Dietary Phosphorus and Metabolic Health in CKD and ESKD

Abstract

The contribution of dietary phosphate (P) in the pathogenesis of CKD-associated mineral bone disease and the management of P intake in patients with CKD are essential to slow down disease progression and improve patient outcomes. In patients with CKD, and most likely in the general population, P retention and overload can affect four critical aspects of the cardiovascular system: increased arterial BP, vascular and valvular calcification, and left ventricular hypertrophy. All of these factors contribute to increased cardiovascular risk and mortality. Intestinal absorption of P from a mixed diet is approximately 60%–70% of the dietary P content, with lower rates for organic P from plant sources and higher rates for inorganic P from processed foods containing additives. The widespread use of phosphate additives in processed foods and the high consumption of animal protein in the Western diet have led to a steady increase in phosphate consumption in recent decades. Although it is unclear whether this high P intake has adverse effects in people with normal kidney function, several studies have found that increased dietary P contributes to the progression of CKD and cardiovascular damage. High P intake may be detrimental, but there is no clear evidence that it should be avoided in the general population. On the contrary, kidney function impairment is the setting in which modulation of P intake is justified and easy to implement by restricting/reducing protein intake. However, it is quite difficult to implement P restriction in patients on dialysis because of the conflicting recommendation of high protein intake. Educational approaches, together with solid motivation and adherence by patients and caregivers, are needed to achieve the goal of successful dietary phosphate management in patients with CKD.

Introduction

A major challenge in the management of patients with CKD is the prevention and treatment of CKD mineral bone disease, which includes vascular calcification, progressive kidney damage, and cardiovascular complications. Hyperphosphatemia, or more generally phosphate retention, plays a pivotal role in the subsequent adaptive and then maladaptive responses leading to adverse clinical outcomes.

Therefore, limiting the dietary phosphate (P) load in reduced kidney function is a rational and understandable intervention (Figure 1) but unfortunately not easy to implement in clinical practice. This is particularly true in patients on dialysis, where phosphate restriction must be combined with high protein intake. The role of the dietitian as part of the CKD clinic team to improve education and adherence to dietary phosphate modulation is therefore well envisaged. This article highlights the evidence for kidney and cardiovascular damage in CKD, with a particular focus on dietary P intake and how this presents a challenge for patients with CKD and ESKD.

Figure 1.

Healthy kidneys are able to excrete high amounts of P after uncontrolled dietary P intake, thus maintaining a neutral external P balance. When kidney function is mildly or moderately reduced, adaptive changes in FGF23 and PTH occur, but a trend toward a positive P balance may occur; in this condition, high dietary P intake must be avoided. In the case of severely reduced kidney function, uncontrolled P intake invariably leads to a P-positive balance, even in the presence of increases in PTH and FGF23; in this condition, accurate restriction of dietary P is mandatory. FGF23, fibroblast growth factor 23; P, phosphate; PTH, parathyroid hormone; VitD, Vitamin D.

Contribution of Dietary P to the Risk and Progression of CKD

CKD is a global health problem affecting millions of people.¹ Recently, a link between phosphate imbalance and kidney pathology has been proposed, providing important insights into the long-overlooked contribution of phosphate to progressive kidney damage. A major factor contributing to the risk and progression of CKD is uncontrolled dietary P intake.

When consumed in excess and in the presence of impaired kidney function, P accumulates in the body, leading to an imbalance in mineral metabolism. High levels of P in the intestine and blood also stimulate the release of fibroblast growth factor 23 (FGF23). It is now clear that as kidney function declines, urinary fractional phosphate excretion increases through the FGF23-Klotho system to maintain serum phosphate levels within the normal range until late in the disease.²

Serum FGF23 levels are elevated in all forms of CKD and are associated with a higher mortality in this population.^3,4 Chronically elevated FGF23 has been associated with the development of cardiovascular disease and kidney complications.⁵

The association between dietary phosphate and CKD progression was first demonstrated in rats that underwent subtotal nephrectomy.^6,7 Consumption of a phosphate-rich diet was associated with increased mineral deposition in the remnant kidney models, whereas feeding a phosphate-restricted diet to rats that underwent subtotal nephrectomy preserved residual kidney function.^8,9 Although long-term studies of nutritional interventions are difficult to replicate in humans, several clinical observations support the view that dietary phosphate intake is a modifiable risk factor for CKD damage. First, several studies have shown that hyperphosphatemia is an independent risk factor of CKD progression and risk of developing ESKD.^10,11 Second, the results of several small clinical trials suggest that restricting dietary phosphate intake may slow the progression in patients with advanced CKD.^12–14

However, because both dietary protein and dietary phosphate intake were restricted in these clinical trials, it is unclear whether the observed results were due to changes in dietary phosphate alone and/or changes in protein intake. Furthermore, not all studies found phosphate restriction to be beneficial for CKD progression. A single prospective study by Williams et al. in a cohort of 95 patients with different CKD etiologies followed for a mean of 19 months after randomization found no clear effect of lowering phosphate intake on CKD progression.¹⁵ Importantly, the phosphate-restricted group in this study showed a decrease in urinary phosphate excretion, suggesting that their intervention was indeed effective in reducing phosphate load.

Further studies that have examined the effect of phosphate binders on long-term clinical outcomes in patients with CKD have not shown any clear benefit in terms of changes in eGFR or risk of ESKD.¹⁶ However, none of these studies were specifically designed to examine kidney function as the primary outcome. Although the animal studies in this field are overall impressive, it remains difficult to draw definitive conclusions about the effect of dietary phosphate restriction on the basis of human data alone because these studies suffer from potential confounding by concurrent protein restriction and are significantly underpowered. In addition, their duration was insufficient to detect more subtle effect sizes or to detect long-term effects on kidney outcomes.

In conclusion, the contribution of dietary P to the risk and progression of CKD should not be overlooked.¹⁷ A deeper understanding of the relationship between tubular phosphate transport and kidney pathology may lead to innovative strategies to improve kidney outcomes in patients with CKD.¹⁸

Contribution of Dietary P to Cardiovascular Health

P homeostasis and cardiovascular health are interdependent.¹⁹ Phosphate retention and overload in patients with CKD, and most likely also in the general population, particularly in men,^20,21 can disrupt the cardiovascular system by inducing elevated arterial BP, vascular and valvular calcification, and left ventricular hypertrophy (LVH), which lead to increased cardiovascular and mortality risk.

Hyperphosphatemia and Mortality Risk

The association between P serum levels and mortality in patients with CKD is well known.²² A meta-analysis focused on non–dialysis-dependent patients with CKD showed that each 1 mg/dl increase in serum P level was independently associated with higher risk of kidney failure (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.20 to 1.55) and mortality (HR, 1.20; 95% CI, 1.05 to 1.37), suggesting that large-scale randomized controlled trials should target impaired P homeostasis in CKD.²³ Similar results were recently reported in patients from the National Health and Nutrition Examination Survey study, where serum P >4.5 mg/dl was significantly associated with a 28% and 57% higher risk of all-cause and cardiovascular mortality, respectively, in nondialysis CKD patients with eGFR <60 ml/min per 1.73 m².²⁴ In >17,000 patients on hemodialysis from the Dialysis Outcomes and Practice Patterns Study, long-term hyperphosphatemia, expressed as area under the curve of serum P levels >4.5 mg/dl over a 6-month run-in period, was associated with a proportional HR increase in cardiovascular mortality, up to 2.03 for the highest P levels, indicating that P overload is strongly associated with cardiovascular mortality.²⁵ In patients receiving kidney transplant, each 1 mg/dl higher serum P level was not associated with a significant increase in cardiovascular risk (HR, 1.06; 95% CI, 0.92 to 1.22), but with a significantly higher risk of transplant failure (HR, 1.36; 95% CI, 1.15 to 1.62) and all-cause mortality (HR, 1.21; 95% CI, 1.04 to 1.40).²⁶ Consistently, serum P, even within the normal range, is associated with a higher risk of all-cause mortality and cardiovascular disease also in the general population.²⁷ However, in individuals with normal kidney function, no close relationship exists between serum P levels and dietary P intake because various mechanisms regulate circulating levels. Indeed, National Health and Nutrition Examination Survey III data showed that dietary intakes of P were associated only weakly with serum P levels, if at all.²⁸

Hypophosphatemia and Mortality Risk

While hyperphosphatemia has been more consistently associated with adverse cardiovascular outcomes and higher mortality in patients with CKD, low serum P levels in CKD may be associated with malnutrition and frailty and may be markers of malnutrition or wasting syndrome, which are independent predictors of poor outcomes and mortality in CKD. In addition, hypophosphatemia can be associated with impaired muscle function and bone demineralization, which increases risk of fractures. In a large dialysis cohort, Tiong et al.²⁹ found that both high (>8.5 mg/dl, HR, 2.13; 95% CI, 1.93 to 2.36) and low (<3.1 mg/dl, HR, 1.56; 95% CI, 1.44 to 1.69) serum P levels were independently associated with a higher risk of mortality. Lee et al.³⁰ showed that low serum P was significantly associated with all-cause and infection-related death (HR, 1.43; 95% CI, 1.06 to 1.93 and 1.66; 95% CI, 1.02 to 2.70; respectively), especially in patients older than 65 years or with serum albumin levels below 3.9 g/dl (HR, 2.06; 95% CI, 1.13 to 3.75 and 1.77; 95% CI, 1.00 to 3.13; respectively). These results raise the hypothesis that low serum phosphate might be a nutritional biomarker that predicts increased susceptibility to infection and, in turn, worse outcomes in patients on dialysis. On the other hand, in patients with stages 3–4 CKD, higher P levels were associated with a stepwise increase in mortality, whereas hypophosphatemia was not.³¹

P, Cardiovascular Calcifications, and Cardiovascular Risk

Disturbances in mineral and bone metabolism in patients with CKD are associated with vascular calcification and greater morbidity and mortality.³² A positive calcium balance is a relevant driver of vascular calcification, but elevated serum P levels are also involved. In patients with CKD, hyperphosphatemia is markedly associated with vascular calcification,^33,34 which can take the form of vascular wall ossification, leading to arterial stiffening and significantly increasing the risk of systolic hypertension, ventricular hypertrophy, ischemic and valvular heart disease, heart failure, and stroke. The term vascular wall ossification derives from the observation that vascular smooth muscle cells are transformed into osteoblast-like cells, which can produce bone matrix that is mineralized when the balance of promineralizing factors, including P, outweighs inhibitory factors.³⁵ Even within the normal serum range, higher P concentrations are associated with a greater prevalence of vascular and valvular calcification in people with moderate CKD.³⁶

High serum P levels are detrimental to endothelial function. P dysregulation directly affects arterial vessels by inducing endothelial dysfunction.³⁷ This endothelial damage leads to decreased vascular elasticity, increased inflammation, and a prothrombotic and proatherosclerotic environment, all of which increase cardiovascular risk in patients with CKD.³⁸

P-Mediated FGF23 Abnormalities and Cardiovascular Events

FGF23, a critical hormone involved in the regulation of phosphate balance, is an independent predictor and likely causal effector of cardiovascular events.³⁹ A clear association between FGF23 levels and LVH in patients with CKD has been established.^40,41 FGF23 synthesis in bone is stimulated by high P load and hypersecretion of parathyroid hormone. Elevated levels of circulating FGF23 activate the fibroblast growth factor receptor 4, independently of Klotho, inducing the development of LVH,^42,43 which can also be induced by hypertension, a common complication of CKD with a complex pathophysiology. Elevated levels of FGF23 may contribute to hypertension by activating the renin-angiotensin-aldosterone system. Hyperphosphatemia-induced vascular calcification together with sympathetic nervous system activation also leads to the development of hypertension.³⁹ However, Hidaka et al.⁴⁴ showed that the extent to which LVH mediates the effect of FGF23 on cardiovascular disease or all-cause mortality in patients with CKD is limited because only 7.4%, 11.2%, and 21.9% of the adverse effects of FGF23 on all-cause mortality, atrial fibrillation, and congestive heart failure, respectively, were mediated by LVH. Thus, further research is needed to identify other potential mediators and to clarify the role of FGF23 in long-term adverse health outcomes in patients with CKD because the mediating effect of LVH was smaller than anticipated.

Does the Source of Dietary P Matter?

In foods, P is present in both inorganic and organic forms. Inorganic P is a component of salts that occurs naturally in foods or is added as a preservative, whereas organic P is a component of phosphoproteins, membrane phospholipids, phytate, or nucleic or energy molecules such as ATP, ADP, DNA, and RNA. In a mixed diet of nonfortified foods, the P content is usually proportional to the protein content. Consequently, a high-protein diet will also be high in P, whereas a low-protein diet will naturally be low in P. In a mixed diet, P is approximately 14 mg per gram of protein.⁴⁵

Mechanisms of Intestinal Absorption of P

Although dietary P is introduced into the diet in a variety of molecular forms, it is uniquely absorbed as orthophosphate. There are two main mechanisms of phosphate absorption from the intestinal lumen, either by active transcellular transport or by passive paracellular transport (Figure 2). The former occurs by using sodium/phosphate cotransporters located on the luminal membrane of intestinal epithelial cells. There are three different types of sodium/phosphate (i.e., NPT2a, b, and c), the expression of which is reduced by FGF23. Instead, increased levels of calcitriol or a low-phosphate diet are known to increase the rate of phosphate absorption from approximately 60%–70% up to 80%. This mechanism can also be inhibited by nicotinamide, so it can be used as an effective therapy to reduce intestinal absorption of P.⁴⁶

Figure 2.

Mechanisms of P absorption. P absorption is complex because of several variables. Foods contain both organic and inorganic P. The two main absorption mechanisms are active transcellular transport using Na/Pi cotransporters and passive paracellular transport using tight junctions. Passive absorption is not saturable and, therefore, persists even in the case of hyperphosphatemia. The efficiency of P absorption ranges from 60% to 80%. Na/Pi, sodium/phosphate; NHE3, sodium/hydrogen exchanger isoform 3.

The other mechanism of P absorption consists of passive paracellular flux across the tight junction and, unlike the active transcellular mechanism, is not saturable. It can be reduced by conformational changes in tight junction proteins. This occurs when the activity of sodium/hydrogen exchanger isoform 3 is reduced. Tenapanor, a molecule used in the treatment of irritable bowel disease, is a potent and orally active sodium/hydrogen exchanger isoform 3 inhibitor and so it is able to reduce intestinal phosphate absorption.⁴⁷

Sources of Dietary P Naturally Present in Food

Because P is absorbed in the intestinal tract as orthophosphate, whereas dietary P is present in different molecular forms, there may be differences in the rate of absorption and hence in the effective P load and serum levels. Therefore, an important issue is the digestibility and bioavailability of the different sources of dietary P.⁴⁸

P from animal-based foods, such as poultry, meat, fish, or milk, is much more bioavailable than that from plant-based foods, such as legumes or cereals. The former is present as inorganic salts or as a component of organic molecules, from which it must be cleaved by hydrolases in the intestinal tract and released as inorganic P to be absorbed. Overall, the absorption of P from animal sources is close to 60%–80%.^45,49

The latter is mostly present in the form of phytate, a molecule formed by inositol linked to six molecules of phosphate. Phytates are found in cereals and legumes, particularly in the seeds and fibrous parts. They are therefore abundant in whole-grain products and virtually absent in refined products. Because phytase cleaves phosphate from inositol, but is not expressed in humans, the digestibility and thus the bioavailability of P from plant sources is quite low, close to 30%–40% and depends on the partial degradation of phytate by the intestinal microbiota and to some extent on a nonenzymatic hydrolysis reaction. Therefore, it is not only the amount of dietary P intake, but also its origin, i.e., plant versus animal source, that plays a significant role in the effective P load in patients with CKD.^45,49 Phytates also play additional protective roles in CKD, suggesting their potential use as therapeutic agents.⁵⁰

Dietary P Load from Food Additives

The most relevant lifestyle aspect affecting P intake and effective P load is the widespread use of processed and ultraprocessed foodstuffs, namely those processed with phosphate-containing additives. They are used as acidity regulators (E338–E343) and as emulsifiers and thickeners (E442, E450–E452, E544–E545) to extend shelf life, enhance color, improve flavor, and retain moisture.⁴⁹ These properties make ultraprocessed foods less expensive than regular or fresh foods. As a result, under-resourced individuals are at risk of high consumption of these products and thus very high intakes of dietary phosphates.⁵¹

A recent umbrella review of meta-analyses showed that greater exposure to ultraprocessed foods was associated with higher risk of adverse outcomes,⁵² in particular dysmetabolic, cardiovascular, or mental disorders, up to mortality. It follows that lifestyle changes and public health measures should be taken to reduce dietary exposure to ultraprocessed foods. Unfortunately, the contemporary Western lifestyle is exhibiting an increasing inclination toward dietary habits in which ultraprocessed foods have a greater prevalence in the dietary composition. In recent decades, the availability and variety of ultraprocessed products have expanded significantly and rapidly in countries at different levels of economic development, particularly those with high population density and low-to-middle-income levels.⁵³ In high-income countries, the proportion of dietary energy derived from ultraprocessed foods ranges from 42% to 58% in Australia and the United States, respectively, to only 10% and 25% in Italy and South Korea.⁵⁴

Preservatives are widely used by industry in the preparation of meat products, cheese, precooked and frozen dishes, puddings, sauces, bakery products, soft drinks, and beverages.⁵⁵ It has been estimated that in a typical Western diet, additives increase the P load by up to 1000 mg/d.⁵⁶ In addition, this additional P load is of great concern because of the very high intestinal absorption rate, which, assuming equivalence between digestibility and bioavailability, is believed to be close to 100%. However, the conclusion that P from food additives is completely absorbed has recently been questioned.^57,58 The study by Scanni et al.⁵⁹ showed that 73% of sodium phosphate administered continuously through a nasoduodenal feeding tube over a period of 36 hours was recovered in urine, whereas 100% of sodium phosphate infused intravenously was recovered in urine during 120 hours after the start of PO₄ loading.⁵⁹ In a randomized, double-blind, crossover trial in which the addition of phosphate-fortified beverages and breakfast bars to a basal diet resulted in an increase in total P intake of 842 mg/d, the increase in 24-hour urine P excretion was 505 mg/d, suggesting a net absorption of approximately 60% of the additional inorganic P.⁵⁸ Hence, contrary to expectations, P from food additives seems to be incompletely absorbed, suggesting that there may be a discrepancy between the digestibility and bioavailability of different sources of P. This could be due to the lower intestinal P absorption under conditions of high P intake. These data only mitigate the real concerns about the additional P load from P-containing food additives. It is imperative to ascertain the amount of P from additives to conduct future research in this area: The US Food and Drug Administration should mandate the reporting of P in foods and beverages by food manufacturers.⁶⁰

What Do We Tell Patients with CKD and the General Public about Dietary P?

Excessive intake of P, especially in the form of additives, is of concern not only for the CKD population but also for the health of the general population because of the association between high P intake and alterations in mineral metabolism, vascular calcification, impaired kidney function, bone loss, and atherosclerosis.^61–64

Considerations Regarding Dietary P Intake

From population studies, dietary P intake ranged from 1204 to 1625 mg per day in adults (<65 years) and 1185–1561 mg per day in the elderly (>65 years). The mean dietary P exposure was 16 mg/kg body weight per day in adults and the elderly, with a high exposure (95th percentile) of 24 mg/kg per day.⁶⁵ A recent national cross-sectional study of 3099 adolescents reported that the average P intake was 1538±667 mg/d, and foods containing P additives were consumed by 92% of adolescents.⁶⁶

In 2005, the European Food Safety Authority set the upper limit of total dietary P intake for healthy people at 3000 mg. In 2019, the European Food Safety Authority published the Re-evaluation of Phosphates as Food Additives and defined an acceptable dietary intake for total P of 40 mg/kg body weight per day, corresponding to a daily P intake of 2800 mg for a 70-kg adult, and indicated that inorganic P may contribute to 20%–30% of the total P intake. Thus, a total P intake of up to 40 mg/kg body weight per day, from both food and supplements or additives, can be considered safe for healthy adults because it is significantly below the levels at which clinically relevant adverse effects occurred. Furthermore, no risk of genotoxicity and carcinogenicity has been reported.⁶⁷ Accordingly, in healthy populations with normal kidney function, there is no risk of a positive P balance, even at high dietary intakes, as the kidney has a high P excretion capacity. The situation is different when kidney function is reduced. Decreased GFR is associated with decreased P excretion capacity and with increased FGF23 and parathyroid hormone levels, leading to CKD-associated mineral bone disease with cardiovascular and kidney damage and bone abnormalities.^68,69

Thus, in a healthy population, there is no need to recommend limiting the intake of P because the kidneys can eliminate it and the safety limit of 2800 mg/d is high enough. Nevertheless, the suggestion remains to limit the consumption of ultraprocessed foods in favor of fresh foods as a rule of healthy eating.

Conversely, dietary advice aimed at modulating the effective P load is of clinical relevance in patients with CKD, starting from early stages up to dialysis, where P restriction must be combined with normal/high protein intake.

Dietary P Management: Educational Strategies and Practical Tips

Dietary P management in CKD and ESKD can be implemented in several ways: attention to the content and bioavailability of P in foods, identification of foods and beverages containing P-based additives, and use of preparation and cooking methods to reduce effective P intake and exposure (Figure 3).

Figure 3.

Tips for lifestyle aspects favoring or not the control of dietary P load. Six practical lifestyle and dietary behavior tips to control P load: The correct behaviors are in the left column (green emoji smiley). The six tips are related to (1) quality of foods, (2) P content and protein-to-P ratio of food, (3) where to do shopping, (4) paying attention to nutritional fact labels, (5) cooking methods, and (6) where to consume meals.

Educational strategies to implement dietary regimens include the development of personalized meal plans, which aim to help them purchase appropriate and safe foods and organize their meals, as well as visual tools (such as brochures, posters, recipe books), individual or group educational courses, and digital technologies.⁷⁰ Among the printed visual tools, the “phosphate pyramid” represents a user-friendly aid for nutrition education of both patients and health care professionals.⁷¹ The pyramid uses the properties of shape, color, and iconographic images to accompany verbal counseling and help the patient better memorize the information given during the examination. It consists of six levels with images of foods distributed on the basis of their P content, P-to-protein ratio, and P bioavailability. Each has a colored background that refers to the recommended frequency of intake, ranging from “unrestricted” (i.e., green flat) to “avoid as much as possible” (i.e., red flat).⁷¹

The use of cooking recipes is another strategy often used by renal dietitians to help patients put our recommendations into practice while maintaining a varied and tasty diet.⁷²

Adherence to dietary recommendations in patients with CKD remains a challenge in real-life practice.⁷³ The presence of qualified health professionals can make the difference in improving adherence to dietary recommendations, also by using innovative educational approaches such as telemedicine and digital media,⁷⁴ but also by acting as a filter for the vast amount of sometimes inaccurate information available online.⁷⁵

Counseling strategies are not always effective in establishing and maintaining a change in eating habits. In recent years, the transtheoretical model has proven to be particularly effective when applied to various clinical situations, including the reduction of P levels in patients with CKD.^76–78

In hyperphosphatemic hemodialysis patients, Rizk et al. showed that patients who received a counseling intervention from a dedicated kidney dietitian (15 minutes twice a week) achieved a significant reduction in serum P levels compared with patients assigned to a trained hospital dietitian or to usual care protocols from untrained hospital dietitians.⁷⁶ Vaz de Melo Ribeiro et al. conducted a nutrition intervention on the basis of the transtheoretical model in patients on hemodialysis and obtained a significant change in the intake of energy, macronutrients, and micronutrients, including P, and an improvement in the use of P binders.⁷⁷ Recently, Thongsunti et al. tested the effect of a transtheoretical model–based intervention and motivational interviewing on hyperphosphatemia management using telemedicine among patients on hemodialysis. They observed a reduced intake of P-containing foods and a significant reduction in serum P levels compared with usual care, an improved adherence to phosphate binders and a more appropriate use of these medications.⁷⁸

Finally, a systematic review of online resources for the management of hyperphosphatemia in patients with CKD highlights the presence of restrictive and sometimes inconsistent indications, which may lead to confusion and inappropriate behavior among patients.⁷⁵ For this reason, the presence of qualified health professionals is even more necessary to provide patients with CKD with adequate knowledge to help them manage the sometimes incorrect information available online.

To summarize, the general population does not require P restrictions other than avoiding excessive consumption of ultraprocessed foods. Patients with reduced kidney function require restriction of P intake, which is fairly easy to achieve in the conservative phase, thanks to the concurrent restriction of protein intake. In patients on dialysis, modulation of P intake is more difficult because of the need to increase protein intake. Educational strategies are therefore needed to make patients aware of their condition, to obtain the cooperation of family members and caregivers, and to improve adherence to dietary prescriptions.^79–82

Conclusions

The contribution of dietary P to the risk and progression of CKD is significant. The potential benefits of combining P restriction with new CKD treatments, such as the sodium-glucose cotransporter-2 inhibitors, are not fully understood but are promising.⁸³ Similarly, some evidence exists that the hemodynamic effects of sodium-glucose cotransporter-2 inhibitors, namely reduction in glomerular hypertension and albuminuria, occur at different levels of dietary protein intake, suggesting an additive effect.^84–86

There is currently limited evidence from interventional studies that targeting serum phosphate improves cardiovascular outcomes and mortality. The clinical benefit of dietary or pharmacological interventions to reduce phosphate exposure, while plausible, remains uncertain, largely because of the difficulty of conducting well-designed clinical trials.

According to the Kidney Disease Outcomes Quality Initiative 2020 guidelines, in adults with CKD 3–5 and on maintenance hemodialysis, it is recommended to adjust dietary P intake to maintain serum phosphate levels in the normal range (1B). The Kidney Disease Improving Global Outcomes 024 guidelines for CKD stated (opinion) that in adults with CKD1–5D and post-transplant, it is reasonable to consider the bioavailability of P sources (e.g., animal, plant, and additives) when there is an indication for P restriction treatment. In both cases, the quantity of P intake is not specified, but the objective is to maintain serum P within the normal range.^87,88 In addition, a nonlinear relationship exists between dietary P intake and serum level, given the large substantial differences in the digestibility and bioavailability of dietary P.⁴⁹

Restricted P diets are generally low in protein, so the concern arises that the implementation of a low-P diet in patients on dialysis may increase the risk of protein energy wasting. An interesting study in hypoalbuminemic hemodialysis patients showed that high-protein meals during dialysis in combination with lanthanum carbonate increased serum albumin while maintaining stable serum P levels.⁸⁹

The widespread use of phosphate additives in processed foods and the high consumption of animal protein in the Western diet have led to a steady increase in phosphate consumption in recent decades.^90,91 Although it is unclear whether high phosphate consumption has deleterious effects in individuals with normal kidney function, increased dietary phosphate intake can contribute to the progression of CKD and of cardiovascular damage.⁹²

In healthy individuals, there is no need for substantial dietary advice on P apart from that of avoiding ultraprocessed foods with added P. Instead, a reduction in kidney function is the condition that justifies modulation of P intake, which is easy to achieve when done in parallel with a limitation/reduction of protein intake. On the contrary, it is quite difficult to implement P restriction in patients on dialysis because it conflicts with the recommendation of high protein intake. In this setting, multiple tools and educational approaches are needed, together with strong motivation and adherence by patients and caregivers.

Supplementary Material

cjasn-20-1289-s001.pdf ^{(1.4MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C228.

Funding

None.

Author Contributions

Conceptualization: Mario Cozzolino, Adamasco Cupisti, Claudia D’Alessandro, Maurizio Gallieni, Domenico Giannese, Vincenzo Panichi.

Supervision: Mario Cozzolino, Adamasco Cupisti.

Writing – original draft: Mario Cozzolino, Adamasco Cupisti, Claudia D’Alessandro, Maurizio Gallieni, Domenico Giannese, Vincenzo Panichi.

Writing – review & editing: Mario Cozzolino, Adamasco Cupisti, Claudia D’Alessandro, Maurizio Gallieni, Domenico Giannese, Vincenzo Panichi.