Clinical and Molecular Spectrum of V-Lesion

Abstract Background and Aims Isolated v-lesion is an increasingly recognized but clinically challenging entity. Some studies suggest that isolated v+ early post-transplant may be caused by non-alloimmune etiologies such as ischemic injury. We aimed to characterize the allograft outcomes of isolated v-lesions according to post-transplant time (early: ≤1 month vs. late: >1 month) and further understand the significance of this lesion by characterizing its molecular phenotype in comparison with other forms of rejection v+. Method The NanoString B-HOT panel (770 genes) was used to measure the expression of six literature-derived gene sets in 92 archival FFPE kidney biopsies from two centers, including transplant biopsies with isolated v-lesion (n = 23), antibody-mediated rejection (ABMR) with v+ (n = 26), pure T-cell mediated rejection (TCMR) with v+ (n = 10), mixed rejection v+ (n = 23), and normal implant biopsies (Normal, n = 10). The evaluated gene sets included transcripts previously associated with ABMR, DSA (DSAST), endothelial injury (ENDAT), TCMR, early injury, and late injury. Gene expression was compared between groups using principal component and class comparison analyses. Death-censored graft survival according to diagnosis and time after KT was assessed. Results Isolated v+ early conferred the worst death-censored graft survival one year after the biopsy (40%) when compared to isolated v+ late (100%) or other forms of rejection (≥82%, p = 0.034). The principal component analysis demonstrated significant molecular overlap between sample groups (PC1: 29.4%, PC2: 8.1%). However, gene set analysis showed lower expression of TCMR-related genes in isolated v+ groups compared to TCMR and mixed rejection (p<0.001). Both Isolated v+ early and late had lower ABMR-related genes than ABMR, mixed rejection, and TCMR groups (p ≤ 0.022). Moreover, isolated v+ late showed lower DSAST and ENDAT gene set expression than ABMR (p ≤ 0.046); and lower early injury gene set expression than isolated v+ early, ABMR, TCMR, and mixed rejection (p ≤ 0.026). Late injury gene set expression was highest in TCMR and mixed rejection compared to the other groups (p ≥ 0.034). Conclusion These results suggest that early and late isolated v+ lesions display lower expression of TCMR-related genes than TCMR and mixed rejection and lower expression of ABMR-related genes than ABMR. Isolated v+ early confers a bad prognosis and is associated with higher expression of early injury genes compared to isolated v+ late, suggesting a different ethology.