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.
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.