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.