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Histochemistry and Cell Biology https://doi.org/10.1007/s00418-018-1711-8

REVIEW

Dietary phosphate toxicity: an emerging global health concern

Sarah Erem1 · Mohammed S. Razzaque1,2,3,4

Accepted: 17 August 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018

AbstractPhosphate is a common ingredient in many healthy foods but, it is also present in foods containing additives and preserva-tives. When found in foods, phosphate is absorbed in the intestines and filtered from the blood by the kidneys. Generally, any excess is excreted in the urine. In renal pathologies, however, such as chronic kidney disease, a reduced renal ability to excrete phosphate can result in excess accumulation in the body. This accumulation can be a catalyst for widespread damage to the cellular components, bones, and cardiovascular structures. This in turn can reduce mortality. Because of an incomplete understanding of the mechanism for phosphate homeostasis, and the multiple organ systems that can modulate it, treatment strategies designed to minimize phosphate burden are limited. The Recommended Dietary Allowance (RDA) for phosphorous is around 700 mg/day for adults, but the majority of healthy adult individuals consume far more phosphate (almost double) than the RDA. Studies suggest that low-income populations are particularly at risk for dietary phosphate overload because of the higher amounts of phosphate found in inexpensive, processed foods. Education in nutrition, as well as access to inexpensive healthy food options may reduce risks for excess consumption as well as a wide-range of disorders, ranging from cardiovascular diseases to kidney diseases to tumor formation. Pre-clinical and clinical studies suggest that dietary phosphate overload has toxic and prolonged adverse health effects. Improved regulations for reporting of phosphate concentrations on food labels are necessary so that people can make more informed choices about their diets and phosphate consumption. This is especially the case given the lack of treatments available to mitigate the short and long-term effects of dietary phosphate overload-related toxicity. Phosphate toxicity is quickly becoming a global health concern. Without measures in place to reduce dietary phosphate intake, the conditions associated with phosphate toxicity will likely to cause untold damage to the wellbeing of individuals around the world.

Keywords Phosphate toxicity · Klotho · FGF23 · Kidney · Food additive · Chronic kidney disease

Introduction

Dietary phosphate uptake is obtained from commonly consumed food sources usually considered to be parts of a healthy diet. These include foods such as eggs, milk, meat, fish, soy-based products, or nuts. Phosphate can also be gleaned from foods that contain additives and preservatives (Kalantar-Zadeh et al. 2010). At present there is very little consumer knowledge regarding regular phosphate consump-tion. This is partially due to the fact that the food industry is not required to divulge amounts of phosphate on food ingredient labels. An overall lack of awareness, as well as the common practice of adding excessive phosphate to foods, contributes directly to high levels of phosphate consump-tion and the growing prominence of medical issues caused by phosphate toxicity. Many pre-clinical and clinical stud-ies report that high levels of phosphate can have adverse

* Mohammed S. Razzaque mrazzaque@lecom.edu

1 Department of Pathology, Saba University School of Medicine, Saba, Dutch Caribbean, The Netherlands

2 Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Boston, MA, USA

3 Department of Preventive and Community Dentistry, School of Dentistry, University of Rwanda College of Medicine & Health Sciences, Kigali, Rwanda

4 Department of Pathology, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Boulevard, Room: B2-306, Erie, PA 16509, USA

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health effects for both seemingly healthy individuals and patients suffering other health maladies such as heart, bone or kidney disease. Additionally, those affected by illness may be at further risk of perpetuating increases in circulatory phosphate concentration. Excess phosphate in the body can lead to an acceleration of the progression of disease in a positive feedback or cyclical loop of illness. For the gen-eral population, but particularly for those already suffering from disease, dietary phosphate overload is a significant health risk. Improved understanding of the mechanisms of phosphate regulation into the body is needed and innovative therapeutics combined with other dietary strategies must be designed to improve human health and reduce dietary phos-phate overload.

Phosphorous is a natural element found almost exclu-sively in the phosphorous-containing compound phosphate (PO4). Throughout this article, the term phosphate will be used most typically to describe this element. Phosphate compounds are widely used in commercial products such as fertilizers, explosives, nerve toxins, fireworks, pesticides, toothpaste, detergents, and food additives (Kalantar-Zadeh et al. 2010; Uribarri and Calvo 2003). Phosphate is not natu-rally deleterious. In fact, it is necessary for normal cellu-lar function and is generally abundant in the human body. Approximately 85% of phosphate in the human body is in the bones and teeth in the form of calcium phosphate salt called hydroxyapatite (Osuka and Razzaque 2012). Addi-tionally, phospholipids, which are found in cell membranes, contain phosphate. The addition or removal of phosphate from a molecule is known as phosphorylation and de-phos-phorylation. This process involves the chemical storage and release of energy in cells and the regulation of many enzymes, hormones, and second messengers. Phosphoryla-tion is critical to cellular metabolism and energy storage in the form of adenosine triphosphate.

The range considered normal for phosphate circulating in the body is 2.5–4.5 mg/dl (Craver et al. 2007). From the consumed food, the element is primarily absorbed into the blood through the intestines. At the same time, the kidneys largely modulate serum phosphate concentration, removing phosphate from the serum into the fluid filtered in the kid-neys, reabsorbing phosphate so that the serum maintains the optimal phosphate concentration. Excess phosphate is gen-erally excreted through the urine (Razzaque 2009b, 2011a, 2014). Skeletal-derived fibroblast growth factor 23 (FGF23), produced mainly by the bone cells (osteoblasts and osteo-clasts), can also influence the renal reabsorption of filtrated phosphate (Feng et al. 2006). In vivo studies show that by reducing reabsorption, FGF23, can increase renal excretion of phosphate. Aberrant FGF23 production, coupled with the altered expression of molecules such as alpha-Klotho, has been found to influence imbalances in serum phosphate con-centrations. In experimental studies, mice over-producing

FGF23 (FGF23 transgenic mice) excreted excessive uri-nary phosphate, due to reduced renal reabsorption of fil-trated phosphate, leading to hypophosphatemia (DeLuca et al. 2008; Shimada et al. 2004). In contrast, mice unable to produce FGF23 (FGF23 knockout mice), demonstrated hyperphosphatemia, partly derived from increased renal reabsorption of phosphate (Nakatani et al. 2009b; Sitara et al. 2008). This can lead to pathologies commonly encoun-tered in kidney failure, with phosphate toxicity as the major cause (Razzaque 2009a, 2011b). These molecules (FGF23 and alpha-Klotho), along with parathyroid hormone (PTH), vitamin D, and various phosphate transporters in the kidneys and intestines coordinately regulate phosphate homeostasis (Fig. 1). In addition, genetically inducing phosphate tox-icity in experimental animals has shown extensive tissue injuries in vital organs (Fig. 2), significantly compromis-ing their survival (Razzaque 2009c; Ohnishi and Razzaque 2010; Ohnishi et al. 2009a, b, 2011; Nakatani et al. 2009a).

Dietary phosphate overload

Given the abundance of phosphate in animal cells, meat and meat-based foods contain significant amounts of phos-phate. For example, dairy products, fish, and other types of meat are a major source of phosphate in the human diet. Approximately 40 to 60% of the total dietary phosphate is absorbed in the intestines, transported into the blood serum, and circulated through the body to the kidneys. There is some phosphate in plant-derived foods as well but the digest-ibility of phosphate from animal-derived foods is higher by percentage (Kalantar-Zadeh et al. 2010). Inorganic phos-phate additives and preservatives are absorbed even more readily. These additives often have animal-derived delivery systems as meats may be treated with preservatives that con-tain phosphate. This double dose significantly increases total phosphate content for the consumer. Additionally, preserva-tives and additive salts commonly used in processed foods contain large amounts of phosphate (Kalantar-Zadeh et al. 2010; Sherman and Mehta 2009; Uribarri and Calvo 2003). These food and beverage items can include soft drinks, frozen meals, cereals, snack bars, processed cheeses, and refrigerated bakery products (Murphy-Gutekunst 2005, 2007). Because they are additives, these inorganic sources of phosphate are not bound to proteins and are easily absorbed in the intestine. In fact, around 90% of phosphate from con-sumed inorganic sources is absorbed into the body in the intestines (Sullivan et al. 2007; Calvo 2000; Kalantar-Zadeh et al. 2010). While the Institute of Medicine recommends that adults consume 700 mg of phosphorous per day addi-tives like these may increase phosphate intake as much as 1 g per day (Bell et al. 1977).

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Chemical analyses of meat, poultry, and fish processed with phosphate additives found that these processed foods may contain as much as 14.4 mg of phosphate per gram of protein. This is, as compared to those unprocessed foods that did not contain additives. These were found to contain 9.1 mg of phosphate per gram of protein found in the unpro-cessed foods (Sherman and Mehta 2009).

Effects of excessive phosphate on health

While the effects are worse for those suffering illness, pro-longed consumption of foods high in phosphate can be harm-ful for the healthy individuals. A study of 14 healthy women reported that consumption of foods containing phosphate salt additives resulted in increased serum phosphate levels for as long as 10 or 20 h following consumption of the meal (Karp et al. 2013). Increases in phosphate levels, even short-term spikes in serum phosphate can pose long-term risks to the health of the high phosphate consuming, but otherwise healthy individuals (Marks et al. 2013; Takeda et al. 2012).

Additional studies suggest that phosphate overload can cause predisposition to cardiovascular disorders, even in individuals with normal kidney function (Marks et al. 2013; Tonelli et al. 2005; Cancela et al. 2012). For individuals without apparent renal dysfunction, the risk of coronary artery calcification and mortality is increased in patients within the upper limit of normal range of serum phosphate

levels (Adeney et al. 2009; Tonelli et al. 2005; Foley et al. 2009). In an evaluation of 439 participants, vascular cal-cification and early stages of chronic kidney disease were observed even though patients had phosphate serum levels within the levels considered normal or near normal (Adeney et al. 2009). Another study of 872 outpatients reported that when serum phosphate levels are within the normal range, high FGF23 combined with low urinary fractional phosphate excretion is strongly associated with increased mortality and cardiovascular pathologies (Dominguez et al. 2013). From these studies, it is clear that serum phosphate level is not always reflective of total body phosphate content (Osuka and Razzaque 2012). In a similar study involving 3368 partici-pants, those with serum phosphate levels over 3.5 mg/dl had a 55% higher risk for developing the future cardiovascular disease than individuals with lower serum phosphate levels (Dhingra et al. 2007). For symptom-free aging individuals, gradual increases in phosphate levels may adversely influ-ence cardiovascular health. That, in turn increases phosphate burden making it both the cause and consequence of illness for many elderly individuals.

The long-term consequences of increased phosphate con-sumption in healthy humans on bone structure and func-tion need additional research. Some studies report that an overload of dietary phosphate resulting in high serum phos-phate concentrations can reduce serum calcium. This pro-motes precipitation of calcium–phosphate compounds in the

Fig. 1 Simplified diagram of multi-organ interaction of phosphate regulation: calcium, phosphate, active vitamin D [1,25(OH)2D3], lep-tin, secreted Klotho, iron, and metabolic acidosis can induce skeletal synthesis of FGF23 which can exert effects on intestine and kidney to regulate phosphate homeostasis. FGF23 can inhibit vitamin D

metabolism to reduce intestinal phosphate absorption, and suppress renal NaPi activities to increase urinary phosphate excretion. FGF23 fibroblast growth factor 23, PTH parathyroid hormone, NaPi sodium–phosphate cotransporters, 1α(OH)ase 1 alpha hydroxylase, Pi phos-phorus

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vascular tissues and organs, causing frequent and sustained release of PTH. It has been shown that consistently elevated levels of PTH can adversely impact bone structure, mineral content, and function (Kovesdy et al. 2008).

For individuals with kidney failure, or otherwise sig-nificantly reduced kidney function, higher than normal concentrations of phosphate in the blood can induce vari-ous cardiovascular complications. Chronic kidney disease (CKD), a disease that results in progressive loss of kidney function, affects over 20 million Americans (Kovesdy et al. 2006). The results of this illness are a reduced ability of the kidneys to filtrate and reabsorb phosphate with the effect of increased retention of phosphate in the body. Increased

phosphate concentration in the serum is a biochemical indi-cator of later stage CKD, which can lead to cardiovascular morbidity and mortality (Block et al. 1998). Negative effects of high phosphate concentrations are further exacerbated in patients on dialysis, an artificial maneuver to improve kid-ney function (Block et al. 1998). A survey of 224 patients with kidney dysfunction who were undergoing dialysis found that higher dietary phosphate consumption (in com-parison to overall protein consumption) was associated with an increased 5-year death risk (Kalantar-Zadeh et al. 2010; Noori et al. 2010).

CKD patients have two types of risk factors for develop-ing cardiovascular disease (Sarnak 2003). The traditional risk factors for any human to develop cardiovascular disease include hypertension, smoking, diabetes, hypertension, and being of the male sex. Additionally, kidney dysfunction can lead to increased levels of PTH due to hyperphosphatemia. In a database review of studies performed between 1947 and 2012, higher levels of PTH were shown to be associated with increased risk of cardiovascular disease (van Ballegooijen et al. 2013). Therefore, kidney dysfunction that modulates FGF23 and PTH (perhaps secondarily to phosphate dysregu-lation) may independently increase the risk for cardiovascu-lar disease and mortality. In comorbidity with cardiovascular complications, patients with CKD often experience muscle wasting. In fact, an association between hyperphosphatemia and skeletal muscle atrophy is noted in experimental models of phosphate toxicity (Yoshikawa et al. 2018; Zhang et al. 2018) (Fig. 3). Taken together, these findings suggest that excessive phosphate levels can significantly impact systemic bone and cardiovascular health in both healthy individuals and those with pre-existing conditions.

Phosphate overload and mortality

Clinical observation of the harmful effects of phosphate burden on systemic organ function is supported by experi-mental studies. An in vivo study on rats with modulated renal activity induced by uni- or partial nephrectomy and a high phosphate diet resulted in kidney dysfunction and an increase in calcium phosphate deposition in the kidney (Haut et al. 1980). In a separate study, mice that were modi-fied to have inhibited kidney dysfunction via renal abla-tion and then were given a high phosphate-containing diet, experienced extensive arterial calcification (El-Abbadi et al. 2009). These mice also had elevated serum levels of FGF23, which is likely to be a secondary consequence of hyperphos-phatemia (El-Abbadi et al. 2009). Similar calcified lesions in vascular structures are also noted in genetically induced phosphate toxicity models (Razzaque et al. 2005; Razzaque and Lanske 2006; Ohnishi et al. 2009a; Brown et al. 2015; Brown and Razzaque 2015) (Fig. 4). An additional in vivo study suggests that serum phosphate regulates circulating

Fig. 2 Phosphate toxicity can induce renal structural damages: Semi-thin sections of kidneys of mice with normal serum phosphate level (a) and high serum phosphate level (b). Note the comparative glo-merular structures (white arrows) and tubulointerstitial structures (white circular areas) in the kidneys with normal (a) and high (b) serum phosphate levels. Glomerular shrinkage and loss of tubuloint-erstitial uniformity are noted in kidneys exposed to a high phosphate microenvironment for around 6  weeks (b). Phosphate toxicity (b) was induced by genetically manipulating phosphate-regulating genes (Nakatani et al. 2009b). (Toluidine blue staining; Bar 10 μm)

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FGF23, which influences both the kidneys and bone func-tions via PTH (Saito et al. 2005). Nephrectomized rats with inhibited kidney function that were fed a high phosphate diet showed a fivefold increase in serum FGF23 as compared to the controls (Saito et al. 2005). The effects of phosphate in aging were also studied in genetically modified mice. Klotho knockout mice and FGF23 knock out mice were found to develop severe hyperphosphatemia and that compromised survival (Ohnishi and Razzaque 2010). Additionally, by low-ering the phosphate burden, phosphate toxicity-induced pre-mature aging in these mice could be modified. This suggests that phosphate toxicity has a significant role in mammalian aging (Ohnishi and Razzaque 2010). These studies indicate a strong correlation between total body phosphate content, and kidney function, FGF23, PTH and mortality risk factors such

as cardiovascular disease. In addition, hyperphosphatemia, has also been shown to accelerate kidney dysfunction in CKD patients and can intensify the risk of developing dia-betes (Mancini et al. 2017; Schwarz et al. 2006).

When increased phosphate levels gleaned from high rates of processed foods consumption are seen alongside the increased rates of type II diabetes, anecdotal reports sug-gest a relationship. To test this hypothesis, between 1993 and 2011, French women were regularly, evaluated for, among many other parameters, the incidence of type II diabetes and phosphate intake. Of the 71,270 women whose health was monitored, a total of 1845 women developed type II diabe-tes (Mancini et al. 2017). Overall average phosphate con-sumption for these women was 1477 mg/day with a standard

Fig. 3 Phosphate toxicity can induce skeletal muscle atrophy: skeletal muscle sections, prepared from the mice with a normal serum phos-phate level (a) and high serum phosphate level (b). Note the com-parative fiber size (black circular areas) in the skeletal muscle with normal (a) and high (b) serum phosphate levels. In addition to severe atrophy of the muscle fibers, there are focal areas of muscle injury due to the accumulation of calcified materials (yellow arrows) in the skeletal muscle exposed to a high phosphate microenvironment (b). Periodic acid methenamine silver staining; Bar 10 μm)

Fig. 4 Phosphate toxicity can induce renovascular calcification: Renal sections, prepared from the mice with a normal serum phosphate level (a) and high serum phosphate level (b). Note the comparative glomerular structures (black arrows) and tubulointerstitial structures in the kidneys with normal (a) and high (b) serum phosphate levels. The kidney section prepared from a mouse with high serum phos-phate levels showed vascular calcification (blue arrow) (b). Glomer-ular shrinkage and deposition of calcified materials are noted in the tubulointerstitium of the kidney exposed to a high phosphate micro-environment (b). (von Kossa staining; Bar 10 μm)

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deviation of 391 mg/day. This is significantly higher than the 700 mg/day that is the recommended daily intake of phos-phate for adults (Mancini et al. 2017). In the study, women who consumed the most phosphate had the highest rate of incidence of type II diabetes. More studies are necessary to understand the underlying mechanism for dietary phosphate consumption and the resultant development of type II diabe-tes; however, this study strongly suggests that a regular diet high in phosphate results in a high risk for type II diabetes. Most diabetes related public health campaigns focus on diets high in sugar, but the results of the recent studies show that diets high in phosphate should also be put forward as a risk factor.

Some reviews of clinical and pre-clinical studies of phos-phate and cancer suggest that a diet high in phosphate-con-taining foods also increases the risk for cancer or tumorigen-esis. This connection is elaborated in a recently published article, and interested readers are referred to that publication (Brown and Razzaque 2018). In brief, studies show that cel-lular phosphate burden stimulates tumorigenesis, possibly by exerting mitogenic effects on tumor cells; promoting angio-genesis, inducing chromosome instability, and facilitating metastasis (Ward and Griffin 1955; Lin et al. 2015; Chudek et al. 2007; Bobko et al. 2017).

Race and economics of phosphate overload

The effects of dietary phosphate overload on patients with CKD have particular implications for low-income popula-tions. Processed foods tend to be less expensive than fresh foods and they are often high in the phosphate rich additives that are more readily absorbed into the body than organic sources of phosphate. As a result, low-income patients with CKD are more than twice as likely as high-income patients to develop hyperphosphatemia (Marks et al. 2013; Gutierrez et al. 2010). Limited regulation and reporting of phosphate in food create a great deal of CKD risk. This is compounded in low-income communities where access to medical edu-cation is scarce. Because of this, low-income individuals and communities may not be given the opportunity to make many educated choices about their diets, particularly in the consideration of reducing phosphate consumption.

Accordingly, when a cross-sectional analysis of race, socioeconomic status, and serum phosphate was performed among 2879 patients, those either unemployed or in the lowest income brackets recorded higher levels of serum phosphate (Gutierrez et al. 2010). Some studies have sug-gested an association between race and hyperphosphatemia, however, this particular study found no racial association in the low-income group that was most affected by the disease (Gutierrez et al. 2010). Studies have shown that African Americans can experience an increased likelihood for car-diovascular disease and mortality in early stages of CKD.

However, this may be the result of a lack of nutritional edu-cation and medical care among lower socioeconomic groups that are made up of largely minority populations (Gutierrez et al. 2010; Mehrotra et al. 2008; Weiner et al. 2004). Other studies suggest that race may influence biological differ-ences at the subcellular level, including mineral metabolism, which may account for differences in pathologies associ-ated with CKD among various racial groups (Gutierrez et al. 2010; Kao et al. 2008). While there is limited data on any differences in phosphate metabolism across races, these data suggest that African Americans experience increased risk for CKD as a risk factor for cardiovascular disease. Because minority and African Americans populations make up a large percentage of low-income communities in the US, the harmful effects of dietary phosphate overload are magnified in this population. Increased education and access to fresh foods with lower phosphate content is critical to help lower rates of CKD and cardiovascular diseases in low-income communities.

Given the current clinical and pre-clinical data, it appears that income level is a strong indicator of CKD risk and that low-income status is a high-risk factor for kidney dysfunc-tion due to increased dietary phosphate consumption. For all of these data together, it is clear that regardless of race low-income patients may suffer more significant health effects of CKD and cardiovascular disease compounded by diets high in phosphate. Dietary education and access to fresh foods may be critical to improving health among low-income communities. Standards and education on dietary phosphate intake have become a global concern since many developing countries do not have the resources to adequately regulate and review their foods.

Regulation and reporting of phosphate in food

Currently, the food industry and the Food & Drug Admin-istration (FDA) do not require food manufacturers or retail-ers to report per serving phosphate levels on food labels. Even when phosphate-containing additives are reported on labels, long chemical names obscure which additives include phosphate (Marks et al. 2013; Uribarri 2009). The resources available in books and software programs commonly used to calculate phosphate per serving have been shown to under-estimate phosphate amounts contained in foods (Uribarri 2009). In fact, a comparison of the phosphate content of foods derived from chemical analysis revealed that the soft-ware programs underestimated phosphate content of the same foods by an average of 250 mg/day (Kovesdy et al. 2010). In another study, the chemical analysis of different samples of commercially available chicken was compared to the reported value on the food labels (Cancela et al. 2012). In each type of chicken product, the actual phosphate con-centration derived from chemical analysis was much higher

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than the content reported for those food items in nutritional databases (Cancela et al. 2012). With this in mind, enhanced meat and poultry products may contain phosphate additives that increase total consumed phosphate content by two or threefold (Uribarri 2009). Because of this, consumers may unintentionally be consuming a high phosphate diet. This is significant for several reasons, not the least of which is that one major treatment strategy for patients with hypophos-phatemia and CKD is diet regulation. However, dietary phosphate overload may increase future health risk for indi-viduals, even those without kidney disease.

Conclusion

Pre-clinical and clinical studies suggest that the degree and nature of phosphate consumed, either organic or inorganic, influences the body’s absorption rates. This, in turn, influ-ences the body’s natural ability to modulate circulating phosphate concentrations. For individuals with compro-mised kidney function or cancer, overload of phosphate is clearly detrimental (Razzaque 2011b, 2013; Brown and Razzaque 2016; Ohnishi and Razzaque 2010). While there are pharmaceuticals and biomedical devices to filter the blood or mitigate absorption of phosphate from food into the body, these strategies have limited efficacy. A regimen of low phosphate-containing food may thus be appropriate as a recommendation for patients with hyperphosphatemia. However, the FDA does not currently require food labels to report phosphate values per serving, so this strategy for monitoring and reducing phosphate consumption becomes challenging. This issue is further compounded by increased absorption of phosphate from inorganic sources also omitted from food labels, such as the additives contained in pro-cessed, inexpensive foods. Because of their low cost, these foods are disproportionately dietary staples for low-income patients.

Phosphate is an element essential to healthy cell function; however, an overload of phosphate is clearly harmful. To lessen risks of adverse effects, further studies are necessary to investigate the mechanisms behind physiologic absorp-tion and storage of phosphate and the ability of various pathologies to modify this process. In addition, more robust therapeutics must be generated to prevent and treat hyper-phosphatemia. But perhaps most importantly, an educational initiative to raise awareness of the risks posed by dietary items with hidden phosphate ingredients is critical to reduce adverse health effects related to dietary phosphate toxicity (Shutto et al. 2011, 2013). Standards and education on die-tary phosphate intake have now become a global concern. Many developing countries do not have adequate resources to regulate and review foods for phosphate; they depend on the review process and approval of any safety systems set in

place in countries with more resources (Komolprasert and Turowski 2015). This underscores the importance of creat-ing comprehensive protocols to act as a template for the global health standards. These protocols should be enacted immediately to stop phosphate toxicity from becoming a global health crisis.

Acknowledgements Thanks to Rufsa H. Afroze for carefully reading the manuscript and providing useful suggestions. Dr. Razzaque is a Visiting Professor at the Harvard School of Dental Medicine, Boston (USA), and an Honorary Professor at the University of Rwanda College of Medicine & Health Sciences in Kigali (Rwanda).

Compliance with ethical standards

Conflict of interest The authors declare no conflict of interest.

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