Nutritional Guideline for the Management of Mexican Patients with CKD and Hyperphosphatemia

Chronic kidney disease (CKD) represents a serious concern for the Mexican population since the main predisposing diseases (diabetes, hypertension, etc.) have a high prevalence in the country. The development of frequent comorbidities during CKD such as anemia, metabolic disorders, and hyperphosphatemia increases the costs, symptoms, and death risks of the patients. Hyperphosphatemia is likely the only CKD comorbidity in which pharmaceutical options are restricted to phosphate binders and where nutritional management seems to play an important role for the improvement of biochemical and clinical parameters. Nutritional interventions aiming to control serum phosphate levels need to be based on food tables, which should be specifically elaborated for the cultural context of each population. Until now, there are no available food charts compiling a high amount of Mexican foods and describing phosphorus content as well as the phosphate to protein ratio for nutritional management of hyperphosphatemia in CKD. In this work, we elaborate a highly complete food chart as a reference for Mexican clinicians and include charts of additives and drug phosphate contents to consider extra sources of inorganic phosphate intake. We aim to provide an easy guideline to contribute to the implementation of more nutritional interventions focusing on this population in the country.


Introduction
In Mexico, chronic non-communicable diseases represent about 70% of all deaths [1] and one of the most urgent priorities for public health policies is chronic kidney disease (CKD). Since there is no centralized national registry of cases of CKD in Mexico, there are no precise reports of cases to date. However, it is well known that diabetes mellitus (DM) is the leading cause of CKD in both developing and developed countries [2]. The National Health and Nutrition Survey [3] reports that, in Mexico, DM was present in 10.3% (8.6 million) of the total population of the country aged 20 and over (82.7 million), representing an 1.1% increase in the last six years and many of those cases are not even aware of their kidney deterioration [1]. In addition, we need to consider other causes of CKD, such as systemic arterial hypertension (15.2 million adults in Mexico), autoimmune diseases, drug-related illnesses, etc., which also show an increasing-rate behavior. CKD is not included as such in the Universal Catalog of Table 1 shows the nutrimental food content with equivalents, which focuses on CKD relevant data: protein, phosphorus, PPR, potassium, and sodium. We also added a column of "level of recommendation," which is divided in three colors: red stands for "not recommended" for foods with a PPR above 16 mg/g, gray stands for "upon specialist criteria" for foods between 10 and 16 mg/g, and green stands for "recommended" for foods below 10 mg/g. The table, which includes 363 foods, is divided into the following groups: fruits, vegetables, type A cereals, type B cereals, legumes, animal source foods, oils and fats, others, and beverages. For most divisions, an additional table of "most consumed foods in Mexico" was included based on previous studies and on Mexican-supermarkets data collection. In the case of some processed foods, an additional column of phosphate-based additives was included. Most of the foods not included in this table had no known reported value of phosphorus content.

Results
Until now, no strict threshold for PPR is accepted. Recommendations vary between 10 and 16 mg/g depending on each practitioner and author [10,15,16], which is why we categorized all foods with a PPR inside this range as possible to be consumed but only if recommended by a specialist. We believe that flexibility between 10 and 16 mg/g of PPR allows the nutritionist to widen the variety of foods without major risks of lowering protein and increasing phosphate intake. Since PPR aims to keep a protein-phosphate balance for the patient, it should be considered for protein-rich foods such as animal-derived products. In the case of fruits, vegetables, and cereals, we must focus on the net phosphate content to avoid misleading values of PPR. In case the food contains no phosphate and no protein, like the oils, then the PPR calculation is not possible. In cases where the food contains phosphorus but no protein, it is also not possible to calculate the ratio, but specialists should take care of phosphate food content in order to calculate daily consumption, which should stay below 700 mg/d [16], depending on the goal.     Level of recommendation: green = recommended, gray = upon specialist criteria, red = not recommended. The nutritional information of each food presented was compiled from refs. [17][18][19][20][21][22]. The nutritional information of processed foods was compiled through their official pages of the respective brands and from some tours to self-service stores such as Bodega Aurrera, Wal-Mart de México, and Tiendas Gran Bodega. Table 2 shows the list of names of 25 phosphate-containing additives and how common they are when used in Mexico. It is very important that the names, as well as their code, are easily accessible for health professionals and patients in order to identify food sources of inorganic phosphates with high bioavailability. Monosodium di-hydrogen phosphate E339ii Disodium mono-hydrogen phosphate E339iii Tri-sodium phosphate E340iii Tri-potassium phosphate E341ii Calcium hydrogen phosphate E341iii Tri-calcium phosphate E442 Ammonium phosphatides E450ii Tri-sodium di-phosphate E450iii Tetra-sodium pyrophosphate E451 Tri-phosphates E451i Penta-sodium tri-phosphate E452 Polyphosphates E452i Sodium polyphosphate E541 Sodium aluminium phosphate E1414 Acetylated di-starch phosphate Next, we present the last table (Table 3) showing the most common medications used in CKD patients in Mexico. Out of 24 drugs, only six drugs (25%) have known phosphate content. In Mexico, according to the NOM-072-SSA1-2012 (Mexican official policy), it is an optional requirement to describe the vehicle content of pharmaceuticals. Administrating medications with unknown phosphate content represent a potential source of inorganic phosphate that contributes to the phosphate load of the patients. Finally, we provide a graphical abstract entitled "The Low Phosphate Plate" (Figure 1). This abstract aims to provide visual guidance in order to remember which food types should be avoided, and emphasize the sources of inorganic phosphorus. The Low Phosphate Plate includes fruits and vegetables as the main food group, highlighting those that should be avoided. The other segments include cereals, animal-derived foods, and legumes. Here, the calculation of PPR becomes crucial in order to maintain a low phosphate intake without diminishing protein intake. The plate also includes oils and fats that are only recommended for consumption in small proportions.

Discussion
Phosphorus is contained in most nutrients, especially protein-rich foods, phytates (in plants), and food additives. A high protein content diet is strongly associated with a high phosphorus intake. Some previous recommendations in CKD suggest avoiding excess protein intake. However, low and very low protein diets may cause malnutrition, especially in patients with CKD, causing proteinenergy wasting (PEW), and increasing risks for hospitalization, low quality life, and mortality [17].
The gastrointestinal absorption rate from plant-derived foods is between 10%-30%. In animal foods, it is up to 40%-60%, whereas phosphorus from inorganic sources found in medicines and additives has the highest absorption, up to 90%-100%, according to Noori et al. [16]. Vitamin D also affects the absorption because it can stimulate the expression of type IIb sodium-dependent phosphate transporters. On the other hand, nicotinamide functions as an inhibitor of intestinal phosphorus absorption [18].
A recently discovered way to reduce the phosphorus intake is to consider the PPR, which relates the phosphorus content per gram of protein. It has several advantages as a dietary management for patients with hyperphosphatemia in CKD, such as: 1. Its independent of the portion size or serving. 2. It focuses simultaneous attention on both proteins and phosphates, which are transcendental for the nutritional treatment of CDK. 3. The ratio allows you to choose from two similar options with different amounts of phosphorus but almost equal amounts of protein [16].
PPR is, therefore, a transcendental value when calculating the daily protein and phosphorus intake for these patients. The nutritionist should take special care of maintaining a proper protein intake including foods with low PPR so that they do not imply a high phosphate load, and also take care of low phosphate vegetables, fruits, and cereals for dishes' preparation. For example, a typical Mexican dish called "Enchiladas" is prepared with chicken, tortilla, and a sauce (tomato and chili).

Discussion
Phosphorus is contained in most nutrients, especially protein-rich foods, phytates (in plants), and food additives. A high protein content diet is strongly associated with a high phosphorus intake. Some previous recommendations in CKD suggest avoiding excess protein intake. However, low and very low protein diets may cause malnutrition, especially in patients with CKD, causing protein-energy wasting (PEW), and increasing risks for hospitalization, low quality life, and mortality [23].
The gastrointestinal absorption rate from plant-derived foods is between 10%-30%. In animal foods, it is up to 40%-60%, whereas phosphorus from inorganic sources found in medicines and additives has the highest absorption, up to 90%-100%, according to Noori et al. [16]. Vitamin D also affects the absorption because it can stimulate the expression of type IIb sodium-dependent phosphate transporters. On the other hand, nicotinamide functions as an inhibitor of intestinal phosphorus absorption [24].
A recently discovered way to reduce the phosphorus intake is to consider the PPR, which relates the phosphorus content per gram of protein. It has several advantages as a dietary management for patients with hyperphosphatemia in CKD, such as: 1.
Its independent of the portion size or serving.

2.
It focuses simultaneous attention on both proteins and phosphates, which are transcendental for the nutritional treatment of CDK.

3.
The ratio allows you to choose from two similar options with different amounts of phosphorus but almost equal amounts of protein [16].
PPR is, therefore, a transcendental value when calculating the daily protein and phosphorus intake for these patients. The nutritionist should take special care of maintaining a proper protein intake including foods with low PPR so that they do not imply a high phosphate load, and also take care of low phosphate vegetables, fruits, and cereals for dishes' preparation. For example, a typical Mexican dish called "Enchiladas" is prepared with chicken, tortilla, and a sauce (tomato and chili). For patients with hyperphosphatemia, the recommendation would be to use two wheat flour tortillas that have no phosphate content (instead of three corn tortillas typically used for the dish containing 282 mg of phosphorus), to use "poblano pepper" for the sauce, which contains only 9.5 mg of per portion, to use only one red tomato (12.4 mg of phosphorus), and, finally, to use 25 g of boiled breast chicken that has a PPR of 5.6 mg/g (without reusing the boiled water rich in phosphates). This version of the dish would provide 13.3 g of protein, 62 mg of phosphorus, and 527.4 mg of potassium for a final PPR of the dish of 4.6 mg/g, which is completely acceptable for the patient and preserves the cultural gastronomy.
Some studies suggest that plant-based diets can be effective to reduce the phosphorus concentration levels. However, increased phytate intake may cause deficiencies of some minerals such as iron, zinc, and calcium. Mexican gastronomy culture is not known for being well balanced, and the high overweight and obesity rates are a good reflection of it. Depending on the social status, nutrition can either include dishes predominantly from vegetable origin or with an excess of animal origin foods. A transition to achieve better nutrimental habits represents an enormous challenge, and specialized regional guidelines are the first steps toward the goal [25].
In many countries, including Mexico, food companies do not have an obligation to indicate the amount of phosphorus contained in their products nor the additives. Until new policies for nutritional labeling are established, all processed foods should be considered an important source of inorganic phosphate, unless otherwise specified.
Previous publications from Spain, Colombia, and Argentina [10][11][12] have shown the importance of compiling regional food charts for PPR calculations in order to improve nutritional management for patients with hyperphosphatemia. Those studies and the following to come from other countries represent a call from nutritional scientists to federal policies to take action toward better reports and regulations on phosphorus food content. Regarding the publications on the Mexican population, we have already mentioned the works by Osuna and Puchulu [13,14] that provide useful information for nutritional management of hyperphosphatemia in CKD. Compared to those publications, our work offers new content. We have expanded the chart to all food groups, and, although PPR is mainly useful for animal-derived foods, knowledge about phosphorus content in fruits, vegetables, and cereals is relevant for the calculations of dietary phosphorus intake below 700 mg/d. In addition, we offer a format with equivalents, which is the most used method for dietary management. Therefore, this version facilitates the use of the guide. We also provide a level of recommendation that offers a visual guidance of the best foods that can be included during the nutritional management. We provide the name and code of the most used additives with phosphates in the country so that specialists and patients can be aware of inorganic phosphate sources in the products of their choice. We also present a list of the most used medications in CKD patients, which show the lack of information regarding phosphate content in most of them, leaving the warning that the medications not reporting levels of phosphates should be taken as potential phosphorus sources. This is the first work to compile nutrimental and pharmaceutical information in such a complete way for the Mexican population. Finally, we provide an improved visual guide called the "low phosphate plate" (Figure 1), which depicts the dietary recommendations in a better way. Some previous works have shown "low phosphate pyramids" [11,14]. However, it has been nationally accepted that the pyramid designs do not clearly represent a nutritional recommendation since it depicts the least recommended foods at the top, while, for Mexicans, the top of a pyramid represents the most valuable place, which can lead to misunderstandings. Therefore, Mexico now uses the "plato del bien comer" (good eating plate) and, according to that same philosophy, we believe our "low phosphate plate" is a better representation of the dietary recommendations.
Nutritional education is an important aspect of clinical management to improve the patient's lifestyle and, thereby, prevent the CKD-related complications. Martins et al. demonstrated that, after a four-month educational program based on the trans-theoretical model of behavioral change, serum phosphate levels decreased significantly, showing better results when combined with phosphate binders. The intervention consisted of lectures about nutrition presenting illustrative flip charts about food, phosphate binders, and the digestive system [26]. Other authors have also reported significant effects on serum phosphate levels after nutritional educational interventions [27].
There are, until now, no reported studies in Mexico analyzing the impact of nutritional interventions on biochemical and clinical parameters of patients with hyperphosphatemia and CKD. This may be partly due to the lack of bibliography and sources that summarize the current knowledge of food phosphate contents. Another important role of guidelines that systematize food phosphate content is to make evident the fact that this mineral is not regularly reported and represents a potential harm to all patients in the early stages of the disease. This represents increasing costs if hyperphosphatemia is developed. Regarding the benefits that this guide could provide to increase and improve nutritional interventions for serum phosphate control in CKD, we consider the following: - To provide a complete food chart considering highly consumed products in Mexico of all food groups with an equivalent format and visual classification of the recommendation level of each food. - To stress the necessity of new labeling policies in foods that could help complete the present food table and improve dietetic management of patients, - To highlight the importance of phosphorus hidden in additives and medications often used in CKD, which contribute to the phosphorus load of the patients, and - To use the image of our "Low Phosphate Plate" to spread the nutritional recommendations among our targeted patients throughout the country.
We are convinced that, with the use of this guide, the production of good quality pedagogic material for nutritional interventions will be easier and applicable either in individual private practice or in cohorts of patients in public clinics and hospitals. By using this guideline together with the previously cited Mexican works and proper pharmaceutical management, the control of phosphate serum can be enforced in the entire country with beneficial outcomes for the patients who already have hyperphosphatemia and as preventive measures for patients in the early stages of CKD.