Complement-binding anti-HLA DSA have demonstrated higher rejection rate and decreased allograft survival. However, their specific effects on rejection pathogenesis have not been identified. We investigated whether the complement-binding capacity of circulating DSA is associated with specific gene expression signature in allografts.

We prospectively enrolled 931 kidney recipients transplanted between 2011 and 2014 in 2 Paris centers, with systematic screening for anti-HLA DSA in the first year post-transplantation. We assessed DSA specificity, MFI, C1q-binding ability and IgG1-4 subclasses using SAB. All patients underwent allograft biopsy at the time of detection of post-transplant DSA to assess gene expression using unsupervised microarray analysis. We compared the intragraft gene expression in patients with C1q-binding and non-C1q-binding DSA. The importance of the top 50 genes for discriminating DSA C1q-binding status with respect to conventional histology parameters was determined using random forests.

We identified 157 (17%) patients with post-transplant DSA, 44 (28%) with C1q-binding DSA and 113 (72%) with non-C1q-binding DSA. C1q-binding DSA showed higher MFI (9483±747 vs. 2978±278; P<0.001) and greater prevalence of IgG1 (96% vs. 62%; P<0.001) and IgG3 (57% vs 17%; P<0.001) subclasses than non-C1q-binding DSA. Among 9954 IQR-filtered genes, those that were most significantly expressed in C1q-binding DSA patients were composed primarily of NK selective, NK, endothelial, interferon gamma, macrophage and effector T cell genes. We defined a highly discriminative set of 5 genes for DSA C1q-binding status: CXCL11, CCL4, MS4A6A, GBP1 and MS4A7. The 5-gene set predicted the C1q-binding capacity of DSA independently of DSA MFI and IgG subclass composition.The 5-gene set capacity to predict the DSA C1q-binding status outperformed that of conventional histology: AUC of 0.85 vs. 0.76, P=0.006. The integration of the 5-gene set to conventional histology parameters in unsupervised clustering and PCA allowed to identify a distinct pattern of allograft injury reflecting the complement-binding capacity of DSA.

We identified a specific gene expression signature of kidney allograft injury related to the complement-binding capacity of circulating DSA that outperformed the conventional histology evaluation.

CITATION INFORMATION: Lefaucheur C, Viglietti D, Hidalgo L, Aubert O, Zeevi A, Halloran P, Loupy A. Specific Gene Expression Signature of Complement-Activating Donor Specific Anti-HLA Antibody-Mediated Rejection in Kidney Allografts. Am J Transplant. 2017;17 (suppl 3).

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