title: Urinary metabolomics for noninvasive detection of borderline and acute T cell-mediated rejection in children after kidney transplantation.
abstract: The goal of this study was to evaluate the utility of urinary metabolomics for noninvasive diagnosis of T cell-mediated rejection (TCMR) in pediatric kidney transplant recipients. Urine samples (n = 277) from 57 patients with surveillance or indication kidney biopsies were assayed for 134 unique metabolites by quantitative mass spectrometry. Samples without TCMR (n = 183) were compared to borderline tubulitis (n = 54) and TCMR (n = 30). Partial least squares discriminant analysis identified distinct classifiers for TCMR (area under receiver operating characteristic curve [AUC] = 0.892; 95% confidence interval [CI] 0.827-0.957) and borderline tubulitis (AUC = 0.836; 95% CI 0.781-0.892), respectively. Application of the TCMR classifier to borderline tubulitis samples yielded a discriminant score (-0.47 ± 0.33) mid-way between TCMR (-0.20 ± 0.34) and No TCMR (-0.80 ± 0.32) (p < 0.001 for all comparisons). Discriminant scoring for combined borderline/TCMR versus No TCMR (AUC = 0.900; 95% CI 0.859-0.940) applied to a validation cohort robustly distinguished between samples with (-0.08 ± 0.52) and without (-0.65 ± 0.54, p < 0.001) borderline/TCMR (p < 0.001). The TCMR discriminant score was driven by histological t-score, ct-score, donor-specific antibody and biopsy indication, and was unaffected by renal function, interstitial or microcirculatory inflammation, interstitial fibrosis or pyuria. These preliminary findings suggest that urinary metabolomics is a sensitive, specific and noninvasive tool for TCMR identification that is superior to serum creatinine, with minimal confounding by other allograft injury processes.
authors.affiliation: Department of Pediatrics and Child Health (Nephrology), University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, MB, Canada.
authors.forename: T D
authors.initials: TD
authors.lastname: Blydt-Hansen
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.forename: I W
authors.initials: IW
authors.lastname: Gibson
authors.forename: R
authors.initials: R
authors.lastname: Mandal
authors.forename: D S
authors.initials: DS
authors.lastname: Wishart
mesh_terms: D000293:Adolescent; D002648:Child; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D013601:T-Lymphocytes / Q000276:immunology*; D014556:Urine
keywords: Biomarker; clinical research; kidney transplantation; metabolomics; nephrology; pediatrics; practice; protocol biopsy; rejection: T cell-mediated (TCMR); rejection: acute; science; translational research