EBioMedicine (Feb 2019)
Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantationResearch in context
- Sean Agbor-Enoh,
- Yan Wang,
- Ilker Tunc,
- Moon Kyoo Jang,
- Andrew Davis,
- Iwijn De Vlaminck,
- Helen Luikart,
- Pali D. Shah,
- Irina Timofte,
- Anne W. Brown,
- Argit Marishta,
- Kenneth Bhatti,
- Sasha Gorham,
- Ulgen Fideli,
- Jennifer Wylie,
- David Grimm,
- Natalie Goodwin,
- Yanqin Yang,
- Kapil Patel,
- Jun Zhu,
- Aldo Iacono,
- Jonathan B. Orens,
- Steven D. Nathan,
- Charles Marboe,
- Gerald J. Berry,
- Stephen R. Quake,
- Kiran Khush,
- Hannah A. Valantine
Affiliations
- Sean Agbor-Enoh
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, MD, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Yan Wang
- University of Maryland Medical Center, Baltimore, MD, United States
- Ilker Tunc
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Moon Kyoo Jang
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Andrew Davis
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Iwijn De Vlaminck
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States
- Helen Luikart
- Stanford University School of Medicine, Palo Alto, CA, United States
- Pali D. Shah
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, MD, United States
- Irina Timofte
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; University of Maryland Medical Center, Baltimore, MD, United States
- Anne W. Brown
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Inova Fairfax Hospital, Fairfax, VA, United States
- Argit Marishta
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Kenneth Bhatti
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Sasha Gorham
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Ulgen Fideli
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Jennifer Wylie
- Stanford University School of Medicine, Palo Alto, CA, United States
- David Grimm
- Stanford University School of Medicine, Palo Alto, CA, United States
- Natalie Goodwin
- Stanford University School of Medicine, Palo Alto, CA, United States
- Yanqin Yang
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Kapil Patel
- Stanford University School of Medicine, Palo Alto, CA, United States
- Jun Zhu
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States
- Aldo Iacono
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; University of Maryland Medical Center, Baltimore, MD, United States
- Jonathan B. Orens
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, MD, United States
- Steven D. Nathan
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Inova Fairfax Hospital, Fairfax, VA, United States
- Charles Marboe
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Department of Pathology, New York Presbyterian University Hospital of Cornell and Columbia, NY, New York, USA
- Gerald J. Berry
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Stanford University School of Medicine, Palo Alto, CA, United States
- Stephen R. Quake
- Department of Bioengineering, Stanford University, Palo Alto, CA, USA
- Kiran Khush
- Stanford University School of Medicine, Palo Alto, CA, United States; Correspondence to: K. Khush Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5406, USA.
- Hannah A. Valantine
- Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Correspondence to: H. A. Valantine Laboratory of Organ Transplant Genomics, Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, 50 Center Dr. Rm 4249, Bethesda, MD 20892, USA.
- Journal volume & issue
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Vol. 40
pp. 541 – 553
Abstract
Background: Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure. Methods: This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis. Findings: avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%–9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6–19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable. Interpretation: Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. Fund: National Institutes of Health.