title: Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody-Mediated Kidney Allograft Rejection.
abstract: Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P<0.001) and microvascular (g+ptc score; all P<0.001) inflammation. CXCL10:Cr diagnosed TCMR (area under the curve [AUC]=0.80; 95% confidence interval [95% CI], 0.68 to 0.92; P<0.001) and ABMR (AUC=0.76; 95% CI, 0.69 to 0.82; P<0.001) with high accuracy, even in the absence of tubulointerstitial inflammation (AUC=0.70; 95% CI, 0.61 to 0.79; P<0.001). Although mean fluorescence intensity of the immunodominant DSA diagnosed ABMR (AUC=0.75; 95% CI, 0.68 to 0.82; P<0.001), combining urinary CXCL10:Cr with immunodominant DSA levels improved the diagnosis of ABMR (AUC=0.83; 95% CI, 0.77 to 0.89; P<0.001). At the time of ABMR, urinary CXCL10:Cr ratio was independently associated with an increased risk of graft loss. In conclusion, urinary CXCL10:Cr ratio associates with tubulointerstitial and microvascular inflammation of the renal allograft. Combining the urinary CXCL10:Cr ratio with DSA monitoring significantly improves the noninvasive diagnosis of ABMR and the stratification of patients at high risk for graft loss.
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France; Paris Descartes, Sorbonne Paris Cité University, Paris, France; Pathology Department and.
authors.forename: Marion
authors.initials: M
authors.lastname: Rabant
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France;
authors.forename: Lucile
authors.initials: L
authors.lastname: Amrouche
authors.affiliation: Department of Nephrology and Kidney Transplantation, Necker Hospital, and Centaure Foundation and Labex Transplantex, Necker Hospital, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Lebreton
authors.affiliation: Department of Nephrology and Kidney Transplantation, Necker Hospital, and.
authors.forename: Florence
authors.initials: F
authors.lastname: Aulagnon
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France;
authors.forename: Aurélien
authors.initials: A
authors.lastname: Benon
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France;
authors.forename: Virginia
authors.initials: V
authors.lastname: Sauvaget
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France;
authors.forename: Raja
authors.initials: R
authors.lastname: Bonifay
authors.affiliation: Department of Nephrology and Kidney Transplantation, Necker Hospital, and.
authors.forename: Lise
authors.initials: L
authors.lastname: Morin
authors.affiliation: Department of Nephrology and Kidney Transplantation, Necker Hospital, and.
authors.forename: Anne
authors.initials: A
authors.lastname: Scemla
authors.affiliation: Department of Nephrology and Kidney Transplantation, Necker Hospital, and.
authors.forename: Marianne
authors.initials: M
authors.lastname: Delville
authors.affiliation: Department of Nephrology and Kidney Transplantation, Necker Hospital, and.
authors.forename: Frank
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Paris Descartes, Sorbonne Paris Cité University, Paris, France; Department of Urology, Georges Pompidou European Hospital-Necker, Assistance Publique-Hôpitaux de Paris, Paris, France; and.
authors.forename: Marc Olivier
authors.initials: MO
authors.lastname: Timsit
authors.affiliation: Paris Descartes, Sorbonne Paris Cité University, Paris, France; Pathology Department and.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Duong Van Huyen
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France; Paris Descartes, Sorbonne Paris Cité University, Paris, France; Department of Nephrology and Kidney Transplantation, Necker Hospital, and Centaure Foundation and Labex Transplantex, Necker Hospital, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France;
authors.forename: Fabiola
authors.initials: F
authors.lastname: Terzi
authors.affiliation: Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France; Paris Descartes, Sorbonne Paris Cité University, Paris, France; Department of Nephrology and Kidney Transplantation, Necker Hospital, and Centaure Foundation and Labex Transplantex, Necker Hospital, Paris, France dany.anglicheau@nck.aphp.fr.
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
mesh_terms: D000328:Adult; D000906:Antibodies / Q000097:blood; D019540:Area Under Curve; D015415:Biomarkers / Q000652:urine; D001706:Biopsy; D054357:Chemokine CXCL10 / Q000652:urine*; D054370:Chemokine CXCL9 / Q000652:urine; D015331:Cohort Studies; D003404:Creatinine / Q000652:urine; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D051437:Renal Insufficiency / Q000175:diagnosis* / Q000276:immunology* / Q000652:urine; D015203:Reproducibility of Results; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D015415:Biomarkers; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D007371:Interferon-gamma; D003404:Creatinine
keywords: antibody-mediated rejection; biomarker; kidney transplantation; noninvasive diagnosis