*Purpose: Histologic lesions (I+T) to characterize T-cell mediated rejection (TCMR) can be non-specific. In some cases the inflammation may represent a ‘response to wounding’ rather than cognate T-cell recognition. The molecular microscope (MMDx; ATAGC; Canada) could complement histology by identifying TCMR that may not require therapy due to absence of a ‘molecular rejection phenotype’. The clinical outcomes of untreated kidney transplant (KT) biopsies that have histological TCMR but molecular quiescence are unknown.

*Methods: Under an IRB approved protocol, we evaluated eGFR, graft and patient survival of all KT biopsies (N=21) that met Banff criteria for TCMR but had a MMDX not consistent with rejection and were not treated (H+M-Rx-). Biopsies which met histologic and molecular criteria for TCMR and underwent therapy (H+M+Rx+; N=22) were also evaluated. Biopsies with viral/bacterial nephritis or mixed rejection were excluded. Our control group (N=136) was all ‘for-cause’ biopsies that did not have molecular and histological rejection (H-M-Rx-). Based on severity, the H+M+Rx+ group was treated with steroids and/or rATG.

*Results: At index biopsy, eGFR was numerically worse in the H+M+Rx+ group (35±20ml/min/1.73m2) when compared to the non-therapy H+M-Rx- (40±20ml/min/1.73m2; p=0.46) and H-M-Rx- (46.5±24ml/min/1.73m2; p=0.04) groups. At a median follow-up of 15.6 months (IQR: 6-35), eGFR declined in the H+M+Rx+ (30.9±25ml/min/1.73m2) while being stable in the H+M-Rx- (42±24ml/min/1.73m2; p=0.15) and H-M-Rx- (46.3±25ml/min/1.73m2; p=0.007). The MMDx rejection score was low in the two non-therapy H+M-Rx- and H-M-Rx- groups (0.14±0.14 vs 0.11±0.14; p=0.32). Interestingly, the H+M-Rx- group had higher MMDx Global Disturbance Score (GDS) (-1.21±1.71 vs 0.30±2.43; p<0.001) and I+T score (0.68±0.86 vs 3.76±1.44; p<0.001) when compared to the control H-M-Rx- group. These scores were much higher in the treated H+M+Rx+ group with I+T score of 4.63±1.26 (p<0.0001), MMDx total rejection (0.72±0.22; p<0.001), TCMR score (0.56±0.32; p<0.001) and GDS (3.68±2.59 p<0.01) compared to the other groups. Histologically there were more cases of borderline (N=8) and 1A rejection (N=8) in the H+M-Rx- group as compared to the H+M+Rx+ group (Borderline=3; 1A=5). There was no difference in death-censored graft survival between the H+M-Rx- group and the H-M-Rx- group (86% vs 94%; p=0.54). However, the H+M+Rx+ group had a much lower graft survival of 68% (p=0.0012).

*Conclusions: In this first report, in the absence of TCMR therapy, biopsies with histology consistent with TCMR but molecular quiescence had clinical outcomes comparable to untreated controls. MMDx may be able to increase precision of KT diagnostics and avoid over-treatment. Patients with TCMR on histology and MMDx had significantly worse outcomes pointing towards the inadequacy of current therapies.

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