Current Dietary Phosphorus Intake: Are there Potential Implications for Public Health?

Agenda

* Presentation titles and times are subject to change.

Abstracts

The Essential Role of Phosphorus Containing Additives in Food Processing
Lucina E. Lampila, PhD, RD, Louisiana State University, Baton Rouge

The uses and functions of phosphorus containing food ingredients vary widely across the food industry. Ortho- and pyrophosphates are essential to the acid-base reaction for leaving of baked goods. Low levels of condensed phosphates act synergistically with salt in meat processing resulting in a reduction of sodium used in processing. This presentation will cover common uses of phosphorus containing food ingredients to include food quality, safety and nutrition.

The Role of Phosphorus on the Pathogenesis of Secondary Hyperparathyroidism
Eduardo Slatopolsky, MD, Washington University, Department of Medicine, St. Louis

Alterations in phosphorus, calcium and vitamin D metabolism play a critical role in the development of secondary hyperparathyroidism (S.H.) in patients with chronic renal disease (CKD). Calcium regulates the secretion of PTH on a minute to minute basis. Active vitamin D compounds suppresses PTH at the transcriptional level. Phosphorus stimulates the secretion of PTH post-transcriptional by stabilizing the PTH mRNA in addition it induces parathyroid hyperplasia by activating the complex TGFalpha-Epidermal Growth Factor Receptor. Phosphorus stimulates FGF-23 that with its cofactor Klotho decreases the level of the renal 1, hydroxylase and increases the levels of 24 hydroxylase responsible for the catabolism of calcitriol. We had demonstrated in experimental animals with chronic renal disease that a low phosphorus diet prevents the development of S.H. and parathyroid gland hyperplasia, the opposite is seen when the animals are fed a high in phosphorus diet. Correction of hyperphosphatemia is imperative to reduce not only S.H. but vascular calcification and other morbid effects including death. Numerous epidemiological studies have demonstrated a correlation between serum phosphorus and death. These effects were also seen in patients with moderate renal failure. Thus, it is mandatory that we control serum phosphorus in patients with CKD by combining special diets, phosphate binders and effective hemodialysis to prevent or ameliorate the devastating effects induced by phosphorus retention.

Regulators of Phosphorus Homeostasis: Approaches to Control Phosphorus Excess
Harald W. Jüppner, MD, Massachusetts General Hospital and Harvard Medical School, Boston

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are the main regulators of phosphate homeostasis that promote urinary phosphate excretion and thus help maintain serum phosphorus levels within normal limits. Both hormones affect vitamin D metabolism differently; while PTH increases the renal 1-alpha vitamin D hydroxylase, FGF23 suppresses the synthesis of this enzyme and stimulates the 24-hydroxylase, thereby reducing 1,25(OH)2 vitamin D levels through two different mechanisms. Additional factors involved in the regulation of phosphate homeostasis were established by defining the molecular basis of different FGF23-dependent hypophosphatemic disorders. These efforts led to the identification of several proteins, including PHEX, DMP1, Fam20C, and ENPP1, that contribute to the regulation of FGF23 synthesis. Hypophosphatemia can occur also independent of FGF23, namely by homozygous or compound heterozygous mutations in the renal phosphate transporters NaPi-IIa or NaPi-IIc, or by homozygous mutations in the glucose transporter GLUT2, suggesting that these proteins could be therapeutic targets. FGF23 levels are elevated in patients with oncogenic osteomalacia (OOM) and several other inherited disorders, thus explaining the increase in urinary phosphate excretion and the inappropriately normal or reduced 1,25(OH)2 vitamin D levels observed in these disorders. FGF23 levels are furthermore dramatically elevated in the absence of membrane-bound Klotho (mKL), the FGF23 co-receptor, and when a cleaved form of Klotho (cKL) is produced in excess. The levels of C-terminal FGF23, but not of intact FGF23, are elevated in hyperphosphatemic tumoral calcinosis (TC) that is caused by homozygous inactivating mutations in GALNT3, the enzyme that initiates O-glycosylation of FGF23. The lack of this post-translational modification thus leads to abnormal FGF23 processing, which increases the secretion of biologically inactive C-terminal fragments; a similar increase in C-terminal FGF23 fragments is observed with severe iron deficiency. FGF23 levels rise early during the course of acute or chronic kidney disease indicating that this hormone is an early biomarker of abnormal phosphate homeostasis. Since elevated FGF23 levels are associated with kidney disease progression and cardiovascular disease/mortality, it would be important to prevent or limit the FGF23 rise early during the course of CKD, possibly through the use of oral phosphate binders or through PTH analogs/mimetics that selectively promote urinary phosphate excretion.

Health Concerns for Phosphorus Intake:  Historic Perspectives of Early Research Findings Concerning the Dietary Calcium to Phosphorus Ratio and Bone Health
Mona S.Calvo , PhD, U.S. Food and Drug Administration, Laurel, Maryland

Phosphorus intake in the United States has been high relative to calcium intake since we began monitoring nutrient intakes of the healthy general population. For the majority, phosphorus intake greatly exceeds the established dietary guidelines for nutrient requirements (the average estimated requirement, EAR), while calcium intake often does not meet the EAR. Growing evidence suggests that phosphorus intakes are actually higher than reported and seemingly continues to rise as a result of the increasing consumption of highly processed foods that rely on the many functional properties of added phosphorus ingredients needed to achieve a desired outcome such as texture or other characteristics. Phosphorus intake in excess of the nutrient needs of healthy men and women and far exceeding the recommended calcium to phosphorus intake ratio of 1:1 (mg:mg) have long been thought to disrupt the hormonal regulation of phosphorus, calcium and vitamin D resulting in bone loss or impaired peak bone mass. To gain insight into the potential for bone health concerns, we review the evidence from studies examining high phosphorus, low calcium experimental diets and diets containing low calcium, high phosphorus from natural food sources reported in recent Gambian field studies, as well as, findings from studies using defined diets prepared exclusively from common grocery store purchased foods rich in phosphorus additives. Changes in hormonal factors negatively impacting bone accretion or evidence of a direct impact on bone associated with specific processed foods raise concern for phosphorus intakes that exceed nutrient requirements, especially when calcium intake is limited.

Phosphorus Intake and Kidney Function
Jaime Uribarri, MD, Department of Medicine, The Mount Sinai School of Medicine,
New York, New York

High serum phosphorus is linked to poor health outcome and mortality in chronic kidney disease (CKD) patients before or after the initiation of dialysis. Therefore, maintenance of normal serum phosphorus levels is a major concern in the clinical care of this population with dietary phosphorus restriction and/or use of oral phosphate binders considered the best corrective care. This subject has been the focus of several 2012 National Kidney Foundation conferences/ workshops, an International Consensus Conference on Dietary Phosphorus Intake in CKD, as well as numerous articles in prominent medical journals. Effectively limiting phosphorus intake is difficult for both the CKD patient and healthy individuals because of problems in estimating total dietary phosphorus intake. One such problem is the wide range in bioavailability of phosphorus from different food sources that prevents accurate estimates of absorbed phosphorus. A second problem in estimating the dietary phosphorus load is the increasing use of phosphate salts as functional ingredients in processed foods and as inert ingredients in commonly used medications and the lack of phosphorus content information on these product labels. In the current presentation, we will briefly review these and other phosphorus related issues with repercussion in kidney patients and those seemingly healthy patients in the general population. We will also review the current experimental evidence suggesting that dietary phosphorus excess is an important factor determining progression of renal disease.

Is Dietary Phosphorus a Risk Factor for Cardiovascular Disease?
Joachim H. Ix, MD, MAS, Division of Nephrology, Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System

Initial studies from end-stage renal disease (ESRD) patients demonstrated strong associations of higher serum phosphorus concentrations with all-cause and cardiovascular mortality. Animal and in vitro studies have delineated mechanisms through which higher extra-cellular phosphorus concentrations transform vascular cells into bone-like cells and contribute to deposition of calcium and phosphorus in the vascular wall. Recently, similar associations have been extended to the general population where higher serum phosphorus concentrations have also been associated with vascular calcification, arterial stiffness, cardiovascular disease events, and, all-cause mortality. Moreover, higher phosphorus concentrations stimulate higher concentrations of the counter-regulatory hormones, including parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF23), which have themselves been linked with bone loss and cardiovascular disease. Most Americans consume phosphorus in excess of recommended daily allowance, andphosphorus is efficiently absorbed. Thus, it is possible that lowering dietary phosphorus consumption may translate into lowered serum phosphorus concentrations, and by extension, potential improvements in cardiovascular and bone health. However, in the general population, among persons with normal kidney function, there are only limited data linking dietary phosphorus intake with changes in serum phosphorus concentrations and cardiovascular disease. Such studies are critical before considering public health or policy interventions to alter phosphorus in the food supply. Thus, in this presentation, I will review recent studies evaluating (1) the link between dietary phosphorus consumption with serum phosphorus concentrations, and, (2) the link between dietary phosphorus consumption with adverse health outcomes in the general population.

Potential Health Concerns of Dietary Phosphorus: Cancer, Obesity, and Hypertension
John J.B. Anderson, PhD, University of North Carolina, Gillings School of Global Public Health, Chapel Hill

Typically Americans consume on average 1400 mg of phosphorus daily or more in meals, thus far exceeding the recommended dietary allowance (RDA). After a meal, phosphorus is efficiently (50% or higher) and rapidly absorbed, and hormonal mechanisms act swiftly to maintain the serum inorganic phosphate (Pi) concentration within fairly narrow limits. Both parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) reduce serum phosphate during postprandial periods through their actions on the kidney. However, exposure of cells to a brief high Pi concentration may alter cell functions that contribute to deleterious effects and, more likely, to elevated serum FGF-23 or PTH that may be harmful to specific cell types. FGF-23 is known to inhibit PTH secretion by a direct action on the parathyroids. Examples of adverse effects of one or the other of these two factors on three chronic diseases are reviewed in the context of potential mechanisms. In the case of high-phosphate induced cancer, phosphate ions are readily transported by NPT 2 or 3 across epithelial cells, e.g., lung, and participate in activating insulin receptors and participating in the Akt (protein kinase B) pathway that enhances glucose entry via production of GLUT 4 or 2 and insertion in cell membranes. This system supports the anaerobic degradation of glucose needed for cell transformation. Phosphate ions are also thought to contribute to tumorigenesis of altered cells. Less is known about the possible direct role of FGF-23 or PTH in cancer cells. In the case of obesity, adipocytes require inorganic phosphate for the phosphorylation of glucose. A ready supply of this ion supports glucose conversion to glycerol-P and entry into the lipogenic pathways. FGF-23 may play a supportive role with insulin in the expansion of fat cell size and possibly number, but little is known. An elevation of PTH has been found to be associated with an increased risk of obesity and obesity is typically accompanied by an increase in serum PTH in healthy elders. In the case of hypertension, smooth muscle cells of the vasculature (smooth muscle myocytes) require Pi to drive the energy pathways involving glucose and fatty acids that produce sustained contractions leading to chronic elevations of blood pressure. A diet high in Pi, however, has been shown in a 6-year prospective population-based study to be associated with a reduced risk of hypertension when most of the Pi is provided by dairy foods. The long term role of high dietary Pi in blood pressure regulation has not been evaluated in terms of non-dairy sources of phosphate. A specific role of FGF-23 or PTH in hypertension has not been assessed. In summary, high dietary phosphorus, especially from foods processed with phosphate salts, may contribute to two of these three chronic diseases, lung cancer and obesity, because of the direct actions of phosphate ions or from the indirect actions of FGF-23 or PTHon cells. The public health significance of the adverse effects of high phosphorus intakes on specific cell types remains under-appreciated, and further investigation is needed to establish its importance within the large segment of our population who regularly consume high-phosphate diets.

Data Needs for Evidence Linking Dietary Phosphorus Excess to Health Problems in the General Population
Katherine L. Tucker, PhD, Northeastern University, Boston, Massachusetts

Changes in the food supply over recent decades have led to increasing amounts of phosphorus in our diets. Although phosphorus is an important nutrient found naturally in most foods, it is now also added as a preservative, emulsifier, acidificant, flavor enhancer or for other characteristics of processed foods. Although the phosphorus content of many of these foods is known, food analysis studies have shown that nutrient databases may underestimate phosphorus in some foods by 20% or more. Importantly, this added phosphorus is much more bioavailable, perhaps twice or more, than natural phosphate esters in animal foods, and phytates in plant foods. When assessing the dietary intake of phosphorus, however, it remains standard practice to sum the phosphorus measures in the nutrient database without adjustment. Using this approach, very few individuals appear to exceed the upper level (UL) for phosphorus. However, to the extent that the databases underestimate total phosphorus intake, and the UL does not consider enhanced bioavailability of added phosphorus ingredients, those with excess intakes are likely to be underestimated. Additionally, foods enhanced with phosphorus compounds may lack other minerals that exist in natural foods, and which work together to either slow absorption, or to clear phosphorus in the blood more quickly. Foods such as cola, with added phosphoric acid, but no calcium, magnesium or other minerals, may lead to short periods of highly bioavailable phosphorus exposure that may have more negative health effects than the same amount of phosphorus from natural sources. These variations, not dissimilar to variations in bioavailability of natural folate vs added folic acid, suggest the need to develop an algorithm to consider phosphate bioavailability when calculating total phosphorus exposure from nutrient databases for use in studies of diet and health.

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