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 1

Description of study cohorts.

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Description of study cohorts. The study included 235 GoCAR kidney transp...
The study included 235 GoCAR kidney transplant recipients with good-quality pretransplant blood RNA samples. Of the 235, 155 had pretransplant biopsies and serial after transplant surveillance biopsies until 24 months after transplant per protocol, whereas 80 had only late surveillance biopsies only between 6 and 24 months after transplant. Out of 155 patients with early surveillance biopsy, 81 were used as the discovery set (D) for identification of a gene set for prediction of early acute cellular rejection (EAR), i.e., before 6 months after transplant. We used 74 patients as the independent V set. Combined V and additional 80 patients with late surveillance biopsies (Late/L, n = 80) cohorts (VL, n = 154) were used to estimate association of gene set–derived risk score with late acute rejection (LAR) after 6 months, antibody-mediated rejection (ABMR), de novo donor-specific antibodies (DSAs) after transplant, or graft loss. All the patients had been followed up for at least 5 years or until graft loss or patient death.