Abstract 12032: Chronic Kidney Disease Augments Vein Graft Disease Through Interleukin-9-dependent Mechanisms

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Chronic kidney disease (CKD, glomerular filtration rate (GFR) <60 ml/min/1.73 m 2 ) is a powerful independent predictor of cardiovascular events, and CKD increases the risk of vein graft occlusion in CABG patients by 62%. Because CKD impairs clearance of small proteins, we tested the hypothesis that CKD exacerbates vein graft disease by elevating serum levels of critical cytokines that promote neointimal hyperplasia. We modeled CKD in C57BL/6 mice with 5/6ths nephrectomy and modeled vein grafting with IVC-to-carotid interposition grafting. Two wk after 5/6 th s nephrectomy, GFR was 60±10% less than in sham-operated (control) mice, as determined by FITC-inulin clearance ( p <0.05); parallel mouse cohorts were used for either blood collection or vein grafting. Of 23 serum cytokines measured by a Luminex-based assay, the following were elevated in CKD (n=12) compared with control mice (n=9): IL-9 (5-fold), IL-12 (1.8-fold), MCP-1 (1.3-fold), TNF (1.3-fold), and RANTES (1.8-fold) ( p < 0.0003 for each). Four wk after grafting, CKD (n=7) and control mouse (n=7) vein graft neointimas comprised predominantly smooth muscle cells (SMCs), of equivalent prevalence. However, vein graft neointimal area was 4±0.5-fold fold greater in CKD mice: 0.23±0.2 vs. 0.052±0.004 mm 2 ( p <0.01). By quantitative immunofluorescence, vein grafts from CKD mice showed equivalent neointimal expression of NFκB p65 but ~2-fold greater neointimal activation of NFκB, as judged by phosphorylation of p65 on Ser536 and by expression of VCAM-1 ( p <0.01). Vein graft protein levels of IL-9 and IL-9 receptor-α were 3.0±0.6- and 1.7±0.3-fold higher in CKD than control mice ( p <0.01). We then treated CKD mice with IL-9-neutralizing (n=7) or isotype control IgG (n=7) for 4 wk after vein grafting. Control IgG did not affect vein graft neointimal area (0.19±0.02 mm 2 ). However, anti-IL-9 IgG treatment reduced vein graft neointimal area 4-fold (to 0.044±0.004 mm 2 , p < 0.01), and reduced neointimal levels of phospho-p65, IL-9, and IL-9Rα by 40-50% ( p <0.05). Of the 5 serum cytokines elevated by CKD, only IL-9 and IL-6 were reduced by anti-IL-9 IgG treatment: 26±3% and 70±20%, respectively ( p <0.001). We conclude that CKD aggravates vein graft disease dramatically, in large part by elevating plasma levels of IL-9.