Higher Levels of Donor-Derived Cell-Free DNA Are Associated with Acute Cellular Rejection but Not with Severe PGD After Lung Transplantation

Abstract

<h3>Purpose</h3> Circulating donor-derived cell-free DNA (dd-cfDNA) levels have been proposed as a potential tool for the diagnosis of graft injury (rejection, infection, ischemia/reperfusion injury). In this study, we prospectively investigated dd-cfDNA plasma levels and their association with severe primary graft dysfunction at 72 hours and acute cellular rejection in the first month after lung transplant. <h3>Methods</h3> Thirty-five subjects undergoing double lung transplants at our institution between Jun.2020-Oct.2021 were included in this study. Primary Graft Dysfunction (PGD) was graded according to ISHLT criteria. Our protocol includes a surveillance bronchoscopy with transbronchial biopsy at 3 weeks post-transplant. Acute cellular rejection was diagnosed and graded by a pulmonary pathologist after evaluation of histopathology slides. Blood samples were collected at various time points before and after lung transplant. Dd-cfDNA in samples were determined using AlloSure dd-cfDNA test kits (CareDx, Inc.). <h3>Results</h3> We observed a rapid increase of dd-cfDNA in blood of recipients after lung transplantation compared to baseline. The levels of dd-cfDNA decreased during the first two weeks (Figure A). The peak was observed within 72 hours after transplantation. The peak values of dd-cfDNA varied among subjects and had no correlation with PGD grade 3 occurrences at 72 hours. (Figure B, p=0.85). We observed an association between levels of dd-cfDNA from blood collected at the time of transbronchial biopsy and the histological diagnosis of ACR at 3 weeks. (Figure C, mean 2.7% versus 1.5%, p=0.015) <h3>Conclusion</h3> This preliminary data shows that circulating dd-cfDNA levels are associated with ACR early after transplantation but not with severe PGD at 72hours. Plasma levels of dd-cfDNA may be a less invasive tool to estimate graft rejection after lung transplantation however larger studies are still necessary to better identify thresholds.