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 journalArticlepeer-review

24 Scopus citations


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
Issue number8
StatePublished - Aug 2019

ASJC Scopus subject areas

  • Nephrology


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