Normalization dynamics of donor-derived cell-free DNA predicts future kidney transplant rejection

This is the authors' abstract. We don't add key points for this paper.

To the Editor, The intimate link between the ischemia-reperfusion injury (IRI) and the development of rejection is based on enhanced antigen presentation and inflammation, two essential conditions for T lymphocyte activation [1, 2]. Massive ischemic damage usually translates into the need of dialysis during the first week after kidney transplantation, which is the classical definition of delayed graft function (DGF), an indirect way to measure the effects of the IRI on clinical grounds. However, this definition is physician-flawed and does not capture patients with minor degrees of IRI that can still affect graft outcomes [3, 4]. We propose herein donor-derived cell-free DNA (ddcfDNA) as a biomarker of graft injury that can objectively estimate the real magnitude of IRI and predict the future development of rejection. The Prospective Assessment of Renal Graft Events After Transplantation (PRAS-KAT) study included recipients of either living or deceased donor kidney grafts, whose levels of ddcfDNA were determined at 24 hours after reperfusion and at 7, 14, and 30 days after transplantation. Previous results already highlighted the association of ddcfDNA with short- (DGF), medium (6-month eGFR), and long-term (iBox-estimated graft survival) outcomes [5]. Detailed methods are included in the Supplementary material. Here, we present a post hoc analysis about immunological outcomes, the primary outcome being the 1-year incidence of rejection. The secondary outcome was the generation of de novo donor-specific antibodies (DSAs). Considering the post hoc nature of the present analysis, a formal calculation on the sample size for the rejection outcome was not performed. Patients were categorized into two categories, according to the persistence of graft injury during the first 2 weeks after kidney transplantation assessed by means of ddcfDNA. The cut-off of normality was set to 1.0% [6] and patients with a “slow clearance” of ddcfDNA were defined as those whose ddcfDNA was higher than this cut-off at 7 or 14 days after kidney transplantation. This is based on the observation that >90% of the recipients of a deceased donor normalized the ddcfDNA <1.0% within this time frame [5]. Conversely, patients who maintained ddcDNA levels <1.0% at both 7 and 14 days were considered to have overcome the initial injury and were defined as the “fast clearance” group.