Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Abstract

Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, ²H₃]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = -0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD.

Fig. 1.

Isotope enrichment of apoC-III of VLDL (squares) and HDL (diamonds), expressed as tracer-to-tracee ratios, is shown for up to 96 h after a single bolus injection of ³D-leucine in a representative CKD subject.

Fig. 2.

Compartment model describes apoC-III tracer kinetics. Leucine tracer is injected into plasma (compartment 2) and distributes to extravascular compartments (compartments 1, 3, and 4). Compartments 1–4 are required to describe leucine tracer kinetics observed in plasma. Compartment 1 is connected to an intracellular delay compartment (compartment 5) that account for the synthesis, assembly, and secretion of apoC-III. Compartment 6 describes the kinetics of plasma apoC-III.

Fig. 3.

Concentrations (A), fractional catabolic rates (B), and production rates (C) for plasma apoC-III in CKD and control subjects

Fig. 4.

VLDL apoC-III tracer enrichment curves for CKD (▪) and control (⋄) subjects.