Donor-derived cell-free DNA and its utility in kidney transplantation: A myth or a reality

Renal allograft rejection and its detection are challenging problems for transplant clinicians. Transplant physicians rely on serum creatinine, estimated glomerular filtration rate, proteinuria, donor-specific antibodies, and graft biopsy to detect rejection. The sensitivity and specificity in these blood and urine tests are low, and the invasiveness of graft biopsy has led transplant clinicians to seek alternative diagnostic tools. Cell-free DNA (cfDNA) is a fragment of DNA released from cell death due to necrosis and apoptosis. Donor-derived cfDNA (dd-cfDNA) has been proposed as a potential non-invasive biomarker for detecting rejection. However, one must interpret it cautiously in conditions such as ischemia-reperfusion injury, delayed graft function, BK virus nephropathy, post-kidney biopsy, and dual kidney transplantation, which may cause dd-cfDNA elevation. There is a lack of standardized cutoff values for diagnosing various types of rejections. Low specificity, higher cost, and lack of universal availability are the multiple obstacles to using this tool. There is a need to establish clinical guidelines for its future utility in early rejection detection, graft surveillance, and tailoring of immunosuppression.