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J Am Soc Nephrol. 2019 Aug;30(8):1481-1494. doi: 10.1681/ASN.2018111098. Epub 2019 Jul 5.

A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection.

Author information

1
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
2
Department of Medicine, Westmead Clinical School, The University of Sydney, Sydney, New South Wales, Australia.
3
Department of Microbiology and Immunology, Cornell Medical Center, New York, New York.
4
Department of Medicine-Nephrology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
5
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
6
Division of Nephrology, Department of Medicine, Henry Ford Hospital, Detroit, Michigan.
7
Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, Wisconsin.
8
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
9
Departments of Pathology and.
10
Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Leuven, Belgium.
11
Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium; and.
12
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; barbara.murphy@mssm.edu.

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.

KEYWORDS:

acute rejection; gene expression; renal transplantation; whole blood

PMID:
31278196
PMCID:
PMC6683710
[Available on 2020-08-01]
DOI:
10.1681/ASN.2018111098

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