40 2015 Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health

Serum phosphorus concentration depends on dietary phosphorusintake, gastrointestinal absorption across the duodenum andjejunum, translocation into intracellular sites, skeletal absorp-tion, and excretion of phosphorus into the urine. The kidneysplay a crucial role in regulating phosphorus concentrations,with a narrow range maintained in health. Young growinganimals often have higher serum phosphorus levels thanadults (up to 9.0 mg/dl). The normal serum phosphorus rangeof many laboratories includes that of adults and growing animals, which may make it difficult to detect early increasesin serum phosphorus. The typical reference range for serumphosphorus for adult dogs and cats is 2.5 to 6.0 mg/dL (0.81to 1.94 mmol/L).

RENAL SECONDARY HYPERPARATHYROIDISM

Normophosphatemic and hyperphosphatemic forms of phos-phorus retention occur in patients with chronic kidney disease(CKD), leading to the development of renal secondary hyper-parathyroidism (2-HPTH; Figures 1 & 2). Phosphate retentionand hyperphosphatemia are primarily due to impaired renalphosphate excretion. Hyperphosphatemia during progressiveearly CKD is transient, as normophosphatemia is quicklyrestored under the influence of increased secretion ofparathyroid hormone (PTH) and fibroblast growth factor-23(FGF-23), which increase urinary phosphate excretion.

Renal 2-HPTH is commonly documented in dogs and cats withCKD. Overall frequency of renal 2-HPTH was 76% in a recentstudy of dogs with CKD, encountered in 36% with International

Renal Interest Society (IRIS) stage 1 CKD, 50% with stage 2,96% with stage 3, and 100% with stage 4.1 An increasingfrequency of renal 2-HPTH was similarly found in cats withCKD,2,3 affecting 84% of cats overall (from 47% of cats withstable azotemia but without clinical signs, to 100% of catswith decompensated CKD). Hyperphosphatemia is commonlyin CKD patients with 2-HPTH, but 2-HPTH can be encoun-tered in both dogs and cats with serum phosphorus withinthe normal reference range. Hyperphosphatemia was noted in18% and renal 2-HPTH in 36 % of dogs with IRIS stage 1 CKD.1

The concept that renal 2-HPTH can precede development ofhyperphosphatemia in CKD has not been well appreciated inveterinary medicine. Serum phosphorus in the upper normalreference range has recently been associated with increased PTHin dogs with CKD,1 confirming earlier reports of this association.4,5

Excess PTH is toxic to a variety of tissues, including the kidneys,during CKD.

Decreasing Total Body PhosphorusBurden in Chronic Kidney Disease Dennis J. Chew, DVM, DACVIM

Valerie J. Parker, DVM, DACVIM, DACVN The Ohio State University, Columbus, Ohio

Figure 1. Deleterious effects of increasing total body phosphorus burden in CKD.

PTH = parathyroid hormonePTG = parathyroid glandiCa++ = ionized calciumFGF = fibroblast growth factorPi = inorganic phosphorus

Figure 2. The role of fibroblast growth factor (FGF)-23/Klotho in early chronic kidney disease. As glomerular filtration rate (GFR) declines, increases in phosphorus burden cause an increase in FGF-23 production. Calcitriol production increases under the influence of increased parathyroid hormone (PTH), which helps to restore ionized calcium (iCa) concentration. In this stage of kidney disease, a normal ionized calcium concentra-tion with elevated PTH concentration and normal to high serum phosphorus (S-Pi) concentration may be observed. With further absolute decrease in renal tubular tissue, there is decreased Klotho expression in the kidneys and parathyroidglands, with end-organ resistance to the actions of FGF-23. Thus, FGF-23 actions to excrete phosphorus or blunt PTH synthesis become less effective. In addition, the up-regulationof 24-hydroxylase increases the degradation of any remainingcalcitriol. GI = gastrointestinal.

2015 Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health 41

The complex interactions that occur between circulating ionizedcalcium, inorganic phosphorus, PTH, 25(OH)-vitamin D, calcitriol(1,25(OH)2-vitamin D), FGF-23, and Klotho (circulating and tissueexpression) during CKD were recently reviewed in detail.6

Relative and absolute deficits of the most biologically activevitamin D metabolite, calcitriol, are central in the genesis ofrenal 2-HPTH through various underlying mechanisms.Though not traditionally emphasized until very recently,deficits of 25(OH)-vitamin D are also common in CKD andmay contribute to renal 2-HPTH and other adverse systemiceffects. Total body phosphorus burden and increasing concen-tration of circulating phosphorus play a pivotal role in thedevelopment of renal 2-HPTH and are intimately related todynamics of calcitriol and FGF-23/Klotho (Figures 2 & 3). LessFGF-23 is required to decrease calcitriol synthesis than to promotephosphaturia, so decreases in serum calcitriol concentrationoccur prior to phosphaturia in very early CKD.7 High concen-trations of circulating FGF-23 (for left ventricular hypertrophyand congestive heart failure) and serum phosphorus (for vascular calcification and endothelial dysfunction) have beenidentified as cardiovascular risk factors in humans withadvanced CKD,8 but this has not been investigated in veterinarymedicine. In CKD, the increased secretion of FGF-23 may be aprotective mechanism to stabilize serum phosphorus concen-tration with a decreasing number of nephrons. Thus, FGF-23increases urinary phosphate excretion, decreases gastrointestinalabsorption (indirectly), decreases calcitriol synthesis throughinhibition of 1-α-hydroxylase, and increases calcitriol degradationthrough enhanced activity of 24,25-hydroxylase. These effectsallow serum phosphorus to be maintained within a normalrange until CKD becomes more advanced.

Higher concentrations of serum phosphorus predicted anincrease in serum creatinine >25% above baseline over 12months in 47% of cats with CKD.9 Serum phosphorus was theonly clinicopathologic variable predictive of survival in one studyof CKD cats. There was an increase in risk of death of nearly12% for each mg/dL increase in phosphorus in that study.10

Higher phosphorus concentration was associated with a higherrisk of death within 1 month in another study.11 Even whenserum phosphorus was within the reference range, cats withCKD and phosphorus concentration >4.7 but <6.8 mg/dL hada higher risk of death, compared with that in cats with CKSand phosphorus <4.7 mg/dL.12

REDUCING TOTAL BODY PHOSPHATE BURDEN

An overarching principle of initial treatment of CKD is toreduce the degree of phosphorus retention within the body.Less phosphorus retention relieves the inhibitory effect ofphosphorus on renal 1–α–hydroxylase activity, resulting in theincreased production of endogenous calcitriol and subsequentinhibition of PTH synthesis. Less phosphorus burden alsodecreases circulating FGF-23 and increases ionized calcium.

Measures to decrease gastrointestinal (GI) absorption of dietaryphosphorus are central in decreasing total body phosphateburden. Consumption of diets with lower total phosphoruscontent and/or decreased phosphate bioavailability and the

addition of intestinal phosphate binders to the diet are usefulmethods to decrease phosphate entry into the body.13 Dietaryphosphorus restriction alone may decrease PTH or FGF-23 orprevent their increases in early stages of CKD in cats anddogs. However, diet alone will become ineffective to controlPTH or FGF-23 as CKD advances, especially as serum phos-phorus concentration increases. Restoration of normophos-phatemia normalized PTH in many cats with early uremia,14,15

but was successful in only a portion of uremic dogs, many ofwhich required calcitriol to normalize PTH.4 Serum phosphorusin the upper reference range was associated with increasedPTH in dogs with CKD in 2 studies.1,5 Concentrations of FGF-23were higher in cats with IRIS stage 2 CKD when serum phos-phorus was >4.5 mg/dL vs. <4.5 mg/dL. Cats of the samestudy with IRIS stage 3 CKD had much higher concentrationsof FGF-23 when serum phosphorus was >5.0 mg/dL vs. <5.0mg/dL.16 Feeding a renal diet to cats with IRIS Stage 2, 3, or 4 CKD that were hyperphosphatemic (>4.5, >5.0 , 6.0 mg/dLby IRIS stage) resulted in lower serum phosphorus, PTH, andFGF-23. Cats with CKD classified as normophosphatemic fortheir IRIS stage and fed the same renal diet decreased theircirculating concentration of FGF-23, despite no change in PTHor serum phosphorus.17

Figure 3. Algorithm for use of diet and phosphate binders to achieve targeted serum phosphorus control in patients with chronic kidney disease.S = serum; Pi = inorganic phosphorus.

42 2015 Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health

RESTRICTING DIETARY PHOSPHORUS CONTENT

The average pet foods from the grocery store for dogs andcats contain 5 to 6 times as much phosphorus, on a mg/100kcal-of-intake basis, than the average phosphorus intake forhumans eating a Western-type diet (50 mg/100 kcal). Somepet foods contain up to 500 mg of phosphorus/100 kcal. Thismakes it difficult to achieve adequate dietary phosphorusrestriction during CKD when feeding nontherapeutic diets.Veterinary renal diets are designed to have a phosphorus content lower than AAFCO minimal requirements for adultmaintenance (dogs, 140 mg/100 kcal; cats, 125 mg/100 kcal).Commercial renal diets for dogs provide 48 to 120 mg ofphosphorus/100 kcal and for cats, 80 to 117 mg/100 kcal.Although some “senior” or “mature” diets are restricted inphosphorus or protein content, these dietary constituents insuch diets vary widely on a mg/100 kcal basis.18 Comparingthe phosphorus content on an energy basis (mg/100 kcal),rather than on a dry matter basis (%), is important to allowfor comparison between dry and canned diets, as well as dietsof different caloric concentrations.

Diets with the same phosphorus content may result in differentphosphorus absorption across the intestine due to differencesin bioavailability. Despite similar total dietary phosphorus intake,substantial differences in phosphorus bioavailability weredemonstrated in a study of cats provided phosphorus derivedmostly from poultry, meat, and fish meal (less biovavailable),compared with inorganc phosphorus derived from neutralmonobasic/dibasic salts (more bioavailable).19 Animal proteinsgenerally provide more phosphorus than vegetable proteins;however, most of the phosphorus in commercial diets typicallycomes from specific phosphate-containing mineral supplements(e.g., calcium phosphate, ammonium phosphate). Phytatesfrom vegetable sources can limit calcium and phosphorusabsorption across the intestine. The dietary calcium-to-inorganicphosphorus (Ca:Pi) ratio also affects intestinal phosphorusabsorption. In most adult maintenance diets, Ca:Pi is about1:1 to 2:1, whereas a ratio as high as 3.5:1 can be found insome veterinary renal therapeutic foods. A Ca:Pi in this rangecould act as an inherent binder to further limit Pi absorption.

For owners who prefer to feed home-cooked diets, consultationwith a veterinary nutritionist is advised. When a large numberof home-prepared diets designed for management of CKD indogs and cats were analyzed, many of these recipes werefound to be inadequate for meeting the nutritional and clinicalneeds of CKD patients.20 Treats given to animals with CKD,

including foods that may be used as palatability enhancers,should provide <10% of the animal’s total daily intake to avoidunbalancing the diet. Fresh or frozen fruits and vegetablesgenerally make good low-phosphorus treats; the amount to befed will depend on the individual animal’s size and desired caloricintake. A good resource for determining nutrient concentrationsof specific “people” foods is the USDA Nutrient Database(http://ndb.nal.usda.gov/). Commercial pet treats can varytremendously in phosphorus concentration.

USE OF INTESTINAL PHOSPHATE-BINDING AGENTS

Despite the known benefits of targeted control of phosphorusburden, intestinal phosphate binders appear to be underutilizedduring treatment of CKD in cats and dogs. In a study of treat-ment for cats with CKD, intestinal phosphate binders wereprescribed for only 22% of the cats.21 Similar data are notavailable for how frequently intestinal phosphate binders areprescribed for dogs with CKD.

Phosphorus binding agents are given orally to trap phosphorusin the gut and increase insoluble phosphate salt excretion intofeces. Phosphate binders work because the cation in thebinder combines with dietary phosphate, producing insoluble,non-absorbable phosphate compounds. Intestinal phosphatebinders function best when given with meals or within 2hours of feeding. Other drugs should be given 1 hour beforeor 3 hours after any intestinal phosphate binder, to limit theeffect on drug absorption. The dose of any phosphate bindershould be based on the meal size (phosphorus intake) and theprevailing serum phosphorus level for each CKD patient, andis titrated to effect. No phosphate binders have yet beenlicensed as a drug in veterinary medicine, as they have inhuman nephrology.22

All phosphate binders work best when given in the food tobind phosphorus or reduce digestibility of phosphorus in thefood. The ideal intestinal phosphate binder avidly binds Piwithin the intestinal lumen to increase fecal excretion of dietaryphosphorus. Phosphate binders can be given within a fewhours of eating, but the decrease in phosphorus absorption isnot as efficient. Various classes of Pi binders (Table 1) can besimilarly effective in control of serum phosphorus, but may bequite different in the degree of FGF-23 control achieved.13

Special consideration should be given in selection of class ofintestinal phosphate binder when calcitriol will also be prescribed.Sevelamer interfered with absorption of orally administeredcalcitriol when lanthanum did not.23 Calcium-based intestinalphosphate binders are now rarely used in human nephrology,in part because of the increased use of calcitriol or other activatedvitamin D metabolites to provide vitamin D-receptor activationand concerns for development of vascular calcification.24 Allcalcium salts can result in ionized hypercalcemia as an adverseeffect. The use of calcium salts could have an advantage inCKD patients that remain hypocalcemic following reduction inserum phosphorus concentrations.

Despite the known benefits of targeted controlof phosphorus burden, intestinal phosphate bindersappear to be underutilized during treatment ofCKD in cats and dogs.

2015 Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health 43

CKD=chronic kidney disease; Pi = inorganic phosphorus

Table 1. Dosage for treatment with intestinal phosphate binders in CKD. All binders should be given with a meal or preferably in the meal. Unless specified otherwise, all dosages are for dogs and cats.

Intestinal Phosphate Binder

Aluminum Salts

Aluminum hydroxide

• Alternagel®

o 600 mg/5 ml

• Phos-Bind®

o 200 g containero 500 mg/scoop o Rx Vitamins for Pets

• ConSeal-AlH®

o Chewable; 200 mg/chewo Bock Vet Pharma

• Sucralfate o Inefficient provider of aluminum binding

Calcium Salts

Calcium carbonate

• Tums® regular strength o 500 mg/tablet

• Avoid magnesium-containing formulations

Calcium acetate

• More Pi binding & less hypercalcemia than carbonate salt

Epakitin®

• Vetoquinol

• Chitosan, 10% calcium carbonate

Sevelamer Salts

Lanthanum carbonate

• Fosrenol® Shire Co

• 500 mg chewable tablets

Emerging Binders

Pronefra®

• Calcium carbonate, magnesium carbonate

• Virbac

Lenziaren®

• Iron oxide with sucrose and starch

• Novartis

Niacin

• Cheap and effective

Dosage

No safe dose is known in human CKD. Measure serum aluminum?

30 mg/kg, PO, every 8 hours

45 mg/kg, PO, every 12 hours

Measure serum calcium; ionized calcium preferred over total calcium in CKD

30 mg/kg, PO, every 8 hours

45 mg/kg, PO, every 12 hours

30 mg/kg, PO, every 8 hours

45 mg/kg, PO, every 12 hours

1 g/10 lb., twice daily with food

Organic poymer; can bind vitamins at high doses; coagulopathy at very high doses

35-100 mg/kg/day, PO, divided in food

Not fully evaluated in dogs or cats with clinical CKD

Evaluated in normal cats only

Measure serum magnesium in CKD?

0.5 ml/kg/day in food

Evaluated only in cats

0.50 to 1.0 g/cat/day for maintenance food

0.25 to1.0 g/cat/day for renal food

Humans only – 1,000 to 1,500 mg/day

44 2015 Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health

Intestinal phosphate binders should be mixed in food at appro-priate doses to achieve a specific targeted serum phosphorus,PTH, or FGF-23 concentration. Optimal PTH control occurs indogs with CKD when a targeted serum phosphorus of < 4.5mg/dL1,5 or when the middle of the reference range is achieved.Return of serum phosphorus to within the normal referencerange is an initial goal, but does not guarantee adequate controlof PTH or FGF-23 production.

Serial measurement of serum phosphate concentration isimportant for patients with CKD managed with a renal dietand when intestinal phosphate binders are prescribed (Figure 3).Monitoring is usually monthly until the target concentrationhas been achieved, and then every 2 to 4 months thereafter if stable. Serum phosphorus concentration may increase inCKD patients that increase their food intake following othersupportive CKD treatments. Achieving mid-reference rangetarget phosphate concentrations is more difficult in those with more advanced levels of azotemia. Less stringent targetguidelines for serum phosphorus control (<6.0 mg/dL or 1.94mmol/L for Stage 4; <5.0 mg/dL or 1.61 mmol/L, stage 3;<4.5 mg/dL or 1.45 mmol/L, stage 2), based on IRIS stage ofCKD, have been suggested.25 Measuring ionized calcium, inconjunction with PTH, as additional targets is ideal.

Adverse effects of phosphate binders can occur. Althoughhypophosphatemia is one such possible consequence, it is difficult to develop with initially high concentrations of serumphosphorus and reduced glomerular filtration rate. Constipationand GI effects can occur following use of some intestinalphosphate binders. Chemicals from the phosphate binder maybe absorbed and accumulate in body tissues, and may produceadverse effects. Some binders also can decrease GI absorptionof vitamins.

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