ABNORMALITIES OF CALCIUM-

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1 ORIGINAL RESEARCH Extra-Phosphate Load From Food Additives in Commonly Eaten Foods: A Real and Insidious Danger for Renal Patients Omar Benini, DSc,* Claudia D Alessandro, RD, Daniela Gianfaldoni, VS,* and Adamasco Cupisti, MD, PhD Background: Restriction of dietary phosphorus is a major aspect of patient care in those with renal disease. Restriction of dietary phosphorus is necessary to control for phosphate balance during both conservative therapy and dialysis treatment. The extra amount of phosphorus which is consumed as a result of phosphate-containing food additives is a real challenge for patients with renal disease and for dieticians because it represents a hidden phosphate load. The objective of this study was to measure phosphorus content in foods, common protein sources in particular, and comprised both those which included a listing of phosphate additives and those which did not. Methods: Determinations of dry matter, nitrogen, total and soluble phosphate ions were carried out in 60 samples of foods, namely cooked ham, roast breast turkey, and roast breast chicken, of which, 30 were with declared phosphate additives and the other 30 similar items were without additives. Results: Total phosphorus ( mg/100 g vs mg/100 g, P,.001) and soluble phosphorus ( mg/100 g vs mg/100 g, P,.001) content were higher in products containing additives than in foods without additives. No difference was detected between the 2 groups regarding dry matter ( g/ 100 g vs g/100 g) or total nitrogen ( g/100 g vs g/100 g). Consequently, phosphorus intake per gram of protein was much greater in the foods containing phosphorus additives ( mg/g vs mg/g, P,.001). Conclusions: Our results show that those foods which contain phosphate additives have a phosphorus content nearly 70% higher than the samples which did not contain additives. This creates a special concern because this extra amount of phosphorus is almost completely absorbed by the intestinal tract. These hidden phosphates worsen phosphate balance control and increase the need for phosphate binders and related costs. Information and educational programs are essential to make patients with renal disease aware of the existence of foods with phosphate additives. Moreover, these facts highlight the need for national and international authorities to devote more attention to food labels which should clearly report the amount of natural or added phosphorus. Ó 2011 by the National Kidney Foundation, Inc. All rights reserved. This article has an online CPE activity available at *Department of Animal Pathology, Prophylaxis and Food Hygiene, University of Pisa, Pisa, Italy. Division of Nephrology, Department of Internal Medicine, University of Pisa, Pisa, Italy. Address reprint requests to Adamasco Cupisti, MD, PhD, Division of Nephrology, Department of Internal Medicine, University of Pisa, Via Roma 67, Pisa, Italy. acupisti@ med.unipi.it Ó 2011 by the National Kidney Foundation, Inc. All rights reserved /$36.00 doi: /j.jrn ABNORMALITIES OF CALCIUM- PHOSPHATE metabolism are common in patients with renal disease. Hyperphosphatemia, increased calcium-phosphate product, and hyperparathyroidism are associated with cardiovascular diseases and events, especially in dialysis patients. 1 3 A positive phosphate balance plays a crucial role in the pathogenesis of these abnormalities 4 ; therefore, phosphate balance control is a major aspect of patient care in those with Journal of Renal Nutrition, Vol 21, No 4 (July), 2011: pp

2 304 BENINI ET AL renal disease among both those using conservative therapy and dialysis treatment. 5,6 A reduction of dietary phosphorus intake is a very important feature of their nutritional treatment. However, phosphorus restriction is quite difficult to achieve, particularly in the case of hemodialysis patients where a conflict exists with the high dietary protein requirement. 7 Phosphates are natural components of almost all types of foods, and in particular of dietary protein sources, such as dairy products, meat, fish, and poultry, where they are an integral part of the energy delivery molecules (e.g., adenosine triphosphate [ATP], adenosine diphosphate [ADP], and phosphocreatine) for proteins and cell walls. 8,9 It is well known that the phosphate supply of a mixed diet is strictly related to its protein content, that is, phosphorus dietary intake is close to 14 to 16 mg/g of protein. 10 This estimation is related to the content of edible raw food, which does not include the changes which result from food processing. 11 Besides the natural dietary phosphate present in food, phosphates are contained in functional food additives in a wide range of food preparations. This additional amount of phosphorus is not reported in the tables of food composition, so it does not manifest itself in the analysis of dietary recalls or interviews, or in the compositions of prescribed dietary schedules. It represents the so-called hidden phosphorus. 12,13 Phosphate-containing additives work by sequestration of metal ions and dissociation of the acto myosin complex, bringing about an increase in water-holding capacity. Another important reason for using phosphates as food additives is their ability to increase meat ph and to slow discoloration by stabilizing vitamin C. 8 Poly- and pyro-phosphates are the most commonly used additives in the meat industry. 14 They are used for reducing cooking losses, retarding the oxidative rancidity, maintaining color, improving protection against microbial growth, and improving textural properties. Identification of the additional amount of phosphorus resulting from phosphate additives is not easy because manufacturers are not required to list the amount of phosphorus added on food labels. It is noteworthy that naturally occurring phosphorus in food is generally not reported either. Moreover, protein-rich foods such as meat contain natural phosphorus compounds (nucleotides, phospholipids, etc.) along with naturally occurring orthophosphates; hence, the direct identification of added phosphates in meat products is difficult. 9 The amount of added phosphate is normally calculated by the difference between the total phosphorus and phosphorus-related protein content. 8 Although different analytical techniques were used for determination of total phosphates in meat products, 14,15 the amount of phosphorus associated with proteins is calculated indirectly from the concentration of nitrogen (Kjeldahl method) and from the expected phosphorus to protein ratio of a specific kind of meat. 8,16 However, a wide variability in phosphorus content exists in raw meats and the content will depend on the anatomical part of the animal from which the meat originated. 16 In addition, phosphorus to protein ratio values are approximated and their use is not appropriate for processed foods, where the addition of ingredients can increase (e.g., eggs, milk) or decrease (e.g., flour, starch) the total phosphorus to protein ratio. 8 In several cases, the real dietary intake of phosphorus is difficult to define, and there is an increasing risk of an overload of phosphorus as a result of modern dietary habits. This is a crucial problem for patients with renal disease because not only phosphatemia, but also dietary phosphorus intake is associated with increased risk of mortality in dialysis patients. 17 The aim of this study was to measure and differentiate total phosphorus contents and soluble phosphate ions (such as additives) in similar food portions of commonly eaten foods which do or do not contain phosphate additives. Materials and Methods Source and Preparation of Samples A total of 20 lots of cooked ham (10 brands with and 10 without listed phosphates), 20 lots of roast breast turkey (10 brands with and 10 without listed phosphates), and 20 lots of roast breast chicken (10 brands with and 10 without listed phosphates) were purchased at a common grocery market. Foods with phosphate additives were recognized by the wording containing polyphosphates or by the initials E338-E341, E on the food label. The samples were minced, homogenized with a plate of 3-mm diameter holes, frozen, and stored at 220 C until it was examined.

3 PHOSPHATE LOAD FROM FOOD ADDITIVES 305 Physical and Chemical Analyses Determinations of dry matter, total nitrogen, total phosphorus, and soluble phosphate ions were carried out in duplicate for each sample. Dry matter was determined according to International Standard Organization 1442:1973. Total nitrogen was determined according to the Association of Analytical Chemists (1995) and crude protein was calculated using the formula total nitrogen Total phosphorus was determined as described previously. 11 Soluble phosphate ions (free phosphorus) were extracted according to Jastrzębska et al. 14 with a slight modification in the procedure. The samples ( g fresh mass) were extracted with 10.0 ml of 1 mm NaOH using an orbital shaker for 60 minutes. The extracts were separated using a centrifuge at 9,000 g for 30 minutes. The supernatant was filtered with a Whatman No. 1 filter paper, and the filtrates were transferred into 50- ml volumetric flasks, and filled up to the mark with bidistilled water. Because the filtration step was rather difficult because of the fact that polyphosphates bind in water, this step was accomplished by using a vacuum system. Five milliliters sample solution was then pipetted in a 125 ml digestion flask and digested at a final temperature of 420 C with 5 ml of 96% sulfuric acid and 5 ml of 35% H 2 O 2, until the mixture was clear. Cool digest was diluted to 100 ml with bidistilled water. A sample of 0.8 ml of previous solution was transferred to a 10-mL volumetric flask and the following was added: 0.4 ml of 1.80% ammonium molibdate solution, 0.4 ml of 2.5% ascorbic acid solution, bidistilled water, and sulfuric acid solution (taking care to ensure that the final acid sulfuric concentration had a range from 0.35 to 0.45 N and that the volume was about 9 ml). The flask was placed in boiling water for 30 minutes to form characteristic molybdenum blue species. The solution was then cooled to room temperature, filled up to the mark with bidistilled water, and the absorbance was measured by spectrophotometry at 650 nm versus blank. Phosphate standard solution was prepared to obtain a calibration curve. 18 Laboratory technicians were blinded to labeled nutritional content of the foods. Statistical Analysis A statistical package, StatView 5 release (SAS Institute Inc, USA), for personal computer was used for processing data. Descriptive statistics are given as mean 6 standard deviation. Statistical analysis was performed by Student s t- test for unpaired data and by one-way analysis of variance. Differences were considered statistically significant when P,.05. Results As a whole, no difference between products with phosphorus-containing additives and regular items was observed regarding dry matter ( g/100 g vs g/100 g) and total nitrogen ( g/100 g vs g/100 g). Meanwhile, as expected, total phosphorus ( mg/100 g vs mg/100 g, P,.001) and soluble phosphate ions ( mg/100 g vs mg/100 g, P,.001) were markedly higher in enhanced food than in nonphosphate listed-items. Consequently, the food containing Table 1. Composition of the Cooked Ham, Roast Breast Turkey and Roast Breast Chicken per 100 g of Edible Part Dry Matter (g/100 g) Total Nitrogen (g/100 g) Total Phosphorus (mg/100 g) Free Phosphorus (mg/100 g) Cooked ham Without additives (n 5 10) With additives (n 5 10) * * * Roast breast turkey Without additives (n 5 10) With additives (n 5 10) * * Roast breast chicken Without additives (n 5 10) With additives (n 5 10) * * * * P,.001 versus items without phosphate-containing additives. P,.05 versus cooked ham and roast breast turkey with phosphate-containing additives.

4 306 BENINI ET AL phosphorus additives supplied a significantly higher amount of phosphorus per gram of protein than items without listed-phosphorus ( mg/g vs mg/g, P,.001). Table 1 shows the percentages of dry matter, protein, total phosphate, and soluble phosphate ions in the 3 groups of food with or without listed-phosphorus. These data show that there are no differences in dry matter content either in cooked ham or roast breast turkey, whereas crude protein content was slightly lower in cooked ham with added polyphosphates. As expected, total phosphorus and soluble phosphate ions were much higher (50% to 80% greater) in items with phosphorus-containing additives; consequently, the phosphorus content expressed as mg per gram of protein was increased greatly as well (Figs. 1 and 2). The content of extra phosphorus was slightly lower in chicken as compared with ham and turkey (Table 1). Discussion The results of this study clearly show that phosphorus-containing food additives significantly increase the phosphorus load from food sources of protein. This extra-phosphorus burden dramatically worsens the phosphate balance and phosphatemia, thus increasing the need for phosphate binder agents and resulting in additional costs. The severity of the issue is compounded by the fact that this extra phosphorus is completely absorbed in the intestinal tract. Food sources of protein which contain phosphate additives provided an average of.100 mg of additional phosphorus per 100 g of protein food source. This led to an increase in the phosphorus to protein ratio; the results were an average of 15.3 mg/g protein in phosphate-supplemented foods as compared with 9.2 mg/g protein for those which did not contain phosphate supplements. These results are well in keeping with data from Sherman and Mehta who reported almost identical results in a similar study in the United States. 19 The first step to counteract the challenge presented by this study is the dissemination of information and increased education. The addition of phosphate content to nutritional food labels would be very useful for renal patients with CKD, especially for those on dialysis, 20 who must be vigilant about the great diffusion and danger of phosphorus-containing food additives. As previously reported, these substances are widely used and the less affluent component of the population, in particular, may be at an increased risk of consuming large amounts of processed food which may contain phosphorus-based additives because these products are cheaper than fresh, unprocessed items. Current food safety policy is designed to protect human health and consumers interests in addition to fostering smooth operations on the European Union (EU) single market. Article 153 of the Treaty of Maastricht on European Union (now article 169 of Consolidated Version of The Treaty on the Functioning of the European Union) says: In order to promote the interests of consumers and to ensure a high level of consumer protection, the Union shall contribute to protecting the health, safety and economic interests of consumers, as well as to promoting their right to information, education and to organise themselves in order to safeguard their interests. Figure 1. Total phosphorus to protein ratio in cooked ham, roast breast turkey or roast breast chicken without (dashed columns) or with (empty columns) phosphate-containing food additives. Figure 2. Free (soluble) phosphorus to protein ratio in cooked ham, roast breast turkey or roast breast chicken without (dashed columns) or with (empty columns) phosphate-containing food additives.

5 PHOSPHATE LOAD FROM FOOD ADDITIVES 307 Table 2. Hypothetical Ranges of Daily Dose Requirement of Phosphate Binders Needed to Neutralize an Extra-Phosphorus Load of 100 to 300 mg/day From Additives; the Related Number of Pills and Their Costs per Month are Calculated Daily Dose mg/day Pills/Month n Cost/Month V Calcium acetate, 667 mg pill 2,000-6, Sevelamer, 800 mg pill 3,030-9, Lanthanum carbonate, 750 mg pill 870-2, We assumed the phosphorus binding capacity of calcium acetate (50 mg/g, that is, 33 mg per 667 mg pill), sevelamer (33 mg/g, that is, 26 mg per 800 mg pill) and lanthanum carbonate (115 mg/g, that is, 86.2 mg per 750 mg pill) as reported in the literature Costs are given as Euros (V) and estimated on the basis of the drug price, calculated per pill, in Italy. The legal framework concerning foodstuff labeling in the EU is designed to guarantee consumer access to complete information on the content and composition of products to protect their health and best interests. It is well known that hyperphosphatemia and high phosphate intake may endanger the health of a specific group of consumers, namely patients with renal disease and those on dialysis; therefore the lack of label disclosure about total phosphorus and phosphorus to protein ratio can make a food unsafe for this category of consumers. In our opinion, authorities should mandate the clear reporting of the amounts of phosphorus and phosphoruscontaining additives on food labels. Although this is very important for patients with renal disease, it may also be important for patients with cardiovascular disease and even for the general population, where a relationship has been reported between serum phosphate levels and cardiovascular disease or mortality Currently, EU has prohibited the use of phosphates in unprocessed food, like raw meats, but they are permitted in other foodstuffs, like cooked meats. The total amount of added phosphates to meat product is limited in the EU to 5,000 mg kg 21 (expressed as P 2 O 5 ) by legal framework concerning food additives (European Parliament and Council Directive No. 95/2/EC). This legal limit is equivalent to an industrial limit because the use of added phosphates at levels approaching 5,000 mg kg 21 may bind important metals ions (calcium and magnesium) 8 and lead to the development of significant slick feel in the mouth and metallic, soapy, or baking soda-like off-flavors. 24 Data from the United States reported that the additional phosphorus intake which stems from phosphate-containing food additives increased from 400 mg/day in the 1990s to 1,000 mg/day in the 2000s. 13 Making matters even more challenging is the aforementioned fact that in Europe, a limited amount of information is provided in a conspicuous manner on food labels. Our data show that the extra amount of phosphorus is roughly more than 100 mg/100 g serving of cooked ham or roast turkey. Considering the very wide presence of added polyphosphates in the food processing industry and trading, even in Europe, we can extrapolate that a patient on hemodialysis easily approaches a daily average of at least 100 to 300 mg extra phosphorus intake by additives. On the basis of the reported data about phosphate-binding capacity, the amount of extra phosphate binders needed and the additional number of pills and costs that would counteract the increased intestinal load of phosphorus can be estimated. This scenario is depicted in Table 2. The increase in number of pills and costs that appears necessary to maintain the same phosphate balance in the presence of even a low estimation of extra-phosphorus intake is noteworthy. This finding also suggests that even a high intake of phosphate binders is ineffective to control phosphatemia in the presence of an uncontrolled phosphorus intake in the form of additives. This could also explain, in part at least, the existence of patients who do not respond to phosphate binder therapy. In conclusion, our results show that cooked ham and roast breast turkey with phosphate additives had a phosphorus content 70% higher than samples containing no additives. The severity of the issue is compounded by the fact that phosphorus is almost completely absorbed by the intestines after ingestion. The hidden phosphates invariably worsen phosphate balance control and increase the need of phosphate binders and related costs; therefore, information and education programs are essential to make patients with renal disease aware of the existence of foods with phosphate additives, and to lobby national and international authorities

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