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

Resources

Jaime Uribarri

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Sherer DW, Singer G, Uribarri J, et al. Oral phosphate binders in the treatment of pseudoxanthoma elasticum. J Am Acad Dermatol. 2005;53(4):610-5.

Uribarri J. Phosphorus additives in food and their effect in dialysis patients. Clin J Am Soc Nephrol. 2009;4(8):1290-2.

Uribarri J. Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake. Semin Dial. 2007;20(4):295-301.

Uribarri J. Unrecognized sources of dietary phosphate. Semin Dial. 2002;15(5):376.

Uribarri J, Calvo MS. Hidden sources of phosphorus in the typical American diet: does it matter in nephrology? Semin Dial. 2003;16(3):186-8.

Vlassara H, Cai W, Chen X, et al. Managing chronic inflammation in the aging diabetic patient with CKD by diet or sevelamer carbonate: a modern paradigm shift. J Gerontol A Biol Sci Med Sci. 2012;67(12):1410-6.

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Vlassara H, Uribarri J, Cai W, et al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol. 2012;7(6):934-42.

Vassalotti JA, Uribarri J, Chen SC, et al. Trends in mineral metabolism: Kidney Early Evaluation Program (KEEP) and the National Health and Nutrition Examination Survey (NHANES) 1999–2004. Am J Kidney Dis. 2008;51(4 Suppl 2):S56-68.

Mona S. Calvo

Calvo MS, Eastell R, Offord KP, Bergstralh EJ, Burritt MF. Circadian variation in ionized calcium and intact parathyroid hormone: evidence for sex differences in calcium homeostasis. J Clin Endocrinol Metab. 1991;72(1):69-76.

Calvo MS, Kumar R, Heath H. Persistently elevated parathyroid hormone secretion and action in young women after four weeks of ingesting high phosphorus, low calcium diets. J Clin Endocrinol Metab. 1990;70(5):1334-40.

Calvo MS, Park YK. Changing phosphorus content of the U.S. diet: potential for adverse effects on bone. J Nutr. 1996;126(4 Suppl):1168S-80S.

Calvo MS, Uribarri J. Contributions to total phosphorus intake: all sources considered. Semin Dial. 2013;26(1):54-61.

Oenning LL, Vogel J, Calvo MS. Accuracy of methods estimating calcium and phosphorus intake in daily diets. J Am Diet Assoc. 1988;88(9):1076-80.

John J. B. Anderson

Anderson JJ. Calcium requirements during adolescence to maximize bone health. J Am Coll Nutr. 2001;20(2 Suppl):186S-191S.

Anderson JJ, Roggenkamp KJ, Suchindran CM. Calcium intakes and femoral and lumbar bone density of elderly U.S. men and women: National Health and Nutrition Examination Survey 2005–2006 analysis. J Clin Endocrinol Metab. 2012;97(12):4531-9.

Anderson JJ, Suchindran CM, Roggenkamp KJ. Micronutrient intakes in two US populations of older adults: lipid research clinics program prevalence study findings. J Nutr Health Aging. 2009;13(7):595-600.

Joachim H. Ix

Criqui MH, Kamineni A, Allison MA, et al. Risk factor differences for aortic versus coronary calcified atherosclerosis: the multiethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30(11):2289-96.

Ix JH, de Boer IH, Peralta CA, et al. Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA. Clin J Am Soc Nephrol. 2009;4(3):609-15.

Kendrick J, Ix JH, Targher G, Smits G, Chonchol M. Relation of serum phosphorus levels to ankle brachial pressure index (from the Third National Health and Nutrition Examination Survey). Am J Cardiol. 2010;106(4):564-8.

Meng J, Wassel CL, Kestenbaum BR, et al. Serum phosphorus levels and the spectrum of ankle-brachial index in older men: the Osteoporotic Fractures in Men (MrOS) study. Am J Epidemiol. 2010;171(8):909-16.

Newsome B, Ix JH, Tighiouart H, et al. Effect of protein restriction on serum and urine phosphate in the modification of diet in renal disease (MDRD) study. Am J Kidney Dis. [Epub ahead of print]

Harald W. Jüppner

Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med. 2010;61(1):91-104.

Jüppner H. Phosphate and FGF-23. Kidney Int Suppl. 2011; 79(121):S24-S27.

Jüppner H, Wolf M, Salusky IB. FGF-23: More than a regulator of renal phosphate handling? J Bone Miner Res. 2010;25(10):2091-7.

Shimada T, Urakawa I, Isakova T, et al. Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active. J Clin Endocrinol Metab. 2010;95(2):578-85.

Lucina E. Lampila

Obritsch JA, Ryu D, Lampila LE, Bullerman LB. Antibacterial effects of long-chain polyphosphates on selected spoilage and pathogenic bacteria. J Food Prot. 2008;71(7):1401-5.

Eduardo Slatopolsky

Dusso AS, Sato T, Arcidiacono MV, et al. Pathogenic mechanisms for parathyroid hyperplasia. Kidney Int Suppl. 2006;70(102):S8-11.

Martin DR, Ritter CS, Slatopolsky E, Brown AJ. Acute regulation of parathyroid hormone by dietary phosphate. Am J Physiol Endocrinol Metab. 2005;289(4):E279-34.

Silver J, Rodriguez M, Slatopolsky E. FGF23 and PTH—double agents at the heart of CKD. Nephrol Dial Transplant. 2012;27(5):1715-20.

Slatopolsky E. The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder. Kidney Int Suppl. 2011;79(S121):S3-8.

Slatopolsky E, Caglar S, Gradowska L, Canterbury J, Reiss E, Bricker NS. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using "proportional reduction" of dietary phosphorus intake. Kidney Int. 1972;2(3)147-51.

Slatopolsky E, Caglar S, Pennell JP, et al. On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest. 1971;50(3):492-9.

Slatopolsky E, Finch J, Denda M, et al. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest. 1996;97(11):2534-40.

Takahashi F, Denda M, Finch JL, Brown AJ, Slatopolsky E. Hyperplasia of the parathyroid gland without secondary hyperparathyroidism. Kidney Int. 2002;61(4):1332-8.

Katherine L. Tucker

Berndt SI, Carter HB, Landis PK, et al. Calcium intake and prostate cancer risk in a long-term aging study: the Baltimore Longitudinal Study of Aging. Urology. 2002;60(6):1118-23.

Bhupathiraju SN, Tucker KL. Coronary heart disease prevention: nutrients, foods, and dietary patterns. Clin Chim Acta. 2011;412(17-18):1493-514.

Farina EK, Kiel DP, Roubenoff R, Schaefer EJ, Cupples LA, Tucker KL. Plasma phosphatidylcholine concentrations of polyunsaturated fatty acids are differentially associated with hip bone mineral density and hip fracture in older adults: the Framingham Osteoporosis Study. J Bone Miner Res. 2012;27(5):1222-30.

Sahni S, Tucker KL, Kiel DP, Quach L, Casey VA, Hannan MT. Milk and yogurt consumption are linked with higher bone mineral density but not with hip fracture: the Framingham Offspring Study. Arch Osteoporos. 2013;8(1-2):119.

Samelson EJ, Booth SL, Fox CS, et al. Calcium intake is not associated with increased coronary artery calcification: the Framingham Study. Am J Clin Nutr. 2012;96(6):1274-80.

Tucker KL, Morita K, Qiao N, Hannan MT, Cupples LA, Kiel DP. Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: The Framingham Osteoporosis Study. Am J Clin Nutr. 2006;84(4):936-42.

Related Journal Articles

ADHR Consortium. Autosomal dominant hypophosphaetemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345-8.

Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab. 2006;91(8):3144-9.

Bellasi A, Mandreoli M, Baldrati L, et al. Chronic kidney disease progression and outcome according to serum phosphorus in mild-to-moderate kidney dysfunction. Clin J Am Soc Nephrol. 2011;6(4):883-91.

Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15(8):2208-18.

Block GA, Wheeler DC, Persky MS, et al. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol. 2012;23(8):1407-15.

Chue CD, Edwards NC, Davis LJ, Steeds RP, Townend JN, Ferro CJ. Serum phosphate but not pulse wave velocity predicts decline in renal function in patients with early chronic kidney disease. Nephrol Dial Transplant. 2011;26(8):2576-82.

Chue CD, Edwards NC, Moody WE, Steeds RP, Townend JN, Ferro CJ. Serum phosphate is associated with left ventricular mass in patients with chronic kidney disease: a cardiac magnetic resonance study. Heart. 2012;98(3):219-24.

de Boer IH, Rue TC, Kestenbaum B. Serum phosphorus concentrations in the third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis. 2009;53(3):399-407.

Dhingra R, Gona P, Benjamin EJ, et al. Relations of serum phosphorus levels to echocardiographic left ventricular mass and incidence of heart failure in the community. Eur J Heart Fail. 2010;12(8):812-8.

Dhingra R, Sullivan LM, Fox CS, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med. 2007;167(9):879-85.

Farrow EG, Yu X, Summers LJ, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A. 2011;108(46):E1146-55.

Fliser D, Kollerits B, Neyer U, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) study. J Am Soc Nephrol. 2007;18(9):2600-8.

Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA. Serum phosphorus levels associated with coronary atherosclerosis in young adults. J Am Soc Nephrol. 2009;20(2):397-404.

Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296-305.

Grimm M, Müller A, Hein G, Fünfstück R, Jahreis G. High phosphorus intake only slightly affects serum minerals, urinary pyridinium crosslinks and renal function in young women. Eur J Clin Nutr. 2001;55(3)153-61.

Huttunen MM, Tillman I, Viljakainen HT, et al. High dietary phosphate intake reduces bone strength in the growing rat skeleton. J Bone Miner Res. 2007;22(1):83-92.

Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011;96(11):3541-9.

Jin H, Xu CX, Lim HT, et al. High dietary inorganic phosphate increases lung tumorigenesis and alters Akt signaling. Am J Respir Crit Care Med. 2009;179(1);59-68.

Kalantar-Zadeh K, Gutekunst L, Mehrotra R, et al. Understanding sources of dietary phosphorus in the treatment of patients with chronic kidney disease. Clin J Am Soc Nephrol. 2010;5(3):519-30.

Kemi VE, Kärkkäinen MU, Rita HJ, Laaksonen MM, Outila TA, Lamberg-Allardt CJ. Low calcium:phosphorus ratio in habitual diets affects serum parathyroid hormone concentration and calcium metabolism in healthy women with adequate calcium intake. Br J Nutr. 2010;103(4):561-8.

Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16(2):520-8.

Moe SM, Zidehsarai MP, Chambers MA, et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(2):257-64.

Nishida Y, Taketani Y, Yamanaka-Okumura H, et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int. 2006;70(12):214-217.

O'Seaghdha CM, Hwang SJ, Muntner P, Melamed ML, Fox CS. Serum phosphorus predicts incident chronic kidney disease and end-stage renal disease. Nephrol Dial Transplant. 2011;26(9):2885-90.

Portale AA, Halloran BP, Morris RC Jr. Physiologic regulation of the serum concentration of 1,25-dihydroxyvitamin D by phosphorus in normal men. J Clin Invest. 1989;83(5):1494-9.

Ritz E, Hahn K, Ketteler M, Kuhlmann MK, Mann J. Phosphate additives in food—a health risk. Dtsch Arztebl Int. 2012;109(4):49-55.

Savica V, Calò LA, Monardo P, et al. Salivary phosphate-binding chewing gum reduces hyperphosphatemia in dialysis patients. J Am Soc Nephrol. 2009;20(3);639-44.

Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1(4):825-31.

Sherman RA, Mehta O. Phosphorus and potassium content of enhanced meat and poultry products: implications for patients who receive dialysis. Clin J Am Soc Nephrol. 2009;4(8):1370-3.

Sigrist M, Tang M, Beaulieu M, et al. Responsiveness of FGF-23 and mineral metabolism to altered dietary phosphate intake in chronic kidney disease (CKD): results of a randomized trial. Nephrol Dial Transplant. 2013;28(1):161-9.

Slatopolsky E, Caglar S, Gradowska L, Canterbury J, Reiss E, Bricker NS. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using "proportional reduction" of dietary phosphorus intake. Kidney Int. 1972;2(3)147-51.

Smith ER, Cai MM, McMahon LP, Holt SG. Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab. 2012;97(9):3357-65.

Smith RC, O'Bryan LM, Farrow EG, et al. Circulating αKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest. 2012;122(12):4710-5.

Sullivan C, Sayre SS, Leon JB, et al. Effect of food additives on hyperphosphatemia among patients with end-stage renal disease: a randomized controlled trial. JAMA. 2009;310(6):629-35.

Sullivan CM, Leon JB, Sehgal AR. Phosphorus-containing food additives and the accuracy of nutrient databases: Implications for renal patients. J Ren Nutr. 2007;17(5):350-4.

Vervloet MG, van Ittersum FJ, Büttler RM, Heijboer AC, Blankenstein MA, ter Wee PM. Effects of dietary phosphate and calcium intake on fibroblast growth-factor-23. Clin J Am Soc Nephrol. 2011;6(2):383-9.

Voormolen N, Noordzij M, Grootendorst DC, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant. 2007;22(10):2909-16.

Zoccali C, Ruggenenti P, Perna A, et al. Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition. J Am Soc Nephrol. 2011;22(10):1923-30.

Websites and Reports

Centers for Disease Control and Prevention: National Health and Nutrition Examination Survey

International Food Additives Council: Phosphates

Grocery Manufacturers Association

Kidney Health Initiative

USDA Food Surveys Research Group — Agricultural Research Service

National Research Council. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC. The National Academies Press; 1997.

Sponsors

Phosphorus is an essential nutrient found in many foods. Because of its high reactivity, phosphorus is rarely found as a free element and usually exists as phosphate (PO₄³⁻), in combination with oxygen. Phosphorus has many commercial uses, such as replacing the phosphorus found in the soil in agricultural fertilizers and as a food processing aid and preservative.

In the human body about 85% of phosphorus is found in hydroxyapatite, a calcium phosphate salt that is a major structural component of bone. Phosphates are also found in nucleic acids, in the cellular energy transfer and storage molecule adenosine triphosphate (ATP), in the phospholipids that form most biological membranes, and in several cellular second messengers, such as cyclic AMP and inositol triphosphate.

Dietary phosphorus is obtained from organic phosphorus compounds found naturally in foods and from inorganic phosphate food additives. Organic molecules must be hydrolyzed enzymatically to be absorbed, so phosphorus in this form is less bioavailable—approximately 40% to 60% is absorbed—than inorganic phosphate, which is almost 100% bioavailable. Plant-derived phosphorus, especially in beans, seeds, and nuts, is found mainly in the form of phytate, which is less bioavailable than animal-derived phosphorus.

The average adult consumes approximately 1400 mg of phosphorus per day, approximately 60% of which is absorbed by the small intestine. A healthy adult's serum phosphate concentration ranges from 2.5–4.5 mg/dL and is controlled by a balance between intestinal absorption, skeletal storage, urinary excretion, and kidney reabsorption.

Phosphorus homeostasis in the body. (Image courtesy of Jaime Uribarri)

At the molecular level, phosphorus homeostasis is primarily regulated by parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). PTH downregulates the expression of sodium-phosphate co-transporters NPT2a and NPT2c—which transport phosphorus back to the bloodstream from the kidneys—to increase urinary phosphate excretion. It also stimulates production of biologically active vitamin D to enhance intestinal phosphate absorption through NPT2b, to inhibit PTH production, and to stimulate FGF23 production. Like PTH, FGF23 reduces the expression of sodium-phosphate co-transporters in the kidney, but unlike PTH, it inhibits the production of biologically active vitamin D.

Hormonal regulation of phosphate homeostasis by parathyroid hormone, vitamin D, and FGF23. (Image courtesy of Harald W. Jüppner)

Abnormally high serum phosphate is linked to cardiovascular disease in patients with chronic kidney disease, whose malfunctioning kidneys retain many substances that are normally excreted, including phosphorus. The increasing prevalence of phosphorus in the diet results from its addition to processed foods. It is, however, unclear whether high dietary phosphorus intake or elevated serum phosphorus levels have health implications for the general population. The conference reviewed the health risks associated with excessive phosphorus intake, the mechanisms that regulate serum phosphate, and the implications of recent findings for future research and nutrition policy.

Speakers:
Jaime Uribarri, The Mount Sinai School of Medicine
Mona S. Calvo, U.S. Food and Drug Administration
Lucina E. Lampila, Louisiana State University

Highlights

• Epidemiological studies link high serum phosphate to cardiovascular disease in patients with chronic kidney disease and in the general population.
• Many Americans consume phosphorus in excess of daily nutritional requirements.
• Inorganic phosphates are frequently added to processed foods to improve texture, taste, color, water retention, shelf life, and other properties.

Concerns about dietary phosphorus

Jaime Uribarri from Mount Sinai School of Medicine opened the meeting by surveying the health concerns surrounding dietary phosphorus. According to Uribarri, these concerns stem from studies of chronic kidney disease, in which hyperphosphatemia—abnormally high serum phosphate—develops as kidney function declines. Phosphate retention results in secondary hyperparathyroidism—parathyroid gland enlargement and PTH overproduction—which leads to decreased bone density and bone disease. High serum phosphate is also associated with increased mortality in dialysis-dependent patients, as well as in individuals with less severe chronic kidney disease. Surprisingly, mortality is not primarily caused by bone disease, but by cardiovascular disease. Epidemiological studies link increased serum phosphate to cardiovascular disease in the general population, even within the normal range for serum phosphate. Uribarri called for research to explore the potential toxicity of phosphorus additives in light of their increased use in processed foods.

Dietary guidelines and current intake levels

Dietary Recommended Intakes for phosphorus (mg/day). (Image courtesy of Mona S. Calvo)

 

Mona S. Calvo, a nutrition scientist, discussed the guidelines for dietary phosphorus intake established by the Institute of Medicine of the U.S. National Academy of Sciences. These Dietary Reference Intakes (DRI) include the Estimated Average Requirement (EAR), expected to meet the needs of half of a given age group; the Recommended Dietary Allowance (RDA), mathematically derived from EAR and expected to meet the needs of 97.5% of each age group; and the Tolerable Upper Intake Level (UL), the maximum daily intake considered safe. The FDA developed the Daily Value (DV) for the Nutrition Facts labels on processed foods to help consumers determine the nutritional composition of foods. However, because manufacturers are not required to include phosphorus content on these labels, in many cases the only way to find out whether a product has added phosphorus is to read the list of ingredients, Calvo explained.

Calvo outlined evidence that dietary phosphorus intake is increasing in the U.S., warranting research into its effects. Although consumption of processed foods containing phosphorus additives has increased in recent decades, adults' average phosphorus intake, estimated from nationally representative surveys, has seemingly not increased significantly in the past 10 years. Nonetheless, at least half of the U.S. population in all age groups except adolescents consume phosphorus in excess of EAR; and evidence suggests that the current methods of estimating intake using computer programs can underestimate the phosphorus content of foods, and thus dietary intake, by 30% or more. Therefore, phosphorus intake by some individuals may be close to the upper safe intake level of 4000 mg/day.

Phosphorus in food processing

Lucina E. Lampila from Louisiana State University described the functions of inorganic phosphates in food processing. These phosphates are used in processed foods such as leavened baked goods, meat, seafood, dairy, and beverages as chemical leavening agents, preservatives, cryoprotectants, emulsifying agents, acidifying agents, and buffers that improve properties like texture, taste, color, water retention, and shelf life. Phosphates are also used as processing aids for procedures that that do not increase the phosphates content of the final product, such as mechanical shrimp peeling and to prevent discoloration in processed potato products, such as French fries.

Phosphorus additives in foods. (Image courtesy of Katherine L. Tucker)

Speakers:
Eduardo Slatopolsky, Washington University in St. Louis
Harald W. Jüppner, Massachusetts General Hospital

Highlights

• Dietary phosphorus acutely regulates parathyroid hormone levels in experimental kidney disease animal models.
• Strategies to increase urinary phosphate excretion and lower serum phosphate could include modulating the synthesis, secretion, or degradation of FGF23.

Chronic kidney disease and secondary hyperparathyroidism

Eduardo Slatopolsky of Washington University in St. Louis presented his work on secondary hyperparathyroidism—overproduction of PTH—which frequently occurs in patients with chronic kidney disease and causes bone disease. His research provided early clues that phosphorus contributes to the pathogenesis of secondary hyperparathyroidism. His initial studies showed that dogs with experimentally induced kidney disease exhibited a sharp increase in PTH when fed a high-phosphorus diet. He later demonstrated that secondary hyperparathyroidism could be prevented in these animals by reducing phosphorus intake in direct proportion to the degree of decline in kidney function. Finally, he found that treating normal rat parathyroid glands with phosphorus in vitro increased PTH levels, providing evidence that phosphorus has a direct effect on PTH secretion.

Secondary hyperparathyroidism in chronic kidney disease. (Image courtesy of Eduardo Slatopolsky)

Subsequent studies in rats with experimentally induced kidney disease revealed that a high-phosphorus diet enlarged the parathyroid gland by modulating the expression of proteins that control cell division and growth. After just hours on a low-phosphorus diet, the rats' serum PTH dropped rapidly—lack of serum phosphate suppressed the release of PTH from the parathyroid gland—and returned to normal within a week. Injecting a low-phosphorus diet directly into the small intestines decreased PTH within 15 minutes, demonstrating that dietary phosphate acutely regulates PTH levels. Evidence suggests that this effect may be mediated by a phosphorus sensor and an intestine-derived hormone, although these have not been identified.

Rats with experimentally induced kidney disease fed a high phosphorus diet for 3 months developed aortal calcium deposits, while healthy animals on the same diet did not. When the diseased rats were returned to a low-phosphorus diet, phosphate, PTH, and FGF23 returned to normal; kidney function improved; aortal calcium deposits decreased; and lifespan increased compared with rats with kidney failure on a high-phosphorus diet. Slatopolsky would like to follow up this work by investigating whether phosphorus restriction reduces mortality in humans with kidney disease.

Approaches to control excessive phosphorus intake

Regulators of serum phosphate homeostasis—FGF23, PTH, and NPT2 phosphate transporters—are potential targets for drug therapy. Methods to lower circulating phosphate could include modifying the synthesis or secretion of FGF23, reducing the expression of phosphate transporters in the kidney and intestinal tract, enhancing FGF23 stability, increasing PTH levels, and targeting events downstream of the PTH receptor. Harald W. Jüppner from Massachusetts General Hospital reviewed the pathways that regulate phosphate balance and described insights from rare inherited disorders involving defects in FGF23, PTH, and NPT2.

FGF23 increases in the early stages of kidney malfunction in chronic kidney disease, and elevated FGF23 is associated with progression to end-stage kidney disease, suggesting that FGF23 may predict kidney disease progression. In dialysis patients with end-stage kidney disease, Jüppner has found that FGF23 serum levels can be 100- to 10 000-fold higher than normal, possibly leading to enlargement of the left ventricle of the heart and increased vascular calcium deposits.

Because FGF23 increases urinary phosphate excretion, strategies that prevent FGF23 degradation could help to regulate serum phosphate. FGF23 is normally degraded into biologically inactive N- and C-terminal fragments by a furin-like proprotein convertase, which acts at a specific site known as the RXXR motif. Studies in patients with autosomal dominant hypophosphatemic rickets (ADHR) have revealed that mutations in this motif render FGF23 insensitive to proteolytic cleavage, resulting in increased FGF23 and low serum phosphate. Furthermore, mice with ADHR mutations in FGF23 exhibit normal serum calcium and phosphate until they are placed on an iron-deficient diet, which induces FGF23 expression; because these animals cannot degrade FGF23 protein, it accumulates and leads to a decrease in serum phosphate. Wild-type mice placed on an iron-deficient diet also exhibit increased FGF23 gene expression, but they do not develop low phosphate because they are able to degrade FGF23 protein normally. Thus, FGF23 degradation may maintain normal levels of biologically active FGF23 in the circulation when FGF23 expression is induced by iron deficiency in wild-type mice. Molecules involved in iron homeostasis could be potential targets for increasing urinary phosphate excretion.

Regulation of FGF23 expression in iron-deficient mice. (Image courtesy of Harald W. Jüppner)

Proteins that inhibit FGF23 production, including DMP1, PHEX, ENPP1, Fam20c, and ABCC6, are potential drug targets. Inactivating mutations in any of these proteins increases FGF23 production and urinary phosphate excretion and decreases serum phosphate levels. Studies indicate that a cleaved version of Klotho protein, a co-receptor for FGF23, also stimulates FGF23 expression.

Phosphate levels can also be lowered independently of FGF23. Hereditary inactivating mutations in NPT2a and NPT2c, the phosphate transporters expressed in the kidneys, enhance urinary phosphate excretion and lead to low serum phosphate levels. However, individuals with inactivating NPT2 mutations have increased vitamin D production, causing increased urinary calcium excretion, kidney stones, and kidney dysfunction. Therefore, Jüppner concluded that the NPT2s probably do not represent good targets for promoting urinary phosphate excretion.

Speakers:
Mona S. Calvo, U.S. Food and Drug Administration
Jaime Uribarri, The Mount Sinai School of Medicine
Joachim H. Ix, University of California, San Diego
John J. B. Anderson, University of North Carolina at Chapel Hill

Highlights

• Excess dietary phosphorus may pose a risk to bone health, but confounding variables make this risk difficult to assess.
• Limiting dietary phosphorus intake reduces serum phosphorus in dialysis patients; it is unclear whether this effect would be seen in the general population.
• Excess dietary phosphorus may have adverse outcomes such as lung cancer, obesity, and high blood pressure.

Phosphorus, calcium, and bone health

Mona S. Calvo returned to the podium to address the effect of excess dietary phosphorus on bone health. This is difficult to assess, Calvo said, because of three confounding variables: the calcium-to-phosphorus mass ratio of the diet, the circadian variation in serum phopshorus, and the bioavailability of dietary phosphorus.

A high-phosphorus diet has been known to be detrimental to bone health since the 1960s. The importance of the calcium-to-phosphorus ratio in the diet emerged in early studies with animal models. In rats, a calcium-to-phosphorus intake ratio of 0.5 or lower is detrimental to bone mass and strength. A study of Finnish women found that those with a ratio of 0.56 or lower had significantly higher levels of PTH than women with higher ratios (persistently elevated PTH levels can reduce bone mass and increase the risk of osteoporosis). Furthermore, among U.S. women who consumed cola—a beverage containing high levels of phosphoric acid—those who consumed more than three 12-ounce servings daily had a lower bone density than those who consumed less than one serving. According to a 2013 analysis, approximately 25% of American adults have a calcium-to-phosphorus intake ratio of 0.6 or lower.

These studies demonstrate an association between phosphorus intake and bone health, but do not show causation. Therefore, studies need to directly compare a high-phosphorus diet with an adequate-phosphorus diet to determine its effects on bone. Serum phosphorus levels and changes in hormones that regulate phosphorus and bone accretion would serve as biomarkers for its effects on bone.The problem, Calvo explained, is that serum phosphate levels exhibit pronounced circadian variation, peaking in the afternoon and early morning hours, so it is difficult to establish an association between dietary phosphorus intake and serum phosphate concentrations. Serum PTH also displays circadian variation. Therefore blood samples taken throughout the day would be needed to determine how dietary phosphorus intake affects serum phosphate and PTH.

Circadian variations in serum phosphate and PTH. (Image courtesy of Mona S. Calvo)

In a comparison of meat-based and vegetarian diets—with phosphorus primarily obtained from animal proteins or grains and other plants, respectively—individuals consuming a meat-based diet had higher serum phosphate, reflecting the greater bioavailability of phosphorus in this form, as well as higher FGF23 levels and higher urinary excretion of phosphate.

To assess whether excess dietary phosphorus negatively affects bone health, Calvo recommended that future studies establish a significant association between excess phosphorus intake, elevated serum phosphate, and adverse changes in bone-regulating hormones and other bone-health markers. Researchers should use a cross-over design to assess chronic changes in dietary intake; account for circadian variation in circulating bone markers, hormones, and minerals; use commercially available foods, confirming the mineral contents by direct analyses; and examine varied dietary patterns with a range of calcium-to-phosphorus ratios.

Kidney function

Relationship between chronic kidney disease and bone and mineral metabolism. (Image courtesy of Jaime Uribarri)

In his earlier talk, Jaime Uribarri of Mount Sinai School of Medicine identified the association between elevated phosphorus and adverse outcomes in kidney disease as the basis for health concerns surrounding phosphorus intake. Chronic kidney disease is linked with bone disease and cardiovascular disease; both conditions may result from elevated serum phosphate as kidney function declines. Elevated phosphate is associated with left ventricular enlargement, an indirect marker of cardiovascular disease; an increased rate of cardiovascular events; and increased vascular calcification from bone disease, which also compounds the risk of death due to cardiovascular disease.

Serum phosphate is also linked with the development and progression of kidney dysfunction itself. A prospective study of the general population found that serum phosphate levels at the high end of the normal range approximately doubled the risk of chronic kidney disease or end-stage renal disease. Similarly, in patients with chronic kidney disease, higher serum phosphate is associated with a progression to end-stage renal disease. These associations have been demonstrated in several studies and patient populations.

To lower serum phosphate, dialysis patients are advised to limit their intake of phosphorus-rich foods and are often prescribed oral phosphorus binders—chewing gums that reduce phosphorus absorption. A randomized controlled trial with end-stage renal disease patients found that reducing dietary phosphorus for 3 months significantly decreased serum phosphate; another study found similar results in dialysis patients using oral phosphorus binders, suggesting that dietary phosphorus intake regulates serum phosphate in patients with kidney disease. Uribarri recommended that prospective randomized interventional trials should examine whether modifying phosphorus intake translates into different health outcomes in kidney disease.

Cardiovascular disease

Joachim H. Ix of the University of California, San Diego explored the evidence linking dietary phosphorus intake to serum phosphate concentrations and cardiovascular disease in the general population. Epidemiological studies in the general population support the hypothesis that high serum phosphate increases vascular calcification and stiffness, leading to enlarged left ventricular mass, heart failure, and cardiovascular disease, Ix said. Nonetheless, dietary restriction may not influence serum phosphate levels or cardiovascular disease risk. Although its benefits in dialysis patients are clear, the effects of limiting dietary phosphorus are different in people whose kidneys function normally and can therefore counteract high dietary intake by increasing urinary excretion.

Several studies have found minimal change in serum phosphate in response to dietary restriction in non-dialysis kidney disease patients and in the general population. Furthermore, observational studies suggest that low phosphorus intake may be associated with a higher risk of cardiovascular disease and mortality in these populations. Further studies are needed to determine why some individuals have high serum phosphorus levels and whether non-dietary factors are involved in phosphorus regulation.

Cancer, obesity, and hypertension

John J. B. Anderson of the University of North Carolina at Chapel Hill presented evidence that phosphorus increases the risk of lung cancer, obesity, and high blood pressure. In a mouse model of lung cancer, high dietary phosphorus intake increased expression of the phosphate transporter NPT2b in the lungs, activated the signaling protein Akt, and promoted lung tumor development. Anderson speculated that if phosphorus also stimulates NPT2b expression and increases phosphate ion uptake in adipose tissue, it could increase fat storage. PTH and FGF23 are often elevated in obese individuals because of an increased synthesis and secretion of leptin, a possible explanation for the low levels of vitamin D they often exhibit. High serum phosphate may increase the uptake of phosphate by vascular smooth muscle cells, causing prolonged arterial contractions and elevated blood pressure. It may also promote calcification of the coronary arteries, aorta, heart valves, and other sites, increasing the risk of cardiovascular disease. Anderson said that the brain might be similarly affected, compromising blood distribution in the brain and contributing to depression, Alzheimer's disease, and other central nervous system conditions.

Tissues and organs that may be affected by high phosphorus intake. (Image courtesy of John J. B. Anderson)

Speakers:
Katherine L. Tucker, Northeastern University
Mona S. Calvo, U.S. Food and Drug Administration
 
Panel Moderator:
Mona S. Calvo, U.S. Food and Drug Administration
 
Panelists:
Patrick Archdeacon, U.S. Food and Drug Administration
Robert Burns, Grocery Manufacturers Association
Lucina E. Lampila, Louisiana State University
Alanna J. Moshfegh, U.S. Department of Agriculture
Katherine L. Tucker, Northeastern University

Highlights

• Nutrient databases may underestimate the amount of phosphorus in some foods.
• Dietary Guidelines for Americans, a report issued by the U.S. Department of Agriculture and the Department of Health and Human Services, is designed to promote health and reduce the risk of chronic disease.
• The U.S. Food and Drug Administration recently established the Kidney Health Initiative, which aims to advance the scientific understanding of kidney health and disease.

Data gaps

Katherine L. Tucker of Northeastern University described the nutrient databases that are used to evaluate phosphorus intake. Data from the U.S. National Health and Nutrition Examination Survey (NHANES) suggests that 0.1%–2% of the population consumes phosphorus in excess of the tolerable upper limit. However, this estimate is derived from nutrient databases that may underestimate the amount of phosphorus actually consumed: one study found a higher phosphorus content in chicken products containing phosphorus additives than the predicted content based on nutrient databases. In addition, estimates of dietary phosphorus intake do not account for the fact that phosphorus in food additives tends to be more bioavailable than phosphorus in natural food sources. Tucker called for updated information on the phosphorus content of processed foods, improved labeling, and research studies that consider the varied sources of dietary phosphorus.

Strategies for action

The USDA's Dietary Guidelines for Americans is designed to promote health and reduce the risk of chronic disease and is aimed at policy makers, nutrition educators, and health professionals. Mona S. Calvo suggested that this report would be an appropriate vehicle to disseminate new findings about dietary phosphorus, particularly if high intake is validated by further research as a public health concern. The report is issued and updated every five years by the U.S. Department of Agriculture (USDA) and the Department of Health and Human Services (HHS). The committee responsible for the 2015 report is scheduled to convene a series of public meetings beginning in April 2013 to give stakeholders an opportunity to highlight nutrition concerns. The committee will evaluate evidence and submit a report to the USDA and HHS to be compiled into a policy document and implemented by federal programs.

Calvo suggested requiring that food labels include phosphorus content and express it in milligrams rather than as a percent of DV to mitigate confusion about dietary guidelines for phosphorus. Because there is evidence demonstrating that phosphorus intake near the tolerable upper level of 4000 mg/day may be harmful for the millions of people with chronic kidney disease, Calvo also questioned whether the tolerable upper level should be reevaluated.

Panel discussion

A panel discussion moderated by Calvo focused on the need for further research on dietary phosphorus. Alanna J. Moshfegh of the USDA discussed dietary intake studies and the USDA's Food and Nutrient Database for Dietary Studies. She noted that the USDA recently updated its database on phosphorus content and cautioned that data discussed at the conference were likely based on older nutrient composition analyses that may no longer be relevant to the food supply or to food consumption patterns. Robert Burns of the Grocery Manufacturers Association called for randomized controlled trials to examine how altering phosphorus intake affects the cardiovascular health of healthy individuals and questioned whether studies based on dietary recall accurately reflect phosphorus intake. He said that consequences such as food safety and palatability should be considered in determining whether to lower the phosphorus content of food. Patrick Archdeacon of the FDA briefly described the organization's new Kidney Health Initiative, a public–private partnership with the American Society of Nephrology that works with patient groups, industry, and health care providers to advance our understanding of kidney health and disease. Archdeacon said that the initiative is currently identifying priorities and projects. Lucina E. Lampila of Louisiana State University clarified that added phosphates are not all alike: those with a single phosphate group tend to have high bioavailability, but as the length of the phosphate chain increases, the bioavailability of the molecule decreases dramatically.

Is phosphorus intake in excess of nutritional requirements a concern for public health?

Do the guidelines for phosphorus intake need to be reevaluated?

Does lowering phosphorus intake in dialysis patients improve health outcomes?

What is the relationship between dietary phosphorus intake and serum phosphorus concentration in individuals with functional kidneys?

What enzyme regulates the cleavage of FGF23? Is this enzyme a potential drug target for normalizing serum phosphate levels?

Does excess dietary phosphorus intake increase serum phosphorus concentrations and the risk of cardiovascular disease in the general population?

Does excess dietary phosphorus intake increase the risk of lung cancer, obesity, or high blood pressure?

Are there any non-dietary factors that could help to explain why some individuals have higher serum phosphorus levels than others?