Abstract
Background: Screening for donor-specific antibodies (DSA) has limited diagnostic value in patients with late antibody-mediated rejection (ABMR). Here, we evaluated whether biomarkers reflecting microcirculation inflammation or tissue injury—as an adjunct to DSA detection—are able to improve non-invasive ABMR monitoring.Methods: Upon prospective cross-sectional antibody screening of 741 long-term kidney transplant recipients with a silent clinical course, 86 DSA-positive patients were identified and biopsied. Serum and urine levels of E-selectin/CD62E, vascular cell adhesion molecule 1 (VCAM-1), granzyme B, hepatocyte growth factor (HGF), C-C motif chemokine ligand (CCL)3, CCL4, C-X-C motif chemokine ligand (CXCL)9, CXCL10, and CXCL11 in DSA-positive recipients were investigated applying multiplexed bead-based immunoassays.Results: Diagnosis of ABMR (50 patients) was associated with significantly higher levels of CXCL9 and CXCL10 in blood and urine and of HGF in blood. Overall, urinary CXCL9 had the highest diagnostic accuracy for ABMR (area under the receiver operating characteristic curve: 0.77; accuracy: 80%) and its combined evaluation with the mean fluorescence intensity of the immunodominant DSA (DSAmax MFI) revealed a net reclassification improvement of 73% compared to DSAmax MFI alone.Conclusions: Our results suggest urinary CXCL9 testing, combined with DSA analysis, as a valuable non-invasive tool to uncover clinically silent ABMR late after transplantation.
Highlights
Antibody-mediated rejection (ABMR) is a major cause of allograft failure in the long-term [1]
Urinary CXCL9 had the highest diagnostic accuracy for antibody-mediated rejection (ABMR) and its combined evaluation with the mean fluorescence intensity of the immunodominant donor-specific antibodies (DSA) (DSAmax mean fluorescent intensity (MFI)) revealed a net reclassification improvement of 73% compared to DSAmax MFI alone
The study cohort consisted of 86 DSA+ recipients who were identified upon cross-sectional screening ≥180 days posttransplantation and who were all subjected to protocol biopsies 5 years after transplantation
Summary
Antibody-mediated rejection (ABMR) is a major cause of allograft failure in the long-term [1]. This type of rejection is diagnosed on the basis of donor-specific antibody (DSA) detection in serum and a variety of biopsy-based morphological and molecular criteria. One strategy toward improved non-invasive ABMR prediction in DSA-positive subjects might be the detailed characterization of DSA properties, such as antibody binding strength or complement fixation. Such parameters may still not precisely reflect the actual pathogenic potential of a given HLA antibody pattern [5]. We evaluated whether biomarkers reflecting microcirculation inflammation or tissue injury—as an adjunct to DSA detection—are able to improve non-invasive ABMR monitoring
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