Mild renal dysfunction and metabolites tied to low HDL cholesterol are associated with monocytosis and atherosclerosis

Abstract

Background: The number of circulating blood monocytes impacts atherosclerotic lesion size, and in mouse models, elevated levels of high-density lipoprotein cholesterol suppress blood monocyte counts and atherosclerosis. We hypothesized that individuals with mild renal dysfunction at increased cardiovascular risk would have reduced high-density lipoprotein levels, high blood monocyte counts, and accelerated atherosclerosis.

Methods and results: To test whether mild renal dysfunction is associated with an increase in a leukocyte subpopulation rich in monocytes that has a known association with future coronary events, we divided individuals from the Malmö Diet and Cancer study (MDC) into baseline cystatin C quintiles (n=4757). Lower levels of renal function were accompanied by higher monocyte counts, and monocytes were independently associated with carotid bulb intima-media thickness cross-sectionally (P=0.02). Cystatin C levels were positively and plasma high-density lipoprotein cholesterol levels negatively associated with monocyte counts at baseline, after adjustment for traditional risk factors. Several amino acid metabolites tied to low levels of high-density lipoprotein cholesterol and insulin resistance measured in a subset of individuals (n=752) by use of liquid chromatography-mass spectrometry were independently associated with a 22% to 34% increased risk of being in the top quartile of monocytes (P<0.05).

Conclusions: A low high-density lipoprotein cholesterol, insulin resistance phenotype occurs in subjects with mild renal dysfunction and is associated with elevated monocytes and atherosclerosis. High blood monocyte counts may represent a previously unrecognized mechanism underlying the strong relationship between cystatin C and cardiovascular risk.

Figure

Mild renal dysfunction is linked to a low level of high-density lipoprotein (HDL) cholesterol, a high triglyceride level, and high numbers of monocytes. In cross-sectional analysis of 4662 to 4757 individuals in the cardiovascular cohort of the Malmö Diet and Cancer Study who had available covariate data, lower levels of renal function marked by higher cystatin C concentrations were associated with lower fasting plasma HDL levels (A), higher fasting plasma triglyceride levels (B), and higher monocyte counts (C) (P<0.001 for each, ANOVA). Results are shown as the mean of each variable by cystatin C quintile, with error bars representing the 95% confidence interval (CI). Monocytes were derived by an automatic cell counter 3-part differential method that distinguished cells on the basis of their size (lymphocytes, monocytes plus rare basophils/eosinophils, and neutrophils).