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

Abstract

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. Lung Transplant recipients (n=52) enrolled in two prospective cohort studies were included. Serial post-transplant clinical data and plasma samples were obtained. 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. Plasma %ddcfDNA on Day 1, Day 3, Day 7 were quantified by shotgun sequencing. Within subject mean values for Day 1-7 were computed. %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. 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). 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.