Abstract 264: Oral Activated Charcoal Adsorbent (AST-120) Inhibition of Chronic Kidney Disease-induced Atherosclerosis Involves Modulation of Intestinal Immunity

Abstract

Introduction and Aims: Although patients with chronic kidney disease (CKD) are at the highest risk for atherosclerotic cardiovascular disease (CVD), current interventions (e.g. statins) that are consistently effective in other high-risk groups have been found to be insufficiently effective in CKD. Serum levels of uremic toxins including indoxyl sulphate have been implicated in cardiovascular mortality. The oral charcoal absorbent AST-120 reduces serum levels of indoxyl sulphate through adsorption of indole converted from dietary tryptophan in the gastrointestinal tract. Previously, we reported the inhibitory effects of AST-120 on progression of atherosclerosis in apoE-deficient hyperlipidemic mice. Because gut immunity can affect systemic inflammatory responses and atherogenesis, we hypothesized that the AST-120-mediated benefits in CKD-acceleration of atherosclerosis involve modulation of intestinal immune cells. Methods: Eleven week old apoE-deficient mice underwent a reduction in renal mass through subtotal nephrectomy (sNx, n=34) or sham-operation (S, n=14). Two weeks later, each of the 2 groups was further divided into AST-120-treated or untreated mice. Six weeks later, we used flow cytometry and real time PCR to examine the population of immune cells in intestinal Peyer’s patches and mesenteric lymph nodes. Results: AST-120 had no significant effect on cellular populations of Peyer’s patch or mesenteric lymph nodes in mice with intact kidneys. Interestingly, however, in sNX mice treatment with AST-120 significantly decreased numbers of Peyer’s patch cytotoxic T cells (-19.6%; P=0.008), CD8 + central memory T cells (-33.9%; P=0.014), and CD8 + naïve T cells (-42.6%; P=0.004) compared to controls. In mesenteric lymph nodes of sNX animals, AST-120 did not affect CD4 + T helper cell number, but reduced early activated CD4 + T cells (-13.1%; P=0.04). Cytokine expression in mesenteric lymph nodes of AST-treated sNX mice showed increases in TGF-β (+47.2%; P=0.022) and IL-10 (+36.5%). Conclusions: The mechanism underlying the ability of oral activated charcoal adsorbent AST-120 to inhibit the acceleration of atherosclerosis in the setting of CKD may involve modulation of immune cells in the gut mucosa.