Prospective evaluation of donor-derived cell-free DNA (dd-cfDNA) in monitoring response to anti-rejection treatment in kidney transplant recipients with indication biopsy

Abstract

Purpose: Donor-derived cell-free DNA (dd-cfDNA) is a marker of allograft injury in kidney transplant recipients (KTR). Little is known about the possible use of dd-cfDNA in evaluating response to anti-rejection treatment in KTR showing histopathological signs of rejection. Methods: We are currently prospectively evaluating the diagnostic benefit of dd-cfDNA in 100 KTR undergoing indication biopsy. dd-cfDNA is quantified in the AlloSeq cfDNA assay (CareDx) at time of biopsy to estimate the association of dd-cfDNA levels with histopathological reporting. To assess the utility of dd-cfDNA in monitoring response to therapy, dd-cfDNA levels are quantified after initiation of treatment on days 7, 30, and 90 following biopsy. Results: Since December 2020, 56 KTR have been enrolled and 21/56 (38%) biopsies were graded as different types of rejection. Patients showing signs of active rejection had significantly higher levels of dd-cfDNA at time of biopsy than patients without any signs for rejection, whereas estimated glomerular filtration rate (eGFR) did not differ significantly between the two groups (P<0.01 and P=0.55, respectively, Figure 1A). In patients with antibody-mediated rejection (ABMR) or T-cell mediated rejection (TCMR), median (IQR) dd-cfDNA levels were highest with 3.4% (1.6-11.3) compared to the 0.4% (0.2-1.2) measured in patients with borderline changes and 0.2% (0.1-0.5) in patients with no signs of rejection. When considering only patients with ABMR or TCMR, we observe decreasing levels of dd-cfDNA following initiation of therapy (pooled slope -0.02; Figure 1B). In patients with borderline changes and low levels of dd-cfDNA (<1%) at time of biopsy we see an increase in eGFR after initiation of corticosteroid pulse therapy, whereas patients with high levels of dd-cfDNA (≥1%) show subsequent eGFR decline (Figure 1C). Conclusions: dd-cfDNA significantly discriminates active rejection at time of biopsy in KTR. Decreasing levels of dd-cfDNA may indicate treatment response in patients with ABMR and TCMR. dd-cfDNA may further help to identify borderline changes with favorable outcome from changes where additional therapy and closer monitoring is needed.