Damage of the Endothelial Glycocalyx in Dialysis Patients

Abstract

Damage to the endothelial glycocalyx, which helps maintain vascular homeostasis, heightens the sensitivity of the vasculature to atherogenic stimuli. Patients with renal failure have endothelial dysfunction and increased risk for cardiovascular morbidity and mortality, but the state of the endothelial glycocalyx in these patients is unknown. Here, we used Sidestream Darkfield imaging to detect changes in glycocalyx dimension in dialysis patients and healthy controls from in vivo recordings of the sublingual microcirculation. Dialysis patients had increased perfused boundary region and perfused diameters, consistent with deeper penetration of erythrocytes into glycocalyx, indicating a loss of glycocalyx barrier properties. These patients also had higher serum levels of the glycocalyx constituents hyaluronan and syndecan-1 and increased hyaluronidase activity, suggesting the shedding of these components. Loss of residual renal function had no influence on the imaging parameters but did associate with greater shedding of hyaluronan in blood. Furthermore, patients with higher levels of inflammation had more significant damage to the glycocalyx barrier. In conclusion, these data suggest that dialysis patients have an impaired glycocalyx barrier and shed its constituents into blood, likely contributing to the sustained endothelial cell activation observed in ESRD.

Patients with chronic renal failure have endothelial dysfunction and accelerated vascular disease leading to increased morbidity and mortality as a result of cardiovascular events.1–4 The mechanisms responsible are unclear, controversial, and presumed to be multifactorial. The vascular endothelium is coated on the luminal side by the glycocalyx, a negatively charged mesh of proteoglycans (PGs) and associated glycosaminoglycans.5 It is involved in mediating shear-induced release of nitric oxide and contributes to the endothelial permeability barrier, the regulation of redox state, and the inhibition of coagulation as well as leukocyte and platelet adhesion.6–9 Perturbation of glycocalyx occurs after provocation with inflammatory or atherogenic stimuli (such as ischemia reperfusion,10 infusion of oxidized LDL,9,11 administration of TNF-α12 or endotoxin,13 and during hyperglycemia14) and after stimulation with thrombin,15 atrial natriuretic peptide,16 or abnormal blood shear stress.17,18 Consequences of glycocalyx perturbation include a wide range of vascular abnormalities in experimental models, including increased vascular permeability followed by generation of tissue edema,19 increased rolling and adhesion of leukocytes,6 and increased platelet adhesion.9 Therefore, disruption of the glycocalyx leads to enhanced sensitivity of vasculature to atherogenic stimuli. Based on these observations, the importance of integrity of the endothelial glycocalyx in vascular homeostasis has become evident.

Attempts to assess the impairment of endothelial function in vivo are a challenge given the multifunctional nature of endothelial cells and lack of standardized tools to noninvasively assess endothelial function in a patient-friendly manner. We recently developed an imaging-based method to detect changes in glycocalyx dimension from in vivo recordings of the sublingual microcirculation, enabling us to assess the microvascular glycocalyx in vivo in patients. Previous studies have shown that, in healthy volunteers, the glycocalyx is disrupted by acute hyperglycemia.14 Subsequently, a significant reduction in glycocalyx volume was found in patients with type 1 diabetes.20 This disruption may contribute to the known predisposition of these patients to vascular disease.

No data are available on the state of the endothelial glycocalyx in patients with chronic renal failure. However, it is reasonable to hypothesize that the endothelial glycocalyx is affected in these patients given their predisposition to endothelial dysfunction and vascular disease. A damaged glycocalyx may lead to increased vulnerability and susceptibility of endothelial cells to vascular risk factors present in uremia. Therefore, the objective of this study was to answer the following questions. (1) Is the microvascular endothelial glycocalyx damaged in patients with ESRD on both hemodialysis (HD) and peritoneal dialysis (PD) compared with age- and sex-matched healthy controls? (2) Do dialysis patients have increased serum concentrations of glycocalyx constituents reflecting increased shedding? (3) Do the changes in endothelial glycocalyx correlate with other serum markers of endothelial activation, like sE-selectin?