Molecular Profiling of Acute and Chronic Rejections of Renal Allografts

Both antibody mediated (AMR) and T-cell mediated (TCMR) rejections either acute or chronic represent the main reason for late graft dysfunction. In this study we aimed to evaluate differences in the intrarenal expression patterns of immune system related genes in acute and chronic rejections. Graft biopsies were performed and evaluated according to Banff classification. Using the TaqMan Low Density Array, the intrarenal expressions of 376 genes relating to immune response (B-cell activation, T-cell activation, chemokines, growth factors, immune regulators, and apoptosis) were analyzed in the four rejection categories: chronic AMR, chronic TCMR, acute AMR, and acute TCMR. The set of genes significantly upregulated in acute TCMR as compared to acute AMR was identified, while no difference in gene expressions between chronic rejections groups was found. In comparison with functioning grafts, grafts that failed within the next 24 months after the chronic rejection morphological confirmation presented at biopsy already established severe graft injury (low eGFR, higher proteinuria), longer followup, higher expression of CDC20, CXCL6, DIABLO, GABRP, KIAA0101, ME2, MMP7, NFATC4, and TGFB3 mRNA, and lower expression of CCL19 and TRADD mRNA. In conclusion, both Banff 2007 chronic rejection categories did not differ in intrarenal expression of 376 selected genes associated with immune response. 1. Introduction Both acute and chronic rejections have been shown to affect the long-term outcome of kidney transplantation. Chronic rejection is thought to be associated with both cellular and humoral alloimmune responses [1]. Chronic active antibody mediated rejection (CAMR) is characterized by C4d deposition in peritubular capillaries, the presence of circulating anti-donor antibodies, and morphologic evidence of chronic tissue injury such as glomerular double contours and peritubular capillary basement membrane multilayering and interstitial fibrosis/tubular atrophy (IF/TA) and fibrous arterial intimal thickening. The diagnosis of this entity is problematic since C4d deposits are not permanent and antibody mediated rejection was described to be associated also with different pathways where C4d is not involved [2]. Similarly, the chronic T-cell mediated rejection, albeit well described at Banff scheme, is of unclear pathogenesis. Moreover, the therapy of both processes remains to be insufficient. Beside conventional morphological evaluation, molecular histology offers better insight into rejection pathogenesis and prognosis. Moreover, molecular phenotype may better