title: Cell-Free DNA and Active Rejection in Kidney Allografts.
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.
authors.affiliation: Department of Medicine, University of Pennsylvania, Perelman School of Medicine and Penn Kidney Pancreas Transplant Program, Philadelphia, Pennsylvania.
authors.forename: Roy D
authors.initials: RD
authors.lastname: Bloom
authors.affiliation: Department of Surgery and Department of Microbiology and Immunology and.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
authors.affiliation: Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Emilio D
authors.initials: ED
authors.lastname: Poggio
authors.affiliation: Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
authors.forename: Suphamai
authors.initials: S
authors.lastname: Bunnapradist
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, and Medical Specialties Clinic, Veteran Affairs Hospital Renal Transplant Program, Nashville, Tennessee.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Langone
authors.affiliation: Thomas Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Puneet
authors.initials: P
authors.lastname: Sood
authors.affiliation: Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Matas
authors.affiliation: Division of Nephrology, Department of Medicine, and.
authors.forename: Shikha
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Division of Nephrology, Department of Medicine, and.|Division Transplantation, University of Alabama School of Medicine, Birmingham, Alabama.
authors.forename: Roslyn B
authors.initials: RB
authors.lastname: Mannon
authors.affiliation: Division of Nephrology and Transplant, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Asif
authors.initials: A
authors.lastname: Sharfuddin
authors.affiliation: Baylor Research Institute, Dallas, Texas.
authors.forename: Bernard
authors.initials: B
authors.lastname: Fischbach
authors.affiliation: Division of Nephrology & Hypertension, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors.forename: Mohanram
authors.initials: M
authors.lastname: Narayanan
authors.affiliation: 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.
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
authors.affiliation: Department of Surgery, Columbia University Medical Center, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Weir
authors.affiliation: Biostatistics.
authors.forename: David
authors.initials: D
authors.lastname: Hiller
authors.affiliation: Clinical Research.
authors.forename: Preethi
authors.initials: P
authors.lastname: Prasad
authors.affiliation: Research and Development, CareDx, Inc., Brisbane, California; and.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Woodward
authors.affiliation: Research and Development, CareDx, Inc., Brisbane, California; and.
authors.forename: Marica
authors.initials: M
authors.lastname: Grskovic
authors.affiliation: Research and Development, CareDx, Inc., Brisbane, California; and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Sninsky
authors.affiliation: Baylor Research Institute, Dallas, Texas.
authors.forename: James P
authors.initials: JP
authors.lastname: Yee
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri dbrennan@dom.wustl.edu.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Brennan
mesh_terms: D064591:Allografts; D004247:DNA / Q000097:blood*; D005260:Female; D006084:Graft Rejection / Q000097:blood*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000097:blood*
chemical_list: D004247:DNA
keywords: DART; biomarker; cell-free DNA; kidney; rejection; transplant