Dynamic Response of Donor-Derived Cell-Free DNA Following Treatment of Acute Rejection in Kidney Allografts.

Background: The quantification of rejection treatment efficacy has been insufficient using traditional markers due, in part, to the lagging response of serum creatinine and histologic alterations on biopsy specimens. Donor-derived cell-free DNA (dd-cfDNA) is a molecular marker of injury that may assess allograft injury after rejection. Methods: Retrospective review of the DART study identified 70 patients who had a clinically indicated biopsy, simultaneous dd-cfDNA measurement, and at least one follow-up dd-cfDNA within 3 months post-treatment. Thirty-five patients had no biopsy-proven rejection and no rejection treatment (NR), 16 patients had no biopsy-proven rejection but did receive rejection treatment (CR), 9 patients had diagnosis of ABMR/mixed rejection on biopsy and received rejection treatment (ABMR), and 10 patients had diagnosis of TCMR and received rejection treatment (TCMR). The CR, ABMR, and TCMR groups combined to form a rejection (R) group. Results: In the R group, median dd-cfDNA values at baseline and 1 month were 0.62% and 0.35% (n=21 pairs, p=0.34), and at baseline and 2-3 months were 0.77% and 0.21% (n=23 pairs, p=0.002). In TCMR, median dd-cfDNA values at baseline and 1 month were 1.13% and 0.37% (n=5 pairs, p=0.63), and at baseline and 2-3 months were 0.25% and 0.12% (n=9 pairs, p=0.004). In ABMR, median dd-cfDNA values at baseline and 1 month were 1.61% and 1.2 % (n=6 pairs, p>0.99), and at baseline and 2-3 months were 3.85% and 1.32% (n=6 pairs, p=0.09). In CR, median dd-cfDNA values at baseline and 1 month were 0.31% and 0.29% (n=10 pairs, p=0.38), and at baseline and 2-3 months were 0.38% and 0.17% (n=8 pairs, p=0.31). Lastly, in NR, median dd-cfDNA values at baseline and 1 month were 0.23% and 0.18% (n=21 pairs, p=0.10), and at baseline and 2-3 months were 0.33% and 0.17% (n=26 pairs, p=0.003). Changes in serum creatinine across 1 month and 2-3 months following rejection were similar. Conclusions: dd-cfDNA may be a useful dynamic biomarker to assess the health of the kidney allograft following rejection treatment.

Remote monitoring using donor-derived, cell-free DNA after kidney transplantation during the coronavirus disease 2019 pandemic.

BACKGROUND: Donor-derived, cell-free DNA (dd-cfDNA) level correlates with allograft injury with clinical validity and utility for quiescence and active acute rejection (AR) in kidney transplant recipients. We analyzed trends in dd-cfDNA level immediately preceding and during the coronavirus disease 2019 (COVID-19) pandemic with implemented "shelter in place" and a tele-health strategy with remote home phlebotomy to limit COVID-19 exposure. METHODS: During COVID-19 in the United States (US), we surveyed weekly (January 6, 2020-May 25, 2020) metrics for dd-cfDNA corresponding to both a low risk for active rejection (dd-cfDNA < 0.5%) and cohorts with indeterminate levels of 0.5% to 1.0% and > 1.0%. During the study timeframe, over 11,000 patient samples (67%) from 150 kidney transplantation centers were transitioned from standard facility-based to remote phlebotomy. RESULTS: The proportion of dd-cfDNA samples, analyzed in 21 weekly aggregated cohorts by risk-stratification category, was unchanged during the COVID-19 escalation in the US. Linearized slopes for numbers of samples corresponding to indeterminate risk for AR cohorts of > 1.0% and 0.5% to 1.0% were -0.31 and -0.12, respectively; indicating that prevalence of these "at risk for AR cohorts" decreased during remote surveillance. Approximately 73% of samples corresponded to low risk of AR (dd-cfDNA < 0.5%), while an additional 15% of samples had dd-cfDNA level ≤ 1.0%. CONCLUSION: The combination of remote home phlebotomy including dd-cfDNA analysis and a tele-health program offer a new paradigm that may substantially improve patient compliance and assuage anxiety regarding the state of kidney allograft health during the COVID-19 pandemic. Further prospective multi-center studies with robust outcomes data are warranted.