*Purpose: We hypothesized that the timing of subclinical acute rejection (subAR) diagnosed with biopsy, gene expression profile or donor-derived cell-free DNA is associated with poor graft outcomes.

*Methods: The surveillance biopsy samples from a previously selected cohort were paired with a gene expression profile (GEP) and a donor-derived cell-free DNA (dd-cfDNA) results. 2- year composite endpoints (2Y-CCE) were defined as 1) any evidence of ≥ Banff grade II IFTA at 24-month biopsy, 2) biopsy-proven rejection on “for-cause biopsy,” 3) a decrease in estimated glomerular infiltration rate (eGFR) by >10 m/min/1.3m². We used logistic regression to analyze the timing of subAR (histology, GEP, dd-cfDNA) and 2Y-CCE.

*Results: 349 samples were studied (histology, GEP, dd-cfDNA), derived from 161 subjects. Of 161 subjects, 70 reached the 2Y-CCE. SubAR within 6 months post-transplant by histology was significantly associated with more 2Y-CCE than the no rejection group (odds ratio [OR] 4.25, 95% CI 1.04-17.36, p=0.04). Patients with biopsy-proven subAR within 12 months did not associate with 2Y- CCE (OR 2.08, 95% CI 1-4.35, p=0.052). SubAR by GEP at 12 months (OR 2.81, 95% CI 1.11 – 7.09, p=0.03) was associated with 2 Y-CCE. We found that subAR diagnosed with dd-cfDNA within 6 months and 12 months was not associated with 2Y-CCE. However, any positive GEP (OR 2.23, 95% confidence interval [CI] 1.16-4.29, p=0.02) or dd-cfDNA (OR 2.25, 95% CI 1.04 – 4.84, p=0.04) for subAR within the first 12 months were significantly associated with 2Y-CCE as the sample size increased (Table 1).

*Conclusions: We found that subAR diagnosed by GEP and dd-cfDNA at different times post kidney transplant was associated with poor graft outcomes. Further protocols using early genetic and serologic markers of subAR need to be established in post-transplant follow-up.

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