PHOS-BIND™ - R X Vitamins

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SAFETY of CALCITRIOL• The half-life of calcitriol in the blood is 4-6 hours, which allows for the rapidcorrection of hypercalcemia within about 4-6 days should it occur.• The intestinal mucosal cells that are programmed for increased calciumabsorption by calcitriol are only the newly-formed cells from the crypts ofLieberkuhn prior to their full differentiation, and they only have a tissue life spanof about a week.• Thus lowering the amount of calcitriol administered will very rapidly result indiminished 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 tocalcitriol’s high margin of safety in veterinary patients.PARATHYROID HORMONE TOXICITYPTH in excess is a uremic toxin which causes tissue damage and promotes theprogression of CKD pathology (1, 2). PTH toxicity has been shown to contributeto 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 erythropoietinformation as well as other mechanisms of action leading to uremic anemia• PTH excess in uremia also contributes to leukocyte malfunctions, including failuresof immunologic response, which helps explain the increased tendency of uremicpatients to infection• Interferes with the insulin-secreting response of the pancreatic beta cells to dietaryglucose which leads to carbohydrate intolerance in uremic patients.o One of the first changes in uremic patients where calcitriol therapy has beeninitiated is a return of appetiteo Calcitriol directly facilitates insulin secretion by the beta cells independent ofits effect on PTHPTH toxicity is caused by the following mechanisms of action:1. Increases levels of intracellular ionic calciuma. Activates enzymes which digest cell membranes, proteins and nucleic acids, aswell as disrupting mitochondrial production of ATP, thus also diminishingavailable energy to the tissues2. 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 ionizedcalcium levels3. Renal tubular cells have high concentrations of the PTH receptor, thus the kidney isaffected early in PTH toxicitya. Calcium influx into tubular cells causes cytotoxicity by activating autolyticenzymes and interfering with mitochondrial ATP productionb. Progressively, calcium phosphate precipitates within tubular lumens whichfurther contributes to renal lesions. Increased loss of renal tissue worsensthe hyperparathyroidism, and the subsequent increased PTH furtherworsens the kidney damage, creating a destructive vicious cycleMechanisms of Injury Caused By Elevated Serum Phosphorus (8, 12)Phos-Bind 2013 4
1. Aspects Related to Stimulation of PTH Increased Secretion• Direct Stimulation of PTH Synthesis and Secretiono Due in part to phosphorus-mediated stabilization of the mRNA for PTH(7)§PTH mRNA and PTH serum level duration are shortened byincreased ionic calciumo High phosphorus suppresses arachidonic acid production by PTG cellswhich is stimulated by ionic calcium in its suppression of PTH secretion(9)• Suppression of renal calcitriol formation relieves PTG cells of the regulatoryeffects of calcitriol to block transcription of the PTH gene• Marked stimulation of parathyroid cellular hyperplasia generating many morePTH producing cells each of which has a basal (non-suppressible) level of PTHproduction.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” PTGcell nuclear proteins P21 and P27 which are induced by calcitriol to help itsuppress PTG cellular hyperplasia2. Aspects Related to the Most Immediate Cause of Death in Uremia (Cardiac Failure)• Coronary arteriolar mineralizations (vascular calcifications) are directlystimulated by high serum phosphorus which drives conversion of vascularmyoepithelial cells in the vessel wall into an osteoblastic phenotype which readilyforms boney tissue in vessel walls. (Osseous metaplasia)• Recent evidence indicates that high levels of the phosphatonin, FGF23, which isdriven by high serum phosphorus, are cardiotoxic, causing myocardial cellularhypertrophy, thus contributing to hypertrophic cardiomyopathy. (10)3. Aspects Related to Emerging Mechanisms of Toxicity of Excessive Serum PhosphorusLevels (11)• Partial blockage of renoprotective effects of the use of ACE-inhibitors in CKDtherapySAFETY of ALUMINUM-BASED <strong>PHOS</strong>PHATE BINDERS• Aluminum from AL(OH) 3 absorbed
Page 1 and 2: TECHNICAL REPORTfor USE by VETERINA
Page 3: 5. Check ionized calcium in 10-14 d

PHOS-BIND™ - R X Vitamins

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