Developing a Molecular Diagnosis of Antibody Mediated Rejection: Can Molecular Assessments Replace C4d?
Banu Sis, Luis Hidalgo, Gunilla Einecke, Michael Mengel, Jeff Reeve, Konrad Famulski, Arthur Matas, Bert Kasiske, Bruce Kaplan, Philip Halloran. University of Alberta, Edmonton, Canada; University of Minnesota, Minneapolis; University of Arizona, Tucson
Background: When microcirculation lesions and HLA-antibody were used to define antibody-mediated rejection (ABMR), 63% of late kidney failures were attributable to ABMR, but many were C4d negative, suggesting that detection of this phenotype requires new diagnostic criteria (AJT 2009;9:2520-31). We previously showed that high endothelial gene set expression in kidney transplant biopsies with donor specific antibody (DSA) indicates active ABMR and predicts poor graft survival (AJT 2009;9:2312-23).
We hypothesized that measurement of individual endothelial transcripts in biopsies is a sensitive and specific method to diagnose ABMR.
Design: We studied 403 kidney transplant biopsies for cause from 315 patients by histopathology, C4d staining (368/403), antibody testing (355/403), and microarrays. ABMR was defined by histology/serology: microcirculation lesions (g>0 and/or ptc>0 and/or cg>0) plus DSA: Of 403 biopsies, 24 had C4d+ ABMR, 45 C4d negative ABMR, and 14 mixed rejection. The new molecular/serology definition of ABMR included high endothelial gene expression in the presence of DSA.
Results: We evaluated expression of three endothelial transcripts: SOX7 (SRY-box 7), CDH5 (cadherin 5), and VWF (von Willebrand factor). In a training set (n=201), we selected a cut-off signal for each gene for detecting ABMR (histology/serology) with at least 80% sensitivity by ROC curve analysis.
Applying the same cut-offs in an independent set (n=202), SOX7 plus DSA showed 88% sensitivity and 90% specificity, and combined SOX2/CDH5/VWF plus DSA showed 90% sensitivity and 86% specificity for ABMR, whereas, C4d showed 49% sensitivity and 96% specificity.
Conclusions: Thus measuring a few endothelial transcripts in biopsies from kidneys with alloantibody is a highly sensitive and specific method to detect ABMR, and is more sensitive than C4d. Endothelial molecular parameters should be incorporated into the Banff classification to improve diagnosis of ABMR.
Category: Kidney (does not include tumors)
Monday, February 28, 2011 2:15 PM
Platform Session: Section H, Monday Afternoon