Background: Our multi-center study (Genomics of Chronic Allograft Rejection, GoCAR) revealed that early acute rejection (EAR, developed before 6 months post-transplant) is associated with later acute rejection and diminished long-term graft survival. Identification of EAR predictors at the time of transplant would allow to titrate immunosuppression on the basis of single-patient needs.

Methods: To test the hypothesis that the molecular profiles in the recipients prior to transplant predicts the risk for acute rejection more accurately than baseline demographic characteristics, we performed RNA sequencing of baseline (before transplant) PBMC in 238 kidney transplant recipients from three cohorts with similar demographic characteristics [one discovery set (N=81) and two validation sets with (N=74, V1) or without (N=83, V2) biopsy before 6 months post transplant) and evaluated relationship with acute rejection (AR) and graft loss (GL).

Results: In the discovery set, we identified 653 down- and 688 up-regulated genes in PBMC from the recipients who developed EAR compared to those who did not. The down-regulated genes were enriched for transcripts of NK cell mediated function, whereas the up-regulated genes were involved in cytokine production and expressed in neutrophils and monocytes. By using a permutation-based statistical approach in combination with correlation network analysis, we identified a set of 23 genes that predicted EAR in the discovery set with an AUC=0.80 using the risk score based on the gene expression value. 7 of these 23 genes are involved in NK cell-mediated immune response. The gene set was able to predict EAR with an overall AUC=0.74 in the validation set (V1) and a higher accuracy (AUC=0.89) within recipients of grafts with 4 HLA allele mismatches or less. The risk scores derived from the gene set were significantly associated with AR after 6 months post-transplant and long-term graft loss in the two validation sets (P=0.041 for AR and P=0.013 for GL), especially within recipients with fewer HLA mismatches (P=0.005 for AR and P=0.003 for GL).

Conclusion: We identified a 23-gene set related to NK cell function in the PBMC from recipients before transplant that predicts the risk of early AR and is associated with late AR and graft loss, especially in subjects with low HLA mismatches.

CITATION INFORMATION: Zhang W., Yi Z., Cravedi P., Li L., Keung K., Wei C., Menon M., Dudley J., O'Connell P., Murphy B. A Transcriptomic Signature in PBMC from Kidney Transplant Recipients at Baseline Predicts Early Acute Rejection Am J Transplant. 2017;17 (suppl 3).

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