Concerns related to dietary phosphorus intake in cats

Jonathan Stockman College of Veterinary Medicine, Long Island University, Brookville, NY 11548.

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Cecilia Villaverde Expert Pet Nutrition, Fermoy, Ireland.

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 BVSc, PhD

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Introduction

Phosphorus is the 11th most abundant mineral on earth and is present in all living organisms. It is found in every part of the cell, including the phospholipid bilayer membrane, the mitochondria, and the nucleus. Phosphorylation is important for regulation of enzyme activity and results in both activation and inactivation of various key enzymes. The largest pool of phosphorus in vertebrates is skeletal tissue, which acts as a storage depot and may release or absorb phosphorus as needed. Overall, phosphorus comprises about 1% of the total body weight of an adult person, with 85% in skeletal tissue and bone, 14% in other cells, and 1% in serum and extracellular fluid.1

An adequate dietary intake of phosphorus is needed to maintain health; however, high serum (inorganic) phosphorus concentration is a risk factor for morbidity and mortality in dogs and cats with CKD. There is also a growing body of evidence indicating that a high phosphorus intake may have harmful consequences in otherwise healthy individuals of multiple species, including cats, particularly when the dietary calcium to phosphorus ratio is low and dietary phosphorus is in a highly bioavailable form.2,3,4 These findings suggest that it may be time to reevaluate current guidelines for phosphorus content in dog and cat foods.

Phosphorus Regulation

Serum phosphorus concentration is regulated to allow for bone mineralization and other organic functions without risking soft tissue mineralization. Regulation of phosphorus in the body is connected with regulation of calcium, and many of the hormones that regulate calcium homeostasis have an effect on phosphorus homeostasis as well.

Several mechanisms are involved in preventing hypophosphatemia. Approximately 70% of phosphorus absorption occurs in the duodenum and jejunum, through a combination of passive diffusion and a sodium-dependent active transport mechanism stimulated by calcitriol. Parathyroid hormone and a low serum phosphorus concentration stimulate intestinal absorption through activation of vitamin D to calcitriol.5

The kidneys also play an important role in preventing hypophosphatemia, because renal excretion is the predominant method by which phosphorus is eliminated once it is absorbed through the gastrointestinal tract. Phosphorus is freely filtered across the glomerulus, and 80% to 90% is then reabsorbed by the renal tubules. Phosphorus acts as a buffer for hydrogen ion secretion in the distal renal tubules, and phosphorus reabsorption is required for the reabsorption of sodium in the proximal convoluted tubules.

The proximal renal tubules are the predominant site of phosphorus reabsorption, with a high serum phosphorus concentration resulting in internalization of tubular transporters so that phosphorus reabsorption is decreased and vice versa.5,6 In addition, growth hormone, insulin, and thyroid hormone have been suggested to increase renal phosphorus reabsorption.5

Serum phosphorus concentration is determined by several key factors, including intestinal absorption, renal excretion, and phosphorus uptake into cells. Calcitriol increases phosphorus absorption from the gastrointestinal tract and from skeletal tissue, and PTH causes bone resorption and activates calcitriol.6 In addition, there is a group of peptides, including FGF-23, that act to reduce serum phosphorus concentration when it exceeds physiologic levels.7 Fibroblast growth factor 23 is synthesized by and secreted from bone in response to high serum phosphorus concentrations.8 Its effect is to reduce the amount of phosphorus in the circulation by reducing intestinal absorption and increasing renal excretion of phosphorus (Figure 1).9 The activity of FGF-23 requires binding to a tissue receptor and to Klotho, a transmembrane protein present in the parathyroid glands, kidneys, and other locations. Fibroblast growth factor 23 cannot reduce serum phosphorus concentration without Klotho, and Klotho deficiency may result in hyperphosphatemia, vascular calcification, increased erythrocyte death, and reduced lifespan in mice.10,11,12 The FGF-R is expressed in various tissues, and Klotho forms binary complexes with the FGF-R, converting it to a specific receptor for FGF-23.13,14 Both PTH and FGF-23 decrease renal phosphorus reabsorption by reducing cell surface expression of sodium-phosphate cotransporters types 2a and 2c in the renal tubules.6 Notably, in cats, minimum phosphorus reabsorption is 30%, regardless of PTH and FGF-23 activity, possibly to maintain adequate sodium reabsorption.15 Calcitriol, the activated form of vitamin D, has a PTH-dependent effect on bone mineralization, in that it stimulates mineralization when PTH concentration is low.6 Fibroblast growth factor 23 decreases vitamin D activation by inhibiting 1α-hydroxylase activity and stimulating 24-hydroxylase activity, resulting in a reduction in the calcitriol concentration and an increase in the concentration of the inactive metabolite 24,25-hydroxyvitamin D.6 Serum concentrations of both PTH and FGF-23 are increased in patients with a high serum phosphorus concentration.

Figure 1
Figure 1

Illustration of how FGF-23 leads to a reduction in serum (inorganic) phosphorus (Pi) concentration in healthy animals. High serum Pi concentration induces secretion of FGF-23 from bone, which decreases vitamin D activation by inhibiting 1α-hydroxylase activity and stimulating 24-hydroxylase activity, resulting in a reduction in serum calcitriol concentration and decreased gastrointestinal (GI) absorption of Pi. In addition, FGF-23 binds to FGF-R and Klotho, a transmembrane protein, in the kidneys, reducing cell surface expression of sodium-phosphate cotransporters types 2a and 2c (Na/Pi IIa [c]) in the renal tubules and resulting in decreased tubular reabsorption of Pi. In the parathyroid gland (PTG), binding of FGF-23 to the FGF-R and Klotho leads to reduced secretion of PTH. Adapted from: de Brito Galvao JF, Nagode LA, Schenck PA, et al. Calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 interactions in chronic kidney disease. J Vet Emerg Crit Care (San Antonio) 2013;23:134–162. Used with permission of the authors and publisher.

Citation: Journal of the American Veterinary Medical Association 258, 12; 10.2460/javma.258.12.1325

Dietary Phosphorus Requirements in Cats

In cats, adequate phosphorus intake is important throughout all life stages; however, phosphorus requirements are highest during growth, when skeletal tissue is being formed, and during late gestation and peak lactation. Growing cats require at least 1.2 g of phosphorus/1,000 kcal of ME to maintain a neutral phosphorus balance, approximately 2 to 3 times the maintenance requirement of adult cats.16,17,18 Acute phosphorus deficiency in adult cats is uncommon but could lead to hemolytic anemia, decreased mobility, and metabolic acidosis. All of these abnormalities were documented in cats fed a diet with a very low phosphorus content and high calcium-to-phosphorus ratio (8.3 g of calcium and 2.1 g of phosphorus/kg of dry matter, for a calcium-to-phosphorus ratio of 4).16,17

Although phosphorus requirements for pregnant cats have not been specifically determined, required phosphorus intake is likely increased during pregnancy, because phosphorus is needed for embryonic tissue development and, in particular, skeletal development.18,19 For lactating queens, the requirement likely depends on the number of kittens and has been estimated to range from 100 to 300 mg of phosphorus/kg of body weight/d (45 to 136 mg/lb/d) for cats being fed a diet with phosphorus bioavailability of 35%.19

Not much is known regarding phosphorus requirements in wild cats or how requirements for wild cats may differ from those for domesticated cats. However, it might be expected that wild cats that consume their prey whole would have a relatively high phosphorus intake because of ingested skeletal tissue.20,21

Finally, phosphorus intake depends not only on the phosphorus content of the diet and the physiologic and nutritional status of the cat, but also on the form of phosphorus and the content of other minerals, such as calcium and magnesium, that may impact phosphorus absorption and bioavailability.22,23,24,25

Phosphorus in Cat Food

Phosphorus is present in pet food in 2 main forms26: organic (or natural) and inorganic. Organic phosphorus may be present because of added supplements, but primarily originates from the raw materials (eg, bone ash) used in the diet. Inorganic phosphorus is present because of the addition of phosphate-containing flavor-enhancing agents, preservatives, leavening agents, and humectants and the inclusion of calcium-binding phosphates (sometimes added to reduce tartar formation). Phosphorus present as inorganic, water-soluble, phosphate-containing salts is generally more bioavailable than phosphorus originating from organic sources.27 Additional phosphorus content in foods may come from plants, fruits, or vegetables that are included in the formula; however, this phosphorus is largely bound to phytates and likely has very low bioavailability in cats, as is the case for other species.28

Several studies have evaluated the impact of the form of phosphorus on its bioavailability and metabolism. In 1 study,29 cats were fed diets containing the same amount of phosphorus but provided as either organic or inorganic phosphorus. Cats fed the diet with inorganic phosphorus had higher plasma and urine phosphorus concentrations than did cats fed the diet containing organic phosphorus. A recent study24 evaluated the postprandial effect of a diet containing 4.8 g of phosphorus/1,000 kcal of ME, with 3.5 g of phosphorus/1,000 kcal of ME originating from sodium dihydrogen phosphate and a calcium-to-phosphorus ratio of 0.6. This diet caused marked increases in plasma phosphorus and PTH concentrations, whereas a diet containing 3.38 g of phosphorus/1,000 kcal of ME, without added inorganic phosphorus and a calcium-to-phosphorus ratio of 1.55, resulted in a postprandial decrease in plasma phosphorus concentration. In that same study, when diets containing a fixed amount of inorganic phosphorus (1.5 g of phosphorus/1,000 kcal of ME) with various amounts of organic phosphorus (2.09 to 3.0 g of phosphorus/1,000 kcal of ME) were fed, there were no significant differences in postprandial plasma phosphorus concentrations. However, the study found a dose-response relationship between inorganic phosphorus content and postprandial plasma phosphorus concentration.

These findings suggest that acute postprandial changes in plasma phosphorus concentration reflect the higher bioavailability and faster absorption of inorganic phosphorus, compared with organic phosphorus. However, these were short-term feeding studies, and results may not accurately reflect long-term physiologic responses or outcomes or possible adaptations to different dietary phosphorus contents.

Several studies have evaluated the regulation of phosphorus metabolism by determining the impact of feeding increasing amounts of calcium and phosphorus in healthy cats. In a short-term feeding study30 involving cats, increasing the dietary phosphorus content with dicalcium phosphate while maintaining a calcium-to-phosphorus ratio of 1:1 to 1.2:1 was not associated with increases in phosphorus absorption or serum phosphorus concentrations. In another study,31 altering the calcium content of feline diets was found to affect serum phosphorus concentration. When cats were fed a diet with 1.5 g of inorganic phosphorus (sodium dihydrogen phosphate)/1,000 kcal of ME and a high calcium-to-phosphorus ratio (1.5:1 or 2:1), there was a lesser increase in serum phosphorus concentration postprandially, compared with the increase when cats were fed a diet with the same phosphorus content but a lower calcium-to-phosphorus ratio (1:1). Cats fed a diet with the same low calcium-to-phosphorus ratio (1:1) but a lower phosphorus content (0.75 g of inorganic phosphorus/1,000 kcal of ME) had a much smaller increase in serum phosphorus concentration, as determined on the basis of both peak serum phosphorus concentration and area under the serum phosphorus concentration-versus-time curve. This was different from findings in a study2 that evaluated continued feeding of a diet with a high inorganic phosphorus content. In that study, fasting blood samples had a low plasma phosphorus concentration and high plasma FGF-23 concentration, possibly indicating some adaptation with longer-term feeding.

Similarly, dietary magnesium content may affect phosphorus bioavailability. High dietary magnesium content (> 0.32 g of magnesium/1,000 kcal of ME) reduces phosphorus intestinal absorption by 13%, compared with a lower dietary magnesium content (0.04 g of magnesium/1,000 kcal of ME).25 The mechanism for this reduced absorption in cats is not entirely clear. However, it is thought to be due to formation of magnesium, phosphorus, and calcium complexes in the intestinal tract.25

Dietary Phosphorus Content and Progression of Renal Disease

Chronic kidney disease is common in older cats, although it can be diagnosed in younger animals, too. Approximately 35% of cats > 12 years old that are referred to tertiary-care veterinary specialty hospitals have issues related to CKD.32 Importantly, a high serum phosphorus concentration is associated with a higher risk of death and shorter survival time in cats with CKD.33,34,35 In these patients, the reduction in the number of functioning nephrons is thought to reduce the kidneys' capacity to excrete phosphorus as a result of a decrease in total glomerular filtration. The subsequent increase in serum phosphorus concentration triggers compensatory responses, but eventually, serum phosphorus concentration will increase unless dietary phosphorus intake is decreased. Phosphorus retention may lead to multiple complications, including soft tissue mineralization and hyperphosphatemia.36 Mineralization readily occurs in the kidneys, which may result in further progression of CKD. In addition, high serum PTH concentration resulting from hyperphosphatemia and low serum ionized calcium concentration may lead to other negative effects, such as osteodystrophy, pathological fractures, and so-called rubber jaw.36

As functional renal mass decreases in cats with CKD, less 1α-hydroxylase, which is necessary for production of calcitriol, is available. A decreased calcitriol concentration reduces calcium absorption from the intestines, resulting in increased secretion of PTH. Although FGF-23 normally inhibits PTH secretion, renal disease ultimately results in depletion of Klotho, the cofactor for FGF-23, and a decrease in the number of FGF-Rs in the parathyroid gland, which contributes to the lack of PTH inhibition.37 The increase in the secretion of FGF-23 as a result of high serum phosphorus concentration further reduces calcitriol concentration and increases PTH concentration while serum phosphorus concentrations are adjusting, provided there are sufficient functioning nephrons remaining.

As a result of these regulatory mechanisms, many measures of renal function (eg, glomerular filtration rate, urine concentration, and serum creatinine, PTH, and FGF-23 concentrations) may be altered before serum phosphorus concentration increases in cats with early CKD.9 Therefore, serum phosphorus concentration may be misleading in the clinical assessment of cats with CKD. Serum PTH and FGF-23 concentrations are not commonly evaluated in routine serum biochemistry panels, and there are no commercially available diagnostic tests for FGF-23 concentration in cats, although it can be measured in research settings.

Dietary phosphorus restriction (ie, feeding a diet with a phosphorus content at or below the minimum accepted dietary requirement) may slow disease progression and reduce related health complications in cats with CKD.38,39,40,41,42 It has been reported that in geriatric cats with early CKD but not azotemia, there is an association between concentrations of FGF-23 and symmetric dimethylarginine, a biomarker for decreased glomerular filtration.43,44 This suggests that alterations in phosphorus metabolism precede alterations in other indicators of reduced kidney function in cats.

High Dietary Phosphorus as a Cause for Renal Disease in Cats

High dietary phosphorus content is considered a risk factor for all-cause mortality (including cardiovascular and renal disease) in multiple species, including humans.4,45 In people, it has been suggested that high phosphorus intake may be related to socio-economic factors and dietary patterns. In particular, highly processed food may be a source of many phosphorus-containing inorganic salts, potentially leading to poor health.46

Cumulative evidence suggests that high dietary intake of phosphorus in a bioavailable form may be a cause for development of CKD in adult cats. The first study to suggest a link between high dietary phosphorus intake and reduced renal function in healthy adult cats was published by Pastoor et al22 in 1995. In that study, healthy adult cats were fed a test diet containing 3.6 g of phosphorus/1,000 kcal of ME with a calcium-to-phosphorus ratio of 0.3 for 4 weeks. The authors documented a small, but significant, reduction in endogenous creatinine clearance in cats fed the test diet, compared with clearance in cats fed a diet with ≤ 2.3 g of phosphorus/1,000 kcal of ME. A later study3 evaluated healthy adult cats fed a home-cooked diet supplemented with inorganic phosphorus (monophosphate) and containing 3.0 g of phosphorus/1,000 kcal of ME, with a low calcium-to-phosphorus ratio of 0.4, for 4 weeks. Feeding this diet resulted in potentially reversible changes in renal function, including a reduction in endogenous creatinine clearance, glucosuria, and microalbuminuria.

In another study,2 feeding adult cats extruded dry foods containing phosphorus contents > 3.6 g/1,000 kcal of ME and with a calcium-to-phosphorus ratio of 0.9 resulted in renal echogenicity changes and nephrolithiasis within 28 weeks, whereas feeding a control food with 1.2 to 1.3 g of organic phosphorus/1,000 kcal of ME did not. One cat in the group fed the high phosphorus diet also developed an acute uremic crisis and had to be euthanized, because it did not respond to supportive care. The same report documented more substantial renal impairment in cats fed an extruded diet with 4.8 g of phosphorus/1,000 kcal of ME and a calcium-to-phosphorus ratio of 0.6 for 4 weeks. In this cohort, reduced glomerular filtration rate and increased serum creatinine concentration were documented in addition to ultrasonographic changes. It is possible that the negative effects of high dietary inorganic phosphorus intake in this study were enhanced by a low dietary protein intake, in that low protein intake may decrease glomerular filtration rate and increase phosphorus sojourn time.47

It is possible that the adverse effects noted in these studies were due to the inclusion of a high inorganic phosphorus content, and there are, as yet, no long-term studies evaluating the effects of feeding diets with a similarly high organic phosphorus content. Furthermore, there is no reliable method to accurately determine the amount of bioavailable dietary phosphorus, although attempts have been made to establish a method for this purpose that uses water-soluble phosphorus as a proxy.23 It should be noted that studies that evaluated the health impacts of high dietary phosphorus intake in cats had several limitations, including differences in the calcium-to-phosphorus ratio between the test and control diets, and that a calcium-to-phosphorus ratio < 1 in the test diet could have increased the absorption of phosphorus. However, the authors believe that the consistency of findings across multiple studies is a strong indication that high dietary phosphorus intake may have a determinantal impact on renal health. It is yet to be determined whether this may be affected by factors such as dietary protein, potassium, or magnesium content or the calcium-to-phosphorus ratio. Currently there is no consensus regarding the causative relationship between high inorganic phosphorus intake and CKD in cats, particularly client-owned cats.

The pathogenesis for the renal damage that results from high dietary phosphorus intake in cats is unknown. However, a high concentration of extracellular phosphorus may be toxic to cells and can lead to premature cellular aging. Increased dietary phosphorus intake can lead to an increased renal phosphate burden, tubular injury, and interstitial fibrosis.48,49 Additionally, both PTH and FGF-23 may have negative health effects that include metastatic calcification and negative effects on cardiovascular health.4,50 These changes may not always be associated with measurable changes in serum phosphorus concentrations.

High tissue phosphorus concentrations contribute to increased oxidative stress in the endothelium,4,51 resulting in impaired function. As already discussed, high serum phosphorus concentration has an inhibitory effect on renal activation of vitamin D, which may also have a role in the pathogenesis of endothelial lesions. In addition, high serum phosphorus concentration may lead to transdifferentiation of vascular smooth muscle cells to bone-forming cells, thereby leading to cardiovascular abnormalities.4,52 This effect may be inhibited by magnesium in vitro, suggesting that plasma magnesium concentration may have prognostic importance in cats with CKD.53

Dietary Phosphorus Regulations

Minimum dietary requirements for phosphorus, calcium, and magnesium in cats have been established, along with regulatory minimum contents for commercial cat foods. However, there are no maximum dietary calcium and phosphorus contents included in globally accepted feline nutrition guidelines, including those from the National Research Council,18 the Association of American Feed Control Officials,54 and the European Pet Food Industry Federation,55 although the European Pet Food Industry Federation has introduced guidelines indicating that the calcium-to-phosphorus ratio for adult cat foods should be in the range of 1:1 to 2:1. Our current understanding of phosphorus bioavailability as related to its organic or inorganic form complicates establishment of regulatory standards, particularly because there is no standard test to differentiate types of phosphorus compounds in pet foods. Although attempts to determine the bioavailability of phosphorus in dog and cat foods with a water extraction method have been made,23 this method requires further validation, and measured water-soluble phosphorus content is not equivalent to inorganic phosphorus content reported in studies in which renal disease was induced in healthy adult cats.2 Furthermore, there is a lack of published long-term feeding studies evaluating the safety and physiologic impact of high dietary organic phosphorus intake in healthy cats.

A recent survey56 of commercial cat foods available in North America found substantial variability in total phosphorus content. This survey, which included 82 products, found that 27 foods (33%) contained total phosphorus contents ≥ 3.6 g/1,000 kcal of ME (range, 3.6 to 5.8 g of phosphorus/1,000 kcal of ME), including 7 that had total phosphorus contents > 4.6 g/1,000 kcal of ME. However, inorganic phosphorus content was not quantified. Thirteen (16%) foods had a calcium-to-phosphorus ratio ≤ 1.1 (range, 1:2 to 1:1), but none of the 82 study foods had a calcium-to-phosphorus ratio > 2.1.

These findings, combined with concerns regarding the potential risks of phosphorus, especially inorganic phosphorus salts, raise concerns regarding the current lack of regulatory guidelines for maximum dietary calcium and phosphorus contents and the potential risk for diet-related kidney damage in a subset of pet cats. We believe that interim limits on total dietary phosphorus content and acceptable calcium-to-phosphorus ratios should be considered until a safe limit for dietary phosphorus content in its various forms can be established. Specifically, we suggest an interim maximum total phosphorus content of 4.0 g/1,000 kcal of ME, a maximum added inorganic phosphorus content of 1 g/1,000 kcal of ME, and a calcium-to-phosphorus ratio between 1:1 to 2:1 until further data are available to inform permanent guidelines. Long-term feeding trials are required to establish the safety of organic and inorganic forms of phosphorus, rather than total phosphorus content alone, and the impact of dietary protein content and the content of other minerals such as calcium and magnesium. Additionally, studies are needed to evaluate whether a high total dietary phosphorus intake, high inorganic phosphorus or soluble phosphorus intake, and a dietary calcium-to-phosphorus ratio < 1 may be risk factors for renal dysfunction in client-owned adult cats and whether changing to a diet with a lower total or inorganic phosphorus content can help reduce the risk.

Clinical Summary

Phosphorus is an essential nutrient, and sufficient dietary phosphorus intake is needed to maintain health. This is true for cats of all ages but particularly for growing cats and reproducing queens. Restrictions in dietary phosphorus intake have long been recognized as paramount in the management of CKD in cats, as this slows the progression of advanced CKD. Restrictions in dietary phosphorus intake also likely have a role in the treatment of earlier stages of CKD, as evidenced by findings suggesting increases in FGF-23 concentration may serve as an early biomarker of CKD in cats.43,44 Recent studies2,3 have demonstrated that a high dietary intake of inorganic phosphorus in combination with a low calcium-to-phosphorus ratio can induce renal dysfunction in previously healthy adult cats. The lack of regulatory guidelines regarding maximum dietary phosphorus content and recent findings indicating that many commercial feline diets are high in dietary phosphorus content56 are of concern.

Acknowledgments

Dr. Stockman has been a consultant and shareholder for Petco Animal Supplies Inc and has received funding for research from Royal Canin. He has participated as an attendee in continuing education events sponsored or organized by Royal Canin, Nestlé Purina PetCare, and Hill's Pet Nutrition.

Dr. Villaverde has done consulting work for a variety of pet food companies, including Nestlé Purina, Royal Canin, Mars Pet Care, and Dechra Specific. She has participated as an investigator in clinical trials sponsored by Royal Canin and Affinity Pet Care and has developed educational materials for the Mark Morris Institute. She served on the scientific advisory board of the European Pet Food Industry Federation and as a member of the Global Nutrition Committee of the World Small Animal Veterinary Association. She has participated as a speaker or attendee in continuing education events sponsored or organized by Royal Canin, Nestlé Purina PetCare, and Hill's Pet Nutrition. Both authors have received travel stipends from Nestlé Purina.

The authors thank Dr. Jonathan Elliott and Dr. Richard Butterwick for their review of the manuscript and their helpful suggestions.

Abbreviations

CKD

Chronic kidney disease

FGF-23

Fibroblast growth factor 23

FGF-R

Fibroblast growth factor receptor

ME

Metabolizable energy

PTH

Parathyroid hormone

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