Vascular Toxicity of Phosphate in Chronic Kidney Disease

Abstract

In epidemiological studies of CKD patients and the general population, high phosphate levels are associated with CV disease (CVD). The association is even observed in early-stage CKD and is independent of other traditional CV risk factors. 5, 6 Along with other factors, hyperphosphatemia is involved in the development of vascular calcification (VC) and endothelial dysfunction (ED), 7-9 both of which are major nontraditional CV risk factors for CKD. Phosphate is able to act either directly on these parameters or indirectly via the FGF23/Klotho and PTH axes (Figure 1).We review the various effects of hyperphosphatemia on CV parameters, with a focus on its emerging role in ED. The efficacy of current therapies for improving phosphate-related CV outcomes is also discussed. Direct Effects of Phosphate on CV Calcification and ED Epidemiological and Interventional StudiesVC is deposition of calcium/phosphate, mostly as apatite, in the blood vessels, myocardium and cardiac valves. Calcification of both the intima and media occurs in CKD, 10 resulting in the stiffness of the large arteries (as evidenced by a higher pulse wave velocity) and thus promotion of CV morbidity/ mortality. The results of several epidemiological studies have highlighted an association between serum phosphate levels and VC in stage 5D CKD patients, 11,12 in early-stage CKD patients and in the general population (in whom serum phosphate levels are still within the normal range). 13, 14 Indeed, 2 elegant prospective studies of large cohorts of hosphate, principally provided by food, is involved in many physiological processes: it buffers the intracellular pH, ensures the stability of the skeleton and contributes to many essential biological functions (eg, DNA synthesis, cell membrane phospholipids, energy metabolism and intracellular signaling pathways that are regulated by phosphorylation/dephosphorylation).The physiological concentration of phosphate (0.8-1.5 mmol/L) is tightly regulated by, among others, the fibroblast growth factor 23 (FGF23)/Klotho axis, parathyroid hormone (PTH) and calcitriol (the active form of vitamin D). 1 In chronic kidney disease (CKD), the progressive loss of functional nephrons induces retention of phosphate, which in turn leads to (1) an increase in calcium/phosphate products and (2) FGF23 synthesis. With the aim of preventing hyperphosphatemia, FGF23 decreases circulating levels of calcitriol, thus inhibiting intestinal phosphate and calcium absorption. PTH, the overexpression of which is triggered by hypocalcemia, stimulates bone resorption for the primary purpose of restoring calcemia but in doing so it increases phosphatemia and thus the calcium/phosphate products. During the course of CKD, Klotho's downregulation in both the parathyroid gland and the kidney results in the loss of FGF23 being able to respectively (1) decrease PTH expression and (2) inhibit renal phosphate reabsorption. In late-stage CKD, the few remaining functional nephrons are no longer able to eliminate phosphate and a vicious circle (referred ...

Effects of oral activated charcoal on hyperphosphatemia and vascular calcification in Chinese patients with stage 3–4 chronic kidney disease

“…As the release of matrix vesicles increases, a large number of vesicles are dissolved, leading to the rapid rise of calcium ion concentration, thereby accelerating cell apoptosis, forming calcification nests, and initiating calcification [20]. The fact that VMSC apoptosis may occur earlier than the occurrence of calcification is an important part of vascular calcification caused by hyperphosphatemia [21]. Fourth, hyperphosphatemia can promote VSMC extracellular matrix remodeling.…”

Characterization and assessment of potential microRNAs involved in phosphate‐induced aortic calcification

“…A series of these microRNAs were shown to regulate physiological osteoblast differentiation, a key step in bone formation and mineralization (Fakhry et al, ; Hu et al, ). In addition, several other microRNAs were also shown to likely modulate trans‐differentiation of VSMCs and vascular calcification (Cui et al, ; Goettsch, Rauner, Pacyna, et al, ; Gross, Six, Kamel, & Massy, ; Panizo et al, ). In this study, we questioned whether a specific microRNA network is implicated in triggering rat artery calcification in response to P i treatment.…”

“…shown to likely modulate trans-differentiation of VSMCs and vascular calcification (Cui et al, 2012;Goettsch, Rauner, Pacyna, et al, 2011;Gross, Six, Kamel, & Massy, 2014;Panizo et al, 2015). In this study, we questioned whether a specific microRNA network is implicated in triggering rat artery calcification in response to P i treatment.…”

Pathogenesis and management of vascular calcification in CKD and dialysis patients

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