Perspective: Plant-based Whole-Grain Foods for Chronic Kidney Disease: The Phytate-Phosphorus Conundrum

ABSTRACT

Restriction of dietary phosphorus intake is an important component of good clinical practice in kidney failure patients, particularly after dialysis initiation. Greater consumption of predominantly plant-based diets, including phytate-rich foods, is increasingly recommended for health maintenance/disease prevention in this population, with the implicit assumption that phytate-phosphorus in whole-grain cereals, legumes, pulses, and nuts is poorly absorbed. Review of human interventions with diets high in phytate-phosphorus indeed suggests an absorption of at least 50%, still less than animal protein–bound phosphorus, but higher than the generally believed 10–30%. Factors largely ignored up to now, but of potential influence on phytate-phosphorus bioavailability, include effect of food processing in releasing phosphorus, action of colonic bacteria that are able to release inorganic phosphorus, and capacity of the colon to absorb phosphorus. These issues may become increasingly important as new plant-based alternatives to meats, all containing phytate, are being rapidly introduced in the market.

Statement of Significance: In our Perspective, we take the position that, in dietary phosphate restriction, kidney failure patients cannot assume that all phytate phosphorus in healthy grain cereals, legumes, pulses, and nuts is poorly absorbed when estimating dietary phosphate intake as current guidelines may lead them to believe. Our Perspective reveals possible safety issues that could impact chronic kidney disease (CKD) patients transitioning from low-level animal-protein dietary sources to greater intakes of plant-based protein foods with their efforts to limit phosphorus intake in the management of their CKD.

Introduction

Restriction of dietary phosphorus intake continues to be an important clinical practice for the nutritional treatment of hyperphosphatemia in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) (1). The 2020 updated Kidney Disease Outcomes Quality Initiative (KDOQI) clinical guidelines for nutrition in CKD recommend adjusting dietary phosphorus intake to maintain serum phosphorus in the normal range, a difficult guideline to follow since people eat food, not an isolated nutrient whose food content listing is absent from most nutrition labels (2). Consistent with the 2020–2025 Dietary Guidelines for Americans, renal dietetic practice is moving away from the previous emphasis on phosphorus intake to practical food-based advice and encouraged adherence to a healthy dietary pattern (3–8). Greater consumption of predominantly plant-based diets is increasingly recommended for health maintenance and disease prevention in both the general population, as well as in those with failing kidney function (3, 9–12). This shift in dietary guidance calls for higher intakes of fruits and vegetables, including whole-grain cereal products, legumes, peas, pulses, and nuts, that comprise the term “whole-grain foods.” In the past, kidney patients were advised to avoid or limit whole-grain foods due to their high phosphorus content (8, 13, 14). These changes in dietary guidance and practice raise possible nutritional concerns for CKD/ESKD patients that relate to the increased consumption of phytate [myo-inositol hexa-phosphate (IP-6)], a natural component of whole cereal grains, legumes, peas, pulses, nuts, and seeds that serves as the plant storage form of phosphorus (15). Whole grains are key foods promoted for their association with multiple health benefits for all Americans (16–19).

Phytate-rich whole-grain foods can contribute a large fraction to dietary phosphorus intake when the phosphorus is liberated from phytate. In its unprocessed raw state, plant phytate is not significantly degraded in the stomach and small intestine since humans and domestic animals do not secrete the enzyme phytase, which is necessary to degrade dietary phytate and release phosphorus for absorption (20). Although the extent of phosphorus release from various phytate-rich foods is unclear, the general understanding among nephrologists is that phosphorus bound to phytate is not efficiently absorbed by humans in the absence of phytase; however, phytase intrinsic in food, such as that contained in flour or bran or activated during leavening (fermenting) as with sourdough bread, can degrade phytate in the food or during digestion, as illustrated in Figure 1. Whole-grain foods containing intact or poorly degraded phytate are thought to have reduced phosphorus absorption efficiency, potentially benefiting CKD/ESKD patients. Reduced phosphorus absorption and the significant association with other health benefits are the basis for reconsidering the previous limitation of these foods in the management of CKD (8, 12, 14). For the health of the general population there may be a downside to consider, since phosphate-intact phytate (IP-6), covalently binds essential cations (Zn, Fe, Mg, and Ca), which is further illustrated in Figure 1. This can increase fecal loss of these nutrients, contributing to the development of mineral deficiencies, notably when these minerals are limited in the diet (21, 22). The aim of this Perspective is to re-evaluate our understanding of the gastrointestinal bioavailability of phosphorus contained in phytate in the context of the anticipated higher intake of phytate-rich foods promoted by the new guidelines. The recent publication of the FAO/International Network of Food Data Systems/International Zinc Nutrition Consultive Group (FAO/INFOODS/IZINCG) global food-composition database for phytate provides the first comprehensive database on phytate content of foods and processing methods that impact their phytate content (23). Although limited in many aspects, this database enables a closer look into how the push for greater whole-grain consumption in the United States and worldwide (16) may impact mineral absorption, particularly that of phosphorus. Here, we discuss new findings and gaps in knowledge that may help resolve the phytate-phosphorus conundrum important to the dietary management of kidney disease.

FIGURE 1.

Schematic of plant phytate degradation in the presence of plant phytase during digestion or prior to ingestion during extrusion or fermentation processing. GIT, gastrointestinal tract.

Importance of Phosphorus in Foods to Kidney Health

The kidneys play a major role in regulating phosphorus homeostasis, and as kidney disease progresses, a sustained dietary intake of phosphorus will lead to a tendency for phosphorus retention and secondary compensations such as high parathyroid hormone (PTH) and high fibroblast growth factor 23 (FGF23) (24). All these abnormalities will become more pronounced as CKD progresses, so by the time patients reach ESKD and are on maintenance dialysis the great majority of them have elevated concentrations of serum phosphorus, PTH, and FGF23. This altered mineral metabolism has been associated with substantial health problems in this population—most importantly, bone and cardiovascular disease (CVD) and even progression of kidney disease itself. A role of dietary phosphorus intake that far exceeds nutritional requirements has also been reported in the general population for CVD risks, kidney stone incidence and recurrence, diabetes, cancer, and bone loss (25–28). There are several potential mechanisms for phosphorus toxicity, including increasing vascular and extraskeletal tissue calcification (29), increasing release of FGF23, which, in turn, affects cardiovascular tissues (30), and increasing release of PTH affecting bone loss (31). The importance of adequate control of serum phosphorus is particularly important in patients with ESKD maintained on dialysis. Current dialytic therapies combined with the use of oral phosphorus binders are usually not enough to maintain a normal serum phosphorus in this population and adequate attention to the diet becomes particularly important (32). Within this background, it is very important to be able to determine phosphorus bioavailability from different sources (1, 2).

Food Sources Contributing to Total Dietary Phosphorus and Phytate Intake

It is evident from Figure 2A that phosphorus intake for men and women (>19 y) participating in the most recent NHANES (2015–2018) far exceeds their Estimated Average Requirement (EAR) of 580 mg/d for >75% of the US population and also exceeds the RDA of 700 mg/d designed to meet the needs of 97% of the US population (33). This is attributed to the natural presence of phosphorus in most foods, as well as the widespread use of phosphorus-containing food additives in processing (Figure 2B). The food additive contribution to food phosphorus intake is not always accounted for in the nutrient content databases, attributed to frequent formula changes in food additive use. Because phosphate additive use is needed for many different functions in food processing, the intake of phosphorus is thought to be even higher for people consuming highly processed foods, as high as 25–30% of intake (34).

FIGURE 2.

4 panels illustrate different aspects of phosphorus intake in the United States. Panel A shows the percentile of mean usual phosphorus intake (mg/d) of men and women estimated from two 2-y cycles of the NHANES surveys conducted from 2015 to 2018. Percentile intakes are shown relative to the EAR and RDA for phosphorus intake in adults >19 y. Only 5% of the US adult population consumes phosphorus at or slightly above the requirement, while 50% consume twice the estimated requirement or even higher from food and beverages. The graph was drawn from intake data reported in reference (33). The panel B table presents examples of plant-based food categories with the number of foods that contained specific phosphate food additives. The numbers in red highlight high use of phosphate additives in packaged processed plant-based foods. The data source is from the author's food label research. Panel C demonstrates the USDA food categories identified as plant-based (shown in red bold font) and the percentage contribution of these foods to total phosphorus intake. Taken together, the plant-based phosphorus contributions total >26% of phosphorus from food, which is greater than from milk and dairy and the sum of animal-based foods (34). The graph was reproduced from publicly available USDA data. Panel D demonstrates the rising grain product contribution to the estimated dietary phosphorus intake (mg/d) relative to that of meat and dairy foods. Phosphorus intakes from each food category were estimated over seven 2-y cycles of NHANES. Phosphorus intakes from grain products surpass those of meat and milk and represent the top food contributor to both phosphorus and dietary phytate in the United States (35). Panel D was reproduced with permission from reference 35. EAR, estimated average requirement.

The major food categories contributing to phosphorus intake are shown in Figure 2C. The percentage contribution of the highest plant-based food categories, when taken together, represent >26% of total food sources consumed in the United States. These plant-based phosphorus-contributing foods are also a source of phytate and comprise the grain food group shown in Figure 2D, where McClure et al. (35) have shown this food group to be the highest contributor to total phosphorus intake over decades of NHANES surveys. The authors demonstrate a clear trend for greater phosphorus intake from plant-based foods, which exceeds that from meat and animal protein sources. Phosphorus content of foods shown in Figure 2C and D does not consider the extensive use of phosphate additives in food processing, especially in baked goods and cereal products (34). This trend in consumption is growing according to a recent National Center for Health Statistics CDC brief confirming whole-grain consumption continues to increase in the United States (36), as will both phytate and phosphate additive consumption from these foods.

In addition to phytate, whole grains contain other bioactive nutrients, such as fiber and polyphenols, with well-recognized benefits to cardiovascular health and reduction of other disease risks, largely attributed to their antioxidant properties (37). Phytate consumed as part of a plant-based dietary pattern also contributes to the antioxidant properties of whole grains as does phytate fed as an isolated compound, recently credited with therapeutic benefits, notably the reduction of tissue calcification in CKD (17, 38, 39).

Effects of Processing on Food Phytate and Phosphorus Content

Phytate phosphorus negative nutrient effects in the absence of processing

One overarching question about phytate's impact on health relevant to the United States concerns the amount typically consumed in Western diets. Estimates of phytate intake are low in Western countries, with men consuming 740 mg/d, with mean lower intakes of 590 mg/d in women in the United States (40), compared with typical intakes in Ghana and Nigeria of 1800 and 2100 mg/d, respectively (41). The level of phytate consumption from whole grains differs significantly among countries, with lower- and middle-income countries (LMICs), which are more dependent on these protein food sources and have lower intakes of essential minerals, having the highest phytate intake. High phytate consumption has a long-held reputation of antinutrient activity in populations consuming predominantly whole grains, cereals, legumes, pulses, and limited dietary sources of essential minerals (zinc, iron, magnesium, and calcium) that are usually contributed by animal protein sources (37, 42–44). The negative impact of high phytate intake on mineral loss is attributed to its strong mineral chelation when all 6 phosphates are present (IP-6) (Figure 1). In LMICs, phytate consumption has a long history of antinutrient effects on growth, immunity, and cognitive development (22, 42). Phytate's antinutrient effects on zinc and iron nutrition are so pronounced that estimates of average national phytate intakes are needed to establish zinc, iron, and calcium requirements in some LMICs where these foods are minimally processed (42, 43).

Omnivorous Western dietary patterns do not typically experience the extreme phytate to essential mineral molar ratios that result in the mineral deficiencies observed in LMICs, easing concerns about phytate's antinutrient reputation in the United States, where diets are adequate in zinc and iron. However, if whole-grain consumption in the United States continues on its current trajectory, there is potential for antinutrient effects on calcium given the sizeable segment of the general US population consuming less than the EAR for calcium (45, 46). Approximately 46% of the population consumed less than the EAR for calcium (800 mg/d for adults aged 19–50 y) from natural or enriched foods estimated in NHANES 2009–2012. Evidence supporting this potential concern for calcium absorption, low serum calcium, and a compensatory increase in PTH in early CKD with high-phytate, plant-based protein diets, despite seemingly adequate dietary calcium (>800 mg/d), is shown in the study by Moe and coworkers (47). Phytate content of the plant-based grain and soy experimental diet was not determined in this study. Both the animal protein diet and grain/soy diets contained similar total protein, phosphorus, and calcium contents, but may not have had an adequate phytate to calcium molar ratio for the level of calcium bioavailability required to maintain calcium homeostasis. This may explain the higher serum PTH and lower serum calcium after 1 wk of consuming the vegetarian grain/soy diet. Other countries with phytate intakes less than those in Africa, but higher than in Western countries, may have problems due to their very low calcium intakes. In a nationwide Chinese study, median daily phytate and calcium intakes were 1186 and 338 mg, respectively, with a median molar ratio of phytate to calcium of 0.22, a molar ratio above the 0.17 threshold of concern for impairing calcium bioavailability (43, 44, 48).

Conditions such as processing and low calcium intake can influence the bioavailability of phytate phosphorus, which was recently demonstrated in a carefully conducted rat model (46). Young rats fed excessive raw-phytate diets with adequate or low calcium levels developed crystal nephropathies, renal wasting, and bone loss on the low-calcium diet that was attributed to high phosphorus gut absorption but very low calcium absorption. The authors showed how high calcium intake can lead to calcium binding to phytate-phosphorus, thus preventing its degradation and phosphorus release, which, in turn, prevented the dysregulation of intestinal calcium and phosphorus absorption that resulted in secondary hyperparathyroidism, bone loss, and soft tissue calcification. The important finding from this study is the clear evidence that phytate can be digested if calcium intake is low (46). Whether this relation observed in rats will occur with high phytate intake in CKD patients consuming low-calcium, minimally processed plant-based food sources remains to be determined.

Phytate phosphorus in whole grains, pulses, and legumes: bioavailability when processed

Our task of determining the impact of plant phytate-phosphorus content on the efficiency of phosphorus absorption is complicated by the questionable accuracy of estimates of both phytate and phosphorus from existing nutrient content databases. The databases in the United States and elsewhere underestimate the quantity of phosphorus in foods processed with phosphorus-containing additives, a widely used processing additive (2). The various databases quantifying phytate content estimates of foods, including the newest, FAO/INFOODS/INZINC Global Foods database, are complicated by huge variability in the accuracy of the methods used to analyze phytate, the growing conditions and natural phytate in different plant cultivars used as ingredients, and most importantly, the processing method used to make the food product (23). Thermal processing that includes canning, autoclaving, prolonged boiling, and extrusion processing can reduce phytate content of foods, as shown in Figure 1, reducing the total IP-6 content and increasing the more readily degraded inositol-penta-phosphate (IP-5), inositol-tetra-phosphate (IP-4), and inositol-tri-phosphate (IP-3) inositol phosphates (49). Phytate loss in processed foods compared with their minimally processed or raw initial ingredients can occur by physically degrading the molecules through processing involving mechanical removal by de-hulling and milling, or by soaking, sprouting, germinating, thermal hydrolysis, and extrusion, as presented in the examples in Table 1. Processing techniques such as water soaking, germinating, and sprouting, or canning, in addition to prolonged boiling in home food preparation and de-hulling prior to milling, can reduce the phytate and phosphorus content of most foods, but not all (50). Phosphorus is lost if, prior to consumption, the cooking, canning, or soaking waters are drained and not consumed (51, 52).

TABLE 1.

Effect of various processing techniques on the phytate content of selected whole-grain foods compared with their minimally processed initial ingredients¹

Processed food product	Processing method	Phytate content, mg/100 g	Unprocessed or less-processed food	Phytate content, mg/100 g
Mechanical removal of phytate by milling and de-hulling
Brown rice flour	Milled	159.8	Brown rice, raw	865.0
Polished rice flour	Milled	187.0	Polished rice, raw	391.5
Oat flour	Milled	270.0	Oats, rolled, raw	947.6
Pigeon pea	De-hulled	297.1	Pigeon pea, raw	727.0
Soybean	De-hulled	317.0	Soybean whole raw	443.0
Ground bean	De-hulled	1350.0	Hulled ground bean, raw	1220.0
Wheat flour, white	Milled/de-hulled	160.0	—
Phytate reduction by soaking, sprouting, germination
Pea	Water-soak	582.0	Whole pea seed	835.7
Lima bean	Water-soak, 9 h	13.8	Lima bean water-soak, 3 h	151.5
Lentil seed	Water-soak, 12 h	210.0	Lentil seeds, raw	507.0
Tofu made with germinated soy	Germinated	130.5	Tofu	196.5
Mung bean	Germinated, 12 h	45.7	Mung bean water soaked	99.4
Soybean	Germinated, 48 h	336.0	Soybean germinated, 24 h	347.0
Brown lentil	Sprouted, 6 h	52.0	Brown lentil, raw	208.1
Chickpea	Sprouted	90.7	Chickpea, raw	710.7
Thermal hydrolysis degrading of phytate by canning and autoclaving
Chickpea	Canned	<LOD2	Chickpea, raw	710.7
Kidney bean	Canned	289.0	Kidney bean, raw	716.0
African Faba bean	Canned	236.6	Faba bean, raw	313.4
Lentils	Autoclaved	219.4	Lentil, dried	561.4
Mung bean	Autoclaved	396.2	Mung bean, raw	523.4
Lima bean	Autoclaved	3.79	Lima bean, dried	17.5
Phytate reduction by enzymatic action of fermentation or addition of phytase
Bread, whole-wheat, hard red winter	Yeast leavened	127.2	Unleavened whole wheat	405.9
Bread, white, wheat-based	Yeast leavened	277.0	Wheat flour, whole grain	555.7
Rye bread	Yeast leavened	52.0	Rye flour, raw	376.0
French bread, white, wheat-based	Yeast leavened	33.0	Wheat flour, white	35.3
Bread corn-based	Yeast leavened	18.0	Bread, corn, unleavened	61.0
Injera bread, wheat-based	Fermented	137.0	Injera, maize, unleavened	282.0
Phytate reduction by extrusion processing
Wheat bran	Ext-165°C	2117.0	Wheat bran, raw, fine	3123.0
Rice bran	Ext-165°C	2003.0	Rice bran, raw	4282
Barley bran	Ext-165°C	1941.0	Barley bran, raw	4030
Oat bran	Ext-165°C	2140	Oat bran, raw	2769
Buckwheat, Kora	Ext-160°C	1378.3	Buckwheat, raw	1518.9
Pea	Ext-129°C	250.5	Pea, dried	305.8
Breakfast cereal, Raisin Bran (Kellogg's)	Extruded mixed grains/bran	695.0	Wheat bran, raw	3578.0
Breakfast cereal, Grape Nuts (Post)	Extruded mixed grains	112.0	Wheat, rye, barley mixed grain flour	464.4

¹Data source from reference 23. Ext, extrusion cooking.

²<LOD indicates phytate content was below the limit of assay detection.

Processing techniques such as extrusion and fermentation degrade the phytate to lower phosphorus-containing inositols, decreasing the total content of IP-6 in the product, but the total phosphorus content is not changed; rather, the processing increases the amount of bioavailable phosphorus. A commonly consumed product where this occurs is sourdough bread compared with wheat bread leavened (fermented) with bakers’ yeast. The longer the sourdough is fermented, the greater the phosphorus bioavailability compared with traditionally leavened wheat bread or the poor bioavailability of phosphorus from unleavened (nonfermented) bread (53). The leavened breads will have variable phytate contents, but total phosphorus content will not change, and these 3 processed bread examples will have different available phosphorus contents. In vitro studies have shown that fermentation processing of whole-grain cereal products increases the amount of bioavailable phosphorus, whereas phosphorus bioavailability of legumes and seeds with minimal processing is relatively poor (54, 55).

Mild extrusion cooking of cereals, pulses, and legumes may only result in small decreases in phytate in the range of 10–15% (23). It is important to note that the greater reduction in phytate content in the popular breakfast cereals shown in Table 2 relative to their initial raw ingredients likely reflects harsher extrusion cooking conditions (higher temperature and pressure). Although these specific extrusion-processing conditions are unknown to us, they represent yet another piece of the puzzle needed before we can fully understand the impact of the growing variety of plant-based extruded foods in the marketplace on phosphorus bioavailability in kidney patients. Extruded products such as ready-to-eat breakfast cereals may contain less phytate, but the product labels indicate high phosphorus content (56). Grape Nuts (Post), a popular extruded breakfast cereal made from mixed wheat, rye, barley, and other grains, is considered a whole-grain product, and according to the product label, contains 300 mg phosphorus per 100 g. We assume that extrusion processing reduces its phytate content to just 112 mg per 100 g cereal, suggesting that only 31 mg of phosphorus is bound as phytate-phosphorus, leaving 269 mg of very absorbable free inorganic phosphorus.

TABLE 2.

Studies on phytate-phosphorus gastrointestinal bioavailability in humans¹

Study, year (reference)	Population	Study design	Percentage of oral phosphorus intake recovery in 24-h urine2
McCance and Widdowson, 1942 (71)	8 English healthy adults	Balance studies performed for 21 d; phytic acid was added daily as a powder mixed with the food to their baseline diet	50%
Cruickshank et al., 1945 (72)	4 Scottish healthy adults	Balance studies were performed in which a constant diet rich in oatmeal was given for 48 d	63%
Hunt et al., 1998 (73)	21 US healthy young women	Balance studies were performed during consumption of controlled lacto-ovovegetarian (phytate = 1656 mg) and nonvegetarian diets (phytate = 542 mg) for 8 wk each in a crossover design; study diets were cooked in study center and provided to participants daily	51% appeared in urine in lacto-ovovegetarians vs. 60% in nonvegetarians
Soroka et al., 1998 (74)	15 Israeli chronic kidney disease patients	Balance studies with two 6-mo periods of 2 different diets (crossover design); the 2 diets had relatively similar Pi intakes but of different sources: mostly plant (soy) protein in the vegetarian diet and mostly meat protein in the animal protein diet	68% recovered in the 24 h urine of the vegetarian diet and 75% in the animal protein diet
Moe et al., 2011 (47)	9 US chronic kidney disease patients	Balance studies with two 7-d periods of 2 different diets (crossover design); the 2 diets had similar Pi intakes but of different sources: 82% of plant protein in the vegetarian diet and 94% meat protein in the meat diet	53% recovered in the 24-h urine of the vegetarian diet and 70% in the meat diet
Karp et al., 2012 (75)	16 Finnish healthy young women	24-h Feeding sessions over a 5-wk period (1 session/wk); in one of the sessions, grain was added to the baseline meal intake with simultaneous measurement of Pi in 24-h urine collection	Only 20% of phosphorus as grain was excreted in 24-h urine
Moorthi et al., 2015 (76)	13 US chronic kidney disease patients	All patients received a diet containing 70% of plant-derived proteins and 30% of animal proteins for 4 wk; there was no control group; average Pi intake was 1142 mg/d	54% of Pi recovered in the 24-h urine collection by 4 wk
Itkonen, et al., 2021 (55)	Finnish healthy women (n = 107) and men (n = 29)	Balance studies were performed in all participants during random assignment for 12 wk to consume 1 of 3 diets: 1) animal (70% animal protein and 30% plant protein), 2) plant (70% plant protein and 30% animal protein and 3), 50/50	64% of Pi was recovered in the animal protein, 62% in the 50/50, and 54% in the plant protein group

¹Pi, inorganic phosphorus.

²Percentage of oral phosphorus intake eliminated as inorganic phosphate in 24-h urine collections in several-day balance studies, except in Karp et al.’s study where both intervention and urine collection were for only one 24-h period. This percentage indicates net gastrointestinal phosphorus absorption, but we do not know with what exactitude how much of the phosphorus intake was only associated with food phytate since some of the diets studied were mixed.

It is clear that processing of whole-grain foods will have significant impact on phosphorus bioavailability from whole-grain cereals, legumes, and pulses that may or may not benefit CKD patients. We believe fermentation and extrusion processing that reduces phytate content will likely afford greater phosphorus bioavailability than the anticipated 10–30% absorption efficiency presently claimed for high-phytate plant-protein foods (57, 58).

Nut consumption and phytate-phosphorus

Longitudinal population surveys have shown that the consumption of diets high in red and processed meat is associated with the increased risk of CKD, in sharp contrast to the consumption of nuts, legumes, and low-fat dairy (59, 60). There is growing interest in tree nut and peanut consumption due to the many associated health benefits linked to changes in glucose and lipid metabolism, oxidative stress, inflammation (61), and the gut microbiome (62), all mechanisms that positively impact chronic disease incidence and mortality risk of cancer (63, 64) and CVD (65, 66), but some question the impact of nut intake on diabetes risk (67). Studies on nut consumption and CKD are scant; 1 recent pilot study examining walnut consumption (30 g/d) in a 30-d randomized controlled crossover design in CKD patients reported some health benefits (68). Walnut consumption reduced blood pressure, LDL cholesterol, and albumin excretion, but there were no remarkable changes in serum phosphorus, potassium, PTH, or FGF23 relative to the control arm when dietary sodium, protein, phosphate, and potassium were controlled in both diets.

As discussed earlier, legumes and pulses are rich in protein and phytate that can be degraded by home processing or canning, lowering inositol phosphates and phosphorus in the consumed food (69). Less is known about the impact of processing on the digestibility of phytate in nuts that are typically dried or roasted, a minimal thermal process that likely does not appreciably degrade phytate but may inactivate endogenous phytase (23). In general, the phytate content of nuts is high. For example, when almond cultivars were analyzed using newer, more accurate techniques, inositol phosphate concentration ranged from 8 to 12 μmol/g in almond meal and 5 to 14 μmol/g in the brown skins, with ∼20% as inositol-hexa-phosphate, which contributed 20–38% of the total phosphorus in the almond meal and 30–52% in brown skins (70). With the growing body of evidence supporting the health benefits of nut consumption in the general population, further study of their safe use as a nutrient-dense protein source in CKD/ESKD patients is warranted.

Consideration of processing effects on plant-based dietary strategies for CKD/ESKD dietary management

Practical strategies for lowering phosphorus intake in CKD/ESKD diets would be expected to benefit more from increased consumption of selected plant-based proteins in combination with some animal protein sources, such as low-fat milk and seafood, rather than from mostly animal protein restriction (4, 59). This would allow greater calcium intake, as well as other important nutrients that may be affected by high phytate intake. Plant-based foods processed through extrusion should be avoided due to their higher phosphorus bioavailability; this largely means avoiding many popular breakfast cereals and snacks. When phytate is hydrolyzed during food processing and cooking, mineral bioavailability is increased, including phosphorus (43). Commonly consumed fruits and vegetables, such as leafy greens and root vegetables including potatoes, are part of a healthy plant-based diet but contribute little phytate, independent of the way they were processed (23). While commonly consumed fruits and vegetables may not contain much phytate, they are often processed with multiple phosphate-containing food additives as shown in Figure 2B, so attention must be paid to the ingredients label. Some brands of frozen fast-food French fries are a good example of this, with organic frozen potatoes usually processed additive-free. Although low in phytate content, fruits and vegetables (23) may contain endogenous plant phytase, as do edible mushrooms. Phytate degradation from corn tortillas and refried beans by endogenous phytases in raw fruit and vegetable extracts has been demonstrated in vitro, but whether this occurs in vivo remains to be determined with mixed diets (77). Mushroom phytase action has been proposed as a means to enhance phytate degradation in bread, if added during sourdough fermentation, thus improving protein and other nutrient content including vitamin D (78, 79). Limitations facing CKD/ESKD dietary management by increasing plant-based protein contributions include the general poorer protein quality, which can be addressed by including a variety of plant protein sources in combination with some animal protein sources. Plant-based proteins also contain other negative nutrients in addition to phytate, like trypsin inhibitors in pulses and legumes, that decrease protein quality and amino acid digestibility, if not inactivated through thermal processing (80).

Possible Phosphorus Absorption in the Large Intestine/Colon

Our general understanding of phosphorus absorption over the entire gastrointestinal tract (GI tract) is available in recent reviews for greater detail (29, 81). There are at least 2 main transport systems for intestinal phosphorus absorption: one sodium-dependent, saturable, and transcellular (NaPi-2b) and another one that is sodium-independent, nonsaturable, and paracellular. In addition to transporter abundance, the actual concentration of phosphorus in the intestinal lumen determines which transporter pathway will dominate. The NaPi-2b transporter is tightly regulated under the control of vitamin D, PTH, and other factors. In contrast, the intestinal paracellular phosphorus absorption pathway is not tightly regulated and depends on the concentration gradient across the epithelium, the electrical gradient (lumen negative), and the permeability of the tight junctions, which are under the control of several claudins (31).

In rats, sodium-dependent transport is detectable in vitro by the presence of NaPi-2b gene transcript in the colon (82). It has been shown that both the small and large intestines have a very high paracellular phosphorus permeability, which may favor monovalent phosphorus fluxes and allow efficient uptake of phosphorus, even in the absence of active transcellular phosphorus uptake (83). The importance of these findings to overall phosphorus balance in humans still remains uncertain, since increasing solidity of distal colonic contents could make soluble phosphate less accessible for absorption and should not be ignored. The finding of significant sodium-independent (paracellular) uptake at high luminal phosphate concentrations in the distal colon is probably relevant to the clinical observation of hyperphosphatemia following the use of high-phosphate-containing enemas (84–86).

Possible Role of Colonic Microbiota in Digesting Phytate and Liberating Phosphorus

Many colonic bacteria produce phytases (myo-inositol hexakisphosphate phosphohydrolases), a special group of phosphatases capable of sequentially hydrolyzing phytate. This results in the stepwise formation of myo-inositol pentakis-, tetrakis-, tris-, bis-, and monophosphates, as well as the liberation of phosphate. Phytases are distributed widely in nature—for example, in plants and certain animal tissues and micro-organisms, including fungi and bacteria. Different types of phytases are known—3-phytases, 4-phytases, and 6-phytases—indicating the predominant attack of the susceptible phosphoester bond. These bacterial phytases in the colon play an important role in both human and domestic animal nutrition.

A phytase isolated from the gut microbe, Escherichia coli, is highly specific for phytate and has the highest specific activity of any of the characterized phytases. E. coli phytase is a member of the histidine acid phosphatase family, a group of enzymes with acidic pH optima that contain the conserved sequence motif RHGXRXP at their active site. Their catalytic action is in a 2-step process consisting of a nucleophilic attack on the phosphorus atom by the histidine in the enzyme active site motif, followed by hydrolysis of the resulting phospho-histidine intermediate (87). Phytases isolated from plants and other sources have long been used in the pretreatment of phytate-rich plant ingredients, the most common of which are those used in leavening bread.

Experiments in rats reported that 56% of phytate was hydrolyzed in conventional rats, while in germfree rats, almost no hydrolysis of phytate was detected (88). These findings in rats, together with studies in pigs (21), support the importance of phytate hydrolysis by the large intestine microbiota; however, to what extent this occurs in humans remains unclear.

Human Studies Examining Phytate and Phosphorus Gastrointestinal Bioavailability

There are few human studies on phytate digestibility. In 2 balance studies in subjects with an intact GI tract (72, 89), it appears that a large percentage of ingested phytate actually gets digested along the entire GI tract. This is consistent with the studies of Schlemmer et al. (15) in pigs, a widely used animal model with similar gut physiology to humans. Sandberg and co-researchers (90) studied adults without an intact GI tract; all 7 patients had ileostomies, enabling collection of the gut contents avoiding the large intestine. These authors determined the extent of phytate digestibility in the upper GI tract in the presence of phytase (control diet) and in the absence of intrinsic plant phytase (extruded diet). Extrusion processing of plant food ingredients with intrinsic phytase, such as wheat bran, purportedly destroys all the endogenous plant phytase activity. These authors found almost complete degradation of phytate when the control diet was fed, with most of the digestion occurring in the stomach and small intestine. When fed the extruded wheat bran, the extruded phytate was resistant to digestion in the human small intestine, likely due to the lost phytase activity or to the formation of indigestible phytate complexes formed during the extrusion cooking. This suggests that if phytate is not degraded in the stomach, degradation may occur in the colon. Sandberg et al.’s study (90) makes a strong case for the lack of phytases along the upper GI tract in humans upon exposure to microbial phytase, a phenomenon that has been confirmed in pigs and other nonruminants (15).

Despite the possible high digestibility of dietary phytate in humans, actual phosphorus bioavailability is less apparent, but it seems to be at least 50% as shown by the human studies in Table 2, which measured amount of phosphorus in phytate recovered as phosphate in 24-h urine collections as an indicator of net gastrointestinal absorption (47, 55, 71–76, 89, 90). There are many other factors affecting phosphorus absorption, such as vitamin D status, the presence of other minerals, particularly calcium, in the intestinal lumen, and the fluidity of the chyme (21). Karp et al. (75) found very low bioavailability of phytate-phosphorus, in sharp contrast to all the other studies, which may have to do with the short duration of the study, only 24 h, possibly inadvertently excluding the action of the colon bacteria on phytate digestibility. Three studies (41, 74, 76) have been performed in CKD patients showing that plant-based diets gave a phosphorus bioavailability >50%. This is further evidence that high-phytate foods do not completely restrict phosphorus absorption.

Future Considerations

In this review we reveal 2 important concepts concerning the contribution of phytate phosphorus to the dietary phosphorus load that a kidney patient may unwittingly be exposed to in their effort to follow current health guidelines promoting plant-based foods. First, although well known to nutrition and food scientists for decades, the effects of thermal processing on phytate-phosphorus bioavailability from plant-based foods may be a new concept to nephrologists and renal dietitians. This concept underscores the fact that, in terms of phosphorus bioavailability, not all high-phytate plant foods have the ability to lower phosphorus absorption and those that are extrusion processed should be avoided or consumed sparingly. Clearly, the second concept of colonic microbiota digestion of phytate and releasing phosphorus and the acceptance of phosphorus absorption in this lower intestinal segment has not previously been considered to be important in kidney patients. These 2 concepts, however, should inform our current way of estimating phytate-phosphorus bioavailability. Although the exact degree of phytate-phosphorus absorption from the lower gut is uncertain, the human data reviewed in Table 2 clearly suggest that at least 50% of phytate-associated phosphorus absorption is absorbed along the GI tract, including the colon, with the understanding that it may be even more. This still affords an advantage in terms of dietary phosphorus allowance when designing dietary recommendations for CKD patients in comparison to phosphorus derived from animal sources, although the dietary allowance would need to be modified, since there is higher phosphorus bioavailability than currently advised in recent clinical guidelines for plant-based diets in CKD (58). This is very important information for renal dietitians.

The data on phytate content from different grains, legumes, nuts, and seeds are at times overwhelming because of their variability not only for the natural content but also for the significant effects introduced by their commercial processing. For example, how would a practicing dietitian know whether or not the endogenous phytase has been destroyed in a particular product? This is an area that certainly requires further research, particularly in view of the growing dietary trend to advise adherence to plant-based dietary patterns for CKD patients (12), CVD patients (9), and even for health maintenance in the general population (3).

The problem with phytate-bound mineral loss creates a duality for general and renal nutritionists. From the perspective of the general nutritionist, this health-adverse characteristic of phytate could easily be overcome by supplying phytase as a food-processing ingredient or as a genetically engineered constituent in plant protein sources that are now common practice in domestic animal feeds (21). Renal dietitians, on the other hand, need to consider that such action would completely eliminate the potential advantage of phytate that provides at least some degree of reduced phosphorus bioavailability.

A serious challenge that the dietary management of renal disease now faces concerns the surge in food market and restaurant availability of plant-based meat alternatives promoted as the future answer to healthy diets and food sustainability. On first consideration, plant-based alternatives to meat may appear to be a solution for both patient and renal dietitian, but on closer inspection, the pros may not out-way the cons. Most plant-based meat alternatives rely on thermal extrusion processing of pea, soy, or other plant ingredient combinations, likely improving phosphorus bioavailability with phytate degradation compared with the lower absorption from vegetarian alternatives not using extrusion processing (e.g., Beyond Burger vs Boca Vegan Ground Burger) (91, 92). The very popular products that closely mimic beef in flavor and texture are extrusion processed, often contain phosphate additives such as modified starch, and may not have the same essential amino acid profile as beef (93).

In conclusion, we leave the reader with the following several key considerations, cautionary guidance concerning healthy whole-grain foods in the dietary management of CKD:

• The current prevailing belief in nephrology is that phytate in foods is poorly digested, thus bound phosphorus is not readily available (10–30% absorption) unless phytases are naturally present or added.

• Previous understanding was not aware that, depending on the processing method, phytate can be significantly degraded, freeing bound phosphorus in food for absorption.

• Degraded phytate and free phosphates can be high in popular extrusion-processed whole-grain products such as breakfast cereals and potentially in some fast-food plant-based meat alternatives.

• Phytases associated with colonic microbiota that degrade phytate releasing inorganic phosphate and the high paracellular phosphate absorption capacity of the colon need to be explored as a potential significant contributor to phosphorus intake in kidney patients.

• Kidney patients and renal dietitians should not assume that all phytate-phosphorus in healthy whole-grain cereals, legumes, pulses, and nuts is poorly absorbed when estimating dietary phosphorus intake since intervention studies looking at urinary phosphorus excretion after high-phytate food consumption suggest phytate-phosphorus absorption of at least 50%.

Notes

Perspective articles allow authors to take a position on a topic of current major importance or controversy in the field of nutrition. As such, these articles could include statements based on author opinions or point of view. Opinions expressed in Perspective articles are those of the author and are not attributable to the funder(s) or the sponsor(s) or the publisher, Editor, or Editorial Board of Advances in Nutrition. Individuals with different positions on the topic of a Perspective are invited to submit their comments in the form of a Perspectives article or in a Letter to the Editor.

Author disclosures: The authors report no conflicts of interest.

The authors reported no funding received for this study.

MSC and JU contributed equally.

Abbreviations used: CKD, chronic kidney disease; CVD, cardiovascular disease; EAR, Estimated Average Requirement; ESKD, end-stage kidney disease; FAO/INFOODS/IZINCG, FAO/International Network of Food Data Systems/International Zinc Nutrition Consultive Group; FGF23, fibroblast growth factor 23; GI tract, gastrointestinal tract; IP-6, myo-inositol hexa-phosphate (phytate); LMIC, lower- and middle-income country; NaPi-2b, sodium-phosphate-2b transcellular co-transporter; PTH, parathyroid hormone.