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Observational Study
. 2021 Jun;40(6):488-493.
doi: 10.1016/j.healun.2021.02.008. Epub 2021 Feb 20.

Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD)

Michael Keller  1 , Errol Bush  2 , Joshua M Diamond  3 , Pali Shah  4 , Joby Matthew  4 , Anne W Brown  5 , Junfeng Sun  6 , Irina Timofte  7 , Hyesik Kong  8 , Ilker Tunc  9 , Helen Luikart  10 , Aldo Iacono  7 , Steven D Nathan  5 , Kiran K Khush  10 , Jonathan Orens  4 , Moon Jang  8 , Sean Agbor-Enoh  11
Affiliations
Observational Study

Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD)

Michael Keller et al. J Heart Lung Transplant. 2021 Jun.

Abstract

Background: Primary graft dysfunction (PGD) is a risk factor for chronic lung allograft dysfunction (CLAD). However, the association between PGD and degree of allograft injury remains poorly defined. In this study, we leverage a novel biomarker for allograft injury, percentage donor-derived cell-free DNA (%ddcfDNA), to study the association between PGD, degree of allograft injury, and the development of CLAD.

Methods: This prospective cohort study recruited 99 lung transplant recipients and collected plasma samples on days 1, 3, and 7 for %ddcfDNA measurements. Clinical data on day 3 was used to adjudicate for PGD. %ddcfDNA levels were compared between PGD grades. In PGD patients, %ddcfDNA was compared between those who developed CLAD and those who did not.

Results: On posttransplant day 3, %ddcfDNA was higher in PGD than in non-PGD patients (median [IQR]: 12.2% [8.2, 22.0] vs 8.5% [5.6, 13.2] p = 0.01). %ddcfDNA correlated with the severity grade of PGD (r = 0.24, p = 0.02). Within the PGD group, higher levels of %ddcfDNA correlated with increased risk of developing CLAD (log OR(SE) 1.38 (0.53), p = 0.009). PGD patients who developed CLAD showed ∼2-times higher %ddcfDNA levels than patients who did not develop CLAD (median [IQR]: 22.4% [11.8, 27.6] vs 9.9% [6.7, 14.9], p = 0.007).

Conclusion: PGD patients demonstrated increased early posttransplant allograft injury, as measured by %ddcfDNA, in comparison to non-PGD patients, and these high %ddcfDNA levels were associated with subsequent development of CLAD. This study suggests that %ddcfDNA identifies PGD patients at greater risk of CLAD than PGD alone.

Trial registration: ClinicalTrials.gov NCT01985412 NCT02423070.

Keywords: Chronic lung allograft dysfunction (CLAD); Donorderived cell-free DNA (ddcfDNA); Primary graft dysfunction (PGD); Rejection.

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Figures

Figure 1.
Figure 1.
(a) Trend in %ddcfDNA over the first post-transplant week in PGD and non-PGD patients. Each point represents median values with interquartile range. Levels of %ddcfDNA were higher in patients with PGD than in patients without PGD on days 1, 3 and 7 (Day 7 values, median (IQR): 4.7% (3.0,8.9) vs 3.3% (2.4, 5.4), p=0.046) (b) Comparison of day 3 %ddcfDNA between PGD and non-PGD patients displayed with violin plots including all individual data points, median and IQR values PGD patients demonstrated higher levels of %ddcfDNA than non-PGD patients (median (IQR): 12.2% (8.2, 22.0) vs 8.5% (5.6, 13.2), p = 0.01).
Figure 2.
Figure 2.
(a) Trend in %ddcfDNA over the first week post-transplant in PGD+/CLAD+ patients and PGD+/CLAD− patients. Each point represents median values with interquartile range. (b) Comparison of day 3 %ddcfDNA between PGD+/CLAD+ patients vs PGD+/CLAD− patients displayed with violin plots including all individual data points, median and IQR values. PGD+/CLAD+ patients demonstrated higher levels of %ddcfDNA than PGD+/CLAD− patients (Day 3 median (IQR): 22.4% (11.8, 27.6) vs. 9.9% (6.9, 14.9), p = 0.007).
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References

    1. Snell GI, et al., Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant, 2017. 36(10): p. 1097–1103. - PubMed
    1. Kreisel D, et al., Short- and long-term outcomes of 1000 adult lung transplant recipients at a single center. J Thorac Cardiovasc Surg, 2011. 141(1): p. 215–22. - PubMed
    1. Daud SA, et al., Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med, 2007. 175(5): p. 507–13. - PubMed
    1. Gielis EM, et al., Cell-Free DNA: An Upcoming Biomarker in Transplantation. Am J Transplant, 2015. 15(10): p. 2541–51. - PubMed
    1. Bloom RD, et al., Cell-Free DNA and Active Rejection in Kidney Allografts. J Am Soc Nephrol, 2017. 28(7): p. 2221–2232. - PMC - PubMed

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