“…Interestingly, homeostatic levels of cfDNA do not promote pathology, however it is hypothesized changes in methylation status, fragment length, and quantity contribute to the pathogenicity and immunogenicity of cfDNA. In solid organ transplantation, elevations in levels of cfDNA specifically derived from the donor allograft (donor-derived cell-free DNA, dd-cfDNA) is associated both directly with allograft injury, as well as serving as a risk stratification factor for poor clinical outcomes across solid organs in adult and pediatric recipients alike [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Perhaps most strikingly, in a multicenter cohort of prospectively recruited patients all of which presented with biopsy-confirmed T cell-mediated rejection of Banff class 1A or borderline rejection, dd-cfDNA scores above 0.5% at any time during surveillance were associated with significantly higher decline in estimated glomerular filtration rate (eGFR, a standard measure of renal allograft function), a nearly 20-fold increase in the rate of de novo donor-specific antibody (DSA) development, and a significant increase in the rate of rejection recurrence or worsening 3–6 months following dd-cfDNA measurement [ 53 ].…”