Donor-derived cell-free DNA in liver transplantation: Promise, limitations, and future directions

Donor-derived cell-free DNA (dd-cfDNA) is an emerging non-invasive biomarker with growing potential for monitoring graft health and detecting rejection after liver transplantation. Several studies suggest that dd-cfDNA may provide a sensitive approach for assessing graft injury and immune-mediated rejection, although its diagnostic performance remains variable across different clinical settings. Increased levels of dd-cfDNA have been associated with episodes of graft injury and may indicate rejection earlier than some currently used biochemical or immunological assays. Liver biopsy remains the gold standard for diagnosing graft rejection; however, it is an invasive procedure that is generally performed after clinical or laboratory abnormalities become evident. Consequently, by the time these tests indicate any unusual or concerning graft activity, the graft may already be damaged by nearly 50%. Therefore, novel biomarkers such as dd-cfDNA may facilitate earlier detection of graft injury and support more timely therapeutic intervention. This review highlights the role of dd-cfDNA in monitoring post-transplant liver status, discusses the limitations of the current diagnostic methods of graft rejection, and explores the current evidence, challenges, and future perspectives of dd-cfDNA as a biomarker in this context.