A peripheral blood gene expression signature to diagnose subclinical acute rejection

Weijia Zhang, Zhengzi Yi, Karen L. Keung, Huimin Shang, Chengguo Wei, Paolo Cravedi, Zeguo Sun, Caixia Xi, Christopher Woytovich, Samira Farouk, Weiqing Huang, Khadija Banu, Lorenzo Gallon, Ciara N. Magee, Nader Najafian, Milagros Samaniego, Arjang Djamali, Stephen I. Alexander, Ivy A. Rosales, Rex Neal SmithJenny Xiang, Evelyne Lerut, Dirk Kuypers, Maarten Naesens, Philip J. O’connell, Robert Colvin, Madhav C. Menon, Barbara Murphy*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. Methods We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort. Results Study participants with ACR-3 had significantly higher risk than those without ACR-3 of subsequent clinical acute rejection at 12 and 24 months, faster decline in graft function, and decreased graft survival in adjusted Cox analysis. We identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3, and validated it using microarray expression profiles of blood samples from 65 transplant recipients in the GoCAR cohort and three public microarray datasets. In an independent cohort of 110 transplant recipients, tests of the targeted expression assay on the basis of the 17-gene set showed that it identified individuals at higher risk of ongoing acute rejection and future graft loss.Conclusions Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.

Original languageEnglish (US)
Pages (from-to)1481-1494
Number of pages14
JournalJournal of the American Society of Nephrology
Volume30
Issue number8
DOIs
StatePublished - Aug 2019

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Transcriptome
Transplants
Biopsy
Genomics
Kidney
Allografts
Genes
RNA Sequence Analysis
Graft Rejection
Graft Survival
Biomarkers
Transplant Recipients
Inflammation
Costs and Cost Analysis

ASJC Scopus subject areas

  • Nephrology

Cite this

Zhang, Weijia ; Yi, Zhengzi ; Keung, Karen L. ; Shang, Huimin ; Wei, Chengguo ; Cravedi, Paolo ; Sun, Zeguo ; Xi, Caixia ; Woytovich, Christopher ; Farouk, Samira ; Huang, Weiqing ; Banu, Khadija ; Gallon, Lorenzo ; Magee, Ciara N. ; Najafian, Nader ; Samaniego, Milagros ; Djamali, Arjang ; Alexander, Stephen I. ; Rosales, Ivy A. ; Smith, Rex Neal ; Xiang, Jenny ; Lerut, Evelyne ; Kuypers, Dirk ; Naesens, Maarten ; O’connell, Philip J. ; Colvin, Robert ; Menon, Madhav C. ; Murphy, Barbara. / A peripheral blood gene expression signature to diagnose subclinical acute rejection. In: Journal of the American Society of Nephrology. 2019 ; Vol. 30, No. 8. pp. 1481-1494.
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title = "A peripheral blood gene expression signature to diagnose subclinical acute rejection",
abstract = "Background In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. Methods We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort. Results Study participants with ACR-3 had significantly higher risk than those without ACR-3 of subsequent clinical acute rejection at 12 and 24 months, faster decline in graft function, and decreased graft survival in adjusted Cox analysis. We identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3, and validated it using microarray expression profiles of blood samples from 65 transplant recipients in the GoCAR cohort and three public microarray datasets. In an independent cohort of 110 transplant recipients, tests of the targeted expression assay on the basis of the 17-gene set showed that it identified individuals at higher risk of ongoing acute rejection and future graft loss.Conclusions Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.",
author = "Weijia Zhang and Zhengzi Yi and Keung, {Karen L.} and Huimin Shang and Chengguo Wei and Paolo Cravedi and Zeguo Sun and Caixia Xi and Christopher Woytovich and Samira Farouk and Weiqing Huang and Khadija Banu and Lorenzo Gallon and Magee, {Ciara N.} and Nader Najafian and Milagros Samaniego and Arjang Djamali and Alexander, {Stephen I.} and Rosales, {Ivy A.} and Smith, {Rex Neal} and Jenny Xiang and Evelyne Lerut and Dirk Kuypers and Maarten Naesens and O’connell, {Philip J.} and Robert Colvin and Menon, {Madhav C.} and Barbara Murphy",
year = "2019",
month = "8",
doi = "10.1681/ASN.2018111098",
language = "English (US)",
volume = "30",
pages = "1481--1494",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
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Zhang, W, Yi, Z, Keung, KL, Shang, H, Wei, C, Cravedi, P, Sun, Z, Xi, C, Woytovich, C, Farouk, S, Huang, W, Banu, K, Gallon, L, Magee, CN, Najafian, N, Samaniego, M, Djamali, A, Alexander, SI, Rosales, IA, Smith, RN, Xiang, J, Lerut, E, Kuypers, D, Naesens, M, O’connell, PJ, Colvin, R, Menon, MC & Murphy, B 2019, 'A peripheral blood gene expression signature to diagnose subclinical acute rejection', Journal of the American Society of Nephrology, vol. 30, no. 8, pp. 1481-1494. https://doi.org/10.1681/ASN.2018111098

A peripheral blood gene expression signature to diagnose subclinical acute rejection. / Zhang, Weijia; Yi, Zhengzi; Keung, Karen L.; Shang, Huimin; Wei, Chengguo; Cravedi, Paolo; Sun, Zeguo; Xi, Caixia; Woytovich, Christopher; Farouk, Samira; Huang, Weiqing; Banu, Khadija; Gallon, Lorenzo; Magee, Ciara N.; Najafian, Nader; Samaniego, Milagros; Djamali, Arjang; Alexander, Stephen I.; Rosales, Ivy A.; Smith, Rex Neal; Xiang, Jenny; Lerut, Evelyne; Kuypers, Dirk; Naesens, Maarten; O’connell, Philip J.; Colvin, Robert; Menon, Madhav C.; Murphy, Barbara.

In: Journal of the American Society of Nephrology, Vol. 30, No. 8, 08.2019, p. 1481-1494.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A peripheral blood gene expression signature to diagnose subclinical acute rejection

AU - Zhang, Weijia

AU - Yi, Zhengzi

AU - Keung, Karen L.

AU - Shang, Huimin

AU - Wei, Chengguo

AU - Cravedi, Paolo

AU - Sun, Zeguo

AU - Xi, Caixia

AU - Woytovich, Christopher

AU - Farouk, Samira

AU - Huang, Weiqing

AU - Banu, Khadija

AU - Gallon, Lorenzo

AU - Magee, Ciara N.

AU - Najafian, Nader

AU - Samaniego, Milagros

AU - Djamali, Arjang

AU - Alexander, Stephen I.

AU - Rosales, Ivy A.

AU - Smith, Rex Neal

AU - Xiang, Jenny

AU - Lerut, Evelyne

AU - Kuypers, Dirk

AU - Naesens, Maarten

AU - O’connell, Philip J.

AU - Colvin, Robert

AU - Menon, Madhav C.

AU - Murphy, Barbara

PY - 2019/8

Y1 - 2019/8

N2 - Background In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. Methods We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort. Results Study participants with ACR-3 had significantly higher risk than those without ACR-3 of subsequent clinical acute rejection at 12 and 24 months, faster decline in graft function, and decreased graft survival in adjusted Cox analysis. We identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3, and validated it using microarray expression profiles of blood samples from 65 transplant recipients in the GoCAR cohort and three public microarray datasets. In an independent cohort of 110 transplant recipients, tests of the targeted expression assay on the basis of the 17-gene set showed that it identified individuals at higher risk of ongoing acute rejection and future graft loss.Conclusions Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.

AB - Background In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. Methods We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort. Results Study participants with ACR-3 had significantly higher risk than those without ACR-3 of subsequent clinical acute rejection at 12 and 24 months, faster decline in graft function, and decreased graft survival in adjusted Cox analysis. We identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3, and validated it using microarray expression profiles of blood samples from 65 transplant recipients in the GoCAR cohort and three public microarray datasets. In an independent cohort of 110 transplant recipients, tests of the targeted expression assay on the basis of the 17-gene set showed that it identified individuals at higher risk of ongoing acute rejection and future graft loss.Conclusions Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.

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U2 - 10.1681/ASN.2018111098

DO - 10.1681/ASN.2018111098

M3 - Article

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AN - SCOPUS:85070852460

VL - 30

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JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

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