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

Abstract

BACKGROUND: The quantification of rejection treatment efficacy has been insufficient using traditional markers due in part to lagging response of serum creatinine and histologic alterations on biopsy. Donor-derived cell-free DNA (dd-cfDNA) is a molecular marker of injury that may assess allograft injury following 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, dd-cfDNA at diagnosis was 0.62% and 0.35% after 1 month (P = 0.338); 0.77% and 0.21% after 2-3 months (P = 0.002). In TCMR, dd-cfDNA at diagnosis was 1.13% and 0.37% after 1 month (P = 0.625); 0.25% and 0.12% (P = 0.004) after 2-3 months. In ABMR, dd-cfDNA at diagnosis was 1.61% and 1.20% after 1 month (P = 1.000); 3.85% and 1.32% after 2-3 months (P = 0.094). In CR, dd-cfDNA at diagnosis was 0.31% and 0.29% (P = 0.375) after 1 month; 0.38% and 0.17% after 2-3 months (P = 0.313). Lastly, in NR, dd-cfDNA at the index visit was 0.21% and 0.18% after 1 month (P = 0.097); 0.33% and 0.17% after 2-3 months (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.

Use of a donor‐derived cell‐free DNA assay to monitor treatment response in pediatric renal transplant recipients with allograft rejection

“…Both patients in this study with TCMR alone showed a decrease in dd‐cfDNA values, indicating successful treatment of rejection. This is consistent with previous reports of dd‐cfDNA in TCMR 30,31 . In contrast, among patients with AMR or mixed‐type rejection, the dd‐cfDNA values decreased minimally but did not fall to baseline or below 1% (a rule‐in rejection value).…”

Correlation of Donor-derived Cell-free DNA With Histology and Molecular Diagnoses of Kidney Transplant Biopsies

“…In a preliminary abstract using a subanalysis of the DART study, Brennan et al 37 reported that cfDNA improved with treatment of rejection. This study was limited by the unavailability of follow-up biopsies to determine resolution of rejection.…”

“…Additional data including DSA, serial cfDNA surveillance or other blood-based gene expression markers, and clinical decision making (risk of rejection, adherence index, therapeutic drug levels, etc), may be helpful in further risk stratifying these subgroups. 36 In a preliminary abstract using a subanalysis of the DART study, Brennan et al 37 reported that cfDNA improved with treatment of rejection. This study was limited by the unavailability of follow-up biopsies to determine resolution of rejection.…”

Clinical outcomes from the Assessing Donor-derived cell-free DNA Monitoring Insights of kidney Allografts with Longitudinal surveillance (ADMIRAL) study

“…1 Routine monitoring with donor-derived cell-free DNA (dd-cfDNA) after solid organ transplantation has been shown to accurately identify and characterize allograft injury, [1][2][3] correlate with pathologic findings, [4][5][6] and assess response to therapy including treatment of rejection. 7,8 Importantly, evaluation in dd-cfDNA have been demonstrated to occur ahead of clinically apparent organ injury. 9,10 Consequently, allograft monitoring with plasma dd-cfDNA levels can support noninvasive identification of pathologies including cellular and humoral allograft rejection, viral injury, and drug toxicity.…”

“…3,6 dd-cfDNA can also be employed in the setting of acute allograft injury to guide further diagnostic testing and assess improvement following clinical intervention. 7 The routine use of dd-cfDNA to detect, characterize, or exclude ongoing allograft injury is a valuable addition in current post-transplant surveillance.…”