Purpose: Donor-derived cell-free DNA (dd-cfDNA) levels >1% are associated with active rejection in renal transplant recipients. This report defines the clinically relevant variation of dd-cfDNA in a cohort of patients without rejection who had up to 11 tests at surveillance visits during the first 2 years post-transplantation. Methods: 204 patients with 1164 tests between 2 weeks and 2 years post-transplantation and no biopsy confirmed rejection were examined from the DART study. The coefficient of variation (CV) and derived reference change values (RCV; the % change in serial results from an individual that exceeds variation attributable to analytical and normal biological variation) and index of individuality (II; the ratio of within-subject to between-subject CV) were calculated for dd-cfDNA. Time-dependent dd-cfDNA values post-transplant were also evaluated. Results: The surveillance population had a median dd-cfDNA of 0.19% (interquartile range [0.10%, 0.35%]). The median dd-cfDNA in this cohort was higher in the first 2 months post-transplant than months 3-24, but the fraction of values > 1% was not significantly higher. 66 samples (5.7%) had dd-cfDNA values >1%, of which 20 were < 60 days post-transplant. Only 26 patients had one and 15/204 patients had at least two dd-cfDNA values >1%. In 14 of these 15 patients, elevated dd-cfDNA occurred in consecutive visits. Within-subject CV was less than the between-subject CV (II = 0.39). The RCV was 63% and was exceeded in 8% of 499 adjacent tests. Conclusions: The reference ranges in this report may help guide the clinical Interpretation of a single dd-cfDNA result. In addition, because of the low within-subject variability of dd-cfDNA relative to group variability, clinical interpretation may be enhanced by considering the relative change in value since a prior baseline measurement. An RCV increase in dd-cfDNA of >63% may be clinically relevant even if the values are below the threshold of 1% as previously established for probability of active rejection or other injury. The utility of specific RCV in serial testing will be confirmed in a planned registry of outcomes in patients managed with serial dd-cfDNA testing.

CITATION INFORMATION: Narayanan M., Alhamad T., Hiller D., Yee J., Woodward R., Bromberg J. Clinically Relevant Variation of Donor-Derived Cell-Free DNA during Longitudinal Surveillance of Renal Allografts Am J Transplant. 2017;17 (suppl 3).

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