The role of phosphorus in feline chronic renal disease (Proceedings)

Article

Less than 1% of the total body phosphorus is in the plasma with 1/3 of this as inorganic phosphate ions, most of which are unbound. Laboratory analysis of serum phosphorus measures all forms of H3PO4 (H3PO4, H2PO4, HPO4) referred to as inorganic phosphate. Serum phosphate levels are higher in serum than plasma due to the clotting process that releases phosphorus from cells and platelets.

Less than 1% of the total body phosphorus is in the plasma with 1/3 of this as inorganic phosphate ions, most of which are unbound. Laboratory analysis of serum phosphorus measures all forms of H3PO4 (H3PO4, H2PO4, HPO4) referred to as inorganic phosphate. Serum phosphate levels are higher in serum than plasma due to the clotting process that releases phosphorus from cells and platelets.

Serum phosphate is maintained within a narrow range in health. Levels of serum phosphate are often higher in young growing animals than in adults possibly owing to the effects of higher levels of growth hormone that increases renal tubular reabsorption of phosphorus; higher levels of calcitriol during growth may also contribute. The normal range for many laboratories unfortunately includes that of adult and growing animals, making it difficult or impossible to detect early rises in serum phosphorus above normal. Serum phosphate concentration is less than 5.5 mg/dl in most healthy adults.

Serum phosphorus concentration depends on the dietary phosphorus intake, the degree of GI absorption across the duodenum and jejunum, translocation into intracellular sites, and how much is excreted into the urine. The kidney is the major organ for regulation of serum phosphate concentration. Renal excretion depends on how much phosphorus undergoes glomerular filtration and how much is subsequently reabsorbed by the tubules. Most of the reabsorption of phosphorus occurs in the proximal tubules, an effect that is largely controlled by the expression of Na-phosphate co-transporters on the brush border. PTH, increasing concentrations of circulating phosphate, and metabolic acidosis are known for their ability to reduce the expression of this transport system, which results in more phosphorus excreted into urine (phosphaturia). Na-phosphate transporters under the control of calcitriol exist in the intestine. Increased levels of PTH can keep serum phosphorus within the normal range by this adaptive renal mechanism despite continued loss of renal mass and function in patients with CKD until more than 85% nephron mass has been lost, at which point the serum phosphate concentration progressively increases.

Pathophysiology of Phosphorus in Renal Disease, and Renal Failure

Total phosphorus burden/retention during chronic renal failure adversely affects renal function, renal histopathology, and soft tissue mineralization in the kidneys and other organs. It is not possible to evaluate the damaging effects of phosphate retention as a separate entity since circulating phosphate has a complex relationship that affects and is affected by PTH, ionized calcium, and calcitriol. Deleterious effects of phosphate accumulation in the body (eventually leading to hyperphsophatemia) can be a direct consequence of phosphate, from calcium phosphate precipitates into the tissues (increased calcium x phosphate product), decreased ionized calcium, and increased PTH (from insufficient calcitriol, low ionized calcium, and or a direct effect of phosphate to stabilize mRNA for PTH synthesis in the parathyroid gland).

It has been known since the early 1980's that dietary phosphorus restriction provided dramatic benefits to the histologic renal architecture of cats with the remnant model of chronic renal failure. Though renal function was not different over time in cats of this study, cats fed the normal maintenance diet had obvious mineralization, fibrosis, and mononuclear cell infiltration whereas the kidneys of cats fed the phosphate-restricted diet had minimal or no changes. Serum phosphorus and PTH concentrations were considerably increased in cats fed the normal phosphate diet compared to those fed the restricted phosphate diet (Ross 1982).

In a study of 50 CKD cats (mean serum creatinine near 3.0 mg/dL), twenty-four of 50 cats were hyperphosphatemic at the start of the study. Plasma phosphate concentration at the mid-survival time point increased over baseline in 62% of those eating a normal diet (n = 21) and decreased in 76% of cats eating the renal veterinary diet (n = 29). Forty-six of 50 cats had increased PTH at the start of the study. PTH declined in 69% of cats that were eating the veterinary renal diet at the mid-survival time point, whereas PTH increased in 62% of those eating a maintenance diet. Intestinal phosphate binders were added as treatment when serum phosphorus remained increased within 4 months of feeding the renal diet in 4 cats; an additional 6 cats required the addition of an intestinal phosphate binder throughout the study for a total of 34% (10/29). Survival time for CKD cats eating the renal diet was considerably longer for cats eating the renal diet (633 median and 616 mean days) compared to those eating a maintenance diet (264 median and 383 mean days) [Elliott JSAP 2000].

Increased levels of serum phosphorus have been associated with increased all-cause mortality, cardiovascular mortality, vascular calcification and valvular calcification in humans with CKD. One human study showed that end-stage renal failure patients with a serum phosphorus level >6.5 mg/dl (>2.10 mmol/l) had a 27% higher mortality risk than patients with a phosphorus level of 2.4–6.5 mg/dl (0.78–2.10 mmol/l); and that patients with a calcium x phosphate (Ca x P) product >72 mg2/dl2 had a 34% higher risk of death compared with those with a Ca x P product between 42 and 52 mg2/dl2 (Block Am J Kidney Ds 1998). Vascular mineralization and death due to cardiac effects is a major cause of death in people with CKD. Death related to cardiovascular system abnormalities was reported to be second to renal related causes of death in one study of cats with CKD, though detailed micropathology of vascular structures was not provided (Elliott JSAP 2000). In one retrospective study in cats, the only clinicopathologic variable that was associated with survival in animals with naturally occurring CKD was serum phosphorus. For each 1 unit increase in phosphorus there was an 11.8% increase in the risk of death (Boyd JVIM 2008). In another study, increased plasma phosphate concentration was found to be highly significantly associated with shorter renal survival times (King JVIM 2007).

Treatment of Increased Total Body Phosphate Burden

Conventional wisdom and evidence dictates the importance of correcting the hyperphosphatemia of CKD. Restoration of normophosphatemia is an initial goal but phosphorus restriction still may be beneficial in reversing existing renal secondary hyperparathyroidism in patients that are not hyperphosphatemic at the time of initial evaluation. Secondary hyperparathyroidism can exist despite normal ionized calcium and serum phosphorus status as was shown in one study of cats (Barber and Elliot 1998 JSAP). If serum phosphorus is increased, there is a very high chance that the serum PTH level will be increased but there is no guarantee that if the serum phosphorus is normal that the PTH level will also be normal.

Dietary modification and intestinal phosphate binders are pivotal treatments to provide optimal phosphorus and PTH control. Compared to humans consuming an average diet, cats consume 6 times as much dietary phosphorus when eating commercial maintenance foods. With such a high starting point, it is difficult to achieve the degree of phosphorus restriction that is targeted in human medicine. Dietary phosphorus restriction in CRF has been shown to blunt or reverse renal secondary hyperparathyroidism in cats of one study (Elliott 2000) but not in another (Ross 2006).

Proportional reduction of dietary phosphorus intake that matches decreases in GFR will keep serum phosphorus within the normal range without increases in PTH. Although this would be ideal, it is not easy to do this clinically. Extremely phosphorusdepleted diets are unpalatable (due to very low levels of protein needed to provide this phosphorus restriction). Diets moderately restricted in phosphorus may provide adequate phosphate control (normal serum phosphate and PTH) during early stages of chronic renal failure. Diet alone is not successful in adequate phosphorus control as chronic renal disease becomes more advanced. In these instances serum phosphorus concentration increases above the normal range or stays in the upper half of the normal range.

When CRF is diagnosed, phosphorus restriction is initiated by feeding a low phosphorus, low protein diet. Renal diets achieve phosphate restriction largely by restriction of dietary proteins that contain phosphorus, especially animal origin proteins. The form of phosphate in the diet influences how much is available for absorption. Despite similar dietary phosphorus content and phosphorus intake, the amount of phosphorus absorbed across the gut varied considerably in one study of cats due to differences in phosphorus bioavailability. This effect may depend on the source of the phosphorus as organic vs monobasic or dibasic salts of phosphorus in the diets (Finco 1989). Since the degree of intestinal absorption of phosphorus can vary between 40 and 80% of the ingested load by individual, different levels of phosphate control can be shown in animals with the same phosphorus intake and level of renal dysfunction. So when there are difficulties in achieving the target serum phosphorus or PTH levels during phosphate restriction, it may be due to too much dietary phosphorus intake, an individual patient's high level of GI absorption, or the formulation of the phosphate in the diet.

Goals During Treatment

An initial goal is to attempt to return high serum phosphorus concentrations to within the normal range by the feeding of a phosphate-restricted renal diet. Intestinal phosphate binders should be added as treatment if serum phosphate remains increased after one month of consuming the renal diet. We recommend achieving a target serum phosphate concentration in the mid-normal range. It is important to serially measure serum phosphate concentrations in cats with CKD – we recommend sample intervals monthly until the target concentration has been achieved and then every 3 to 4 months thereafter if the cat is stable. It is important to remember that serum phosphorus concentration often increases in CKD cats that increase their food intake following other supportive CKD treatments.

The minimal goal is to restore and maintain normophosphatemia, preferably in the mid-normal range, in cats with CKD. An optimal goal is to restore PTH to normal levels or to prevent it from increasing even if serum phosphorus is in the normal range. Further phosphorus restriction with diet and phosphorus binders can be titrated to the effect of lowering PTH if possible. In some instances, PTH cannot be controlled despite dietary intervention and use of intestinal phosphate binders. Other treatments with calcitriol and calcimimetics may be indicated in these cases. Fractional excretion of phosphorus can be monitored during treatment, but is not a very sensitive indicator of renal secondary hyperparathyroidism. Serial measurement of PTH and ionized calcium from the same time is recommended as a gold standard of sufficient relief of body phosphorus burden and PTH control.

Adverse effects of phosphate restriction potentially can occur. Although hypophosphatemia is one such possible consequence, it is difficult for this to develop in those with initially high concentrations of serum phosphorus. Hypercalcemia is occasionally encountered when calcium salts are used for intestinal phosphate binding. Hypercalcemia also has been attributed to feeding of renal diets in cats but this is rare; normophosphatemia returns with the feeding of a higher phosphate diet. Adynamic bone disease is of concern during the treatment of humans with CKD as occurs when PTH has been suppressed too much so that healthy bones cannot be maintained – whether this occurs in cats with CKD is not known. Constipation and GI effects can occur following use of some of the intestinal phosphate binders. Absorption of chemicals from the intestinal phosphate binder occurs with resulting accumulation in the tissues in some instances.

Intestinal Phosphate Binders

Despite the fact that intestinal phosphate binders are commonly used in veterinary practice for patients with CKD, there have been few published reports focusing on the safety and efficacy of these products in veterinary medicine. No phosphorus binders are licensed as medications for dogs or cats. Recently, two intestinal phosphorus-binding products have been approved as food additives (Epakitin and Lantharenol (not in US, see below).

Oral phosphorusbinding agents can be added to the treatment regimen to provide additional reduction in serum phosphorus and/or PTH concentration. Phosphorusbinding agents are given orally to trap phosphorus in the gut and increase insoluble phosphate salt excretion into feces. The goal is to increase fecal excretion of phosphorus by not allowing its GI absorption. All intestinal phosphate binders work best when given with meals or within 2 hours of feeding to maximize their binding of dietary phosphorus. Due to varying effects of intestinal phosphate binders to limit absorption of drugs, it is advisable to give other drugs 1 hour before or 3 hours after any intestinal phosphate binder is given. The dose of any phosphate binder should be based on the meal size (phosphorus intake) and the prevailing serum phosphorus level for each CKD patient; the dose is titrated to effect.

Aluminum Salts Aluminum based phosphate binding agents are highly effective in lowering serum phosphate levels due to their powerful intestinal phosphate binding effects and were the preferred intestinal phosphate binder used in humans with end-stage renal failure until approximately the mid 1980's. The gastrointestinal tract is relatively impermeable to aluminum, although, under certain circumstances aluminum can be absorbed from the gastrointestinal tract causing an increase in concentration in the blood and tissue. Normally excess aluminum is excreted by the kidneys and aluminum intoxication is not seen in people with normal renal function. In humans with CKD, significant aluminum may be retained in the body, especially the bone, leading to osteomalacia, adynamic bone disease, microcytic anemia, and encephalopathy. As a result the use of aluminum salts has been limited in human medicine. Recommended guidelines have been established for the use of aluminum based phosphate binders in people (K/DOQI - Kidney Dialysis Outcomes Quality Initiatives). Detrimental effects of aluminum based phosphate binders as described above seen in humans have not been evaluated in small animal patients. A case report describes aluminum toxicity in two dogs with renal failure treated with aluminum hydroxide (Segev C JIVM 2008). As cats with CKD can live for years on treatment, concerns for aluminum accumulation deserve more study as to long-term safety.

Despite the known concerns for toxicity in humans, aluminum salts remain the most commonly prescribed intestinal phosphate binders in veterinary medicine as they are very effective phosphate binders and are inexpensive. Aluminum hydroxide or aluminum carbonate initially is used at a dosage of 20-30 mg/kg q8h or 30-45 mg/kg q12h given with food. Constipation is the most common side effect encountered during treatment with aluminum phosphate binders. Lactulose treatment helps alleviate constipation in these instances but may contribute to dehydration due to extra fluid loss in the stool.

Calcium Salts Calcium-based phosphate binders took the place of aluminum salts in humans with end-stage real disease following reports of aluminum accumulation and toxicity. They are effective in lowering serum phosphorous via binding in the gastrointestinal tract, but can be associated with adverse effects during treatment in humans with end-stage renal disease: hypercalcemia from absorption of calcium from the gastrointestinal tract, increased incidence of adynamic bone disease due to over-suppression of PTH production as a result of chronic hypercalcemia, and increased incidence of soft tissue and vascular calcification from chronic hypercalcemia and increased Ca x P product. Soft tissue and vascular calcifications have been associated with significant morbidity and mortality in children and adults with end-stage renal disease.

The most commonly used calcium based phosphate binders are calcium carbonate and calcium acetate. Calcium carbonate can be used at a starting dosage of 30-mg/kg q8h or 45-mg/kg q12h given with food. It has maximal phosphorous binding capacity at a pH of 1.5 and is poorly soluble in neutral solutions. Many CKD patients receive inhibitors of gastric acid secretion potentially reducing calcium carbonates ability to bind phosphorous. Calcium acetate has been shown to be more effective than calcium carbonate as a phosphorus binder, is comparable to aluminum salts in potency for phosphate binding, and can bind phosphate over a wide range of pH. Calcium acetate has been shown to cause less hypercalcemia than calcium carbonate when activated vitamin D metabolites are not also being used. It can be used at a slightly lower dosage than calcium carbonate. Doses of 20, 30, or 40 mg/kg given with each meal approximate doses recommended for humans with dialysis dependent CKD. Animals should be monitored for development of hypercalcemia whenever calcium-containing phosphorus binders are used. Non-calcium containing salts are preferred treatment when CKD treatments include calcitriol or activated vitamin D metabolites to lessen chances for the development of hypercalcemia.

Sevelamer Sevelamer hydrochloride is a relatively new phosphorus binder used in human patients on dialysis. Its effects on dogs and cats with clinical CRF have not been reported. Sevelamer is an organic polymer that does not contain aluminum or calcium and is not systemically absorbed (excreted entirely in feces). It is hydrophilic but not soluble in water. Pills should be given intact -since sevelamer is hydrophilic it will expand in water. Sevelamer may be associated with gastrointestinal side effects including constipation. At extremely high dosages in dogs (6 to 100 times the recommended dosage in humans) sevelamer may be associated with impaired absorption of folic acid and vitamins K, D, and E. Since it is administered as an acid salt there is theoretical concern for exacerbation of metabolic acidosis. An additional benefit of Sevelamer is its ability to bind and sequester bile acids resulting in a favorable lipid profile: reduction in LDL and total cholesterol. Lipid abnormalities in cats with CKD have not been well studied.

Chitosan Epakitin ® (Vetoquinol) is marketed as a food additive on the veterinary market. It contains the adsorbent chitosan (8% crab and shrimp shell extract) and 10% calcium carbonate designed to reduce GI phosphorus absorption and to lower urea nitrogen due to effects of reduced protein digestibility. Its long-term beneficial effects in clinical cats with CRF have yet to be demonstrated. We have observed the development of hypercalcemia occasionally results during treatment.

There is one short-term study of a small number of normal and CKD cats. Ten normal cats were fed a maintenance diet supplemented with a chitosan and calcium carbonate product (Ipakatine, Vetoquinol, Lure Cedex, France; 8% crab shell, 10 % calcium carbonate, 82% lactose) for 21 days at a dose of 1 g/5 kg of body weight. Compared to control cats fed the same diet, the apparent digestibility was reduced for crude protein, crude fiber, and gross energy. The apparent digestibility of phosphorus was reduced greater than 50% and calcium over 100% during the treatment period. Urinary excretion of phosphorus and calcium did not change during treatment). Six cats diagnosed with CKD based on increased BUN and clinical signs were fed the same diet and supplement as the normal cats for 35 days. Significant reduction in BUN and serum phosphorus was detected at day 35 (initial BUN mean of 85.6 mg/dl [14.3 mmol/L] to 61.2 mg/dl [10.2 mmol/L; initial phosphorus mean of 5.2 mg/dl [1.7 mmol/L] to 3.4 mg/dl [1.1 mmol] ). BUN and serum phosphorus were reduced in each cat; serum creatinine did not change at 1.2 mg/dl [ 106 mmol/L]. The reduction in protein and phosphorus digestibility along with the decreases in BUN and serum phosphorus in cats eating a normal maintenance diet suggest that this supplement could be an alternative to prescription of renal veterinary diets thereby allowing some cats to continue on their regular diets while still reducing the risks for progression of CKD associated with total body phosphorus burden (Wagner 2004).

Lanthanum Salts Lanthanum carbonate was developed as a non-aluminum and non-calcium containing intestinal phosphate binder. It appears to be a very effective intestinal phosphate binder. Free lanthanum ions become available following exposure of lanthanum carbonate to the acidic environment of the stomach. Highly insoluble lanthanum phosphate complexes develop which are not absorbed across the GI tract. Very little lanthanum is absorbed across GI tract in humans. Lanthanum accumulates to a far less degree following absorption compared to aluminum since lanthanum undergoes extensive hepatic excretion whereas aluminum is excreted mostly by the kidneys. Lanthanum appears to have minimal toxicity in humans, but it has been in use for a short time. Reports of its use in cats are emerging. Cats receiving a 10-fold increase over recommended dose did not show signs of toxicity in a relatively short-term study (European Food Safety Authority 2007). Toxicity studies in dogs show that lanthanum increases in many tissues (especially GI tract, bone and liver) during treatment. Tissue levels remained detectable for longer than 6 months in dogs following discontinuation of treatment.

In 2007 the European Food Safety Authority approved lanthanum carbonate octahydrate (Lantharenol® Bayer) as an additive to maintenance food for adult cats in order to decrease intestinal phosphate absorption. The approved dose was 1500 to 7500 mg per kg of complete feed; decreased phosphorus absorption was documented at the lowest dose. Four groups of 8 normal European Shorthair cats were fed a canned maintenance food supplemented with lanthanum carbonate at 0, 0.3, 1.0, or 3.0 grams per kg of food as fed (1.6-16 g per kg of standard dry food) for 2 weeks. Phosphorus excretion into feces increased while phosphorus excretion into urine decreased in a dose–related manner; serum phosphorus did not differ between dose groups. Food intake did not change during treatment (Schmidt 2006). Renalzin® (Bayer) is the proprietary name for the delivery system of Lantharenol® using a pump to deliver the appropriate liquid dose to food. Renalzin also contains kaolin for uremic toxin binding effects and vitamin E for its anti-oxidant effects but the benefits of these other compounds has not yet been demonstrated.

Four groups of 9 normal European Shorthair cats were fed a wet veterinary renal diet with 0, 1.5, 4.5, or 7.5 g/kg of complete food. Similar to the normal cats with feeding of maintenance food and lanthanum treatment, veterinary food intake was not changed amongst treatment groups, apparent phosphorus digestibility decreased, intestinal phosphorus absorption was decreased due to increased fecal phosphorus excretion and urinary phosphorus excretion was decreased. Serum phosphorus did not change between treatment groups (Spiecker-Hauser Nov 2007 ESVCN Leipzig; Schmidt 2008 Proc Soc Nutr Physiol).

Ten experimental cats with sub-total nephrectomy were fed wet cat food supplemented with Lantharenol for two weeks at 0.3 to 3 g/kg of wet food (1.77 to 17.7 g /kg of complete food). All were asymptomatic, mildly azotemic, and normophosphatemic following renal mass reduction. Food intake was not altered in cats of this study and a dose-dependent decrease in phosphorus availability was demonstrated. Urinary phosphorus excretion was increased unlike that seen with decreased urinary phosphorus excretion in normal cats (Schmidt B, Spiecker-Hauser U, Murphy 2008).

Twenty-three cats with CKD (decreased urinary specific gravity, increased BUN and serum creatinine) finished an 8-week study comparing those fed a veterinary renal diet (9 cats) or a maintenance diet supplemented with Renalzin at 400-600 mg per day (14 cats). Statistical comparisons between the Renalzin treateted (5.9 mg/dl mean serum phosphorus) and the veterinary renal food treated groups (4.3 mg/dl mean serum phosphorus) could not be made, as there was considerable difference in the serum phosphorus at the start of the study. The Renalzin treated group had an improvement in serum phosphorus control, overall clinical status, and behavioral scores for quality of life compared to cats fed the veterinary renal diets. There was a trend toward lower serum phosphorus in the Renalzin treated cats and toward higher serum phosphorus in cats treated with the veterinary renal diets. Cats treated with Renalzin either maintained their food intake or increased it to a degree greater than cats fed the veterinary renal diets (Schmidt B, Adler, K, Hellmann, 2008).

Summary and Horizons

There is an ongoing surge of interest in treatment of cats with CKD using new generation intestinal phosphate binders. Some of these binders challenge the traditional concept that intestinal phosphate binders only should be used in patients that are consuming a phosphate-restricted diet and that they are not effective if given with regular maintenance foods. Studies comparing the safety and efficacy of various classes of intestinal phosphate binders in cats with CKD have yet to be performed. The potential long-term toxicity of aluminum accumulation in CKD cats treated with aluminum salts needs investigation. Long-term toxicity studies of lanthanum in CKD cats treated with lanthanum salts are needed.

Reduction in total body phosphorus burden is a pivotal step in thwarting the progression of CKD, so enhanced treatment efforts to provide optimal phosphorus and PTH control are warranted. Future studies designed to optimize control of phosphorus and PTH dynamics could include drugs that inhibit the sodium-phosphate co-transporters along the intestinal epithelium, calcimimetics, and FGF-23.

Dose rates for intestinal phosphate binder therapy in cats

Aluminum hydroxide (Alternagel; Johnson & Johnson–Merck) 600 mg/5 ml

30 mg/kg PO q8h; 45 mg/kg PO q12h (give with meal)

Calcium carbonate (Tums; GlaxoSmithKline) regular strength 500 mg/tablet

30 mg/kg PO q8h; 45 mg/kg PO q12h (give with meal)

Sevelamer hydrochloride (Renagel; Genzyme) 400 mg tablets

33–54 mg/kg PO q8h; 50–80 mg/kg PO q12h (give with meal)

Chitosan and calcium carbonate (Epakitin/Ipakitine; Vétoquinol)

1 g/10 lb twice daily with food

Lanthanum carbonate (Fosrenol; Shire Pharmaceuticals) 500 mg chewable tablets

12.5–25 mg/kg/day PO 6.25–12.5 mg/kg PO q12h starting dose (give with meal, do not swallow tablet whole)

Lanthanum carbonate octahydrate (Renalzin; Bayer HealthCare) Not available in USA

2 ml applied to cat's food once or twice daily

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