urinary metabolites and CXCL10 demonstrated an AUC of 0.81 (95% CI, 0.74-0.88) and 0.76 (95% CI, 0.68-0.84), respectively, and a combined AUC of 0.84 (95% CI, 0.78-0.91) for detecting alloimmune inflammation that was improved by net reclassification index and integrated discrimination index analyses. Urinary CXCL10 was the best univariate discriminator, followed by acylcarnitines and hexose.
  
  
  CONCLUSIONS
  Urinary metabolomics can noninvasively discriminate noninflamed renal allografts from those with subclinical and clinical inflammation, and the addition of urine CXCL10 had a modest but significant effect on overall diagnostic performance. These data suggest that urinary metabolomics and CXCL10 may be useful for noninvasive monitoring of alloimmune inflammation in renal transplant patients.
authors: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors: Julie
authors: J
authors: Ho
authors: Department of Pediatrics & Child Health, University of Manitoba, Winnipeg, Canada.; Biostatistics Group, George and Fay Yee Centre for Health Innovation, University of Manitoba, Winnipeg, Canada.; Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada.
authors: Atul
authors: A
authors: Sharma
authors: Department of Biological Sciences, University of Alberta, Edmonton, Canada.
authors: Rupasri
authors: R
authors: Mandal
authors: Department of Biological Sciences, University of Alberta, Edmonton, Canada.; Department of Computing Science, University of Alberta, Edmonton, Canada.; National Research Council, National Institute for Nanotechnology (NINT) Edmonton, Canada.
authors: David S
authors: DS
authors: Wishart
authors: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors: Chris
authors: C
authors: Wiebe
authors: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors: Leroy
authors: L
authors: Storsley
authors: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors: Martin
authors: M
authors: Karpinski
authors: Department of Pathology, University of Manitoba, Winnipeg, Canada.
authors: Ian W
authors: IW
authors: Gibson
authors: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors: Peter W
authors: PW
authors: Nickerson
authors: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors: David N
authors: DN
authors: Rush