title: Detection of subclinical tubular injury after renal transplantation: comparison of urine protein analysis with allograft histopathology.
abstract: BACKGROUND
  Tubulointerstitial injury due to rejection leads to tubular atrophy (TA)/interstitial fibrosis (IF) followed by deterioration of allograft function. This study investigated whether urinary tubular injury biomarkers can detect subclinical tubulitis found in protocol biopsies allowing for a noninvasive screening procedure.
  
  
  METHODS
  Four rigidly defined groups (stable transplants with normal tubular histology [n=24], stable transplants with subclinical tubulitis [n=38], patients with clinical tubulitis Ia/Ib [n=18], and patients with other clinical tubular pathologies [n=20]) were compared for differences in urinary intact/cleaved beta2-microglobulin (i/cbeta2m), retinol-binding protein (RBP), neutrophil-gelatinase-associated lipocalin (NGAL), and alpha1-microglobulin (alpha1m).
  
  
  RESULTS
  Tubular proteinuria was present in 38% (RBP) to 79% (alpha1m) of patients in the stable transplant with normal tubular histology group. The stable transplant with subclinical tubulitis group had slightly higher levels of i/cbeta2m (P=0.11), RBP (P=0.17), alpha1m (P=0.09), and NGAL (P=0.06) than the stable transplant with normal tubular histology group with a substantial overlap. The clinical tubulitis Ia/Ib and the other clinical tubular pathology groups had significantly higher levels of RBP, NGAL, and alpha1m than stable transplants with normal tubular histology or stable transplants with subclinical tubulitis (P<0.002).
  
  
  CONCLUSIONS
  None of the investigated biomarkers allow for clear differentiation between stable transplants with normal tubular histology and stable transplants with subclinical tubulitis. Therefore, the protocol allograft biopsy currently remains the preferred tool to screen for subclinical tubulitis. Further longitudinal studies should determine whether tubular proteinuria in stable transplants with normal tubular histology indicates a clear risk for early development of TA/IF.
authors.affiliation: Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland. schaubs@uhbs.ch
authors.forename: Stefan
authors.initials: S
authors.lastname: Schaub
authors.forename: Michael
authors.initials: M
authors.lastname: Mayr
authors.forename: Gideon
authors.initials: G
authors.lastname: Hönger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bestland
authors.forename: Jürg
authors.initials: J
authors.lastname: Steiger
authors.forename: Axel
authors.initials: A
authors.lastname: Regeniter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mihatsch
authors.forename: John A
authors.initials: JA
authors.lastname: Wilkins
authors.forename: David
authors.initials: D
authors.lastname: Rush
authors.forename: Peter
authors.initials: P
authors.lastname: Nickerson
mesh_terms: D000209:Acute-Phase Proteins / Q000652:urine; D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000503:physiopathology; D015415:Biomarkers / Q000652:urine*; D001706:Biopsy / Q000592:standards; D005260:Female; D006084:Graft Rejection / Q000150:complications; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000175:diagnosis* / Q000209:etiology / Q000652:urine; D016030:Kidney Transplantation; D007684:Kidney Tubules; D000071068:Lipocalin-2; D054834:Lipocalins; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000652:urine; D012177:Retinol-Binding Proteins / Q000652:urine; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014184:Transplantation, Homologous; D000511:alpha-Macroglobulins / Q000652:urine; D001613:beta 2-Microglobulin / Q000652:urine
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D012177:Retinol-Binding Proteins; D000511:alpha-Macroglobulins; D001613:beta 2-Microglobulin