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J Am Soc Nephrol. 2017 Jul;28(7):2221-2232. doi: 10.1681/ASN.2016091034. Epub 2017 Mar 9.

Cell-Free DNA and Active Rejection in Kidney Allografts.

Author information

1
Department of Medicine, University of Pennsylvania, Perelman School of Medicine and Penn Kidney Pancreas Transplant Program, Philadelphia, Pennsylvania.
2
Department of Surgery and Department of Microbiology and Immunology and.
3
Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio.
4
Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
5
Department of Medicine, Vanderbilt University Medical Center, and Medical Specialties Clinic, Veteran Affairs Hospital Renal Transplant Program, Nashville, Tennessee.
6
Thomas Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
7
Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
8
Division of Nephrology, Department of Medicine, and.
9
Division Transplantation, University of Alabama School of Medicine, Birmingham, Alabama.
10
Division of Nephrology and Transplant, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
11
Baylor Research Institute, Dallas, Texas.
12
Division of Nephrology & Hypertension, Texas A&M Health Science Center College of Medicine, Temple, Texas.
13
Division of Nephrology, Cedars-Sinai Medical Center, Los Angeles, California.
14
Department of Surgery, Columbia University Medical Center, New York, New York.
15
Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
16
Biostatistics.
17
Clinical Research.
18
Research and Development, CareDx, Inc., Brisbane, California; and.
19
Washington University School of Medicine, St. Louis, Missouri dbrennan@dom.wustl.edu.

Abstract

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P<0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.

KEYWORDS:

DART; biomarker; cell-free DNA; kidney; rejection; transplant

PMID:
28280140
PMCID:
PMC5491290
DOI:
10.1681/ASN.2016091034
[Indexed for MEDLINE]
Free PMC Article

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