Association of chronic inflammation and accelerated atherosclerosis among an indigenous black population with chronic kidney disease

Introduction: Inflammation plays a major role in the development of atherosclerosis and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Toll-like receptor-4 (TLR4) is a major receptor for lipopolysaccharides (endotoxin) and other ligands involved in the pathogenesis of inflammation. We determined whether endotoxin levels and the presence of TLR4 polymorphisms are associated with markers of inflammation and atherosclerosis among South African CKD patients.

Materials and methods:  Endotoxin, lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and carotid intima media thickness (CIMT) were measured in 160 participants (120 CKD patients and 40 controls). Associations between endotoxins and CIMT in the presence of sCD14, IL-8 and MCP-1, were assessed using odds ratios. Participants were screened for the presence of Asp299Gly and Thr399Ile TLR4 polymorphisms, and CIMT and inflammatory markers were compared between subjects with and without TLR4 polymorphisms.

Results: Endotoxin levels correlated with sCD14 (r=0.441, p<0.001) and MCP-1 (r=0.388, p<0.001) levels while increased CIMT was associated with MCP-1 (r=0.448, p<0.001), sCD14 levels (r=0.476, p<0.001), LBP (r=0.340, p<0.001), and IL-8 (r=0.395, p<0.001). Atherosclerosis was associated with endotoxin levels (odds ratio: 4.95; 95% confidence interval: 2.52-9.73; p<0.001), and was predicted by higher serum levels of inflammatory markers. Analysis of patients with TLR4 polymorphisms showed reduced serum levels of inflammatory markers and CIMT values compared with the patients carrying the wild type TLR4 alleles.

Conclusion: The study demonstrated associations between circulating endotoxaemia, systemic inflammation and accelerated atherosclerosis among South African CKD patients, and showed that the atherogenic predictive power of endotoxaemia was significantly increased by the presence of elevated levels of inflammatory markers. Additional findings, which must be confirmed, suggest that TLR4 polymorphisms are associated with low levels of inflammatory markers and CIMT values.

引言：炎症在慢性肾脏病（chronic kidney disease, CKD）患者的动脉粥样硬化发生以及心血管疾病发病与死亡中发挥关键作用。Toll样受体4（Toll-like receptor-4, TLR4）是脂多糖（内毒素）及其他参与炎症发病配体的主要受体。本研究旨在探究南非CKD患者中，内毒素水平与TLR4多态性是否与炎症标志物及动脉粥样硬化相关。

材料与方法：对160名受试者（120名CKD患者及40名健康对照）的内毒素、脂多糖结合蛋白（lipopolysaccharide binding protein, LBP）、血清可溶性CD14（serum CD14, sCD14）、白细胞介素-8（interleukin-8, IL-8）、单核细胞趋化蛋白-1（monocyte chemoattractant protein-1, MCP-1）及颈动脉内膜中层厚度（carotid intima media thickness, CIMT）进行检测。以比值比评估在sCD14、IL-8及MCP-1存在的情况下，内毒素与CIMT的关联。对受试者进行Asp299Gly与Thr399Ile型TLR4多态性筛查，并对比携带与未携带TLR4多态性受试者的CIMT及炎症标志物水平。

结果：内毒素水平与sCD14（r=0.441, p<0.001）及MCP-1（r=0.388, p<0.001）水平呈正相关；而CIMT升高与MCP-1（r=0.448, p<0.001）、sCD14（r=0.476, p<0.001）、LBP（r=0.340, p<0.001）及IL-8（r=0.395, p<0.001）水平显著相关。动脉粥样硬化与内毒素水平相关（比值比：4.95；95%置信区间：2.52~9.73；p<0.001），且可通过血清炎症标志物的高水平进行预测。对携带TLR4多态性患者的分析显示，其血清炎症标志物水平及CIMT值均低于携带野生型TLR4等位基因的患者。

结论：本研究证实，南非CKD患者的循环内毒素血症、全身炎症与加速型动脉粥样硬化之间存在关联，且炎症标志物水平升高可显著增强内毒素血症的动脉粥样硬化预测能力。本研究的额外发现（需进一步验证）提示，TLR4多态性与较低水平的炎症标志物及CIMT值相关。