Medication Summary
Oral phosphate binders are used to decrease the highly efficient gastrointestinal absorption of phosphorus. Calcium salts are widely used but may produce hypercalcemia. Aluminum salts are effective binders but may induce aluminum toxicity. Newer compounds containing iron or bile acid sequestrants are replacing calcium and aluminum binders.
Sodium/hydrogen exchanger 3 (NHE3) inhibitors (tenapanor) is indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis. Also, as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy.
Proximal diuretics are phosphuretic to the same extent that they are natriuretic. Acetazolamide is particularly efficient in promoting renal phosphate excretion.
Diuretics
Class Summary
Diuretics lower phosphate serum levels by enhancing renal excretion.
Furosemide (Lasix)
Furosemide inhibits the resorption of sodium and chloride in the loop of Henle and the proximal and distal tubules of the kidney. Its onset of action is rapid after an intravenous dose. This agent increases the excretion of phosphate.
Acetazolamide (Diamox)
This agent inhibits carbonic anhydrase, the enzyme that catalyzes the hydration of CO2 and dehydration of carbonic acid. Inhibition reduces reabsorption of NaHCO3 in the proximal tubule, leading to natriuresis, bicarbonate, diuresis, and a decreased serum bicarbonate level. As NaHCO3 delivery to the collecting duct increases, the renal excretion of phosphate increases.
Phosphate Binders
Class Summary
The agents bind to dietary phosphate in the gastrointestinal tract. The phosphate is then eliminated in the feces, thus limiting intestinal absorption.
Sevelamer hydrochloride (Renagel, Renvela)
This agent is a polymeric phosphate binder for oral administration. It does not contain aluminum; thus, aluminum intoxication not a concern.
The polymer forms ionic and hydrogen bonds with phosphates and bile acids to promote fecal excretion. It lowers serum phosphate to near normal levels in hemodialysis patients as effectively as calcium acetate without inducing hypercalcemia or increased aluminum levels. Sevelamer hydrochloride maintains stable intact PTH levels and increases alkaline phosphatase levels compared with calcium acetate.
Lanthanum carbonate (Fosrenol)
Lanthanum carbonate is a noncalcium, nonaluminum phosphate binder indicated for the reduction of high phosphorus levels in patients with end-stage renal disease. It directly binds dietary phosphorus in the upper gastrointestinal tract, thereby inhibiting phosphorus absorption.
Sucroferric oxyhydroxide (Velphoro)
Sucroferric oxyhydroxide is an iron-based, calcium-free phosphate binder. When it is taken with meals, dietary phosphate is adsorbed in the gastrointestinal tract and eliminated in the feces. It is indicated for the control of serum phosphorus levels in patients with chronic kidney disease on hemodialysis.
Ferric citrate
Ferric citrate is a phosphate binder. Ferric iron binds dietary phosphate in the GI tract and precipitates as ferric phosphate, which is insoluble and is excreted in the feces. It is indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.
Aluminum hydroxide
Aluminum hydroxide, which is available in tablet or liquid form, is commonly used as an antacid. It is not a first-line therapy for hyperphosphatemia, because of the potential for aluminum intoxication with extended use.
Calcium carbonate (Caltrate 600, Os-Cal, Tums, Oysco 500)
This agent normalizes phosphate concentrations in patients on dialysis. Calcium carbonate combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces. It is marketed in a variety of dosage forms and is relatively inexpensive. Calcium carbonate is available by tablet for chewing or swallowing and is sold in many sizes (250-1000 mg). It is also used as an antacid or a calcium supplement.
Calcium acetate (Calphron, PhosLo, Eliphos)
Calcium acetate combines with dietary phosphorus to form insoluble calcium phosphate, which is excreted in feces.
Calcium chloride
Calcium chloride is administered as an IV preparation; it is used in the treatment of severe symptomatic hypocalcemia. Do not confuse calcium chloride with calcium gluconate; calcium chloride contains approximately 3 times as much elemental calcium per unit weight as calcium gluconate does. In the absence of symptoms, hypocalcemia may be treated with oral supplements rather than IV infusions. Calcium chloride 10% solution contains 100 mg/mL = 1.4 mEq/mL.
Magnesium hydroxide
Magnesium is a divalent cation that is maximally absorbed in the distal small intestine. At low concentrations, it appears to be absorbed in a saturable carrier-mediated process influenced by vitamin D. At high concentrations, absorption appears to occur largely and inefficiently through diffusion. Magnesium hydroxide reduces the absorption of dietary phosphate.
Calcium gluconate (Cal-Glu)
Calcium gluconate is administered as an intravenous (IV) preparation; it is used in the treatment of symptomatic hypocalcemia, being particularly employed for the treatment of tetany. In the absence of symptoms, hypocalcemia may be treated with oral supplements rather than IV infusions. Calcium gluconate 10% solution contains 100 mg/mL = 0.45 mEq elemental calcium/mL.
Sodium/Hydrogen Exchanger 3 (NHE3) Inhibitors
Class Summary
NHE3 inhibition reduces sodium absorption from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in a softer stool consistency.
Inhibition of NHE3 also results in decreased phosphate absorption by reducing phosphate permeability through the paracellular pathway.
Tenapanor (Xphozah)
Indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis. Also, as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy.
-
Approximately 60-70% of dietary phosphate, 1000-1500 mg/day, is absorbed in the small intestine. Although vitamin D can enhance the absorption, especially under conditions of dietary phosphate depletion, intestinal phosphate absorption does not require the presence of active vitamin D. Specifically, high serum phosphate and high dietary phosphate intake do not significantly impair intestinal uptake. The movement of phosphate in and out of bone, the reservoir containing most of the total body phosphate, is generally balanced. Renal excretion of excess dietary phosphate intake ensures maintenance of phosphate homeostasis, maintaining serum phosphate at a level of approximately 3-4 mg/dL in the serum.
-
The vast majority of filtered phosphate is reabsorbed by type 2a sodium phosphate cotransporters located on the apical membrane of the renal proximal tubule. The expression of these cotransporters is increased by low dietary phosphate intake and several growth factors to enhance phosphate absorption. The expression is decreased by high dietary phosphate intake, parathyroid hormone (PTH), FGF23, and dopamine. Phosphate absorption in the remainder of the nephron is generally mediated by type 3 sodium phosphate cotransporters. No direct evidence has been found related to the regulation of these transporters in renal cells under physiologic conditions. The absorption in the proximal tubule is regulated such that the final excretion matches the dietary excess in order to maintain homeostasis.
-
Hyperphosphatemia inhibits 1-alpha hydroxylase in the proximal tubule directly and indirectly through stimulation of FGF23, thus inhibiting the conversion of 25-hydroxy vitamin D3 to the active metabolite, 1,25 dihydroxyvitamin D3. FGF23 additionally increases the expression of 24-hydroxylase, leading to inactivation of active 1,25 dihydroxyvitamin D3. The decrease in active vitamin D production with high phosphate is somewhat offset by the ability of hyperphosphatemia to stimulate the secretion of parathyroid hormone (PTH), which will increase the activity of 1-alpha hydroxylase. The result is generally a neutral effect on intestinal phosphate absorption. Hyperphosphatemia-stimulated PTH secretion is mediated through an as yet unidentified pathway. With normal renal function, the transient increase in PTH and decrease in vitamin D serve to inhibit renal and intestinal absorption of phosphate, resulting in resolution of the hyperphosphatemia. In contrast, under conditions of renal failure, sustained hyperphosphatemia results in sustained hyperparathyroidism. The hyperparathyroidism enhances renal phosphate excretion but also enhances bone resorption, releasing more phosphate into the serum. As renal failure progresses and the ability of the kidney to excrete phosphate continues to diminish, the action of PTH on the bone can exacerbate the already present hyperphosphatemia.
