Early isolated v-lesion may not truly represent a rejection of kidney allograft

Intimal arteritis is known to be a negative prognostic factor for kidney allograft survival. Although Banff classification assesses isolated v-lesion (IV) as a T-cell mediated rejection, its origin and significance remain unclear. To help resolve if IV truly represents acute rejection, molecular study was performed. Transcriptome of early IV, T cell-mediated vascular rejection (TCMRV) and nonrejection histologic findings was compared using microarrays (Illumina Human HT-12 v4 Expression BeadChips). The enrichment of deregulated genes was analysed using DAVID. Differential gene expression analysis identified 310 genes to be deregulated in TCMRV compared to IV. Gene enrichment analysis categorized deregulated genes to be associated with immune and inflammatory response. Principal component and unsupervised hierarchical cluster analysis revealed clear distinction of TCMRV samples but showed similarity of IV with control group. RT-qPCR validation on external sample set (n=20) confirmed upregulation of genes involved in immune response in TCMRV compared to IV. Based on stepwise logistic regression SLA2 gene represented the strongest group classifier [OR 0.106 (95 % CI 0.01- 0.774), p=0.03] with ROC AUC 0.906 [95% CI (0.769-1.0), p=0.003)]. IV reveals weak immunologic signature compared to TCMRV but shows similarity with non-rejection findings. Early IV in a DSA- and C4d- negative patients may feature non-rejection origin and reflect injury distinct from alloimmune response. Study calls for reassessment of current Banff histopathology criteria which considers an intimal arteritis to be TCMR irrespective of TI and supports use of molecular diagnostics as a part of integrative approach. An observational, retrospective, cohort study was performed to compare expression profiles of renal allograft biopsies with histologic findings of TCMRV and IV. IV was defined as an intimal arteritis (v>0) with minimal tubulitis and interstitial inflammation (t<2, i<2), no microvascular inflammation [glomerulitis (g)+ peritubular capilaritis (ptc)=0], with C4d and DSA negativity (n=6). TCMRV was defined as presence of intimal arteritis with significant TI (t>1, i>1) in the absence of C4d and DSA positivity and served as positive control (n=4). Only indication kidney allograft biopsies performed due to graft nonfunction or function deterioration within first month after kidney transplantation were included. As a negative control group, normal histologic findings in 3 months protocol biopsies (C4d negative, no signs of rejection, DSA negative) with no history of previous rejection were included (n=8). As microarray platform, Illumina HumanHT 12 v4.0 Expression BeadChips (Illumina) was used.