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Clinical Research
Open Access

Cell-Free DNA and Active Rejection in Kidney Allografts

Roy D. Bloom, Jonathan S. Bromberg, Emilio D. Poggio, Suphamai Bunnapradist, Anthony J. Langone, Puneet Sood, Arthur J. Matas, Shikha Mehta, Roslyn B. Mannon, Asif Sharfuddin, Bernard Fischbach, Mohanram Narayanan, Stanley C. Jordan, David Cohen, Matthew R. Weir, David Hiller, Preethi Prasad, Robert N. Woodward, Marica Grskovic, John J. Sninsky, James P. Yee and Daniel C. Brennan
JASN July 2017, 28 (7) 2221-2232; DOI: https://doi.org/10.1681/ASN.2016091034
Roy D. Bloom
*Department of Medicine, University of Pennsylvania, Perelman School of Medicine and Penn Kidney Pancreas Transplant Program, Philadelphia, Pennsylvania;
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Jonathan S. Bromberg
†Department of Surgery and Department of Microbiology and Immunology and
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Emilio D. Poggio
‡Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio;
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Suphamai Bunnapradist
§Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California;
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Anthony J. Langone
‖Department of Medicine, Vanderbilt University Medical Center, and Medical Specialties Clinic, Veteran Affairs Hospital Renal Transplant Program, Nashville, Tennessee;
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Puneet Sood
¶Thomas Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
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Arthur J. Matas
**Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota;
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Shikha Mehta
††Division of Nephrology, Department of Medicine, and
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Roslyn B. Mannon
††Division of Nephrology, Department of Medicine, and
‡‡Division Transplantation, University of Alabama School of Medicine, Birmingham, Alabama;
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Asif Sharfuddin
§§Division of Nephrology and Transplant, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
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Bernard Fischbach
‖‖Baylor Research Institute, Dallas, Texas;
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Mohanram Narayanan
¶¶Division of Nephrology & Hypertension, Texas A&M Health Science Center College of Medicine, Temple, Texas;
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Stanley C. Jordan
§Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California;
***Division of Nephrology, Cedars-Sinai Medical Center, Los Angeles, California;
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David Cohen
†††Department of Surgery, Columbia University Medical Center, New York, New York;
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Matthew R. Weir
‡‡‡Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland;
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David Hiller
§§§Biostatistics,
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Preethi Prasad
‖‖‖Clinical Research,
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Robert N. Woodward
¶¶¶Research and Development, CareDx, Inc., Brisbane, California; and
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Marica Grskovic
¶¶¶Research and Development, CareDx, Inc., Brisbane, California; and
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John J. Sninsky
¶¶¶Research and Development, CareDx, Inc., Brisbane, California; and
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James P. Yee
‖‖Baylor Research Institute, Dallas, Texas;
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Daniel C. Brennan
****Washington University School of Medicine, St. Louis, Missouri
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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.

  • cell-free DNA
  • kidney
  • transplant
  • rejection
  • biomarker
  • DART
  • Copyright © 2017 by the American Society of Nephrology

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Journal of the American Society of Nephrology: 28 (7)
Journal of the American Society of Nephrology
Vol. 28, Issue 7
July 2017
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Cell-Free DNA and Active Rejection in Kidney Allografts
Roy D. Bloom, Jonathan S. Bromberg, Emilio D. Poggio, Suphamai Bunnapradist, Anthony J. Langone, Puneet Sood, Arthur J. Matas, Shikha Mehta, Roslyn B. Mannon, Asif Sharfuddin, Bernard Fischbach, Mohanram Narayanan, Stanley C. Jordan, David Cohen, Matthew R. Weir, David Hiller, Preethi Prasad, Robert N. Woodward, Marica Grskovic, John J. Sninsky, James P. Yee, Daniel C. Brennan
JASN Jul 2017, 28 (7) 2221-2232; DOI: 10.1681/ASN.2016091034

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Cell-Free DNA and Active Rejection in Kidney Allografts
Roy D. Bloom, Jonathan S. Bromberg, Emilio D. Poggio, Suphamai Bunnapradist, Anthony J. Langone, Puneet Sood, Arthur J. Matas, Shikha Mehta, Roslyn B. Mannon, Asif Sharfuddin, Bernard Fischbach, Mohanram Narayanan, Stanley C. Jordan, David Cohen, Matthew R. Weir, David Hiller, Preethi Prasad, Robert N. Woodward, Marica Grskovic, John J. Sninsky, James P. Yee, Daniel C. Brennan
JASN Jul 2017, 28 (7) 2221-2232; DOI: 10.1681/ASN.2016091034
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