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Targeted Proteomic Analysis Detects Acute T Cell–Mediated Kidney Allograft Rejection in Belatacept-Treated Patients

van der Zwan, Marieke, MD*; Hesselink, Dennis A., MD, PhD*; Clahsen-van Groningen, Marian C., MD, PhD; Baan, Carla C., PhD*

doi: 10.1097/FTD.0000000000000587
Short Communication

Background: There is an unmet need for reliable minimally invasive diagnostic biomarkers for immunological allograft monitoring and for the detection of acute kidney transplant rejection. Here, targeted proteomic analysis was applied to compare 92 proteins in sera of belatacept-treated patients who had biopsy-proven, acute T-cell–mediated rejection (aTCMR) with patients without aTCMR.

Methods: Proximity extension immunoassay was used to measure 92 inflammation-related protein concentrations in the prerejection and rejection sera of 11 patients with aTCMR and 9 patients without aTCMR. This assay uses 2 matched oligonucleotide-labeled antibody probes for each protein and polymerase chain reaction to measure normalized protein expression values.

Results: Five proteins (CD5, CD8A, NCR1, TNFRSF4, and TNFRSF9) were expressed significantly higher in samples with aTCMR compared with samples without aTCMR (adjusted P-value < 0.014) and had a good predictive capacity for aTCMR [area under the curve in a receiver–operator curve ranged from 0.83 to 0.91 (P < 0.014)]. These proteins are associated with CD8+ cytotoxic T-cell and NK cell functions. Nonhierarchical clustering analysis showed distinct clustering of samples with aTCMR and samples without aTCMR. This clustering was not found in prerejection samples (1 month after transplantation). In prerejection samples, IFN-γ was expressed at a significantly lower level (normalized protein expression value median −0.15, interquartile range: −0.27 to 0.04) than in samples of patients without rejection (median 0.13, interquartile range: −0.07 to 0.15, adjusted P-value = 0.00367).

Conclusions: Targeted proteomic analysis with proximity extension immunoassay is a promising minimally invasive technique to diagnose aTCMR in kidney transplant recipients.

*Division of Nephrology and Transplantation, Department of Internal Medicine, Rotterdam Transplant Group, Erasmus MC, University Medical Center; and

Department of Pathology, Rotterdam Transplant Group, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Correspondence: Marieke van der Zwan, MD, Division of Nephrology and Kidney Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam Transplant Group, Room Na-524, PO Box 2040, 3000 CA Rotterdam, the Netherlands (e-mail:

M. van der Zwan participated in the research design, acquisition of the data, data analysis, and writing of the article. M. C. Clahsen-van Groningen participated in the revision of the kidney biopsies and critical revision of the manuscript. C. C. Baan and D. A. Hesselink participated in the research design, data analysis, and critical revision of the manuscript.

D. A. Hesselink has received grant support from Astellas Pharma and Bristol Myers-Squibb and has received lecture and consulting fees from Astellas Pharma and Chiesi Pharma. The remaining authors have no conflicts of interest to disclose.

Received September 19, 2018

Accepted October 30, 2018

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.