Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Moreover, endotoxin release into the circulation is a potential source of inflammation, and represents an important target for intervention directed towards stemming of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Although previous studies have shown that elevated plasma endotoxin levels were associated with the risk of atherosclerosis, a direct link between endotoxaemia and atherosclerosis is yet to be fully elucidated. This study investigated endotoxaemia across the spectrum of South African CKD patients and also determined the pro-inflammatory effects of endotoxin that are relevant to the development of subclinical atherosclerosis in CKD patients. A prospective cross-sectional study of 120 CKD patients was carried out, comprising 40 each of peritoneal dialysis (PD), haemodialysis (HD) and stage 3 chronic kidney disease (CKD), attending the Charlotte Maxeke Johannesburg Academic Hospital, South Africa; and a comparator cohort of 40 age- and sex-matched controls. Endotoxin levels were measured and the results compared with serum lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), oxidized LDL, interleukin-6 (IL-6), C-reactive protein (CRP), transforming growth factor-β (TGF-β), carotid intima media thickness (CIMT) and plaque occurrence (measured by B-mode ultrasound), and echocardiographic parameters. Bio-impedance spectroscopy was carried out using a body composition monitor (BCM) to assess fluid and nutritional status. Inflammatory cytokines including TGF-β1 and IL-6 were genotyped, and the genotype frequencies compared to the serum concentrations of the cytokines. Data was analysed using the statistical package for social sciences (SPSS) version 16. Volume overload and circulating endotoxaemia were common across the spectrum of CKD patients, and were aggravated by worsening kidney function. Endotoxins levels correlated with both absolute overhydration (r=0.513, p<0.001) and percentage overhydration to extracellular water (OH/ECW%) (r=0.490, p<0.001). Carotid intima media thickness was significant higher among CKD patients compared to the controls (0.58 ± 0.12 versus 0.45 ± 0.05 mm; p<0.001); CIMT was 0.63 ± 0.12; 0.56 ± 0.09 and 0.56 ± 0.12 mm in PD, HD and CKD stage 3 patients respectively. Carotid intima media thickness correlated with overhydration (r=0.442, p<0.001) and OH/ECW% (r=0.421, p<0.001). The risk of atherosclerosis was associated with serum levels of endotoxins (odds ratio: 2.34; confidence interval: 1.26-4.35, p=0.007), with excess risk confined to the group with high endotoxin levels. The risk of subclinical atherosclerosis was predicted by high concentrations of sCD14, IL-8 or MCP-1. Patients with high levels of circulating endotoxaemia in combination with high levels of sCD14, IL-8 or MCP-1 showed markedly elevated risk of atherosclerosis. The lowest Oxidized LDL levels were significantly higher in patients with carotid plaques compared to patients without carotid plaques (472.6 ± 104.6 versus 348.6 ± 110.9 ng/ml, p=0.012). Oxidized LDL showed a strong association with CIMT (r=0.664, p<0.001) among non-dialytic CKD patients. TGF-β isoform were present in lower concentrations in haemodialysis patients compared to the PD, CKD and controls. TGF-β concentrations were significantly lower in the patients with subclinical atherosclerosis compared to patients without atherosclerosis (TGF-β1: 4.1 × 104 ± 1.5 × 104 versus 5.9 × 104 ± 1.6 × 104 pg/ml, p<0.001; TGF-β2: 1.6 × 103 ± 0.3 × 103 versus 1.8 × 103 ± 0.2 × 103 pg/ml, p<0.001; and TGF-β3: 4.2 × 102 ± 0.9 × 102 versus 5.3 × 102 ± 1.1 × 102 pg/ml, p<0.001). TGF-β isoforms had an inverse relationship with CIMT (TGF-β1: r=−0.562, p<0.001; TGF-β2: r=−0.477, p<0.001; TGF-β3: r=−0.442, p<0.001). There was significant association between IL6 polymorphisms (−174G/G and −174G/C) and elevated serum IL-6 levels in CKD patients. Volume overload and circulating endotoxaemia were common across the spectrum of CKD patients. Volume overload was associated with the severity of kidney failure, inflammation, malnutrition, atherosclerosis and cardiac enlargement. Bio-impedance spectroscopy device is a more sensitive tool than IVCD measurement for the assessment of fluid status in clinically euvolaemic non-dialytic stage 3 CKD patients. The findings suggest that the atherogenic predictive power of endotoxin is significantly increased by the presence of high concentrations of immune mediators in CKD patients. The increased risk of atherosclerosis in CKD patients was demonstrated to be due to the inflammation mediated by endotoxin, with protection afforded by TGB-β. Furthermore, there is a close association between IL-6 polymorphisms (G/G and G/C) and elevated serum IL-6 levels in CKD patients.

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The role of circulating endotoxaemia as a proinflammatory mediator of atherosclerosis in chronic kidney disease patients	9

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