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 CravediBarbara Murphy*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Article numbere127543
JournalJCI Insight
Volume4
Issue number11
DOIs
StatePublished - Jun 6 2019

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Area Under Curve
Transplants
Genomics
Kidney Transplantation
Genes
Allografts
Tissue Donors
RNA Sequence Analysis
Antibodies
Immunosuppressive Agents
Cohort Studies
Down-Regulation
Prospective Studies
T-Lymphocytes
Kidney
Biopsy
Therapeutics
Transplant Recipients

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, W., Yi, Z., Wei, C., Keung, K. L., Sun, Z., Xi, C., ... Murphy, B. (2019). Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection. JCI Insight, 4(11), [e127543]. https://doi.org/10.1172/jci.insight.127543
Zhang, Weijia ; Yi, Zhengzi ; Wei, Chengguo ; Keung, Karen L. ; Sun, Zeguo ; Xi, Caixia ; Woytovich, Christopher ; Farouk, Samira ; Gallon, Lorenzo ; Menon, Madhav C. ; Magee, Ciara ; Najafian, Nader ; Samaniego, Milagros D. ; Djamali, Arjang ; Alexander, Stephen I. ; Rosales, Ivy A. ; Smith, Rex Neal ; O’Connell, Philip J. ; Colvin, Robert ; Cravedi, Paolo ; Murphy, Barbara. / Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection. In: JCI Insight. 2019 ; Vol. 4, No. 11.
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title = "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.",
author = "Weijia Zhang and Zhengzi Yi and Chengguo Wei and Keung, {Karen L.} and Zeguo Sun and Caixia Xi and Christopher Woytovich and Samira Farouk and Lorenzo Gallon and Menon, {Madhav C.} and Ciara Magee and Nader Najafian and Samaniego, {Milagros D.} and Arjang Djamali and Alexander, {Stephen I.} and Rosales, {Ivy A.} and Smith, {Rex Neal} and O’Connell, {Philip J.} and Robert Colvin and Paolo Cravedi and Barbara Murphy",
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Zhang, W, Yi, Z, Wei, C, Keung, KL, Sun, Z, Xi, C, Woytovich, C, Farouk, S, Gallon, L, Menon, MC, Magee, C, Najafian, N, Samaniego, MD, Djamali, A, Alexander, SI, Rosales, IA, Smith, RN, O’Connell, PJ, Colvin, R, Cravedi, P & Murphy, B 2019, 'Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection', JCI Insight, vol. 4, no. 11, e127543. https://doi.org/10.1172/jci.insight.127543

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

In: JCI Insight, Vol. 4, No. 11, e127543, 06.06.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection

AU - Zhang, Weijia

AU - Yi, Zhengzi

AU - Wei, Chengguo

AU - Keung, Karen L.

AU - Sun, Zeguo

AU - Xi, Caixia

AU - Woytovich, Christopher

AU - Farouk, Samira

AU - Gallon, Lorenzo

AU - Menon, Madhav C.

AU - Magee, Ciara

AU - Najafian, Nader

AU - Samaniego, Milagros D.

AU - Djamali, Arjang

AU - Alexander, Stephen I.

AU - Rosales, Ivy A.

AU - Smith, Rex Neal

AU - O’Connell, Philip J.

AU - Colvin, Robert

AU - Cravedi, Paolo

AU - Murphy, Barbara

PY - 2019/6/6

Y1 - 2019/6/6

N2 - 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.

AB - 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.

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