ReviewPhosphate: The new cholesterol? The role of the phosphate axis in non-uremic vascular disease
Introduction
Inorganic phosphate plays an essential role in a number of fundamental processes in every cell of every species. Energy metabolism, signal transduction, storage and translation of genetic information and maintenance of lipid membrane structure are all absolutely phosphate-dependent. The majority of phosphate in humans (85%) is found in bone, complexed with calcium as the mineral hydroxyapatite. Disturbances in serum phosphate outside the normal range (0.8–1.5 mM) are well-recognised to have clinical relevance; very low serum phosphate levels occurring in the setting of malnutrition/refeeding cause muscle weakness and circulatory collapse, whilst hyperphosphatemia in advanced kidney disease leads to vascular calcification and secondary hyperparathyroidism. However, recent observational data link cardiovascular morbidity and mortality to phosphate levels within the normal range and to phosphate-regulatory hormone levels in populations without recognised disorders of phosphate metabolism. These observations suggest a potentially important role for the phosphate axis in atherosclerotic vascular disease, the subject of this review.
Section snippets
Serum phosphate and cardiovascular disease risk
Higher serum phosphate levels even well within the ‘normal’ range are associated with substantially increased risks of cardiovascular disease events in observational studies [1], [2], [3], [4], [5], [6], [7], [8], [9] (Table 1). The risk increases are apparent in populations with or without a previous history of cardiovascular disease and persist after adjusting for other recognised risk factors. In fact, lower serum phosphate levels within the normal range are associated with an increased
An unlikely culprit?
Given the ubiquitous roles of inorganic phosphate in cell signalling, structure and energy metabolism it may seem counterintuitive to consider adding this mineral to the list of vascular risk factors, particularly at phosphate increments within the homeostatically regulated range. Cholesterol, however, is also a substance with essential cellular and hormonal biosynthetic functions which is well recognised to play a causative role in vascular pathology (Table 2). Furthermore, interventions to
Determinants of serum phosphate
Serum phosphate levels are maintained within the normal range by a number of regulatory hormones (Fig. 1). These modulate the intestinal uptake of phosphate, its mobilization from bone and renal excretion. A blood-phosphate sensing mechanism, however, remains to be identified. Despite the existence of the phosphate regulatory apparatus, controlled dietary interventions are able to modulate serum phosphate levels substantially [17]. The extent to which the high bioavailable phosphate content of
Calcification: extrapolation from kidney disease?
In the advanced stages of kidney disease serum phosphate levels can climb well above the normal range to >2.5 mM. For years nephrologists have used phosphate binders and dietary phosphate restriction to try to control hyperphosphatemia. Although no trial data exist to show a benefit of lowering serum phosphate, observational data link hyperphosphatemia with vascular calcification and cardiovascular mortality in these patients [20]. Animal models of uremia demonstrate a causative role for dietary
Indirect effects: the phosphate regulatory axis
Most observational studies linking serum phosphate to vascular disease in the absence of kidney disease did not measure the phosphate-regulating hormones concomitantly. The potential role of these hormones in mediating the reported link between higher-normal phosphate and cardiovascular disease is therefore unclear. However, other observational studies have reported associations between the levels of the phosphate-regulatory hormones and cardiovascular event risk even in the absence of
Fibroblast growth factor 23
Fibroblast growth factor-23 (FGF-23) is secreted by osteocytes and osteoblasts in response to an increase in blood phosphate level or dietary phosphate intake [45]. It acts to increase renal phosphate excretion and inhibits the activation of vitamin D to calcitriol by the kidney. Observational data link FGF-23 with atheroma burden, cardiovascular events and endothelial dysfunction in populations with [36], [46], [47] and without kidney impairment [36], [48], [49]. In fact, in observational
Suppression of vitamin D activation
Adverse effects of phosphate on the vasculature could be mediated via the inhibition of vitamin D activation by FGF 23. The conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol), the active hormone, is performed primarily in the kidney, by the enzyme 1-alpha hydroxylase. This enzyme is downregulated by FGF 23, which also upregulates the counter-regulatory enzyme 24-hydroxylase, diverting 25-hydroxyvitamin D to the inactive 24,25-dihydroxyvitamin D. Reducing dietary phosphate
Parathyroid hormone
Parathyroid hormone (PTH) secretion is stimulated by increasing serum phosphate (or dietary phosphate intake [45]) and promotes renal phosphate excretion. Even within the ‘normal’ range, greater PTH levels predicted cardiovascular mortality in a community population, with a hazard ratio of 1.38 for each standard deviation increase in PTH (95% CI 1.18–1.60) [60]. This was despite adjusting for recognised cardiovascular risk factors, renal function and other parameters of bone mineral metabolism
Other bone signalling pathways: the bone-vascular axis
It is unclear why receptors and signalling pathways for these bone mineral regulators are expressed so widely in cells of the cardiovascular system which play no known role in bone mineral regulation. A carry-over of developmental programming resulting from a common origin of bone and vascular cells may cause vascular cells to behave like bone under appropriate pathological stimuli; calcification of aortic vascular smooth muscle cells has been shown to be influenced by their developmental
Dietary phosphate manipulation: are phosphate binders the new statins?
The interactions between components of the phosphate regulatory axis (Fig. 1) mean that manipulating one element will affect the others. For example, calcitriol promotes intestinal phosphate uptake, so supplementing calcitriol may increase time-averaged phosphate exposure and raise FGF-23 levels. Similarly, suppressing PTH may reduce renal phosphate excretion and so also raise phosphate and FGF-23. There is a need to understand the contribution of each component to any causative mechanisms of
Calcium
Though we have considered here the relationship between vascular disease and the phosphate axis, the control of blood calcium is of course also performed by the same regulatory hormones. Nevertheless, the reported observational associations between the components of the phosphate axis and vascular disease are independent of serum calcium levels. Serum calcium has been reported to predict cardiovascular events in some population studies [4], but not others [2]. A recent post hoc analysis of a
Conclusion: the way forward
It is noteworthy that the widespread use of phosphate binders in uremic hyperphosphatemia (costing approximately $1 billion annually worldwide) is not based on any prospective interventional data showing improved outcomes. Risk increases linked to hyperphosphatemia in dialysis patients are actually similar to those linked to higher-normal phosphate in non-uremic populations. Mechanisms relating vascular disease to milder perturbations of the phosphate axis need to be pursued since this may have
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2021, NefrologiaCitation Excerpt :Regarding age, it is widely recognized as one of the main risk factors for calcific aortic stenosis.34,35 It is described the association of elevated P levels with vascular calcification and endothelial dysfunction36,37 with increased risk of atherosclerosis and hypertension38 that may cause rupture of atherosclerotic plaque.39 In other publications of the NEFRONA study, the effect of serum P levels in the presence of subclinical atherosclerosis was analyzed using vascular ultrasound (carotid and femoral).40