title: Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts.
abstract: BACKGROUND
  The positive costimulatory proteins OX40 and OX40L and negative regulatory proteins programmed death (PD)-1, PD ligand 1, and PD ligand 2 have emerged as significant regulators of acute rejection in experimental transplantation models.
  
  
  METHODS
  We obtained 21 urine specimens from 21 renal allograft recipients with graft dysfunction and biopsy-confirmed acute rejection and 25 specimens from 25 recipients with stable graft function and normal biopsy results (stable). Urinary cell levels of mRNAs were measured using real-time quantitative polymerase chain reaction assays, and the levels were correlated with allograft status and outcomes.
  
  
  RESULTS
  Levels of OX40 mRNA (P<0.0001, Mann-Whitney test), OX40L mRNA (P=0.0004), and PD-1 mRNA (P=0.004), but not the mRNA levels of PD ligand 1 (P=0.08) or PD ligand 2 (P=0.20), were significantly higher in the urinary cells from the acute rejection group than the stable group. Receiver operating characteristic curve analysis demonstrated that acute rejection is predicted with a sensitivity of 95% and a specificity of 92% (area under the curve=0.98, 95% confidence interval 0.96-1.0, P<0.0001) using a combination of levels of mRNA for OX40, OX40L, PD-1, and levels of mRNA for the previously identified biomarker Foxp3. Within the acute rejection group, levels of mRNA for OX40 (P=0.0002), OX40L (P=0.0004), and Foxp3 (P=0.04) predicted acute rejection reversal, whereas only OX40 mRNA levels (P=0.04) predicted graft loss after acute rejection.
  
  
  CONCLUSIONS
  A linear combination of urinary cell levels of mRNA for OX40, OX40L, PD-1, and Foxp3 was a strong predictor of acute rejection in human renal allograft biopsies. This prediction model should be validated using an independent cohort of renal allograft recipients.
authors.affiliation: Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY, USA.
authors.forename: Cheguevara
authors.initials: C
authors.lastname: Afaneh
authors.forename: Thangamani
authors.initials: T
authors.lastname: Muthukumar
authors.forename: Michelle
authors.initials: M
authors.lastname: Lubetzky
authors.forename: Ruchuang
authors.initials: R
authors.lastname: Ding
authors.forename: Catherine
authors.initials: C
authors.lastname: Snopkowski
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Sharma
authors.forename: Surya
authors.initials: S
authors.lastname: Seshan
authors.forename: Darshana
authors.initials: D
authors.lastname: Dadhania
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Schwartz
authors.forename: Manikkam
authors.initials: M
authors.lastname: Suthanthiran
mesh_terms: D000208:Acute Disease; D000328:Adult; D015703:Antigens, CD / Q000235:genetics* / Q000652:urine; D000943:Antigens, Differentiation / Q000235:genetics* / Q000652:urine; D060890:B7-H1 Antigen; D003404:Creatinine / Q000097:blood; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000652:urine*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000652:urine; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D053278:OX40 Ligand / Q000235:genetics* / Q000652:urine; D011237:Predictive Value of Tests; D061027:Programmed Cell Death 1 Ligand 2 Protein; D012333:RNA, Messenger / Q000652:urine; D012372:ROC Curve; D044469:Racial Groups; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053278:OX40 Ligand; C406562:OX40Ig; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D012333:RNA, Messenger; D003404:Creatinine