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 language | English (US) |
|---|---|
| Pages (from-to) | 1481-1494 |
| Number of pages | 14 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 30 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2019 |
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ASJC Scopus subject areas
- Nephrology
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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 journal › Article
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
C2 - 31278196
AN - SCOPUS:85070852460
VL - 30
SP - 1481
EP - 1494
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 8
ER -