*Purpose: Associations between non-rejection histologic diagnoses and dd-cfDNA have not been extensively characterized. We explored these associations in kidney transplant recipients enrolled in the Kidney allograft Outcomes AlloSure Registry (KOAR, NCT03326076).

*Methods: For-cause and surveillance biopsies with NR (no rejection or other abnormalities, except IF/TA) or acute tubular injury/necrosis (ATI/ATN), and paired dd-cfDNA within 30 days were included. The incidence of a composite outcome (eGFR decline > 25%, rejection, and de novo donor-specific antibody detection) at 12 months after biopsy was also assessed.

*Results: 166 biopsies (141 patients) with NR and 70 biopsies (64 patients) with ATI/ATN were included; compared to patients with ATI/ATN, patients with NR had lower KDPI (49% vs 64%, p <0.05) and shorter cold ischemia time (13 vs 18 hours, p<0.01). ATI/ATN biopsies were more likely to be for-cause (91.4% vs 59.6%, p<0.001), earlier post-transplant (83.0 vs 116.5 days, p<0.001), and occur at lower eGFRs (43 vs 32 mL/min, p<0.001) [Table 1]. There was no significant difference in median dd-cfDNA between NR (0.23%, IQR: 0.11 – 0.53) and ATI/ATN (0.21%, IQR: 0.13 – 0.55) biopsies (p = 0.993) [Figure 1]. When patients were stratified by dd-cfDNA at the time of their first biopsy (< 0.5% vs ≥ 0.5%), there was a non-significant trend towards a higher incidence of the 12-month clinical composite among those with dd-cfDNA ≥ 0.5% (27.5% vs 12.9%, p=0.53), with eGFR decline being most common (78.5% of events).

*Conclusions: Our findings suggest that acute tubular injury/necrosis is not associated with substantial elevations in dd-cfDNA. The use of dd-cfDNA to identify patients with non-actionable histologic findings (including ATI/ATN) may allow more nuanced clinical decision-making and reduce the number of unnecessary biopsies.

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