The Ubiquitous Nature and Elusive Role of Phosphorus and Vascular Calcification

Recent population studies have suggested that higher serum phosphorus levels, even within the “normal” range, are associated with long-term cardiovascular and all-cause mortality.1, 2 As with all substances, the achieved homeostatic blood level of phosphorus is determined by intake, output, and shift, with multiple regulatory factors determining the ultimate level of phosphorus in the serum. Intestinal absorption and excretion, bone resorption, glomerular filtration, and tubular reabsorption all play a role in maintaining serum phosphorus in the range of 2.5 to 4.5 mg/dL (0.8-1.5 mmol/L).3 In this issue of the American Journal of Kidney Diseases, de Boer et al4 explore the factors that may determine serum phosphorus levels in the general US population.

Phosphorus is a component of many foods. While the animal protein and dairy product food groups are recognized to be among the most concentrated sources of dietary phosphorus, this mineral is ubiquitous throughout the food supply not only because of naturally occurring concentrations, but also because of an increasing use of phosphorus-containing preservatives.

Phosphorus is an integral component of many metabolic pathways and cellular constituents, including mitochondrial energy metabolism and cell membrane phospholipids, and severe hypophosphatemia may have profound systemic consequences. However, hyperphosphatemia is far more common than hypophosphatemia, and elevated serum phosphorus level has been recently associated with increased mortality; this is best seen in individuals with stage 5 chronic kidney disease (CKD). In the kidney failure milieu, phosphorus retention contributes to secondary hyperparathyroidism with the resultant consequences of osteopenia as well as the entire spectrum of bone and mineral abnormalities seen in CKD.5 It has been recently hypothesized that elevated phosphorus concentration may also have adverse vascular effects, with the interaction of hyperphosphatemia with calcium, parathyroid hormone (PTH), vitamin D, and other as-yet unidentified molecules, resulting in vascular calcification and increased mortality.6 As a consequence, patients with chronic kidney failure are instructed to restrict daily dietary phosphorus to no more than 17 mg per kilogram of body weight (on average, 900 mg per day). Accompanied by dietary phosphorus binder use, this level of dietary phosphorus restriction is required to maintain serum phosphorus concentrations in the recommended target range of 3.5 to 5.5 mg/dL. Maintenance of phosphorus concentration is further complicated by agents used to treat secondary hyperparathyroidism, specifically active vitamin D preparations, which increase dietary phosphorus absorption, as well as calcimimetic agents, which prevent shifts from bone and interfere with the phosphaturic effect of PTH.

A broader question is whether dietary phosphorus intake influences the pathophysiology of vascular calcification and clinical manifestations, such as coronary artery disease, for individuals in the general population. de Boer and colleagues4 present a detailed analysis of cross-sectional National Health and Nutrition Examination Survey (NHANES) III data, evaluating dietary phosphorus intake as determinant of serum phosphorus levels in individuals with and without kidney disease. They report a weak relationship between dietary phosphorus intake and serum phosphorus concentration, such that each 500-mg greater intake of dietary phosphorus was associated with a 0.03 mg/dL higher serum phosphorus concentration after adjustment for age, sex, race/ethnicity, time of day, and fasting status (P < 0.001). There was a weak association between percentage of calories from carbohydrates with serum phosphorus levels, while there was no association between percentage of calories from either protein or fat with serum phosphorus concentration. Finally, de Boer et al demonstrate that serum phosphorus concentrations were inversely related to Framingham coronary heart disease risk scores, although the only components of the Framingham risk score associated with higher serum phosphorus concentration were hyperlipidemia and smoking. In their multivariable models, only 12% of the variation in serum phosphorus concentrations could be explained by kidney function, cardiovascular risk factors, diet, and demographics. de Boer et al conclude that the association of serum phosphorus with cardiovascular events appears to be unrelated to factors pertaining to dietary phosphorus intake or to traditional cardiovascular risk factors. Their findings are in agreement with Shinaberger et al,7 whose observational study demonstrated no clear increased mortality in hemodialysis patients eating up to 1.4 g protein/kg/d despite slightly higher serum phosphorus levels, while increased mortality was present among patients consuming 0.9 g or less of protein/kg/d.

These results support the known metabolism of dietary phosphorus in the general population, where serum phosphorus levels are maintained within a narrow range by a large array of metabolic adjustments including the simple concept of maintaining homeostasis by adjusting excretion in response to intake. Although high-normal serum phosphorus levels have been associated with increased cardiovascular morbidity and mortality in non-CKD patients with coronary disease,8 the lack of direct association between dietary phosphorus intake and serum levels does not indicate that lowering serum phosphorus level by diet and the use of phosphorus binders would necessarily impact on vascular calcification in individuals with intact kidney function.

Dietary phosphorus intake for those individuals with normal kidney function may have more of an indirect role in terms of how serum phosphorus is affected by calcium levels, vitamin D, and PTH. The question arises in a metabolic milieu of an atherosclerotic process, is there a role for serum phosphorus that could be influenced by diet or other risk factors of calcification (Fig 1)? Moreover, does phosphorus interface and react with oxidized low-density lipoprotein cholesterol and is that important? If both serum calcium and serum phosphorus are in the high-normal range, will the calcium-phosphorus product result in calcification when interfacing with inflammatory mediators?

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Figure 1. The phosphocalcic interplay during chronic kidney disease.

In closing, while dietary phosphorus intake does not appear to impact on serum phosphorus levels when glomerular filtration rate is in normal and near-normal ranges, this does not preclude the possibility that lowering serum phosphorus, perhaps through the use of phosphorus binders, might be advantageous in CKD. High-protein diets, inherently high in dietary phosphorus and saturated fats, may also play a role in a dietary phosphorus hypothesized association with vascular calcification and inflammation. Interaction of phosphorus with calcium is yet another facet of this complex micro-environment that has an important role. Further research is needed to address these points before any conclusions can be drawn regarding the pathophysiology of dietary phosphorus and vascular calcification.