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Microsoft word - phos-bind technical report-final_7-23-13.docx

TECHNICAL REPORT
for USE by VETERINARIANS ONLY
Chief Medical and Science Officer, RxVitamins for Pets Professor Emeritus Ohio State University College of Veterinary Medicine RxVitamins for Pets
PHOS-BIND™
INGREDIENT LIST: (Active ingredients per scoop)
o Aluminum hydroxide gel dried and powdered (USP) § 500 mg AL(OH)3 per level scoop of Phos-Bind™ ABOUT THIS FORMULA:
Aluminum hydroxide binds to dietary phosphorus in the bowel, thus preventing its
absorption through the intestinal mucosa. Due to this property, aluminum hydroxide has
been recommended in situations where reducing serum phosphorus is beneficial, as with
the renal secondary hyperparathyroidism associated with chronic kidney disease (CKD)
in both dogs and cats.
Current and emerging protocols for the management of CKD in the dog and cat involve
oral administration of the biologically-active Vitamin D metabolite in the tissues,
calcitriol (1,25 dihydroxycholecalciferol), to patients as early as IRIS stage 1-2 of CKD.
Serum ionized calcium, serum PTH and serum phosphorus measurements can give early
indications of the PTH dysregulation associated with CKD.
It is important with the use of calcitriol to keep serum phosphorus levels below 6.0, and
ideally at the low to mid range of normal reference levels (2.5-5.0 mg/dl). This can be
done safely and effectively using Phos-Bind™ or other non-calcium based phosphate
binders.
Intermittent (twice weekly) oral administration of calcitriol has been found to reduce the
chance of hypercalcemia, which can be associated with daily oral calcitriol
administration. Twice weekly oral administration will retain calcitriol’s benefits to the
patient diagnosed with chronic kidney disease.
The administration of exogenous calcium, as with calcium-based phosphate binders or
dietary supplements, above what calcium is required nutritionally, will result in
hypercalcemia and encourage metaplastic ossification of the tissues, especially renal
tissues, thus exacerbating and increasing the progression of CKD.
ADMINISTRATION RECOMMENDATIONS:
Aluminum hydroxide AL(OH)3 is clearly indicated for use in patients with serum
phosphorus of 6.0 or greater. Because of “trade-off” relationships, in which calcium-phosphorus homeostasis is maintained at the expense of increased circulating PTH, elevations in PTH can occur prior to increases of serum phosphorus. For this reason, the early use of phosphate binders is advisable. The starting dosage for AL(OH)3 is 100 mg/kg daily mixed with the food. If after 2 weeks that dosage is not sufficient to reduce serum phosphorus to around 5.0 or less, then it has been recommended to increase the dose of AL(OH)3 to as much as 200-300 mg/kg/day divided among feedings. Phos-Bind 2013 Starting Dosage: 100 mg/kg/d AL(OH)3 divided among feedings
1 scoop Phos-Bind™ = 500 mg AL(OH)3
Note: Dosage can be increased safely to as much as 200-300 mg/kg/day if
needed to maintain serum phosphorus below 6.0 mg/dl

Chronic Kidney Disease (CKD) in the dog and cat is associated with the development of
renal secondary hyperparathyroidism and elevated levels of PTH. It is actually the PTH
which orchestrates many of the pathologies associated with CKD, such as anemia and
depression. By intervening in the course of CKD with the intermittent use of oral
calcitriol (twice weekly), substantial benefits to quality of life and survival times have
been measured and reported in the literature. PTH testing is helpful, but due to cost
concerns, is not always feasible. It has been found that calcitriol can be safely initiated
with benefits including but not restricted to lowering PTH when the phosphorus is 6.0 or
lower, either early in the disease, or following lowering with intestinal phosphate binders
such as Phos-Bind™.
THE MANAGEMENT OF CHRONIC KIDNEY DISEASE (Canine & Feline):
1. Start Renal diet when patient is in IRIS Stage 2 (late) or a higher IRIS Stage to address
concerns about muscle mass loss on lowered protein diets when such diets are started too early in the disease. 2. Maintain serum phosphorus below 5.0 mg/dl using AL(OH)3 at 100-300 mg/kg/day divided among feedings; or consider the use of Lanthanum (Fosrenol™) at 50-100 mg/kg/day. AL(OH)3 and Fosrenol™ can be combined to reduce the cost of Fosrenol™ and any rare side-effects of the aluminum in the AL(OH)3, such as tremoring or hypercalcemia. • Sevelamer-based binders may be best avoided as they bind calcitriol in the gut in addition to their binding of phosphorus a. Recheck serum phosphorus 10-14 days after changing dosage or medications 3. Serial PTH testing isn’t essential but can be helpful in the management of CKD a. Recheck serum PTH levels 8 weeks after initial dose to evaluate effect when appropriate 4. Twice weekly dosing of calcitriol at 9-10 ng/kg PO at the same numerical hour a. Wednesday evening and Sunday morning have been commonly recommended for this twice-weekly administration protocol, but other days of the week are fine as long as the calcitriol is given the night of Day 1 and the morning of Day 4. i. Dose on an empty stomach between meals b. It has been found that twice weekly dosing of calcitriol is at least as effective as daily dosing and reduces the chance of hypercalcemia i. If ionized calcium remains high with twice weekly dosing of calcitriol, and its cause is undetermined (idiopathic), it is recommended to use concurrently a bisphosphonate like Fosamax™ at 10 mg weekly (or multiples of that dose) to reduce serum calcium. c. In cases of ionized calcium too low, it is recommended to dose calcitriol on a twice daily basis, using the starting dosage of 2.5 ng/kg/day to boost intestinal calcium absorption 5. Check ionized calcium in 10-14 days following initiation of calcitriol therapy to check IMPORTANCE OF SERUM PHOSPHORUS CONTROL IN ANIMALS
It has long been recognized that regulation of blood ionized calcium is vital to health.
There are a number of hormones and regulators that maintain adequate calcium levels in
the body. Several of these hormones and regulators also have an important impact upon
phosphorus levels.
In the past ~10 years a specific class of hormones (phosphatonins) has been discovered.
The role of these phosphatonins is primarily to keep serum phosphorus from getting too
high. These mechanisms of action have been the subject of numerous studies. (3, 6,)
The results of these studies have helped us understand that maintaining normal serum
phosphorus levels and thus preventing hyperphosphatemia is critical with respect to the
health of the body. Additionally, these studies into phosphatonin activity have shown that
intestinal phosphate binders, such as Phos-Bind™, are essential for use in the uremic
patient.
CALCITRIOL BENEFITS
1. Down-regulates PTH gene to reduce serum parathyroid hormone (PTH)
a. Blocks synthesis of PTH within the parathyroid gland by preventing transcription of the PTH gene onto mRNA. 2. Induces synthesis of the calcium receptor that is required to block the secretion of PTH as well as the calcitriol receptor (VDR) in the parathyroid gland (PTG) 3. Prevents parathyroid gland hyperplasia during uremia 4. Causes regression of the parathyroid gland from its hyperplastic state in the uremic 5. Comprehensive listing of additional benefits of calcitriol are found on Table 1 in the 6. The CKD patient administered calcitriol will have both a reduction in azotemia and a substantial decline in the rate of progression of the renal lesions. These benefits occur by several mechanisms of action, including the lowering of PTH levels by the calcitriol. 7. Clinical studies and clinician observations confirm that CKD patients receiving calcitriol supplementation have significantly prolonged survival times and substantially improved quality of life. CAUSES OF LOWERED CALCITRIOL
1. In CKD the reduced number of functioning renal tubules reduces the synthesis of
2. High concentrations of serum phosphorus inhibit 1-hydroxylation of 25- hydroxyvitamin D. Serum phosphorus levels can be so high as to actually stop the synthesis of calcitriol. 3. Serum levels of a phosphatonin, Fibroblast Growth Factor 23, (FGF23) are increased by serum phosphorus. FGF23 is a critical and powerful early suppressor of renal calcitriol formation. NOTE: Aluminum hydroxide (Phos-Bind™) has proven itself to be a safe, convenient
and economical way to manage dietary intake of phosphorus in the CKD patient, especially when used concurrently with calcitriol. SAFETY of CALCITRIOL
• The half-life of calcitriol in the blood is 4-6 hours, which allows for the rapid correction of hypercalcemia within about 4-6 days should it occur. • The intestinal mucosal cells that are programmed for increased calcium absorption by calcitriol are only the newly-formed cells from the crypts of Lieberkuhn prior to their full differentiation, and they only have a tissue life span of about a week. • Thus lowering the amount of calcitriol administered will very rapidly result in diminished gut capacity for calcium absorption. • For these reasons, calcitriol is both the most potent (allowing the lowest dosages) and most rapidly-cleared form of vitamin D available, which contributes to calcitriol’s high margin of safety in veterinary patients. PARATHYROID HORMONE TOXICITY
PTH in excess is a uremic toxin
which causes tissue damage and promotes the
progression of CKD pathology (1, 2). PTH toxicity has been shown to contribute to the following problems: • Creates depression by direct effects on the brain • Slows peripheral nerve conduction velocity • Contributes to uremic anemia through the loss of renal sites of erythropoietin formation as well as other mechanisms of action leading to uremic anemia • PTH excess in uremia also contributes to leukocyte malfunctions, including failures of immunologic response, which helps explain the increased tendency of uremic patients to infection • Interferes with the insulin-secreting response of the pancreatic beta cells to dietary glucose which leads to carbohydrate intolerance in uremic patients. o One of the first changes in uremic patients where calcitriol therapy has been o Calcitriol directly facilitates insulin secretion by the beta cells independent of PTH toxicity is caused by the following mechanisms of action:
1. Increases levels of intracellular ionic calcium
a. Activates enzymes which digest cell membranes, proteins and nucleic acids, as well as disrupting mitochondrial production of ATP, thus also diminishing available energy to the tissues 2. PTH can cause cellular damage in the face of normal serum ionized calcium levels, and thus needs to be treated even in the absence of elevated serum ionized calcium levels 3. Renal tubular cells have high concentrations of the PTH receptor, thus the kidney is affected early in PTH toxicity a. Calcium influx into tubular cells causes cytotoxicity by activating autolytic enzymes and interfering with mitochondrial ATP production b. Progressively, calcium phosphate precipitates within tubular lumens which further contributes to renal lesions. Increased loss of renal tissue worsens the hyperparathyroidism, and the subsequent increased PTH further worsens the kidney damage, creating a destructive vicious cycle Mechanisms of Injury Caused By Elevated Serum Phosphorus (8, 12)
1. Aspects Related to Stimulation of PTH Increased Secretion • Direct Stimulation of PTH Synthesis and Secretion o Due in part to phosphorus-mediated stabilization of the mRNA for PTH § PTH mRNA and PTH serum level duration are shortened by o High phosphorus suppresses arachidonic acid production by PTG cells which is stimulated by ionic calcium in its suppression of PTH secretion (9) • Suppression of renal calcitriol formation relieves PTG cells of the regulatory effects of calcitriol to block transcription of the PTH gene • Marked stimulation of parathyroid cellular hyperplasia generating many more PTH producing cells each of which has a basal (non-suppressible) level of PTH production. o Mediated by Transforming Growth Factor alpha (TGFα) and its receptor, which is also known as Epidermal Growth Factor Receptor (EGFR). o Facilitated by serum phosphorus suppression of “cyclin inhibitory” PTG cell nuclear proteins P21 and P27 which are induced by calcitriol to help it suppress PTG cellular hyperplasia 2. Aspects Related to the Most Immediate Cause of Death in Uremia (Cardiac Failure) • Coronary arteriolar mineralizations (vascular calcifications) are directly stimulated by high serum phosphorus which drives conversion of vascular myoepithelial cells in the vessel wall into an osteoblastic phenotype which readily forms boney tissue in vessel walls. (Osseous metaplasia) • Recent evidence indicates that high levels of the phosphatonin, FGF23, which is driven by high serum phosphorus, are cardiotoxic, causing myocardial cellular hypertrophy, thus contributing to hypertrophic cardiomyopathy. (10) 3. Aspects Related to Emerging Mechanisms of Toxicity of Excessive Serum Phosphorus • Partial blockage of renoprotective effects of the use of ACE-inhibitors in CKD SAFETY of ALUMINUM-BASED PHOSPHATE BINDERS
• Aluminum from AL(OH)3 absorbed <0.1% from the gut • Aluminum from Sucralfate absorbed ~0.5% from the gut • Minimal danger of toxicity from oral dosing has occured rarely in nephron- compromised patients at lower than recommended doses, usually manifested by tremoring or other neuro-lesions. Aluminum-based dialysate fluids more likely to cause toxicity. • Concurrent use of AL(OH)3 and potassium citrate-containing enteral medications will exacerbate the potential for aluminum toxicity. AVOID concurrent use! Any salts of citric acid, such as calcium citrate and magnesium citrate should necessarily also be avoided when AL(OH)3 is being used. • CAUTION: Concurrent use of oral citrate compounds such as potassium citrate,
magnesium citrate and calcium citrate can increase the intestinal absorption of aluminum, thus increasing the risk of signs of aluminum toxicity. REFERENCES
1. Nagode LA. and Chew DJ. Nephrocalcinosis caused by hyperparathyroidism in
progression of renal failure: treatment with calcitriol. Semin Vet Med Surg (Small Anim) 1992; 7(3):202–220. 2. 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(6):1293– 1330. 3. Galvao J, Nagode LA, Schenk PA, Chew DJ. Calcitriol, calcidiol, parathyroid hormone and fibroblast growth factor-23 interactions in chronic kidney disease. JVECC 23(2) 2013, pp. 134-162. doi 10.111/vec. 12036 4. Plumb’s Veterinary Formulary 7th Edition, 2011. 5. Gerber B, Hassig M, Reusch CE. Serum concentrations of 1,25- dihydroxycholecalciferol and 25-hydroxycholecalciferol in clinically normal dogs and dogs with acute and chronic renal failure. Am J Vet Res 2003;64[9]:1161-6. 6. Berndt T. and Kumar R. Phosphatonins and the Regulation of Phosphate Homeostasis. Ann. Rev. Physiol 2007; 69:341-359 7. Silver J. and Naveh-Many T. Phosphate and the parathyroid. Kidney Int. 2009; 8. Almaden Y, Hernandez, A, Torregrosa V, et al. High Phosphate Level Directly Stimulates Parathyroid Hormone Secretion and Synthesis by Human Parathyroid Tissue in vitro. J. Am Soc. Nephrol. 1998; 9:1845-1852 9. Almaden Y, Canalejo A, Ballesteros E, et al. Effect of Extracellular Phosphate Concentration on Arachidonic Acid Production by Parathyroid Tissue IN VITRO. J. Am. Soc. Nephrol. 2000; 11:1712-1718 10. Faul C, Ansel O, Amaral BO, et al. FGF23 induces left ventricular hypertrophy. J. 11. Zocali C, Ruggenenti P, Perna A, et al. Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition. J. Am. Soc. Nephrol. 2011; 22:1923-1930 12. Geddes, RF, Finch NC, Syme HM et al. The role of phosphorus in the pathophysiology of chronic kidney disease. JVECC 2013; 23(2)122-133

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