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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis

  • Author Footnotes
    1 These authors have contributed equally to this work.
    Sean Agbor-Enoh
    Footnotes
    1 These authors have contributed equally to this work.
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Author Footnotes
    1 These authors have contributed equally to this work.
    Annette M. Jackson
    Footnotes
    1 These authors have contributed equally to this work.
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • Ilker Tunc
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Gerald J. Berry
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
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  • Adam Cochrane
    Affiliations
    Department of Medicine, Inova Fairfax Hospital, Fairfax, Virginia, USA
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  • David Grimm
    Affiliations
    Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
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  • Andrew Davis
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Pali Shah
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • Anne W. Brown
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Inova Fairfax Hospital, Fairfax, Virginia, USA
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  • Yan Wang
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA
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  • Irina Timofte
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA
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  • Palak Shah
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Inova Fairfax Hospital, Fairfax, Virginia, USA
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  • Sasha Gorham
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Jennifer Wylie
    Affiliations
    Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
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  • Natalie Goodwin
    Affiliations
    Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
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  • Moon Kyoo Jang
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Argit Marishta
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Kenneth Bhatti
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Ulgen Fideli
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Yanqin Yang
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Helen Luikart
    Affiliations
    Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
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  • Zeling Cao
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA
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  • Mehdi Pirooznia
    Affiliations
    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Jun Zhu
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
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  • Charles Marboe
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Pathology, New York Presbyterian University Hospital of Cornell and Columbia, New York, New York, USA
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  • Aldo Iacono
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Inova Fairfax Hospital, Fairfax, Virginia, USA
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  • Steven D. Nathan
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Inova Fairfax Hospital, Fairfax, Virginia, USA
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  • Jonathan Orens
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Department of Medicine, Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • Hannah A. Valantine
    Correspondence
    Reprint requests: Hannah A. Valantine, MD, MRCP, Laboratory of Organ Transplant Genomics, Genomic Research Alliance for Transplantation, National Institutes of Health, 50 Center Drive, Room 4249, Bethesda, MD 20892. Telephone: +301 828 7338. Fax: +301 380 8833.
    Affiliations
    Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA

    Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
    Search for articles by this author
  • Kiran Khush
    Correspondence
    Reprint requests: Kiran Khush, MD, MAS, Associate Professor, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5406. Telephone: +650 721 3241. Fax: +650 725 1599.
    Affiliations
    Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
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  • Author Footnotes
    1 These authors have contributed equally to this work.
Published:February 03, 2018DOI:https://doi.org/10.1016/j.healun.2018.01.1305

      Background

      Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation.

      Methods

      We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs.

      Results

      Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs −0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels.

      Conclusion

      Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

      Keywords

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