Pre-Transplant Transcriptomic Signature in Peripheral Blood Predicts Early Acute Rejection After Kidney Transplant
Zhang W, Yi Z, Wei C, Keung K, Sun Z, Xi C, Woytovich C, Farouk S, Gallon L, Menon M, Magee C, Najafan N, Samaniego M, Djamali A, Alexander S, Rosales I, Smith R, O'Connell P, Colvin R, Cravedi P, and Murphy B. Pre-Transplant Transcriptomic Signature in Peripheral Blood Predicts Early Acute Rejection After Kidney Transplant. Am J Transplant 2019; 19:567.
Am J Transplant
Purpose: Early development of acute rejection after kidney transplantation is associated with diminished long-term graft survival. Predicting early acute rejection (EAR) at the time of transplant is important to risk-stratify patients, but it cannot be achieved with commonly available clinical information. Methods: We performed whole-blood RNA sequencing at the time of transplant in 245 kidney transplant recipients enrolled in a prospective-cohort study [one discovery set (N=81), two validation sets (N=74 and N=80) and BK virus positive set (N=10) and evaluated the relationship with EAR and graft loss. Results: Pre-transplant blood RNA sequencing profiles revealed down-regulation of NK and CD8+ T cell signatures associated with EAR post-transplant. We further identified a set of 23 genes that predicted EAR in the discovery set (AUC = 0.80) and in the validation set (AUC = 0.74). When we excluded the recipients of allografts with > 4 HLA-allele mismatches, the AUC increased to 0·89. The risk score derived from the gene-set was also significantly associated with AR after 6 months post-transplant (p = 0.041), antibody mediated rejection (ABMR) or de novo donor-specific antibodies (DSA; p = 5.17e-4), and long-term graft loss (p = 0.043) in the two validation sets, especially for recipients of allografts with ≤ 4 HLA mismatches (p = 0.005 for AR, p = 3.07e-8 for ABMR or de novo DSA and p = 3·09e-4 for graft loss). Lastly the gene set appears to be associated with autoimmune diseases (such as lupus, inflammatory bowel disease, and diabetes) in publicly available blood expression datasets of autoimmune disease cohorts. Conclusions: We identified a pre-transplant blood 23-gene set that predicts EAR and is associated with ABMR, de novo DSA, and allograft loss. This gene set is an important new tool to risk-stratify recipients before kidney transplantation and help titrating immunosuppression to single-patient needs. This assay could be applied to immune monitor also individuals with autoimmune diseases.