MOLECULAR MECHANISMS OF CHRONIC KIDNEY GRAFT INJURY

P. Hribova¹, I. Brabcova¹, R. Zachoval², J. Slatinska³, E. Honsova⁴, O. Viklicky^3
1Transplant Laboratory, Inst. for Clinical and Experimental Medicine, Prague 4/CZECH REPUBLIC, ²Department Of Urology, Thomayer University Hospital with Polyclinic, Prague 4/CZECH REPUBLIC, ³Department Of Nephrology, Inst. for Clin. and Experim. Medicine, Prague 4/CZECH REPUBLIC, ⁴Dept. Of Clinical And Transplant Pathology, Inst. for Clin. and Experim. Medicine, Prague 4/CZECH REPUBLIC

Body: Introduction Early acute rejection represents a heterogeneous group of immune mechanisms mediated graft injury. Both chronic antibody mediated rejection (CAMR) and chronic T-cell mediated rejection (CTCMR) have been implicated to be the main reason of late kidney allograft loss, however their molecular background remains unclear. Methods Diagnosis of CAMR was based on the presence of donor specific antibodies, C4d positive staining and histological diagnosis including also electron microscopy. Late case biopsies (>3M) were performed in 2007-2009 in CNI/MMF treated patients. Biopsy specimens from patients with CAMR (n=12), CTCMR (n=7) and from control group with stable kidney graft function from protocol biopsies and normal histological findings (n=10) was stabilized in the RNA-later. Using the Taqman Low Density Array, the intrarenal expressions of 378 genes known to have implications in immune response (T-cell activation, B-cell activation, biology of cytokines, chemokines, growth factors, immune regulators and apoptosis were analyzed with respect to the graft outcome. Results Patients with CAMR had eGFR 0.51 ± 0.22 ml/s/1.73m² and proteinuria 2.15 ± 2.7 g/day while patients with CTCMR had eGFR 0.34 ± 0.13 ml/s/1.73m² and proteinuria 1.85 ± 1.20 g/day; n.s. Three patients with CAMR and one with CTCMR lost their grafts during the follow-up. CAMR was associated with up-regulation of chemokines (CCL3, CCL4, CCL5, CCL8, CCL13, CCL19, CCL21, CXCL6, CXCL9, CXCL10, CXCL11, XCL1 and CCRL1), cytokines (TNF, IFNG) and other receptors (TLR2, PTPRC) as compared with control group. Genes participating in humoral immune response (CD27, CD53, ADA, BATF, FASLG, UBD) but also T–lymphocyte-dependent mechanisms (CD2, CD3D, CD3E, CD3G, CD27, CD86, IFNG, PTPRC, LAG3, HLA-DMA, -DMB, -DPA1, -DRA, CD74, all p<0.01) were up-regulated in CAMR as compared to controls. Hierarchical clustering of CAMR and CTCMR gene expression profiles was found to be similar despite the significantly higher expression of IFNG and lower BCL2L11, CCL22, IL2RA, OXCT1 and TYK2 (all p<0.05) in CAMR as compared with CTCMR. Moreover, patients whose graft failed because of CAMR had higher expression of IFNG receptor (IFNGR2), AGR3, CXCL6, CDK2AP1, BFAR, CD59 and GABRP, but lower expression of APOA2 and TLR3 than patients whose graft survived (all p<0.05). Conclusion In this study, interferon gamma dependent mechanisms are likely to play a role in the progressive forms of chronic antibody mediated rejection of kidney allografts.

Disclosure: All authors have declared no conflicts of interest.