Diagnostic Contribution of Donor-Specific Antibody Characteristics to Uncover Late Silent Antibody-Mediated Rejection-Results of a Cross-Sectional Screening Study.
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.
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.
Farsad
F
Eskandary
Gregor
G
Bond
Nicolas
N
Kozakowski
Heinz
H
Regele
Lena
L
Marinova
Markus
M
Wahrmann
Željko
Ž
Kikić
Helmuth
H
Haslacher
Susanne
S
Rasoul-Rockenschaub
Christopher C
CC
Kaltenecker
Franz
F
König
Luis G
LG
Hidalgo
Rainer
R
Oberbauer
Philip F
PF
Halloran
Georg A
GA
Böhmig
D000328:Adult; D019540:Area Under Curve; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016009:Chi-Square Distribution; D003168:Complement Fixation Tests; D003165:Complement System Proteins / Q000032:analysis; D003430:Cross-Sectional Studies; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007518:Isoantibodies / Q000097:blood*; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D015995:Prevalence; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D012698:Serologic Tests; D016896:Treatment Outcome
D015415:Biomarkers; D006680:HLA Antigens; D007074:Immunoglobulin G; D007518:Isoantibodies; D003165:Complement System Proteins