Diminished antioxidant activity of high-density lipoprotein-associated proteins in chronic kidney disease

Abstract

Background: Decreased serum arylesterase activity, catalyzed by the high-density lipoprotein-associated paraoxonase (PON)-1, is associated with increased oxidant stress and atherosclerosis risk. We sought to determine the prognostic value of serum PON-1 activity, as monitored by PON or arylesterase activities, in subjects with chronic kidney disease (CKD), particularly in relation to established cardiac biomarkers.

Methods and results: Serum arylesterase and PON activities were measured in sequential subjects with CKD (n=630; estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m(2)) and an age- and sex-matched control group of non-CKD subjects (n=315) presenting for cardiac evaluations and prospectively followed for incident (3-year) major adverse cardiac events (composite of death, nonfatal myocardial infarction, and stroke). Serum arylesterase activity in CKD subjects was lower compared with that in non-CKD control subjects [median (interquartile range) 94 (77 to 112) versus 103 (85 to 121) μmol(L·min) per mL, P<0.001]; similarly, PON activity in CKD subjects was lower compared with that in non-CKD control subjects [median (interquartile range) 474 (275 to 936) versus 586 (301 to 1118) nmol(L·min) per mL, P<0.001]. Lower serum arylesterase (hazard ratio 1.8, 95% CI 1.26 to 2.57, P<0.01) was a predictor of poorer outcomes. After adjusting for traditional risk factors and medication use, lower serum arylesterase (hazard ratio 1.55, 95% CI 1.08 to 2.23, P<0.05) still conferred an increased risk of major adverse cardiac events at 3 years.

Conclusions: In patients with CKD, decreased serum arylesterase activity, a measure of diminished antioxidant properties of PON-1, predicts higher risk of incident long-term adverse cardiovascular events (heart attack, stroke, or death) in multivariable models adjusting for established clinical and biochemical risk factors.

Figure 1.

Comparison of serum arylesterase activity (left) and serum paraoxonase activity (right) between control subjects (eGFR ≥60 mL/min per 1.73 m²) and patients with chronic kidney disease (eGFR <60 mL/min per 1.73 m²). Probability value <0.001 versus control for arylesterase and paraoxonase by both Wilcoxon and t test. CKD indicates chronic kidney disease; eGFR, estimated glomerular filtration rate.

Figure 2.

Kaplan–Meier analysis of major adverse cardiac events in patients with chronic kidney disease. Patients stratified according to optimal cutoff for serum arylesterase and paraoxonase activity levels as follows: “high” paraoxonase [≥280 nmol(L·min) per mL] or “low” paraoxonase [<280 nmol(L·min) per mL] and “high” arylesterase [≥70 μmol(L·min) per mL] or “low” arylesterase [<70 μmol(L·min) per mL].MI indicates myocardial infarction.