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Dysfunctional HDL takes its Toll on the endothelial glycocalyx. Patients with end-stage renal disease have a high risk of dying from cardiovascular disease that cannot be explained solely by traditional cardiovascular disease risk factors. Hesse et al. suggest that dysfunctional high-density lipoprotein cholesterol generated in patients with end-stage renal disease causes endothelial glycocalyx degradation. Glycocalyx degradation may represent one of the earliest insults leading to atheroma formation, and so this work suggests a novel link between renal failure and cardiovascular disease.