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Urinary Metabolomics for Noninvasive Detection of Borderline and Acute T Cell–Mediated Rejection in Children After Kidney Transplantation
Author(s) -
BlydtHansen T. D.,
Sharma A.,
Gibson I. W.,
Mandal R.,
Wishart D. S.
Publication year - 2014
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.12837
Subject(s) - medicine , pyuria , receiver operating characteristic , creatinine , urinary system , urology , gastroenterology , kidney transplantation , area under the curve , transplantation , renal function , pathology
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.