Abstract
Electronegative low-density lipoprotein (LDL) has been shown to increase coronary artery disease risk in hemodialysis patients, but its effect on the risk of peripheral artery disease (PAD) remains unclear. We separated plasma LDL from 90 uremia patients undergoing hemodialysis into 5 subfractions (L1–L5) according to charge by using fast-protein liquid chromatography with an anion-exchange column and examined the distribution of L5—the most electronegative LDL subfraction—in total LDL (i.e. L5%). During a 5-year period, we followed up with these patients until the occurrence of ischemic lower-extremity PAD. During the follow-up period, ischemic lower-extremity PAD developed in 24.4% of hemodialysis patients. L5% was higher in hemodialysis patients in whom ischemic lower-extremity PAD occurred (3.03% [IQR, 2.36–4.54], n = 22) than in hemodialysis patients in whom PAD did not occur (1.13% [IQR, 0.90–1.83], n = 68) (p < 0.001). Furthermore, L5% significantly increased the adjusted hazard ratio of ischemic lower-extremity PAD (1.54 [95% CI, 1.14–2.10]) (p = 0.005). Flow-mediated dilation was negatively associated with L5% (p < 0.001). Additionally, in vivo experiments from mice showed that L5 compromised endothelium-dependent vascular relaxation through a nitric oxide–related mechanism. Our findings indicate that increased L5% may be associated with the occurrence of ischemic lower-extremity PAD in hemodialysis patients.
Highlights
Non-traumatic peripheral artery disease (PAD) is common among uremia patients, with an incidence up to 10-fold higher than that in non-uremia patients[1]
PAD (+) patients had a higher percentage of diabetes mellitus (DM) and ischemic heart disease (IHD)
We showed that L5% was significantly higher in hemodialysis patients in whom ischemic lower-extremity PAD developed than in hemodialysis patients in whom ischemic lower-extremity PAD did not develop and that L5% increased the hazard ratio for the occurrence of ischemic lower-extremity PAD in this patient population
Summary
Non-traumatic peripheral artery disease (PAD) is common among uremia patients, with an incidence up to 10-fold higher than that in non-uremia patients[1]. Hyperphosphatemia, and hyperparathyroidism are important risk factors of PAD, especially in patients with chronic renal failure or uremia[9, 10]. Dyslipidemia, especially high levels of plasma cholesterol or low-density lipoprotein-cholesterol (LDL-C), is another traditional factor of atherosclerosis, but its role in the development of coronary artery disease in uremia patients remains controversial[12,13,14]. L5, the most electronegative LDL subfraction[18], has been studied extensively for its role in the pathogenesis of atherosclerosis and has been shown to be toxic to both cardiomyocytes and endothelial cells[19]. We conducted a cohort study to examine the occurrence of ischemic lower-extremity PAD among hemodialysis patients and estimated the hazard ratio of L5% on PAD
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