title: Urine Fibrosis Markers and Risk of Allograft Failure in Kidney Transplant Recipients: A Case-Cohort Ancillary Study of the FAVORIT Trial.
abstract: BACKGROUND
  Kidney tubulointerstitial fibrosis marks risk for allograft failure in kidney transplant recipients, but is poorly captured by estimated glomerular filtration rate (eGFR) or urine albumin-creatinine ratio (ACR). Whether urinary markers of tubulointerstitial fibrosis can noninvasively identify risk for allograft failure above and beyond eGFR and ACR is unknown.
  
  
  METHODS
  Case-cohort study.
  
  
  METHODS
  The FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) Trial was a randomized double-blind trial testing vitamin therapy to lower homocysteine levels in stable kidney transplant recipients. We selected a subset of participants at random (n=491) and all individuals with allograft failure during follow-up (cases; n=257).
  
  
  METHODS
  Using spot urine specimens from the baseline visit, we measured 4 urinary proteins known to correlate with tubulointerstitial fibrosis on biopsy (urine α1-microglobulin [A1M], monocyte chemoattractant protein 1 [MCP-1], and procollagen type III and type I amino-terminal amino pro-peptide).
  
  
  RESULTS
  Death-censored allograft failure.
  
  
  RESULTS
  In models adjusted for demographics, chronic kidney disease risk factors, eGFR, and ACR, higher concentrations of urine A1M (HR per doubling, 1.73; 95% CI, 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 95% CI, 1.32-1.93) were strongly associated with allograft failure. When additionally adjusted for concentrations of other urine fibrosis and several urine injury markers, urine A1M (HR per doubling, 1.76; 95% CI, 1.27-2.44]) and MCP-1 levels (HR per doubling, 1.49; 95% CI, 1.17-1.89) remained associated with allograft failure. Urine procollagen type III and type I levels were not associated with allograft failure.
  
  
  CONCLUSIONS
  We lack kidney biopsy data, BK titers, and HLA antibody status.
  
  
  CONCLUSIONS
  Urine measurement of tubulointerstitial fibrosis may provide a noninvasive method to identify kidney transplant recipients at higher risk for future allograft failure, above and beyond eGFR and urine ACR.
authors.affiliation: Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA; Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA. Electronic address: joeix@ucsd.edu.
authors.forename: Joachim H
authors.initials: JH
authors.lastname: Ix
authors.affiliation: Kidney Research Institute, Division of Nephrology, University of Washington, Seattle, WA.
authors.forename: Ronit
authors.initials: R
authors.lastname: Katz
authors.affiliation: Kidney Research Institute, Division of Nephrology, University of Washington, Seattle, WA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Bansal
authors.affiliation: Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, MA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Foster
authors.affiliation: Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, MA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weiner
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT.
authors.forename: Russell
authors.initials: R
authors.lastname: Tracy
authors.affiliation: Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA.
authors.forename: Vasantha
authors.initials: V
authors.lastname: Jotwani
authors.affiliation: Department of Orthopedic Surgery, University of California San Diego, San Diego, CA.
authors.forename: Jan
authors.initials: J
authors.lastname: Hughes-Austin
authors.affiliation: Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA.
authors.forename: Dianne
authors.initials: D
authors.lastname: McKay
authors.affiliation: Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA.
authors.forename: Francis
authors.initials: F
authors.lastname: Gabbai
authors.affiliation: Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Rhode Island Hospital, Providence, RI.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bostom
authors.affiliation: Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, MA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levey
authors.affiliation: General Internal Medicine Section, San Francisco Veterans Affairs Hospital, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA; Division of General Internal Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Shlipak
mesh_terms: D015415:Biomarkers / Q000652:urine; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D005355:Fibrosis / Q000503:physiopathology / Q000652:urine; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000473:pathology* / Q000503:physiopathology / Q000652:urine*; D051437:Renal Insufficiency / Q000473:pathology* / Q000503:physiopathology / Q000652:urine*; D018570:Risk Assessment
chemical_list: D015415:Biomarkers
keywords: Fibrosis; allograft failure; biomarker; case-cohort; end-stage renal disease (ESRD); inflammation; kidney transplant recipient (KTR); kidney transplantation; monocyte chemoattractant protein 1 (MCP-1); risk factor; tubulo-interstitial fibrosis; urinary marker; α(1)-microglobulin (A1M)