*Purpose: Donor-derived cell-free DNA (dd-cfDNA; AlloSure®) and the association with active rejection (AR) was described by Bloom et al, however subsequent insights have suggested this analyte as a molecular marker of injury rather than specific for AR. Since prior validation demonstrated dd-cfDNA with high negative predictive value (NPV) for AR, our aim was to assess value of this biomarker for predicting “quiescence” across aggregated pathological diagnoses putatively associated with allograft injury.

*Methods: 1092 patients from the Assessing dd-cfDNA monitoring insights of renal allograft with longitudinal surveillance (ADMIRAL study; clinicaltrials.gov: NCT04566055219) were analyzed. All patients had dd-cfDNA (AlloSure®; CareDx) with standard post-transplant surveillance and all clinical events captured. “Injury” was defined as the aggregated diagnoses: acute tubular injury, BK nephropathy, de novo DSA, histological AR or “other pathology” as confirmed by paired biopsy ≤20 days after dd-cfDNA measurement.

*Results: 341 unique patients were pooled in the “injury cohort”, with a median dd-cfDNA = 0.52% (IQR:1.3%-0.25%); 693 patients with the absence of specified pathology or no prescribed biopsy were defined as the cohort with “allograft quiescence” with a median dd-cfDNA = 0.24% (IQR:0.39%-0.19%). The AUC for the allograft quiescence analysis was 0.715 [FIGURE 1]. A dd-cfDNA threshold of 0.5% was associated with sensitivity and specificity for quiescence of 70% and 63%, respectively.

*Conclusions: The high NPV for a low dd-cfDNA plasma level supports previous literature in clarifying an absence of significant concurrent pathology, thereby providing value in risk-stratifying the stable patient. This offers a potential “peace of mind” metric to both patient and clinician when developing precision medicine. Conversely, elevation of dd-cfDNA above the threshold of 0.5%, suggests development of significant allograft injury.

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