title: Elevated urinary CXCL10-to-creatinine ratio is associated with subclinical and clinical rejection in pediatric renal transplantation.
abstract: BACKGROUND
  Subclinical and clinical T cell-mediated rejection (TCMR) has significant prognostic implications in pediatric renal transplantation. The goal of this study was to independently validate urinary CXCL10 as a noninvasive biomarker for detecting acute rejection in children and to extend these findings to subclinical rejection.
  
  
  METHODS
  Urines (n = 140) from 51 patients with surveillance or indication biopsies were assayed for urinary CXCL10 using enzyme-linked immunosorbent assay and corrected with urinary creatinine.
  
  
  RESULTS
  Median urinary CXCL10-to-creatinine (Cr) ratio (ng/mmol) was significantly elevated in subclinical TCMR (4.4 [2.6, 25.4], P < 0.001, n = 17); clinical TCMR (24.3 [11.2, 44.8], P < 0.001, n = 9); and antibody-mediated rejection (6.0 [3.3, 13.7], P = 0.002, n = 9) compared to noninflamed histology (1.4 [0.4, 4.2], normal and interstitial fibrosis and tubular atrophy, n = 52), and borderline tubulitis (3.3, [1.3, 4.9], n = 36). Elevated urinary CXCL10:Cr was independently associated with t scores (P < 0.001) and g scores (P = 0.006) on multivariate analysis. The area under receiver operating curve for subclinical and clinical TCMR was 0.81 (P = 0.045) and 0.88 (P = 0.019), respectively. This corresponded to a sensitivity-specificity of 0.59-0.67 and 0.77-0.60 for subclinical and clinical TCMR at cutoffs of 4.82 and 4.72 ng/mmol, respectively.
  
  
  CONCLUSIONS
  This study demonstrates that urinary CXCL10:Cr corresponds with microvascular inflammation and is a sensitive and specific biomarker for subclinical and clinical TCMR in children. This may provide a noninvasive monitoring tool for posttransplant immune surveillance for pediatric renal transplant recipients.
authors.affiliation: 1Department of Pediatrics and Child Health (Nephrology), University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, MB, Canada. 2Department of Pathology, University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada. 3Manitoba Center for Proteomics and Systems Biology, Winnipeg, MB, Canada. 4Department of Community Health Sciences, University of Manitoba, George and Fay Yee Center for Healthcare Innovation, Winnipeg, MB, Canada. 5Manitoba Center for Proteomics and Systems Biology, and Department of Internal Medicine (Nephrology), University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Blydt-Hansen
authors.forename: Ian W
authors.initials: IW
authors.lastname: Gibson
authors.forename: Ang
authors.initials: A
authors.lastname: Gao
authors.forename: Brenden
authors.initials: B
authors.lastname: Dufault
authors.forename: Julie
authors.initials: J
authors.lastname: Ho
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000367:Age Factors; D019540:Area Under Curve; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000652:urine; D001706:Biopsy; D054357:Chemokine CXCL10 / Q000652:urine*; D002648:Child; D003404:Creatinine / Q000652:urine*; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology* / Q000652:urine; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects*; D016015:Logistic Models; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D015203:Reproducibility of Results; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D003404:Creatinine