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)

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.

Published by Elsevier Inc.

Figures

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.

(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).