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Short communication

Targeted proteomic analysis detects acute T cell-mediated kidney allograft rejection in belatacept-treated patients

van der Zwan, Marieke, MD1; Hesselink, Dennis A., MD, PhD1; Clahsen-van Groningen, Marian C., MD, PhD2; Baan, Carla C., PhD1

doi: 10.1097/FTD.0000000000000587
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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 (PEA) was used to measure 92 inflammation-related protein concentrations in the pre-rejection and rejection sera of 11 patients with aTCMR and 9 patients without aTCMR. This assay uses two matched oligonucleotide-labelled antibody probes for each protein and PCR 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. Non-hierarchical clustering analysis showed distinct clustering of samples with aTCMR and samples without aTCMR. This clustering was not found in pre-rejection samples (one month after transplantation). In pre-rejection samples, IFN-γ was expressed at a significantly lower level (NPX value median -0.15, IQR: -0.27-0.04) than in samples of patients without rejection (median 0.13, IQR: -0.07-0.15, adjusted p-value=0.00367).

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

Departments of 1 Internal Medicine, Division of Nephrology and Transplantation and

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

Corresponding Author: M. van der Zwan, M.D, ORCID: 0000-0002-9404-6135, Erasmus MC, University Medical Center Rotterdam, Department of Internal Medicine, Division of Nephrology and Kidney Transplantation, Rotterdam Transplant Group, Room Na-524, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands, Phone: +31-(0)107033471, Email: m.vanderzwan@erasmusmc.nl

Disclosure: 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 authors declare no conflicts of interest.

Authorship: M.v.d.Z. participated in the research design, acquisition of the data, data analysis and writing of the article. M.C.C-v.G. participated in the revision of the kidney biopsies, and critical revision of the manuscript. C.C.B. and D.A.H. and participated in the research design, data analysis and critical revision of the manuscript.

Funding: No sources of funding were used in the preparation of this manuscript

Disclosure: The authors report no conflicts of interest related to this work.

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