Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection
Weijia Zhang, Zhengzi Yi, Chengguo Wei, Karen L. Keung, Zeguo Sun, Caixia Xi, Christopher Woytovich, Samira Farouk, Lorenzo Gallon, Madhav C. Menon, Ciara Magee, Nader Najafian, Milagros D. Samaniego, Arjang Djamali, Stephen I. Alexander, Ivy A. Rosales, Rex Neal Smith, Philip J. O’Connell, Robert Colvin, Paolo Cravedi, Barbara Murphy
Weijia Zhang, Zhengzi Yi, Chengguo Wei, Karen L. Keung, Zeguo Sun, Caixia Xi, Christopher Woytovich, Samira Farouk, Lorenzo Gallon, Madhav C. Menon, Ciara Magee, Nader Najafian, Milagros D. Samaniego, Arjang Djamali, Stephen I. Alexander, Ivy A. Rosales, Rex Neal Smith, Philip J. O’Connell, Robert Colvin, Paolo Cravedi, Barbara Murphy
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Research Article Nephrology Transplantation

Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection

Abstract

Commonly available clinical parameters fail to predict early acute cellular rejection (EAR, occurring within 6 months after transplant), a major risk factor for graft loss after kidney transplantation. We performed whole-blood RNA sequencing at the time of transplant in 235 kidney transplant recipients enrolled in a prospective cohort study (Genomics of Chronic Allograft Rejection [GoCAR]) and evaluated the relationship of pretransplant transcriptomic profiles with EAR. EAR was associated with downregulation of NK and CD8+ T cell gene signatures in pretransplant blood. We identified a 23-gene set that predicted EAR in the discovery (n = 81, and AUC = 0.80) and validation (n = 74, and AUC = 0.74) sets. Exclusion of recipients with 5 or 6 HLA donor mismatches increased the AUC to 0.89. The risk score derived from the gene set was also significantly associated with acute cellular rejection after 6 months, antibody-mediated rejection and/or de novo donor-specific antibodies, and graft loss in a cohort of 154 patients, combining the validation set and additional GoCAR patients with surveillance biopsies between 6 and 24 months (n = 80) posttransplant. This 23-gene set is a potentially important new tool for determination of the recipient’s immunological risk before kidney transplantation, and facilitation of an individualized approach to immunosuppressive therapy.

Authors

Weijia Zhang, Zhengzi Yi, Chengguo Wei, Karen L. Keung, Zeguo Sun, Caixia Xi, Christopher Woytovich, Samira Farouk, Lorenzo Gallon, Madhav C. Menon, Ciara Magee, Nader Najafian, Milagros D. Samaniego, Arjang Djamali, Stephen I. Alexander, Ivy A. Rosales, Rex Neal Smith, Philip J. O’Connell, Robert Colvin, Paolo Cravedi, Barbara Murphy

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Figure 4

Association of gene risk score with clinical outcomes after transplant in VL cohort with no more than 4 HLA mismatches (n = 100).

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Association of gene risk score with clinical outcomes after transplant i...
(A) The violin plot of distribution of risk scores among the patients with AR at borderline and 1A and above, and with no AR beyond 6 months after transplant; P values are significant between the AR and no AR groups (t test P = 0.005) and between the AR and borderline groups (t test P = 0.014). (B) The violin plot of distribution of risk scores between the patients who developed ABMR or de novo DSAs and those without clinical events (t test P = 3.07 × 10–8). (C) The dot plot of the gene risk scores of 12 patients who developed ABMR (gold), de novo DSAs (blue), or both (red). (D) The Kaplan-Meier curve of graft loss with the kidney transplant recipients stratified by high, intermediate, or low risk based on tertile cutoffs (log-rank test P = 3.09 × 10–4). (E) The ROC curve for prediction of graft loss at 2 (black curve, AUC = 0.904) or 5 (red curve, AUC = 0.820) years after transplant. (F) Summary plots of association of gene risk score with clinical outcomes of kidney transplant patients in V and Late/L sets: the heatmap on the top shows the expression of the 23-gene set of the patients with low to high risk scores. The middle dot plot displays the risk scores of the patients who developed graft loss (red), immunological events (AR/ABMR/de novo DSAs, gold), or both (purple). The bottom indicates the clinical events for each patient.