High phosphate and microvascular disease

Besides heart remodelling, microvascular dysfunction plays a key role in chronic kidney diseae (CKD)-associated cardiovascular disease. Our studies identified two new factors and determined the mechanisms by which they negatively affect endothelial cell function: high phosphate (AJP 2008, KI 2013) and soluble VEGF receptor sFlt-1 (JASN 2009).

Hyperphosphatemia, a hallmark of CKD, has emerged as one of the most important risk factors accounting for the devastating prognosis of renal patients. However, not only CKD or dialysis patients are affected. Recently, it has been reported that higher serum phosphate concentration, even within the normal range, is associated with development of atherosclerosis and mortality in patients with normal kidney function. These studies suggest that long-term excessive phosphate loading, even if it does not cause overt hyperphosphatemia, can be a risk factor for cardiovascular disease.

The role of high phosphate in several cellular processes in the vasculature, especially concerning smooth muscle cell biology and calcification, is very well understood. We have been the first, however, to show the direct impact of phosphate on endothelial cell morphology and function both in vitro and in vivo. High phosphate-associated alterations include endothelial cell apoptosis, microparticle formation, decreased annexin II expression, impaired angiogenic competence, and stiffness. These findings have two major implications: 1) they may be useful to better explain the association between phosphate and adverse clinical outcomes in both healthy individuals and patients with CKD, especially in those without history of calcification; and 2) they can help in the rational design of studies that manipulate serum phosphate levels in order to improve vascular function and reduce the burden of cardiovascular disease.

Further studies have focused on the molecular mechanisms involved in high-phosphate associated microvascular dysfunction.