title: Six-Month Urinary CCL2 and CXCL10 Levels Predict Long-term Renal Allograft Outcome.
abstract: BACKGROUND
  Early prognostic markers that identify high-risk patients could lead to increased surveillance, personalized immunosuppression, and improved long-term outcomes. The goal of this study was to validate 6-month urinary chemokine ligand 2 (CCL2) as a noninvasive predictor of long-term outcomes and compare it with 6-month urinary CXCL10.
  
  
  METHODS
  A prospective, observational renal transplant cohort (n = 185; minimum, 5-year follow-up) was evaluated. The primary composite outcome included 1 or more: allograft loss, renal function decline (>20% decrease estimated glomerular filtration rate between 6 months and last follow-up), and biopsy-proven rejection after 6 months. CCL2/CXCL10 are reported in relation to urine creatinine (ng/mmol).
  
  
  RESULTS
  Fifty-two patients (52/185, 28%) reached the primary outcome at a median 6.0 years, and their urinary CCL2:Cr was significantly higher compared with patients with stable allograft function (median [interquartile range], 38.6 ng/mmol [19.7-72.5] vs 25.9 ng/mmol [16.1-45.8], P = 0.009). Low urinary CCL2:Cr (≤70.0 ng/mmol) was associated with 88% 5-year event-free survival compared with 50% with high urinary CCL2:Cr (P < 0.0001). In a multivariate Cox-regression model, the only independent predictors of the primary outcome were high CCL2:Cr (hazard ratio [HR], 2.86; 95% confidence interval [95% CI], 1.33-5.73) and CXCL10:Cr (HR, 2.35; 95% CI, 1.23-4.88; both P = 0.009). Urinary CCL2:Cr/CXCL10:Cr area under the curves were 0.62 (P = 0.001)/0.63 (P = 0.03), respectively. Time-to-endpoint analysis according to combined high or low urinary chemokines demonstrates that endpoint-free survival depends on the overall early chemokine burden.
  
  
  CONCLUSIONS
  This study confirms that urinary CCL2:Cr is an independent predictor of long-term allograft outcomes. Urinary CCL2:Cr/CXCL10:Cr alone have similar prognostic performance, but when both are elevated, this suggests a worse prognosis. Therefore, urinary chemokines may be a useful tool for timely identification of high-risk patients.
authors.affiliation: 1 Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.2 Manitoba Centre for Proteomics and Systems Biology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.3 Section of Nephrology, University of Manitoba, Winnipeg, Manitoba, Canada.4 Institute for Pathology, University Hospital Basel, Basel, Switzerland.5 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hirt-Minkowski
authors.forename: David N
authors.initials: DN
authors.lastname: Rush
authors.forename: Ang
authors.initials: A
authors.lastname: Gao
authors.forename: Helmut
authors.initials: H
authors.lastname: Hopfer
authors.forename: Chris
authors.initials: C
authors.lastname: Wiebe
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nickerson
authors.forename: Stefan
authors.initials: S
authors.lastname: Schaub
authors.forename: Julie
authors.initials: J
authors.lastname: Ho
mesh_terms: D000328:Adult; D064591:Allografts; D019540:Area Under Curve; D015415:Biomarkers / Q000652:urine; D018932:Chemokine CCL2 / Q000652:urine*; D054357:Chemokine CXCL10 / Q000652:urine*; D016009:Chi-Square Distribution; D003404:Creatinine / Q000652:urine; D018572:Disease-Free Survival; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000175:diagnosis / Q000503:physiopathology / Q000652:urine*; D006085:Graft Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000009:adverse effects / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012372:ROC Curve; D015203:Reproducibility of Results; D012307:Risk Factors; D013557:Switzerland; D013997:Time Factors; D016896:Treatment Outcome; D016482:Urinalysis
chemical_list: D015415:Biomarkers; C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D003404:Creatinine