A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection

• Published in: Journal of the American Society of Nephrology Vol. 30; no. 8; pp. 1481 - 1494
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01-08-2019
• Subjects: Adult; Aged; Biomarkers - metabolism; Biopsy; Clinical Research; Female; Gene Expression Profiling; Genomics; Graft Rejection - blood; Graft Rejection - diagnosis; Graft Survival; Humans; Immunosuppressive Agents - therapeutic use; Inflammation; Kaplan-Meier Estimate; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - mortality; Kidney Failure, Chronic - surgery; Kidney Transplantation - adverse effects; Kidney Transplantation - mortality; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Prospective Studies; Risk Factors; Sequence Analysis, RNA; whole blood; acute rejection; renal transplantation; gene expression
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2018111098

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.
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.
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.
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.