The glycocalyx—linking albuminuria with renal and cardiovascular disease

Abstract

Albuminuria is commonly used as a marker of kidney disease progression, but some evidence suggests that albuminuria also contributes to disease progression by inducing renal injury in specific disease conditions. Studies have confirmed that in patients with cardiovascular risk factors, such as diabetes and hypertension, endothelial damage drives progression of kidney disease and cardiovascular disease. A key mechanism that contributes to this process is the loss of the glycocalyx--a polysaccharide gel that lines the luminal endothelial surface and that normally acts as a barrier against albumin filtration. Degradation of the glycocalyx in response to endothelial activation can lead to albuminuria and subsequent renal and vascular inflammation, thus providing a pathophysiological framework for the clinical association of albuminuria with renal and cardiovascular disease progression. In this Review, we examine the likely mechanisms by which glycocalyx dysfunction contributes to kidney injury and explains the link between cardiovascular disease and albuminuria. Evidence suggests that glycocalyx dysfunction is reversible, suggesting that these mechanisms could be considered as therapeutic targets to prevent the progression of renal and cardiovascular disease. This possibility enables the use of existing drugs in new ways, provides an opportunity to develop novel therapies, and indicates that albuminuria should be reconsidered as an end point in clinical trials.

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

“…Although pleiotropic effects have been inferred, improved glycemic control, lowering of blood pressure, decrease in intraglomerular pressure, reduction in albuminuria, and amelioration of volume overload are all plausible protective mechanisms. 4,[13][14][15][16][17][18][19][20][21][22][23] The effects on cardiovascular and renal outcomes observed within this program of two integrated trials are similar to those observed previously with this drug class. 5,6 The favorable direction of effect with respect to stroke observed in this trial program differs from a previously reported possible adverse effect on stroke risk.…”

Vascular Endothelial Growth Factor-A₁₆₅b Restores Normal Glomerular Water Permeability in a Diphtheria-Toxin Mouse Model of Glomerular Injury

“…There is substantial evidence to suggest that structural defects in the GFB are largely a result of albuminuria in specific disease conditions [27], which could explain why we do not see any structural abnormalities in our model.…”

Modeling Loss of Microvascular Wall Homeostasis during Glycocalyx Deterioration and Hypertension that Impacts Plasma Filtration and Solute Exchange

“…Only recently the role of glycocalyx and the adverse effects of its deterioration in several diseases has been accepted [55], for instance, its dysfunction contributes to renal and cardiovascular disease progression, associated with albuminuria [26] and its degradation is recognized in septis with the onset of acute lung injury in most severe cases [56]. In acute lung injury and acute respiratory distress syndrome, pulmonary edema was observed, correlated to glycocalyx deterioration [57].…”

“…Glycocalyx degeneration, induced by reactive oxygen species exposure, has been shown to lead to endothelial dysfunction, with possible onset of microalbuminuria or proteinuria (i.e. the presence of an excess of albumin or other serum proteins in the urine) in clinical diseases [24,25], and subsequently to vascular inflammation and cardiovascular disease progression [26].…”