Diagnostic and Prognostic Value of Donor-Derived Cell-Free DNA in Acute Rejection After Kidney Transplantation: A Narrative Review

Background: Kidney transplantation is the optimal treatment for end-stage renal disease; however, acute rejection remains a major determinant of long-term graft dysfunction and failure. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a minimally invasive biomarker reflecting allograft injury, with growing evidence supporting diagnostic and prognostic utility. Objectives: This structured narrative review aimed to synthesize contemporary evidence (2020–2025) on the diagnostic and prognostic utility of plasma dd-cfDNA and its integration into kidney transplant rejection surveillance. Methods: A narrative literature review was conducted using PubMed to identify studies published or available online ahead of print, between January 2020 and September 2025, evaluating plasma dd-cfDNA in adult kidney transplant recipients. Manual screening of reference lists supplemented the search. Original clinical studies reporting diagnostic or prognostic outcomes were included, and the results were synthesized narratively due to methodological heterogeneity. Results: Across prospective and retrospective cohorts, elevated dd-cfDNA discriminated rejection from non-rejection biopsies, with strongest performance in antibody-mediated and microvascular rejection phenotypes. Longitudinal studies demonstrated that dd-cfDNA elevations often preceded histologically confirmed rejection and predicted adverse graft outcomes, while low levels were associated with immunologic quiescence. Assay variability limited cross-study comparability, whereas integration with donor-specific antibodies, gene expression profiling, or algorithm-based approaches improved diagnostic and prognostic discrimination. Conclusions: Dd-cfDNA is a clinically meaningful biomarker for kidney transplant rejection monitoring, providing diagnostic and prognostic information beyond conventional functional markers. When interpreted longitudinally and in clinical context, dd-cfDNA supports risk stratification and surveillance, with evidence supporting its expanding role in risk-adapted transplant care.