Liquid biopsies: donor-derived cell-free DNA for the detection of kidney allograft injury

In kidney transplantation, the use of minimally invasive damage biomarkers that are more sensitive and specific than plasma creatinine will be crucial to enable early, actionable detection or exclusion of structural kidney damage due to acute or chronic rejection. Donor-derived cell-free DNA (dd-cfDNA), which can be quantified, for example, through next-generation sequencing, droplet digital PCR and quantitative PCR, is a candidate biomarker with great potential for enabling comprehensive monitoring of allograft injury. dd-cfDNA has a favourable overall diagnostic performance for the detection of rejection and its high negative predictive value might be especially useful for avoiding unnecessary biopsies. Elevated dd-cfDNA levels have been shown to be detectable before graft injury can be clinically identified using current diagnostic methods. Moreover, dd-cfDNA falls rapidly to baseline levels after successful treatment for rejection owing to its short half-life. dd-cfDNA can detect graft injury caused by immune activation owing to insufficient immunosuppression and might therefore also help guide immunosuppression dosing. The fractional abundance of dd-cfDNA can be affected by changes in the recipient cfDNA (for example, due to infection or physical exercise) but the use of absolute quantification of dd-cfDNA overcomes this limitation. Serial dd-cfDNA determinations might therefore facilitate cost-effective personalized clinical management of kidney transplant recipients to reduce premature graft loss. In transplantation, liquid biopsies that can detect donor-derived cell-free DNA (dd-cfDNA) might improve monitoring of organ rejection without invasive biopsies, and might enable effective management of anti-rejection drug therapies. Here, the authors discuss dd-cfDNA quantification methods, the clinical validity of these approaches, their limitations and economic implications. Key points Novel approaches that can improve the detection, monitoring and treatment of graft injury, especially due to rejection, are crucially needed in kidney transplantation. Plasma creatinine is an insensitive, non-specific and delayed graft injury biomarker as detectable increases generally only occur 24–48 hours after injury; immunosuppressive drug monitoring can also predict potential toxicity but is not a biomarker of graft damage. Donor-derived cell-free DNA (dd-cfDNA) has been shown to be a useful biomarker for comprehensive monitoring of allograft injury that overcomes t