Donor-Derived-Cell-Free DNA to Identify Primary Graft Dysfunction Patients at Risk of Chronic Lung Allograft Dysfunction

M. B. Keller, P. Shah, E. Bush, J. M. Diamond, J. Matthews, A. W. Brown, I. Timofte, U. S. Fideli, H. Kong, A. Marishta, K. Bhatti, Y. Yang, I. Tunc, H. Luikart, G. Berry, C. Marboe, A. Iacono, S. Nathan, K. K. Khush, J. OrensM. Jang, H. A. Valentine, S. Agbor-Enoh

Research output: Contribution to journalArticle

Abstract

PURPOSE: Primary Graft Dysfunction (PGD) is a risk factor for Chronic Lung Allograft Dysfunction (CLAD). However, this association requires further examination for better risk stratification of PGD patients. Donor-derived cell-free DNA (%ddcfDNA) is a biomarker for lung allograft injury and early post-transplant %ddcfDNA levels may predict long-term outcomes. This study leverages %ddcfDNA to assess the association of PGD and allograft injury, as well as the ability of %ddcfDNA to identify PGD patients who are at greater risk of developing long-term complications. METHODS: Lung Transplant recipients (n=52) enrolled in two prospective cohort studies were included. Serial post-transplant clinical data and plasma samples were obtained. ENDPOINTS: An adjudication committee reviewed Day 3 chest x-rays and arterial blood gases and used standard ISHLT definitions to categorize patients as PGD or non PGD. Other endpoints, such as CLAD were also defined by ISHLT standards. MEASURES: Plasma %ddcfDNA on Day 1, Day 3, Day 7 were quantified by shotgun sequencing. Within subject mean values for Day 1-7 were computed. ANALYSIS: %ddcfDNA levels were compared between PGD versus non PGD patients. In the PGD subgroup, %ddcfDNA levels were also compared between PGD patients who subsequently developed CLAD vs PGD patients who did not develop CLAD. RESULTS: Median post-transplant follow-up was 38.3 months. %ddcfDNA levels were higher in PGD than in non PGD patients; Day 1 (27.5% vs 20.0% p=0.043), Day 3 (11.2% vs 6.6 %, p=0.003), mean Day 1-7 (17.83% vs 10.58%, p=0.008). PGD patients who developed CLAD had higher within-subject Day 1-7 mean %ddcfDNA levels than PGD patients who did not develop CLAD (22.6% vs 15.2%, p = 0.0438). CONCLUSION: PGD patients demonstrated increased early post-transplant allograft injury, as measured by %ddcfDNA, than non PGD patients. In addition, early post-transplant %ddcfDNA levels may serve as a predictor for the development of CLAD in patients who experience PGD.

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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    Keller, M. B., Shah, P., Bush, E., Diamond, J. M., Matthews, J., Brown, A. W., Timofte, I., Fideli, U. S., Kong, H., Marishta, A., Bhatti, K., Yang, Y., Tunc, I., Luikart, H., Berry, G., Marboe, C., Iacono, A., Nathan, S., Khush, K. K., ... Agbor-Enoh, S. (2020). Donor-Derived-Cell-Free DNA to Identify Primary Graft Dysfunction Patients at Risk of Chronic Lung Allograft Dysfunction. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 39(4), S103. https://doi.org/10.1016/j.healun.2020.01.959