title: CD44 and CXCL9 serum protein levels predict the risk of clinically significant allograft rejection after liver transplantation.
abstract: The diagnosis of acute cellular rejection (ACR) after liver transplantation is based on histological analysis of biopsies because noninvasive biomarkers for allograft rejection are not yet established for clinical routines. CD31, CD44, and chemokine (C-X-C motif) ligand (CXCL) 9 have previously been described as biomarkers for cross-organ allograft rejection. Here, we assessed the predictive and diagnostic value of these proteins as serum biomarkers for clinically significant ACR in the first 6 months after liver transplantation in a prospective study. The protein levels were measured in 94 patients immediately before transplantation, at postoperative days (PODs) 1, 3, 7, and 14 and when biopsies were performed during episodes of biochemical graft dysfunction. The CD44 serum protein levels were significantly lower at POD 1 in patients who experienced histologically proven ACR in the follow-up compared with patients without ACR (P < 0.001). CXCL9 was significantly higher before transplantation (P = 0.049) and at POD 1 (P < 0.001) in these patients. Low CD44 values (cutoff, <200.5 ng/mL) or high CXCL9 values (cutoff, >2.7 ng/mL) at POD 1 differentiated between rejection and no rejection with a sensitivity of 88% or 60% and a specificity of 61% or 79%, respectively. The combination of both biomarker cutoffs at POD 1 had a positive predictive value of 91% and a negative predictive value of 67% for clinically significant ACR. Moreover, CD44 was significantly lower at the time of ACR (P < 0.001) and differentiated the rejection group from patients with graft dysfunction due to other reasons. Our results suggest that CD44 and CXCL9 may serve as predictive biomarkers to identify liver allograft recipients at risk for clinically significant ACR.
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Nathanael
authors.initials: N
authors.lastname: Raschzok
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Reutzel-Selke
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Rosa Bianca
authors.initials: RB
authors.lastname: Schmuck
authors.affiliation: Visceral, Transplantation, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany.
authors.forename: Mehmet Haluk
authors.initials: MH
authors.lastname: Morgul
authors.affiliation: Private Statistical Office, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gauger
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kukuh Aji
authors.initials: KA
authors.lastname: Prabowo
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Laura-Marie
authors.initials: LM
authors.lastname: Tannus
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Annekatrin
authors.initials: A
authors.lastname: Leder
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Struecker
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Boas-Knoop
authors.affiliation: Visceral, Transplantation, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bartels
authors.affiliation: Centre Hépato-Biliaire, Hôpital Paul Brousse, Université Paris Sud, Villejuif, France.
authors.forename: Sven
authors.initials: S
authors.lastname: Jonas
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lojewski
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Gero
authors.initials: G
authors.lastname: Puhl
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bahra
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pascher
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.affiliation: General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Igor Maximilian
authors.initials: IM
authors.lastname: Sauer
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D064591:Allografts; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D054370:Chemokine CXCL9 / Q000097:blood*; D003937:Diagnosis, Differential; D005260:Female; D006084:Graft Rejection / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000097:blood*; D053208:Kaplan-Meier Estimate; D016031:Liver Transplantation / Q000009:adverse effects*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C497483:CD44 protein, human; C080810:CXCL9 protein, human; D054370:Chemokine CXCL9; D018960:Hyaluronan Receptors