*Purpose: We have reported the correlation of donor-derived cell-free DNA (dd-cfDNA) with histologic and molecular diagnosis (MMDx) of kidney transplant biopsies (Gupta et al, Transplantation 2021). In the initial cohort of 208 biopsies, only 13 had early TCMR that was reported by histology (H+) but not by MMDx (M-). Here we build on that initial cohort with a larger sample size and provide data on therapy and outcomes.

*Methods: We identified biopsies that were classified as TCMR by histology and/or MMDx. Those with viral/bacterial nephritis or mixed rejection were excluded. Prior to therapy fractional dd-cfDNA (%; Allosure) was measured. Total 37 such biopsies; were divided into two groups, H+M+ (concomitant TCMR; N=18) and H+M- (discordant TCMR; N=19).

*Results: Median dd-cfDNA was significantly lower (p=0.02) in H+M- (0.32%; IQR: 0.15-0.43) compared to H+M+ group (1.03%; IQR: 0.38-1.8). This was reflected in histologic findings where interstitial and tubular inflammation (i+t) (4.8±1.5 vs 3.3±1.2, p=0.002) was worse for H+M+ vs H+M-. There was a graded dose-response between i+t and dd-cfDNA for H+M+ that was not apparent for H+M- (Figure 1a). Borderline/1A rejection was seen more frequently in the H+M- (16/19, 84%) while severe rejection ≥1B or higher was seen in the H+M+ group (12/18, 67%). Molecular tissue scores for TCMR (0.50±0.29 vs 0.02±0.02, p<0.0001) and inflammation (4.6±2.1 vs -0.55±1.5, p<0.0001) were significantly higher in the H+M+ vs H+M- group. eGFR at index biopsy was worse in the H+M+ group (27±19ml/min/1.73m2) when compared to the H+M- (40±23ml/min/1.73m2; p=0.06). A large majority of H+M+ biopsies were treated (16/18; 89%; 14 rATG and 2 steroids only) and only a minority of H+M- patients received rejection-specific steroids only (7/19; 37%). Despite this discrepancy in therapy, there was a significant improvement in eGFR in both groups. At a median follow-up of 14.7 months post-biopsy eGFR improved to 34±24ml/min/1.73m2 in the H+M+ and 49.2±26ml/min/1.73m2 in the H+M- group (Figure 1b). All 4 graft losses and one patient death were seen in the H+M+ group (p=0.02).

*Conclusions: Here, we confirm our initial findings where patients with histologic TCMR not confirmed on molecular gene expression was associated with low dd-cfDNA. As a large majority of patients had improvement in kidney function overtime despite a lack of targeted therapy, this may indicate that low-grade TCMR is a ‘response to wounding’, rather than cognate allo-recognition.

« Back to 2022 American Transplant Congress