*Purpose: Donor-derived cell-free DNA (dd-cfDNA) has been studied and established for acute rejection detection but the impact of early dd-cfDNA changes on graft outcomes has not been well studied. We hypothesized that trends of early dd-cfDNA change can predict long-term kidney allograft outcomes.

*Methods: A posthoc analysis was performed on 184 subjects with at least 2 dd-cfDNA results from a prospective multicenter observational study. dd-cfDNA was reported as a proportion of the donor-derived cfDNA over a total cfDNA. Slopes of dd-cfDNA were calculated based on at least 2 different dd-cfDNA scores done between 1- and 3-months post kidney transplant. Log transformation of dd-cfDNA was performed to improve linearity. Cox proportional hazard model was used to predict graft survival and logistic regression to analyze the odds ratio of reaching a clinical composite study endpoint (CCE) at 2 years.

*Results: The distribution of slope estimates in dd-cfDNA and log (dd-cfDNA) are shown in Figures 1A and 1B. Of 184 subjects, 16 experienced graft failure. One unit increase in the monthly dd-cfDNA slope tends to have increased hazard ratio (HR) of 1.56 (95% CI [0.67 – 3.63], p-value= 0.30). After log transformation, the trend was maintained as HR of graft failure for 1 unit change in monthly log (dd-cfDNA) slope (HR 1.54, 95% CI [0.56-4.23], p-value= 0.41) (Table 1). 157 subjects had information about the CCE at 2 years. One unit increase monthly change in dd-cfDNA tends to have increased OR 1.64 (95% CI 0.87-3.12, p-value =0.13) associated with reaching the CCE at 2 years. This trend remained after log transformation and showed significant association (OR 2.45, 95% CI 1.18-5.08, p-value =0.02) with the CCE (Table 2).

*Conclusions: This study suggests that an early dd-cfDNA increase is associated with a higher risk of reaching adverse composite endpoints. Further study will be needed to confirm this finding and how to interpret early changes in dd-cfDNA.

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