Decreasing Total Body Phosphorus Burden in Chronic Kidney Disease

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1 Decreasing Total Body Phosphorus Burden in Chronic Kidney Disease Dennis J. Chew, DVM, DACVIM Valerie J. Parker, DVM, DACVIM, DACVN The Ohio State University, Columbus, Ohio Serum phosphorus concentration depends on dietary phosphorus intake, gastrointestinal absorption across the duodenum and jejunum, translocation into intracellular sites, skeletal absorption, and excretion of phosphorus into the urine. The kidneys play a crucial role in regulating phosphorus concentrations, with a narrow range maintained in health. Young growing animals often have higher serum phosphorus levels than adults (up to 9.0 mg/dl). The normal serum phosphorus range of many laboratories includes that of adults and growing animals, which may make it difficult to detect early increases in serum phosphorus. The typical reference range for serum phosphorus for adult dogs and cats is 2.5 to 6.0 mg/dl (0.81 to 1.94 mmol/l). RENAL SECONDARY HYPERPARATHYROIDISM Normophosphatemic and hyperphosphatemic forms of phosphorus retention occur in patients with chronic kidney disease (CKD), leading to the development of renal secondary hyperparathyroidism (2-HPTH; Figures 1 & 2). Phosphate retention and hyperphosphatemia are primarily due to impaired renal phosphate excretion. Hyperphosphatemia during progressive early CKD is transient, as normophosphatemia is quickly restored under the influence of increased secretion of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23), which increase urinary phosphate excretion. Renal 2-HPTH is commonly documented in dogs and cats with CKD. Overall frequency of renal 2-HPTH was 76% in a recent study of dogs with CKD, encountered in 36% with International 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 concentration 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 parathyroid glands, 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-regulation of 24-hydroxylase increases the degradation of any remaining calcitriol. GI = gastrointestinal. Figure 1. Deleterious effects of increasing total body phosphorus burden in CKD. PTH = parathyroid hormone PTG = parathyroid gland ica++ = ionized calcium FGF = fibroblast growth factor Pi = inorganic phosphorus Renal Interest Society (IRIS) stage 1 CKD, 50% with stage 2, 96% with stage 3, and 100% with stage 4. 1 An increasing frequency of renal 2-HPTH was similarly found in cats with CKD, 2,3 affecting 84% of cats overall (from 47% of cats with stable azotemia but without clinical signs, to 100% of cats with decompensated CKD). Hyperphosphatemia is commonly in CKD patients with 2-HPTH, but 2-HPTH can be encountered in both dogs and cats with serum phosphorus within the normal reference range. Hyperphosphatemia was noted in 18% and renal 2-HPTH in 36 % of dogs with IRIS stage 1 CKD. 1 The concept that renal 2-HPTH can precede development of hyperphosphatemia in CKD has not been well appreciated in veterinary medicine. Serum phosphorus in the upper normal reference range has recently been associated with increased PTH in 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 Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health

2 The complex interactions that occur between circulating ionized calcium, inorganic phosphorus, PTH, 25(OH)-vitamin D, calcitriol (1,25(OH)2-vitamin D), FGF-23, and Klotho (circulating and tissue expression) during CKD were recently reviewed in detail. 6 Relative and absolute deficits of the most biologically active vitamin D metabolite, calcitriol, are central in the genesis of renal 2-HPTH through various underlying mechanisms. Though not traditionally emphasized until very recently, deficits of 25(OH)-vitamin D are also common in CKD and may contribute to renal 2-HPTH and other adverse systemic effects. Total body phosphorus burden and increasing concentration of circulating phosphorus play a pivotal role in the development of renal 2-HPTH and are intimately related to dynamics of calcitriol and FGF-23/Klotho (Figures 2 & 3). Less FGF-23 is required to decrease calcitriol synthesis than to promote phosphaturia, so decreases in serum calcitriol concentration occur prior to phosphaturia in very early CKD. 7 High concentrations of circulating FGF-23 (for left ventricular hypertrophy and congestive heart failure) and serum phosphorus (for vascular calcification and endothelial dysfunction) have been identified as cardiovascular risk factors in humans with advanced CKD, 8 but this has not been investigated in veterinary medicine. In CKD, the increased secretion of FGF-23 may be a protective mechanism to stabilize serum phosphorus concentration with a decreasing number of nephrons. Thus, FGF-23 increases urinary phosphate excretion, decreases gastrointestinal absorption (indirectly), decreases calcitriol synthesis through inhibition of 1-α-hydroxylase, and increases calcitriol degradation through enhanced activity of 24,25-hydroxylase. These effects allow serum phosphorus to be maintained within a normal range until CKD becomes more advanced. Higher concentrations of serum phosphorus predicted an increase in serum creatinine >25% above baseline over 12 months in 47% of cats with CKD. 9 Serum phosphorus was the only clinicopathologic variable predictive of survival in one study of CKD cats. There was an increase in risk of death of nearly 12% for each mg/dl increase in phosphorus in that study. 10 Higher phosphorus concentration was associated with a higher risk of death within 1 month in another study. 11 Even when serum phosphorus was within the reference range, cats with CKD and phosphorus concentration >4.7 but <6.8 mg/dl had a higher risk of death, compared with that in cats with CKS and phosphorus <4.7 mg/dl. 12 REDUCING TOTAL BODY PHOSPHATE BURDEN An overarching principle of initial treatment of CKD is to reduce the degree of phosphorus retention within the body. Less phosphorus retention relieves the inhibitory effect of phosphorus on renal 1 α hydroxylase activity, resulting in the increased production of endogenous calcitriol and subsequent inhibition of PTH synthesis. Less phosphorus burden also decreases circulating FGF-23 and increases ionized calcium. Measures to decrease gastrointestinal (GI) absorption of dietary phosphorus are central in decreasing total body phosphate burden. Consumption of diets with lower total phosphorus content and/or decreased phosphate bioavailability and the 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. addition of intestinal phosphate binders to the diet are useful methods to decrease phosphate entry into the body. 13 Dietary phosphorus restriction alone may decrease PTH or FGF-23 or prevent their increases in early stages of CKD in cats and dogs. However, diet alone will become ineffective to control PTH or FGF-23 as CKD advances, especially as serum phosphorus concentration increases. Restoration of normophosphatemia normalized PTH in many cats with early uremia, 14,15 but was successful in only a portion of uremic dogs, many of which required calcitriol to normalize PTH. 4 Serum phosphorus in the upper reference range was associated with increased PTH in dogs with CKD in 2 studies. 1,5 Concentrations of FGF-23 were higher in cats with IRIS stage 2 CKD when serum phosphorus was >4.5 mg/dl vs. <4.5 mg/dl. Cats of the same study with IRIS stage 3 CKD had much higher concentrations of FGF-23 when serum phosphorus was >5.0 mg/dl vs. <5.0 mg/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/dl by IRIS stage) resulted in lower serum phosphorus, PTH, and FGF-23. Cats with CKD classified as normophosphatemic for their IRIS stage and fed the same renal diet decreased their circulating concentration of FGF-23, despite no change in PTH or serum phosphorus Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health 41

3 RESTRICTING DIETARY PHOSPHORUS CONTENT The average pet foods from the grocery store for dogs and cats contain 5 to 6 times as much phosphorus, on a mg/100 kcal-of-intake basis, than the average phosphorus intake for humans eating a Western-type diet (50 mg/100 kcal). Some pet foods contain up to 500 mg of phosphorus/100 kcal. This makes it difficult to achieve adequate dietary phosphorus restriction during CKD when feeding nontherapeutic diets. Veterinary renal diets are designed to have a phosphorus content lower than AAFCO minimal requirements for adult maintenance (dogs, 140 mg/100 kcal; cats, 125 mg/100 kcal). Commercial renal diets for dogs provide 48 to 120 mg of phosphorus/100 kcal and for cats, 80 to 117 mg/100 kcal. Although some senior or mature diets are restricted in phosphorus or protein content, these dietary constituents in such diets vary widely on a mg/100 kcal basis. 18 Comparing the phosphorus content on an energy basis (mg/100 kcal), rather than on a dry matter basis (%), is important to allow for comparison between dry and canned diets, as well as diets of different caloric concentrations. Despite the known benefits of targeted control of phosphorus burden, intestinal phosphate binders appear to be underutilized during treatment of CKD in cats and dogs. Diets with the same phosphorus content may result in different phosphorus absorption across the intestine due to differences in bioavailability. Despite similar total dietary phosphorus intake, substantial differences in phosphorus bioavailability were demonstrated in a study of cats provided phosphorus derived mostly from poultry, meat, and fish meal (less biovavailable), compared with inorganc phosphorus derived from neutral monobasic/dibasic salts (more bioavailable). 19 Animal proteins generally provide more phosphorus than vegetable proteins; however, most of the phosphorus in commercial diets typically comes from specific phosphate-containing mineral supplements (e.g., calcium phosphate, ammonium phosphate). Phytates from vegetable sources can limit calcium and phosphorus absorption across the intestine. The dietary calcium-to-inorganic phosphorus (Ca:Pi) ratio also affects intestinal phosphorus absorption. In most adult maintenance diets, Ca:Pi is about 1:1 to 2:1, whereas a ratio as high as 3.5:1 can be found in some veterinary renal therapeutic foods. A Ca:Pi in this range could act as an inherent binder to further limit Pi absorption. For owners who prefer to feed home-cooked diets, consultation with a veterinary nutritionist is advised. When a large number of home-prepared diets designed for management of CKD in dogs and cats were analyzed, many of these recipes were found to be inadequate for meeting the nutritional and clinical needs 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 avoid unbalancing the diet. Fresh or frozen fruits and vegetables generally make good low-phosphorus treats; the amount to be fed will depend on the individual animal s size and desired caloric intake. A good resource for determining nutrient concentrations of specific people foods is the USDA Nutrient Database ( Commercial pet treats can vary tremendously in phosphorus concentration. USE OF INTESTINAL PHOSPHATE-BINDING AGENTS Despite the known benefits of targeted control of phosphorus burden, intestinal phosphate binders appear to be underutilized during treatment of CKD in cats and dogs. In a study of treatment for cats with CKD, intestinal phosphate binders were prescribed for only 22% of the cats. 21 Similar data are not available for how frequently intestinal phosphate binders are prescribed for dogs with CKD. Phosphorus binding agents are given orally to trap phosphorus in the gut and increase insoluble phosphate salt excretion into feces. Phosphate binders work because the cation in the binder combines with dietary phosphate, producing insoluble, non-absorbable phosphate compounds. Intestinal phosphate binders function best when given with meals or within 2 hours of feeding. Other drugs should be given 1 hour before or 3 hours after any intestinal phosphate binder, to limit the effect on drug absorption. 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, and is titrated to effect. No phosphate binders have yet been licensed as a drug in veterinary medicine, as they have in human nephrology. 22 All phosphate binders work best when given in the food to bind phosphorus or reduce digestibility of phosphorus in the food. The ideal intestinal phosphate binder avidly binds Pi within the intestinal lumen to increase fecal excretion of dietary phosphorus. Phosphate binders can be given within a few hours of eating, but the decrease in phosphorus absorption is not as efficient. Various classes of Pi binders (Table 1) can be similarly effective in control of serum phosphorus, but may be quite different in the degree of FGF-23 control achieved. 13 Special consideration should be given in selection of class of intestinal phosphate binder when calcitriol will also be prescribed. Sevelamer interfered with absorption of orally administered calcitriol when lanthanum did not. 23 Calcium-based intestinal phosphate binders are now rarely used in human nephrology, in part because of the increased use of calcitriol or other activated vitamin D metabolites to provide vitamin D-receptor activation and concerns for development of vascular calcification. 24 All calcium salts can result in ionized hypercalcemia as an adverse effect. The use of calcium salts could have an advantage in CKD patients that remain hypocalcemic following reduction in serum phosphorus concentrations Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health

4 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 Dosage No safe dose is known in human CKD. Measure serum aluminum? Phos-Bind o 200 g container o 500 mg/scoop o Rx Vitamins for Pets ConSeal-AlH o Chewable; 200 mg/chew o Bock Vet Pharma Sucralfate o Inefficient provider of aluminum binding Calcium Salts Calcium carbonate Tums regular strength o 500 mg/tablet Measure serum calcium; ionized calcium preferred over total calcium in CKD Avoid magnesium-containing formulations Calcium acetate More Pi binding & less hypercalcemia than carbonate salt Epakitin 1 g/10 lb., twice daily with food Vetoquinol Chitosan, 10% calcium carbonate Sevelamer Salts Lanthanum carbonate Organic poymer; can bind vitamins at high doses; coagulopathy at very high doses mg/kg/day, PO, divided in food 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 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 CKD=chronic kidney disease; Pi = inorganic phosphorus 2015 Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health 43

5 Intestinal phosphate binders should be mixed in food at appropriate doses to achieve a specific targeted serum phosphorus, PTH, or FGF-23 concentration. Optimal PTH control occurs in dogs with CKD when a targeted serum phosphorus of < 4.5 mg/dl 1,5 or when the middle of the reference range is achieved. Return of serum phosphorus to within the normal reference range is an initial goal, but does not guarantee adequate control of PTH or FGF-23 production. Serial measurement of serum phosphate concentration is important for patients with CKD managed with a renal diet and when intestinal phosphate binders are prescribed (Figure 3). Monitoring is usually monthly until the target concentration has been achieved, and then every 2 to 4 months thereafter if stable. Serum phosphorus concentration may increase in CKD patients that increase their food intake following other supportive CKD treatments. Achieving mid-reference range target phosphate concentrations is more difficult in those with more advanced levels of azotemia. Less stringent target guidelines for serum phosphorus control (<6.0 mg/dl or 1.94 mmol/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 of CKD, have been suggested. 25 Measuring ionized calcium, in conjunction with PTH, as additional targets is ideal. Adverse effects of phosphate binders can occur. Although hypophosphatemia is one such possible consequence, it is difficult to develop with initially high concentrations of serum phosphorus and reduced glomerular filtration rate. Constipation and GI effects can occur following use of some intestinal phosphate binders. Chemicals from the phosphate binder may be absorbed and accumulate in body tissues, and may produce adverse effects. Some binders also can decrease GI absorption of vitamins. REFERENCES 1. Cortadellas O, Fernandez del Palacio MJ, Talavera J, Bayon A. Calcium and phosphorus homeostasis in dogs with spontaneous chronic kidney disease at different stages of severity. J Vet Intern Med 2010;24: Elliott J, Barber PJ. Feline chronic renal failure: clinical findings in 80 cases diagnosed between 1992 and J Small Anim Pract 1998;39: Barber PJ, Elliott J. Feline chronic renal failure: calcium homeostasis in 80 cases diagnosed between 1992 and J Small Anim Pract 1998;39: Nagode LA, Chew DJ. Podell M. Benefits of calcitriol therapy and serum phosphorus control in dogs and cats with chronic renal failure. Both are essential to prevent or suppress toxic hyperparathyroidism. Vet Clin North Am Small Anim Pract 1996;26: Nagode LA, Chew DJ. Nephrocalcinosis caused by hyperparathyroidism in progression of renal failure: treatment with calcitriol. Semin Vet Med Surg 1992;7: de Brito Galvao JF, Nagode LA, Schenck PA, Chew DJ. Calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 interactions in chronic kidney disease. J Vet Emerg Crit Care (San Antonio) 2013;23: Williams ME. Chronic kidney disease/bone and mineral metabolism: the imperfect storm. Seminars in Nephrology 2009;29: Scialla JJ, Wolf M. Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nat Rev Nephrol 2014;10: Chakrabarti S, Syme HM, Elliott J. Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease. J Vet Intern Med 2012;26: Boyd LM, Langston C, Thompson K, Zivin K, Imanishi M. Survival in cats with naturally occurring chronic kidney disease ( ). J Vet Intern Med 2008;22: Kuwahara Y, Ohba Y, Kitoh K, Kuwahara N, Kitagawa H. Association of laboratory data and death within one month in cats with chronic renal failure. J Small Anim Pract 2006;47: King JN, Tasker S, Gunn-Moore DA, Strehlau G. Prognostic factors in cats with chronic kidney disease. J Vet Intern Med 2007;21: Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int 2012;82: Elliott J, Rawlings JM, Markwell PJ, Barber PJ. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract 2000;41: Barber PJ, Rawlings JM, Markwell PJ, Elliott J. Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat. J Small Anim Pract 1999;40: Geddes RF, Finch NC, Elliott J, Syme HM. Fibroblast growth factor 23 in feline chronic kidney disease. J Vet Intern Med 2013;27: Geddes RF, Elliott J, Syme HM. The effect of feeding a renal diet on plasma fibroblast growth factor 23 concentrations in cats with stable azotemic chronic kidney disease. J Vet Intern Med 2013;27: Hutchinson D, Freeman LM, Schreiner KE, Terkla DG. Survey of Opinions About Nutritional Requirements of Senior Dogs and Analysis of Nutrient Profiles of Commercially Available Diets for Senior Dogs. Intern J Appl Res Vet Med 2011;9: Finco DR, Barsanti JA, Brown SA. Influence of dietary source of phosphorus on fecal and urinary excretion of phosphorus and other minerals by male cats. Am J Vet Res 1989;50: Larsen JA, Parks EM, Heinze CR, Fascetti AJ. Evaluation of recipes for home-prepared diets for dogs and cats with chronic kidney disease. J Am Vet Med Assoc 2012;240: Markovich JE, Freeman LM, Labato MA, Heinze CR. Survey of and medication practices of owners of cats with chronic kidney disease. J Feline Med Surg Kidder AC, Chew D. Treatment options for hyperphosphatemia in feline CKD: what's out there? J Feline Med Surg 2009;11: Pierce D, Hossack S, Poole L, Robinson A, Van Heusen H, Martin P, Smyth M. The effect of sevelamer carbonate and lanthanum carbonate on the pharmacokinetics of oral calcitriol. Nephrol Dial Transplant 2011;26: Cozzolino M, Mazzaferro S, Brandenburg V. The treatment of hyperphosphataemia in CKD: calcium-based or calcium-free phosphate binders? Nephrol Dial Transplant 2011;26: Geddes RF, Finch NC, Syme HM, Elliott J. The role of phosphorus in the pathophysiology of chronic kidney disease. J Vet Emerg Crit Care (San Antonio) 2013;23: Ohio State & IAMS Symposium Proceedings: Small Animal Renal & Urinary Health