Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation

Sean Agbor-Enoh, Yan Wang, Ilker Tunc, Moon Kyoo Jang, Andrew Davis, Iwijn De Vlaminck, Helen Luikart, Pali Dedhiya 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 ZhuAldo Iacono, Jonathan B Orens, Steven D. Nathan, Charles Marboe, Gerald J. Berry, Stephen R. Quake, Kiran Khush, Hannah A. Valantine

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)541-553
Number of pages13
JournalEBioMedicine
Volume40
DOIs
StatePublished - Feb 1 2019

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Transplantation (surgical)
Lung Transplantation
Allografts
Tissue Donors
Mortality
Transplants
Lung
Wounds and Injuries
Transplantation
National Institutes of Health (U.S.)
Firearms
Grafts
Regression analysis
Respiratory Insufficiency
Cohort Studies
Regression Analysis
Health
Prospective Studies
Confidence Intervals

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Agbor-Enoh, S., Wang, Y., Tunc, I., Jang, M. K., Davis, A., De Vlaminck, I., ... Valantine, H. A. (2019). Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation. EBioMedicine, 40, 541-553. https://doi.org/10.1016/j.ebiom.2018.12.029

Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation. / Agbor-Enoh, Sean; Wang, Yan; Tunc, Ilker; Jang, Moon Kyoo; Davis, Andrew; De Vlaminck, Iwijn; Luikart, Helen; Shah, Pali Dedhiya; Timofte, Irina; Brown, Anne W.; Marishta, Argit; Bhatti, Kenneth; Gorham, Sasha; Fideli, Ulgen; Wylie, Jennifer; Grimm, David; Goodwin, Natalie; Yang, Yanqin; Patel, Kapil; Zhu, Jun; Iacono, Aldo; Orens, Jonathan B; Nathan, Steven D.; Marboe, Charles; Berry, Gerald J.; Quake, Stephen R.; Khush, Kiran; Valantine, Hannah A.

In: EBioMedicine, Vol. 40, 01.02.2019, p. 541-553.

Research output: Contribution to journalArticle

Agbor-Enoh, S, Wang, Y, Tunc, I, Jang, MK, Davis, A, De Vlaminck, I, Luikart, H, Shah, PD, Timofte, I, Brown, AW, Marishta, A, Bhatti, K, Gorham, S, Fideli, U, Wylie, J, Grimm, D, Goodwin, N, Yang, Y, Patel, K, Zhu, J, Iacono, A, Orens, JB, Nathan, SD, Marboe, C, Berry, GJ, Quake, SR, Khush, K & Valantine, HA 2019, 'Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation', EBioMedicine, vol. 40, pp. 541-553. https://doi.org/10.1016/j.ebiom.2018.12.029
Agbor-Enoh, Sean ; Wang, Yan ; Tunc, Ilker ; Jang, Moon Kyoo ; Davis, Andrew ; De Vlaminck, Iwijn ; Luikart, Helen ; Shah, Pali Dedhiya ; Timofte, Irina ; Brown, Anne W. ; Marishta, Argit ; Bhatti, Kenneth ; Gorham, Sasha ; Fideli, Ulgen ; Wylie, Jennifer ; Grimm, David ; Goodwin, Natalie ; Yang, Yanqin ; Patel, Kapil ; Zhu, Jun ; Iacono, Aldo ; Orens, Jonathan B ; Nathan, Steven D. ; Marboe, Charles ; Berry, Gerald J. ; Quake, Stephen R. ; Khush, Kiran ; Valantine, Hannah A. / Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation. In: EBioMedicine. 2019 ; Vol. 40. pp. 541-553.
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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.",
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T1 - Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation

AU - Agbor-Enoh, Sean

AU - Wang, Yan

AU - Tunc, Ilker

AU - Jang, Moon Kyoo

AU - Davis, Andrew

AU - De Vlaminck, Iwijn

AU - Luikart, Helen

AU - Shah, Pali Dedhiya

AU - Timofte, Irina

AU - Brown, Anne W.

AU - Marishta, Argit

AU - Bhatti, Kenneth

AU - Gorham, Sasha

AU - Fideli, Ulgen

AU - Wylie, Jennifer

AU - Grimm, David

AU - Goodwin, Natalie

AU - Yang, Yanqin

AU - Patel, Kapil

AU - Zhu, Jun

AU - Iacono, Aldo

AU - Orens, Jonathan B

AU - Nathan, Steven D.

AU - Marboe, Charles

AU - Berry, Gerald J.

AU - Quake, Stephen R.

AU - Khush, Kiran

AU - Valantine, Hannah A.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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