*Purpose: Antibody-mediated rejection is a leading cause of graft failure after kidney transplantation. The diagnosis of antibody-mediated rejection is made by combining assessment of circulating antibodies with histological assessment of invasive allograft biopsies. Non-invasive biomarkers with sufficient diagnostic accuracy are not available. We sought to identify and validate a blood biomarker for non-invasive detection of antibody-mediated rejection.

*Methods: In this multicentre study, peripheral blood samples were prospectively collected from June 2011 to August 2016 at time of renal allograft biopsies, and then analysed in three phases, following a case-control design (discovery and derivation phase, N=117 and N=183 respectively) and a trans-sectional study for performance assessment (independent validation phase, N=387). Untargeted screening of whole genome transcriptomics was performed for the discovery phase and targeted mRNA expression analysis for the derivation and validation phases.

*Results: In the discovery and derivation phases, we developed and locked a multigene assay of 8 genes in peripheral blood that discriminated cases with (N=49) from cases without (N=134) antibody-mediated rejection (diagnostic accuracy in derivation cohort, 78.1% (95% CI, 70.7 to 85.6, p<0.001). In the independent validation cohort, this 8-gene marker discriminated cases with (N=41) from cases without antibody-mediated rejection (N=346) with similar accuracy (79.9%; 95% CI, 72.6 to 87.2, p<0.001). At the optimal cut-off the marker held a sensitivity of 80.5%, specificity of 71.4%, PPV of 25.0% and NPV of 96.9%.

*Conclusions: We developed and validated a novel 8-gene expression assay in peripheral blood that can be used for non-invasive diagnosis of antibody-mediated rejection of kidney allografts.

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