Recent research suggests a potential expanded role for monitoring of donor-derived cell-free DNA (dd-cfDNA) in the early identification of graft injury after kidney transplantation.
In the Assessing Donor-Derived Cell-Free DNA Monitoring Insights of Kidney Allografts with Longitudinal Surveillance (ADMIRAL) study, published in Kidney International, 1092 kidney transplant recipients were monitored for dd-cfDNA for 3 years after transplantation. The researchers used a targeted sequencing assay that quantified dd-cfDNA using highly polymorphic single nucleotide polymorphisms without the need for separate donor or recipient genotyping. The findings of 5873 dd-cfDNA measurements were analyzed for association with histologic evidence of allograft rejection. The analysis included 219 biopsy-paired dd-cfDNA results from 203 patients; 110 biopsies were performed for cause and 109 for surveillance.
Elevated dd-cfDNA of 0.5% or greater was correlated with clinical and subclinical allograft rejection. At this threshold, dd-cfDNA was associated with an increased risk of de novo donor-specific antibodies with a hazard ratio (HR) of 2.71. The elevated dd-cfDNA values occurred a median of 91 days before donor-specific antibodies were identified. Patients with two or more dd-cfDNA results over the 0.5% threshold were more likely to have a 25% decline in estimated glomerular filtration rate over 3 years with a hazard ratio of 1.97. An elevated dd-cfDNA result had a positive predictive value of 77.5% for graft injury with a negative predictive value of 71.6%.
Clinical trials have shown that routine dd-cfDNA monitoring can detect allograft injury after solid organ transplantation, as well as assess the response to therapy, including anti-rejection therapy. This study validates the effectiveness of dd-cfDNA in identifying clinical and subclinical kidney allograft rejection in a real-world clinical setting. The authors state: “[P]ersistently low dd-cfDNA levels may accurately identify allograft quiescence or absence of injury, paving the way for personalization of immunosuppression trials” [Bu L, et al. Clinical outcomes from the Assessing Donor-Derived Cell-Free DNA Monitoring Insights of Kidney Allografts with Longitudinal Surveillance (ADMIRAL) study. Kidney Int 2022; 101:793−803. doi: 10.1016/j.kint.2021.11.034].