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Diagnostic Contribution of Donor-Specific Antibody Characteristics to Uncover Late Silent Antibody-Mediated RejectionResults of a Cross-Sectional Screening Study

Eskandary, Farsad MD; Bond, Gregor MD, PhD; Kozakowski, Nicolas MD; Regele, Heinz MD; Marinova, Lena; Wahrmann, Markus PhD; Kikić, Željko MD; Haslacher, Helmuth MD; Rasoul-Rockenschaub, Susanne MD; Kaltenecker, Christopher C. BSc; König, Franz PhD; Hidalgo, Luis G. PhD; Oberbauer, Rainer MD, MSc; Halloran, Philip F. MD, PhD; Böhmig, Georg A. MD

doi: 10.1097/TP.0000000000001195
Original Clinical Science-General

Background: Circulating donor-specific antibodies (DSA) detected on bead arrays may not inevitably indicate ongoing antibody-mediated rejection (AMR). Here, we investigated whether detection of complement-fixation, in parallel to IgG mean fluorescence intensity (MFI), allows for improved prediction of AMR.

Methods: Our study included 86 DSA+ kidney transplant recipients subjected to protocol biopsy, who were identified upon cross-sectional antibody screening of 741 recipients with stable graft function at 6 months or longer after transplantation. IgG MFI was analyzed after elimination of prozone effect, and complement-fixation was determined using C1q, C4d, or C3d assays.

Results: Among DSA+ study patients, 44 recipients (51%) had AMR, 24 of them showing C4d-positive rejection. Although DSA number or HLA class specificity were not different, patients with AMR or C4d + AMR showed significantly higher IgG, C1q, and C3d DSA MFI than nonrejecting or C4d-negative patients, respectively. Overall, the predictive value of DSA characteristics was moderate, whereby the highest accuracy was computed for peak IgG MFI (AMR, 0.73; C4d + AMR, 0.71). Combined analysis of antibody characteristics in multivariate models did not improve AMR prediction.

Conclusions: We estimate a 50% prevalence of silent AMR in DSA+ long-term recipients and conclude that assessment of IgG MFI may add predictive accuracy, without an independent diagnostic advantage of detecting complement-fixation.

The authors report their experience on 86 DSA+ kidney transplant recipients with available screening biopsies. They confirm that about 50% of these patients do experience subclinical ABMR and compare the prognostic information given by IgG MFI level, C1q- and C3d-fixing properties of DSAs.

1 Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria.

2 Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, AB, Canada.

3 Department of Clinical Pathology, Medical University Vienna, Vienna, Austria.

4 Department of Laboratory Medicine, Medical University Vienna, Vienna, Austria.

5 Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Vienna, Austria.

6 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.

7 Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Received 4 December 2015. Revision received 15 January 2016.

Accepted 5 February 2016.

The study was funded by a grant from the Austrian Science Fund (FWF; KLI 190).

The authors declare no conflicts of interest.

F.E., G.B., H.R., R.O., and G.A.B. participated in research design, performance of the research, data analysis, and writing of the paper. N.K, L.M., M.W., Z.K., H.H., S.R., C.K., F.K., L.G.H., and P.F.H. participated in data analysis and writing of the article.

Correspondence: Georg A. Böhmig, MD, Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. (georg.boehmig@meduniwien.ac.at).

Clinical trial notification: www.clinicaltrials.org, NCT01873157

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