*Purpose: The value of donor-derived cell-free DNA (dd-cfDNA, AlloSure) as a molecular marker for the early diagnosis of mild T-cell mediated rejection (Banff TCMR 1A and borderline lesions) remains unclear based upon previous studies. This could be partly related to the fact that early histologic lesions used to characterize TCMR lesions can be non-specific. In addition, there may be significant inter-observer variability between biopsy interpretation that may result in over or under-diagnosis of histologic lesions.

*Methods: From June 2017 to May 2019, 79 patients across 11 transplant centers with biopsy defined TCMR 1A (n = 52) or Borderline Rejection (n = 27) (Banff 2017 criteria) were assessed. Patients were stratified by a median AlloSure dd-cfDNA >0.5% (n = 42) and ≤0.5% (n = 37) as well as by protocol biopsy and ‘for cause’ biopsy.

*Results: Using a dd-cfDNA cut off of 0.5%, there were no differences in patient demographics, the proportion of patients who had ‘for cause’ or protocol biopsies, or the proportion of patients across centers. Patients with elevated levels of dd-cfDNA (>0.5%) were associated with adverse outcomes including a mean decline in estimated glomerular filtration rate of 8.5% over a follow-up period of 6 months, compared to no decline in patients <0.5% (p=0.0040). 17/42 (40.5%) patients with dd-cfDNA >0.5% developed de novo donor-specific antibodies compared to 1/37 patients (2.7%) with dd-cfDNA <0.5% (p<0.0001). 9/42 (21.4%) of patients with dd-cfDNA >0.5% also had future or persistent rejection compared to none of the patients with dd-cfDNA <0.5% (p=0.0028).

*Conclusions: Not all TCMR1A/borderline is associated with adverse outcomes, and therefore likely represents a composite of more versus less aggressive pathologic states. There is an unmet need for additional diagnostic tools to strengthen the interpretation of the Banff system. Based upon these results, dd-cfDNA may provide a more complete characterization of rejection heterogeneity and valuable clinical information for high vs low risk lesions, allowing better understanding of allograft prognosis.

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