Updated: Oct 23, 2023
Author: Eleanor Lederer, MD, FASN; Chief Editor: Vecihi Batuman, MD, FASN 


Practice Essentials

Hyperphosphatemia—that is, abnormally high serum phosphate levels—can result from increased phosphate intake, decreased phosphate excretion, or a disorder that shifts intracellular phosphate to extracellular space. However, even severe hyperphosphatemia is for the most part clinically asymptomatic. Morbidity In patients with this condition is more commonly associated with an underlying disease than with increased phosphate values.

The image below illustrates phosphate homeostasis.

Approximately 60-70% of dietary phosphate, 1000-15 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.

Signs and symptoms

Although most patients with hyperphosphatemia are asymptomatic, they occasionally report hypocalcemic symptoms, such as muscle cramps, tetany, and perioral numbness or tingling. Other symptoms include bone and joint pain, pruritus, and rash.

More commonly, patients report symptoms related to the underlying cause of the hyperphosphatemia. These generally are uremic symptoms, such as the following:

  • Fatigue
  • Shortness of breath
  • Anorexia
  • Nausea
  • Vomiting
  • Sleep disturbances

In acute hyperphosphatemia, especially that caused by parenteral phosphate administration, the patient may be hypotensive or exhibit signs of hypocalcemia, such as the following:

  • Positive Trousseau or Chvostek sign
  • Hyperreflexia
  • Carpopedal spasm
  • Seizure

See Clinical Presentation for more detail.


Results from a full chemistry profile can be used as follows in determining the cause of hyperphosphatemia:

  • Low serum calcium levels along with high phosphate levels: Observed with renal failure, hypoparathyroidism, and pseudohypoparathyroidism

  • Blood urea nitrogen (BUN) and creatinine values: Help to determine whether renal failure is the cause of hyperphosphatemia

  • Elevated intact parathyroid hormone (PTH) levels: Higher likelihood in patients with renal failure or pseudohypoparathyroidism

  • Relatively low levels of intact PTH and normal renal function: Found in patients with primary or acquired hypoparathyroidism

  • High serum calcium and phosphate levels: Observed with vitamin D intoxication and milk-alkali syndrome.

  • Relatively low levels of intact PTH and high 25 and 1,25 vitamin D: Also seen in vitamin D intoxication

  • Low levels of PTH and vitamin D: Seen in milk-alkali syndrome

If renal function is normal, then more unusual disorders, such as the following, may be the cause:

  • Vitamin D intoxication
  • Laxative (Phospho-soda) abuse
  • Tumor lysis
  • Rhabdomyolysis
  • Isolated hypoparathyroidism
  • Pseudohypoparathyroidism

Rarely, if the cause of hyperphosphatemia is not clear, 24-hour measurement of urinary phosphate can be performed. Results indicate the following:

  • Fractional renal excretion exceeding 15%: Suggests either massive phosphate ingestion (eg, laxative [Phospho-soda] abuse) or lysis of tissue and resulting release of intracellular phosphate

  • Fractional renal excretion not exceeding 15%: Suggests that renal excretion is impaired because of either renal failure or hypoparathyroidism

See Workup for more detail.


The major strategies for treating hyperphosphatemia are as follows:

  • Diagnose and treat the cause: Eg, hyperphosphatemia due to tumor lysis responds to forced saline diuresis to enhance urinary losses

  • Limit phosphate intake: Renal failure is the clinical condition most often requiring curtailment of phosphate ingestion; patients with advanced renal insufficiency or complete renal failure also require phosphate binders, to inhibit gastrointestinal absorption of phosphate

  • Enhance renal excretion: Used in patients with normal renal function and hyperphosphatemia; it can be accomplished most effectively by using volume repletion with saline coupled with forced diuresis with a loop diuretic such as furosemide or bumetanide

See Treatment and Medication for more detail.


Phosphorus is the sixth most abundant element in the human body. A highly reactive substance, it occurs in nature, including in the human body, as phosphate.

Phosphorus (phosphate) is critical for bone mineralization, cellular structure, genetic coding, and energy metabolism. The adult body contains approximately 1000 g of phosphorus, of which 80-90% is in bone. An additional 10-14% is intracellular and the remaining 1% is extracellular.

Phosphorus is present in nearly all foods, and gastrointestinal (GI) absorption of dietary forms is very efficient. With low dietary intake, 80-90% is absorbed. When intake is greater than 10 mg/kg/day, 70% is absorbed. Normal daily dietary intake varies from 800-1500 mg.

Absorption occurs mainly in the jejunum, although some absorption occurs throughout the GI tract. A small amount of phosphorus is secreted into the GI tract. (See Etiology.)

The phosphorus in plasma is 12-17% protein bound. Free serum compounds represent much less than 1% of the total body phosphorus content. This fraction also varies with shifts between the intracellular and extracellular compartments. Thus, serum phosphorus levels may not reflect accurately the total body phosphorus content. (See Workup.)

Levels are expressed in terms of serum phosphorus mass (mg/dL). One mg/dL of phosphorus is equal to 0.32 mmol of phosphate. The normal adult range for phosphorus is 2.5-4.5 mg/dL (0.81-1.45 mmol/L). Levels are 50% higher in infants and 30% higher in children, because of growth hormone effects.

Hyperphosphatemia is considered significant when levels are greater than 5 mg/dL in adults or 7 mg/dL in children or adolescents. (See Workup and Treatment.)

Cellular function and metabolism

Phosphate is critical for a vast array of cellular processes. In addition to providing mineral strength to bone, it is an integral component of the nucleic acids that make up deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The phosphate bonds of adenosine triphosphate (ATP) carry the energy required for all cellular functions.

The addition and deletion of phosphate groups to enzymes and proteins are common mechanisms for the regulation of their activity. Phosphate also functions as a buffer in bone, serum, and urine. In view of the sheer breadth of influence of phosphorus, phosphate homeostasis (as depicted in the image below) is understandably a highly regulated process.

Approximately 60-70% of dietary phosphate, 1000-15 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.

As previously stated, 80-90% of total body phosphate is in the bone as part of the mineralized extracellular matrix. This phosphate pool is accessible, albeit in a somewhat limited fashion. Approximately 300 mg of phosphate enters and exits bone tissue each day. Excessive losses or failure to add phosphate to bone leads to osteomalacia.

Intracellular concentration and transport

Phosphate is a predominantly intracellular anion (it has a negative charge) with a concentration of approximately 100 mmol/L, although determination of the precise intracellular concentration has been difficult. Most intracellular phosphate is either complexed or bound to proteins or lipids. In response to kinases and phosphatases, these phosphate ions attach and detach from different molecules, forming a constantly shifting pool.

Intracellular phosphate is essential for most, if not all, cellular processes; however, because the intracellular concentration of phosphate is greater than the extracellular concentration, phosphate entry into cells requires a facilitated transport process.

Several sodium-coupled transport proteins have been identified that enable intracellular uptake of phosphate by taking advantage of the steep extracellular-to-intracellular sodium gradient. Type 1 sodium phosphate cotransporters are expressed predominantly in kidney cells on the apical membranes of proximal tubule cells and liver. They are capable of transporting organic ions and stimulating chloride conductance in addition to phosphate. Their role in phosphate homeostasis is not clear. Other sites of expression include the liver and brain.

Type 2 sodium phosphate cotransporters are expressed in kidneys, bone, intestines, and a variety of other epithelial tissues responsible for transepithelial transport.

Type 2a transporters are expressed in the apical membranes of kidney proximal tubules, are very specific for phosphate, and are regulated by several physiologic mediators of phosphate homeostasis, such as parathyroid hormone (PTH), dopamine, and dietary phosphate. Currently, these transporters are believed to be most critical for maintenance of renal phosphate homeostasis. Impaired expression or function of these transporters is associated with nephrolithiasis.[1] Renal regulation of phosphate is depicted in the image below.

The vast majority of filtered phosphate is reabsor 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.

Type 2b transporters are very similar, but not identical, to type 2a transporters. They are expressed in the small intestine and are also upregulated under conditions of dietary phosphate deprivation. Many additional epithelial tissues express type 2b transporters, such as mammary glands, lung epithelium, salivary glands, and testis. It is unlikely that the transporters at these sites contribute to phosphate homeostasis; however, the absence of this transporter can be associated with clinical conditions such as broncholithiasis.

Type 2c transporters, a third member of the Type 2 sodium phosphate cotransporter family, were initially described as growth-related phosphate transporters. They are expressed exclusively on the S1 segment of the proximal tubule and together with Type 2a transporters are essential for normal phosphate homeostasis. Similarly to type 2a transporters, type 2c transporters are also regulated by diet and PTH. Loss of type 2c function results in hereditary hypophosphatemic rickets with hypercalciuria.[2]

Type 3 transporters were initially identified as viral transport proteins. Almost all cells express type 3 sodium phosphate cotransporters; therefore, these transporters presumably play a housekeeping role in ensuring adequate phosphate for all cells. The factors that regulate the activity of these transporter proteins are not completely understood. Evidence suggests, however, that these transporters may also participate in regulation of renal and intestinal transepithelial transport[3, 4] and in regulation of bone mineralization.[5]

Serum phosphate concentration

Circulating phosphate exists as either the univalent or divalent hydrogenated species. Because the ionization constant of acid (pK) of phosphate is 6.8, at the normal ambient serum pH of 7.4 the divalent species is 4 times as prevalent as the monovalent species.

Serum phosphate concentration varies with age, time of day, fasting state, and season. Serum phosphate concentration is higher in children than adults; the reference range is 4-7 mg/dL in children compared with 2.5-4.5 mg/dL in adults. A diurnal variation exists, with the highest phosphate level occurring near noon.

Serum phosphate concentration is regulated by diet, hormones, and physical factors such as pH. Importantly, because phosphate moves in and out of cells under several influences, the serum concentration of phosphate may not reflect true phosphate stores. Often, persons with alcoholism who have severely deficient phosphate stores may present for medical treatment with a normal serum phosphate level. Only after refeeding will serum phosphate levels decline, often abruptly plummeting to dangerously low levels.

Phosphate homeostasis

Phosphate is plentiful in the diet. A normal diet provides approximately 1000-1500 mg of phosphate, two thirds of which is absorbed, predominantly in the proximal small intestine. The fractional absorption of phosphate can be increased by increasing vitamin D intake and by ingesting a very low–phosphate diet. Under these conditions, the intestine expresses sodium-coupled phosphate transporters to enhance phosphate uptake.

Regulation of intestinal phosphate transport overall is poorly understood. Although studies had suggested that the majority of small intestine phosphate uptake was accomplished through unregulated, sodium-independent pathways, subsequent investigations have suggested that regulated sodium-dependent mechanisms may play a greater role in overall intestinal phosphate handling than was previously appreciated. Furthermore, intestinal cells may have a role in renal phosphate handling through elaboration of circulating phosphaturic substances in response to sensing a phosphate load.[6]

Absorption of phosphate can be blocked by commonly used over-the-counter aluminum-, calcium-, and magnesium-containing antacids. Mild to moderate use of such phosphate binders generally poses no threat to phosphate homeostasis, because dietary ingestion greatly exceeds body needs. However, very heavy use of these antacids can cause significant phosphate deficits. Stool losses of phosphate are minor; ie, 100-300 mg/day from sloughed intestinal cells and gastrointestinal secretions. However, diseases that cause severe diarrhea or intestinal malabsorption can dramatically increase these losses.

Bone loses approximately 300 mg of phosphate per day, but that loss is generally balanced by an uptake of 300 mg. Bone metabolism of phosphate is influenced by factors that determine bone formation and destruction; ie, PTH, vitamin D, sex hormones, acid-base balance, and inflammatory status.

PTH and vitamin D

Excess ingested phosphate is excreted by the kidneys to maintain phosphate balance. Major sites of regulation of phosphate excretion are the early proximal renal tubule and the distal convoluted tubule. In the proximal tubule, phosphate reabsorption by type 2 sodium phosphate cotransporters is regulated by dietary phosphate, PTH, and vitamin D. High dietary phosphate intake and elevated PTH levels decrease proximal renal tubule phosphate absorption, thus enhancing renal excretion. Defense against hyperphosphatemia is depicted in the image below.

Hyperphosphatemia inhibits 1-alpha hydroxylase in 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.

Conversely, low dietary phosphate intake, low PTH levels, and high vitamin D levels enhance renal proximal tubule phosphate absorption. To some extent, phosphate regulates its own regulators. High phosphate concentrations in the blood down-regulate the expression of some phosphate transporters, decrease vitamin D production, increase FGF23 release from osteocytes, and increase PTH secretion by the parathyroid gland. Distal tubule phosphate handling is less well understood. PTH increases phosphate absorption in the distal tubule, but the mechanisms by which this occurs are unknown. Renal phosphate excretion can also be increased by the administration of loop diuretics.

PTH and vitamin D were the only recognized regulators of phosphate metabolism until the discovery several novel regulators of mineral homeostasis, identified through studies of serum factors associated with phosphate-wasting syndromes, such as oncogenic osteomalacia and the hereditary forms of hypophosphatemic rickets.


The first to be discovered was a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), a neutral endopeptidase mutated in the syndrome of X-linked hypophosphatemic rickets. The characteristics of this syndrome (ie, hypophosphatemia, renal phosphate wasting, low 1,25-dihydroxyvitamin D levels), as well as the fact that PHEX was identified as an endopeptidase, suggested the possibility that PHEX might be responsible for the catabolism of a non-PTH circulating factor that regulated proximal tubule phosphate transport and vitamin D metabolism. A potential substrate for PHEX was subsequently identified as fibroblast growth factor 23 (FGF23).


Several lines of evidence support a phosphaturic role for FGF23. Another syndrome of hereditary hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, is characterized by a mutation in the FGF23 gene that renders the protein resistant to proteolytic cleavage and thus, presumably more available for inhibition of renal phosphate transport. Administration of recombinant FGF23 produces phosphaturia, and FGF23 knockout mice exhibit hyperphosphatemia.

The syndrome of oncogenic osteomalacia, characterized by acquired hypophosphatemic rickets and renal phosphate wasting in association with specific tumors, is associated with overexpression of FGF23. Interestingly, in this syndrome, overexpression of FGF23 is accompanied by 2 other phosphaturic agents; ie, matrix extracellular phosphoglycoprotein (MEPE) and frizzled related protein-4. The roles of these 2 latter proteins and their relationship with FGF23 and PHEX are unknown.

The physiologic role for FGF23 in regulation of phosphate homeostasis is still under investigation. FGF23 is produced in several tissues, including heart, liver, thyroid/parathyroid, small intestine, and bone tissue. The source of circulating FGF23 has not been conclusively established; however, the highest mRNA expression for FGF23 in mice is in bone, specifically osteocytes.[7, 8] Transgenic mouse models of FGF23 overexpression show hypophosphatemia, phosphaturia, and osteomalacia, while FGF23 deficiency is associated with hyperphosphatemia and a low fractional excretion of phosphate. FGF23 specifically decreases the proximal renal tubule expression of the type 2a and type 2c sodium phosphate cotransporters, accounting for the effect on phosphate homeostasis.

FGF23 production by osteoblasts is stimulated by 1,25 vitamin D.[8] Conversely, individuals with X-linked hypophosphatemic rickets show inappropriately depressed levels of 1,25 vitamin D due to FGF23-mediated suppression of 1-alpha hydroxylase activity. Studies in patients with end-stage renal disease found that FGF23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels. As levels of 1,25 vitamin D fall during the development of progressive chronic kidney disease, levels of FGF23 rise inversely. Elevated FGF23 levels precede the development of secondary hyperparathyroidism and hyperphosphatemia in chronic kidney disease.

Klotho, a transmembrane protein, is an essential cofactor for the effects of FGF23 on renal proximal tubule cells.[9] Inactivation or deletion of Klotho expression results in hyperphosphatemia and accelerated aging. The relationship between these 2 functions of Klotho remains unknown. The loss of klotho expression occurs early in the development of chronic kidney disease. These 2 hormonal alterations, increases in FGF23 and decreases in klotho, have been associated with higher mortality and cardiovascular disease.

A study also demonstrated that FGF23 levels rapidly decreased after kidney transplantation, suggesting that FGF23 is cleared by the kidney.[10] Thus, residual FGF23 could contribute to the hypophosphatemia frequently seen in posttransplant patients. In healthy young men without renal disease, phosphate intake did not significantly increase FGF23 levels, suggesting that FGF23 may not play a role in acute phosphate homeostasis but may be more important for long-term regulation of phosphate homeostasis.[11]

STC1 and STC2

One other family of phosphate-regulating factors is the stanniocalcins (STC1 and STC2). In fish, where it was first described, STC1 inhibits calcium entry into the organism through the gills and intestines. In mammals, however, STC1 stimulates phosphate reabsorption in the small intestine and renal proximal tubules and STC2 inhibits the promoter activity of the type 2 sodium phosphate cotransporter, while the effects on calcium homeostasis are of lesser magnitude. Very little is known about the clinical significance of these newly described mineral-regulating agents or about potential interactions with either the PTH ̶ vitamin D axis or the phosphatonin-PHEX system.


Phosphorus homeostasis is normally maintained through several mechanisms. GI absorption must be matched by renal excretion, and cellular release is balanced by uptake in other tissues. Hyperphosphatemia occurs when the phosphorus load (from GI absorption, exogenous administration, or cellular release) exceeds renal excretion and tissue uptake, an imbalance that can result from any of the following three pathogenic mechanisms:

  • Excessive phosphate intake
  • Decreased phosphate excretion
  • Phosphate shift from intracellular to extracellular space

Regardless of the cause, hyperphosphatemia produces similar signs and symptoms. Because phosphate is predominantly an intracellular anion and because a variety of factors can regulate the actual serum phosphate concentration, an individual can ingest a very substantial phosphate load without exhibiting frank hyperphosphatemia. Conversely, hyperphosphatemia does not always reflect a true increase in total body phosphate stores.

Excessive phosphate intake

Excessive phosphate intake alone is an uncommon cause of hyperphosphatemia, particularly in the presence of normal renal function. The mechanisms for renal excretion allow a person with normal phosphate homeostatic mechanisms to ingest virtually unlimited quantities of phosphate. In healthy persons, higher phosphate ingestion results in higher baseline serum phosphate and higher peaks. Serum phosphate exhibits a diurnal rhythm, with the lowest concentrations being at 8 AM and the highest at 4 PM and 4 AM. Antacids decrease absorption because calcium, aluminum, and magnesium bind phosphorus into insoluble complexes. Aluminum is the most efficient binder found in antacids.

Most often, hyperphosphatemia is caused by a relatively high phosphate intake in the setting of impaired mechanisms for renal phosphate excretion (eg, renal failure, milk-alkali syndrome).

Vitamin D intoxication can produce hyperphosphatemia as a result of excessive gastrointestinal absorption and increased renal reabsorption.

Reports indicate that the excessive use of phosphate-containing laxatives or enemas can also produce hyperphosphatemia. In addition, hyperphosphatemia can result from the short-term parenteral administration of large quantities of phosphate, but again, this most often happens in the setting of impaired renal function.

Decreased phosphate excretion

Renal failure

Decreased excretion of phosphate, especially when coupled with excessive intake, is by far the most common mechanism for the development of hyperphosphatemia. The most common cause of decreased renal phosphate excretion is kidney failure, acute or chronic, of any cause (although marked hyperphosphatemia is unusual in chronic renal insufficiency unless the glomerular filtration rate (GFR) is less than 25 mL/min).

Once renal insufficiency progresses to the loss of 40-50% of renal function, the decrease in the amount of functioning renal tissue does not allow excretion of the full amount of ingested phosphate required to maintain homeostasis, and hyperphosphatemia develops.

Hyperphosphatemia may persist when patients with end-stage renal disease are placed on dialysis. Even in patients who are adherent to diet and prescribed phosphate binders, one or more of the following may be involved[12] :

  • Removal of phosphate by dialysis may vary by >400 mg per treatment
  • Enteral absorption of phosphate may differ by ≥250 mg/d among patients, even with correction for diet and vitamin D intake
  • Efficacy of phosphate binder therapy may vary 2-fold among patients


Hypoparathyroidism causes hyperphosphatemia through a failure of the kidneys to inhibit renal proximal tubule phosphate reabsorption. Syndromes of tubular resistance to PTH manifest hyperphosphatemia because of the same mechanism. These syndromes include the various types of pseudohypoparathyroidism (1a, 1b, 1c, and 2) and severe hypomagnesemia, which impairs PTH secretion and causes peripheral PTH resistance.

Syndromes of tumoral calcinosis

The syndromes of tumoral calcinosis also are characterized by decreased renal excretion of phosphate, resulting in hyperphosphatemia.[13, 14, 15, 16, 17] These syndromes are produced by inactivating mutations of the following:

  • FGF23, a phosphaturic hormone
  • GALNT3, an enzyme that controls FGF23 glycosylation and function
  • Klotho, an essential cofactor for the phosphaturic effect of FGF23 in the renal tubule

Vitamin D intoxication

Vitamin D intoxication, in addition to increasing gastrointestinal phosphate absorption, increases renal phosphate reabsorption, thus enhancing the hyperphosphatemic effect.

Phosphate shift from intracellular to extracellular space

This pathogenic mechanism alone is an uncommon cause of hyperphosphatemia, but it can exacerbate hyperphosphatemia produced by impaired renal excretion. Clinical situations in which a shift to extracellular space is the major cause of hyperphosphatemia include rhabdomyolysis and tumor lysis. Rarely, extracellular shifts of phosphate occur with insulin deficiency or acute acidosis.

Sequelae of hyperphosphatemia

By precipitating calcium, decreasing vitamin D production, and interfering with PTH-mediated bone resorption, hyperphosphatemia can cause hypocalcemia; in severe cases, hypocalcemia can be life-threatening.

Prolonged hyperphosphatemia promotes soft-tissue calcification, in which an abnormal deposition of calcium phosphate occurs in previously healthy connective tissues, such as cardiac valves, and in solid organs, such as muscles.

Excess free serum phosphate is taken up into vascular smooth muscle via a type 3 sodium-phosphate cotransporter. The increased cellular phosphate activates a gene, CBFA1, that triggers a transformation in the vascular cell, causing smooth muscle cells to engage in osteogenesis. Vascular walls become calcified and arteriosclerotic, leading to increased systolic blood pressure, widened pulse pressure, and subsequent left ventricular hypertrophy.

However, although hyperphosphatemia is ultimately responsible for the increase in vascular calcifications, studies have suggested that the process may additionally be influenced by 1,25 vitamin D and an elevated calcium-phosphate product .

Related disorders

Hyperphosphatemia is an independent risk factor contributing to the increased incidence of aortic and mitral stenosis and other cardiovascular diseases among patients who are dependent on dialysis. A peripheral form known as calcific uremic arteriolopathy (calciphylaxis) can induce necrotic ulceration and gangrene in affected extremities.

Hyperphosphatemia-induced resistance to PTH contributes to secondary hyperparathyroidism and renal osteodystrophy.[18]

Cardiovascular effects

Serum phosphate level is associated with cardiovascular risk even in individuals without kidney disease in whom the serum phosphate is within the normal range.[19]

Studies have shown that acute phosphate loads obtained through dietary ingestion cause endothelial cell dysfunction, manifested as a decrease in flow-mediated dilation, in healthy men. This finding raises the possibility that the prolonged and chronic hyperphosphatemia seen in patients with chronic kidney disease could play a direct role in the enhanced cardiovascular morbidity and mortality seen in these patients.[20]  A study in 70 patients who were receiving regular peritoneal dialysis found that hyperphosphatemia (as well as high-sensitivity C-reactive protein) was an independent risk factor for the initiation of coronary artery calcification.[21]  

Osseocartilaginous effects

Phosphate is a major mineral component of bone; not surprisingly, therefore, chronic phosphate excess results in bone pathology, which occurs through several different mechanisms.

Some experimental evidence indicates that high phosphate levels are toxic to some cells. Specifically, a high ambient phosphate level causes apoptosis of chondrocytes and osteoblasts in cell culture. During growth, apoptosis stimulated by high phosphate levels is critical for normal bone development.[22] However, the effect of chronic hyperphosphatemia on bone and cartilage metabolism after closure of the growth plates is unknown.

Hyperphosphatemia complexes serum calcium, leading to lower-than-normal levels of ionized calcium. The decrease in ionized calcium triggers the release of PTH, resulting in a state of secondary hyperparathyroidism; high phosphate levels alone also stimulate PTH release. The elevated PTH levels lead to a high bone turnover state, resulting in the release of calcium, at the expense of bone, to normalize the serum calcium level.

High phosphate levels also inhibit 1-alpha hydroxylase, a renal enzyme that produces active vitamin D by adding a hydroxyl group to circulating 25-hydroxycholecalciferol. This inhibition is most likely a result of the hyperphosphatemia-stimulated increase in FGF23 levels.

The decrease in active vitamin D results in impaired gastrointestinal absorption of calcium, decreased renal reabsorption of calcium and phosphate, and impaired bone mineralization. Over months to years, bone density decreases. Additionally, the PTH and vitamin D derangements result in abnormal bone architecture. Clinically, the skeletal manifestations of chronic hyperphosphatemia include bone pain and fractures.

Soft-tissue calcification

Hyperphosphatemia, especially if present for an extended period, can lead to soft-tissue calcification, that is, the deposition of calcium phosphate in nonosseous sites. For example, patients with renal failure who have chronically uncontrolled hyperphosphatemia develop progressively extensive soft tissue calcifications.

Major sites of calcium deposition include the eyes, joints, and vasculature. Joint deposits can become large and painful, limiting movement and necessitating surgical removal, while eye deposits produce the syndrome of band-shaped keratopathy and conjunctivitis.

Deposition of calcium/phosphate into skin causes a papular rash and may contribute to uremic pruritus and ischemic ulcers. Calcium deposition in tendons and ligaments results in a high frequency of spontaneous rupture.

The long-term complications of chronic hyperphosphatemia can affect any organ system and are potentially devastating.

Vascular calcifications

Undoubtedly, the most significant long-term complication of chronic, uncontrolled hyperphosphatemia is the development of vascular calcifications. These can assume the following 3 basic forms:

  • Capillary and small arteriole calcifications
  • Medial arterial calcifications
  • Cardiac calcifications

Vascular calcifications produce syndromes of accelerated coronary atherosclerosis, medial arterial calcification, and calciphylaxis (which has been recognized and reported for many years in patients with renal failure).

Capillary and small arteriole deposition of calcium is generally the pathology detected in classic calciphylaxis. The blood supply distal to the calcified vessels is impaired, leading to the development of necrotic skin lesions and hemorrhagic subcutaneous lesions.

Although many case reports have been published describing the syndrome of calciphylaxis, research has been lacking; only a few series have included more than several patients. The syndrome’s pathogenesis is not known. Several investigators have suggested a role for hyperparathyroidism, excessive vitamin D, vitamin K deficiency, and high calcium phosphate production. However, many patients may not demonstrate any of these abnormalities. In contrast, most patients have a history of uncontrolled phosphate levels, implicating hyperphosphatemia as a particularly important pathogenic or inciting factor.

Medial arterial calcium deposition has been described in patients with renal failure. Some investigators suggest that smooth muscle cells in the media dedifferentiate into cells with a more osteoblastic phenotype, allowing mineralization of the blood vessel. Support for this theory comes from studies demonstrating the expression of osteoblast-specific proteins, such as alkaline phosphatase and osteopontin, in the medial cells of calcified blood vessels. Other investigators suggest that loss of normal inhibitors of soft tissue calcification, such as matrix GLA protein or osteoprotegerin, may play a role in the pathogenesis.

A study also demonstrated that phosphate uptake through Pit-1, a type III sodium-dependent phosphate cotransporter, is essential for smooth muscle cell calcification in response to elevated phosphate. Studies on coronary calcification have uniformly shown a higher degree of calcification at a younger age in patients with renal failure than in those without renal failure. This premature coronary calcification is thought to play a role in the accelerated cardiovascular mortality observed in patients with renal failure.

Calcium deposited into the heart tissue itself can disrupt the cardiac conduction system, producing significant arrhythmias. Calcium deposition into valves generally does not produce valve dysfunction, but it can serve as a marker for generalized vascular calcification. Aortic valve calcification detected using echocardiography is a poor prognostic factor in patients with renal failure and portends a high chance of mortality.

The precise role of uremia in causing, facilitating, or exacerbating the incidence and effect of vascular calcifications associated with hyperphosphatemia has not been clarified.


The most common cause of hyperphosphatemia is renal failure. Less common causes can be classified according to pathogenesis; ie, increased phosphate intake, decreased phosphate output, or a shift of phosphate from the intracellular to the extracellular space. Often, several mechanisms contribute. Impaired renal excretion is most frequently the major factor, with relatively increased intake or cell breakdown contributing to the problem.

Increased intake

This can result from the following:

  • Excessive oral or rectal use of an oral phosphate-saline laxative (Phospho-soda)
  • Excessive parenteral administration of phosphate
  • Milk-alkali syndrome
  • Vitamin D intoxication

Medications containing phosphorus may increase intake, particularly in patients taking multiple medications. Common drugs with high phosphorus content include[23] :

  • Paroxetine
  • Amlodipine
  • Lisinopril
  • Sitagliptin

Decreased excretion

This can result from the following:

  • Acute kidney injury or chronic kidney disease
  • Hypoparathyroidism
  • Pseudohypoparathyroidism
  • Severe hypomagnesemia
  • Tumoral calcinosis
  • Bisphosphonate therapy

Shift of phosphate from intracellular to extracellular space

This can result from the following:

  • Rhabdomyolysis
  • Tumor lysis
  • Acute hemolysis
  • Acute metabolic or respiratory acidosis


Results that falsely indicate the presence of hyperphosphatemia can result from the following:

  • Blood sample taken from line containing heparin or alteplase [24, 25]
  • High concentrations of paraproteins [26]
  • Hyperbilirubinemia [27]
  • In vitro hemolysis
  • Hyperlipidemia [28]


Occurrence in the United States

Hyperphosphatemia is rare in the general population, but in patients with advanced chronic kidney disease, the rate of hyperphosphatemia is at least 70%. Almost all patients with dialysis-dependent kidney failure experience hyperphosphatemia at some time during the course of their disease. This is true for acute and chronic kidney disease.

International statistics

The prevalence of hyperphosphatemia in the general population and in persons with kidney failure is similar throughout the world.

Race- and sex-related demographics

Hyperphosphatemia, per se, has no racial predilection. However, African Americans, people of Hispanic origin, and indigenous populations (eg, American Indians, aboriginal peoples) have a disproportionately high prevalence of kidney failure, which can lead to hyperphosphatemia.

Women have physiologic elevation of serum phosphate levels after menopause, but this has no known clinical significance. Notably, animal studies have shown that estrogens decrease the transcription and expression of kidney type 2a sodium phosphate cotransporters; thus, it is likely that this inhibitory effect is lost after menopause, accounting for the increase in serum phosphate. What role this mechanism may play in the shifting cardiovascular risk seen in postmenopausal women as opposed to premenopausal women has not been investigated.

Age-related demographics

Hyperphosphatemia can occur in persons of any age. The normally higher level of serum phosphate in neonates, infants, and children (sometimes >6 mg/dL) must be considered when making a diagnosis of hyperphosphatemia.

Because hyperphosphatemia most commonly occurs in the setting of kidney failure and because kidney failure occurs most commonly in elderly persons, the incidence of hyperphosphatemia increases with age, proportionate to the increase in the incidence of kidney failure. Moreover, multiple investigators have suggested that the acute and chronic kidney disease resulting from the use of phosphate-containing bowel cleansing agents is far more prevalent in the elderly population. This observation may be due to the higher prevalence of chronic kidney disease in this population.


Hyperphosphatemia, even of a quite severe degree, is largely a clinically asymptomatic condition. Associated morbidity most commonly results from an underlying condition than it does from the hyperphosphatemia itself.

The short-term complications of hyperphosphatemia include acute hypocalcemia with possible tetany and, more rarely, acute deposition of calcium/phosphate complexes into joints, as well as subcutaneous tissue and other areas of soft tissue. Acute hyperphosphatemia caused by excessive Phospho-soda ingestion may result in acute renal failure and, in some cases, chronic kidney disease.[29, 30, 31, 32] The inciting cause in acute hyperphosphatemia can usually be successfully treated.

In chronic hyperphosphatemia, however, the prognosis can be mixed, and the long-term complications can severely damage any organ system. The organs most commonly affected in chronic hyperphosphatemia include the vascular system, as well as the bones, skin, and heart. The joints are also commonly involved.

Prolonged hyperphosphatemia is an independent risk factor for cardiovascular disease in patients with chronic kidney disease. Patients with chronic phosphate levels above 6.5 mg/dL have an 18-39% higher mortality compared with patients with kidney failure who have near-normal serum phosphate levels.

Even in patients without chronic kidney disease, hyperphosphatemia may be a risk factor. In a Korean study of 92,756 individuals with normal kidney function, higher serum phosphorus levels were an independent predictor for all-cause mortality, particularly in men (hazard ratio 1.43, 95% confidence index, 1.22-1.68).[33]

Hyperphosphatemia in renal disease

Hyperphosphatemia is a risk factor for mortality in multiple populations, including kidney transplant recipients,[34] patients with end-stage renal disease,[35] and patients with chronic kidney disease (CKD).[36]  

If started early in the course of kidney failure, control of phosphate ingestion and absorption by appropriate changes in diet and the use of binders can successfully postpone the development of various complications. This has been demonstrated most convincingly in animal studies; however, and there is a paucity of human studies. On the other hand, if hyperphosphatemia is not adequately addressed early on, the changes that occur in bones, joints, and cardiovascular tissues can be very difficult, if not impossible, to eradicate.

Changes in baseline phosphorus values beyond the recommended targets of the Kidney Disease Outcome Quality Initiative (KDOQI) have been found to be robust predictors of higher death risk. Hyperphosphatemia is associated with cardiovascular disease in CKD patients. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines consider high phosphorus intake a modifiable risk factor even in the absence of hyperphosphatemia.[37]

Interestingly, whether treatment to lower phosphate levels in patients with chronic or end-stage kidney disease results in lower morbidity and mortality has not really been definitively demonstrated. A study showed that patients treated with phosphate binders had a decrease in 1-year mortality, but the effect did not correlate with the degree of hyperphosphatemia.[38] A more recent study demonstrated that when compared with placebo, treatment of patients with chronic kidney disease with one of a variety of phosphate binders resulted in lower serum phosphate but greater acceleration of vascular calcification, a condition associated with a higher mortality.[39] This is an area that requires more intensive investigation.

Patient Education

Dietary education, including on the phosphate content of foods, is very important for patients at risk for recurrent hyperphosphatemia. This information is most effectively provided by a licensed dietitian, who can provide lists of high- and low-phosphate foods and suggest substitutions when needed.[40] Patients must also be taught the importance of consistently taking phosphate binders, maintaining an adequate hydration status, and avoiding phosphorus-containing preparations, such as laxatives, enemas, and supplements.




Typically, most patients with hyperphosphatemia are asymptomatic. Signs and symptoms of acute hyperphosphatemia result from the effects of hypocalcemia, with patients occasionally reporting symptoms such as muscle cramps, tetany, and perioral numbness or tingling. Other symptoms include bone and joint pain, pruritus, and rash.

More commonly, patients report symptoms related to the underlying cause of the hyperphosphatemia, generally uremic symptoms such as fatigue, shortness of breath, anorexia, nausea, vomiting, and sleep disturbances.

Therefore, information related to the causes of hyperphosphatemia, such as a history of diabetes mellitus or hypertension (causes of renal failure), a history of neck surgery or irradiation (causes of hypoparathyroidism), or a history of excessive vitamin D or milk ingestion, is important to obtain.

A search for the following historical clues may help to identify patients who are at risk for increased phosphorus levels:

  • Kidney disease: Past or present hemodialysis; adherence to renal (low phosphorus) diet; use of oral phosphate binders
  • Cancer: Leukemia, lymphoma, bone tumors, other cancers, chemotherapy treatment
  • Endocrinopathies (hypoparathyroidism and pseudohypoparathyroidism)
  • Trauma
  • Burns or heat-related illnesses
  • Prolonged immobilization
  • Metabolic or hematologic disorders, including genetic predisposition
  • Ischemic bowel (possible phosphorus elevations)

The patient’s medication history with regard to the following should also be obtained:

  • Oral phosphate binders
  • Potassium phosphate
  • Antacids
  • Bisphosphonates
  • Laxatives (oral/rectal) and enemas [41]
  • Nutritional supplements or hyperalimentation

Physical Examination

No aspects of the physical examination are specific to or pathognomonic of hyperphosphatemia. If the hyperphosphatemia is acute, especially if it is due to parenteral phosphate administration, the patient may be hypotensive or exhibit signs of hypocalcemia, such as a positive Trousseau or Chvostek sign, hyperreflexia, carpopedal spasm, or seizure.

Cataracts can be an ocular sign of hyperphosphatemia, but the cardiovascular (hypotension and heart failure, prolongation of the QT interval) and nervous systems are the most commonly affected by the condition.

Central nervous system (CNS) and neuromuscular signs and symptoms in patients with hyperphosphatemia include the following:

  • Altered mental status
  • Delirium
  • Obtundation
  • Coma
  • Convulsions and seizures
  • Muscle cramping or tetany
  • Neuromuscular hyperexcitability (ie, Chvostek and Trousseau signs)
  • Paresthesias (particularly perioral and distal extremities)


Diagnostic Considerations

Pseudohyperphosphatemia is most commonly due to paraproteinemia from the following:

  • Waldenström macroglobulinemia
  • Multiple myeloma
  • Monoclonal gammopathy of unknown significance

Other differentials to be considered include the following:

  • Vitamin D intoxication
  • Oral saline laxative (Phospho-soda) abuse
  • Pseudohyperphosphatemia
  • Pseudohypoparathyroidism
  • Rhabdomyolysis

Differential Diagnoses



Approach Considerations

The following measurements are indicated in patients with hyperphosphatemia:

  • Serum phosphate level [42] : Reference range in adults, 2.5-4.5 mg/dL; reference range in children, 3-6 mg/dL; hemolysis or hyperlipidemia of the serum sample may lead to falsely elevated phosphorus levels
  • Serum calcium level
  • Electrolytes
  • Blood urea nitrogen (BUN) and creatinine levels
  • Serum magnesium level (may be low)

No specific procedures are indicated to evaluate hyperphosphatemia. Bone biopsy findings, however, may help in differentiating parathyroid bone disease and osteomalacia in patients with chronic or end-stage renal disease.

Full Chemistry Profile

Measures of serum calcium, magnesium, BUN, and creatinine are of critical importance. The levels of calcium and magnesium, for example, yield information on the status of all divalent ion metabolism.

Low serum calcium levels along with high phosphate levels are observed with renal failure, hypoparathyroidism, and pseudohypoparathyroidism. BUN and creatinine values help to determine whether renal failure is the cause of hyperphosphatemia. Patients with renal failure are also more likely to have elevated intact PTH levels. On the other hand, patients with hypoparathyroidism, either primary or acquired, will have relatively low levels of intact PTH and normal renal function.

High serum calcium and high phosphate levels are observed with vitamin D intoxication and milk-alkali syndrome. Patients with vitamin D intoxication should show relatively low levels of intact PTH and high 25 and 1,25 vitamin D. Patients with milk-alkali syndrome should show low levels of both PTH and vitamin D.

If renal function is normal, then more a unusual disorder, such as one of the following, may be the cause:

  • Vitamin D intoxication
  • Laxative (Phospho-soda) abuse
  • Tumor lysis
  • Rhabdomyolysis
  • Isolated hypoparathyroidism


Urine studies are rarely indicated, but if renal function is normal and PTH levels are high or normal, then a 24-hour urine measurement of cyclic adenosine monophosphate (cAMP) levels can be obtained. Patients with pseudohypoparathyroidism have abnormally low cAMP levels.

Note, however, that most cases of pseudohypoparathyroidism are diagnosed based on clinical grounds, ie, characteristic physical features of Albright hereditary osteodystrophy (eg, short phalanges, short stature, obesity, round face, mental retardation) accompanied by low calcium levels, high phosphate levels, and positive findings from the family history.

In a patient with hyperphosphatemia, the fractional renal excretion of phosphate should be well in excess of 15%. If not, this suggests that renal excretion is impaired either because of renal failure or hypoparathyroidism. If the fractional renal excretion exceeds 15%, this suggests either massive ingestion (eg, laxative [Phospho-soda] abuse) or lysis of tissue with release of intracellular phosphate.

Imaging Studies

Imaging studies are not generally indicated in the evaluation of hyperphosphatemia. If, however, renal failure is discovered, then renal imaging studies (eg, ultrasonography) are indicated.

If significant secondary hyperparathyroidism due to renal failure is found, then long-bone studies may help to assess for the presence of hyperparathyroid bone disease. Likewise, bone densitometry may be desirable for individuals in whom significant bone loss is suggested. Bone biopsy findings may be helpful to differentiate parathyroid bone disease and osteomalacia.

Evaluation of vascular calcification in coronary arteries and peripheral vasculature is being used increasingly, although it is still not in widespread use. Electron beam computed tomography (CT) scanning is the most commonly used modality for imaging and quantitation of coronary artery calcification. The presence of coronary artery and valvular calcification in patients with renal failure and in those on dialysis indicates a poor outcome in some studies. Some investigators suggest that these patients should take sevelamer and not calcium-containing phosphate binders for control of serum phosphorus.

Renal ultrasonography, bone studies, and coronary calcification studies yield data on the chronicity of the process and the patient's prognosis. Shrinkage of the kidneys due to renal failure; changes associated with hyperparathyroidism, based on bone survey results; and coronary calcification are highly suggestive of chronic processes.

Radiography is not necessary for the workup of hyperphosphatemia, but it may reveal evidence of metastatic calcifications (eg, bilateral, symmetrical calcifications of the basal ganglia; periarticular calcifications around large joints; soft tissue calcifications at pressure point areas).



Approach Considerations

The major strategies for treating hyperphosphatemia are as follows:

  • Diagnosis of the cause in order to initiate specific therapy: For example, patients with hyperphosphatemia due to administration of liposomal amphotericin B who continue to require antifungal therapy may be switched to the amphotericin B lipid complex formulation, which contains less inorganic phosphate[43]

  • Limitation of phosphate intake: Patients with chronic kidney disease (CKD) are advised to avoid foods that are especially high in phosphate. High-phosphate foods include dairy products; meats, nuts, and other high-protein foods; processed foods; and dark colas. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines note that it is reasonable to consider phosphate source in making dietary recommendations, as approximately 40-60% of animal-based phosphate is absorbed, compared with 20-50% of plant-based phosphate, and that fresh and homemade foods are preferable to processed foods, which often contain inorganic phosphate additives.[37]

  • Limitation of phosphate absorption: The newest treatment strategy, for patients with CKD who are on dialysis, is use of tenapenor, which decreases gastrointestinal phosphate absorption by inhibiting sodium/hydrogen exchanger isoform 3 (NHE3).

  • Enhancement of renal excretion of phosphate: Hyperphosphatemia due to tumor lysis responds to enhancement of urinary losses through forced saline diuresis

The clinical condition most often requiring curtailment of ingestion is CKD. Because intestinal absorption of phosphate and phosphate content in a typical diet is high, maintenance of phosphate homeostasis depends on renal excretion of the ingested excess. Therefore, when CKD develops and hyperphosphatemia ensues, the sole means of controlling it is limitation of intake.

Serum phosphate levels follow a circadian rhythm, which must be considered when interpreting patient phosphate levels.[44]  Ix et al note a trough at 8 AM, with peaks at 4 AM and 4 PM. In patients with CKD, these authors found that differences in phosphate levels with lowest-phosphate versus highest-phosphate diets were smallest at 8 AM and largest at 4 PM. The low-phosphate diet altered the circadian rhythm such that the 4 AM and 4 PM peaks were absent.[45]

Optimal phosphate control in dialysis patients is extremely challenging. Despite the remarkable improvements made in dialysis techniques over the years, phosphate control has not been substantially improved. In addition, variances in dialytic removal of phosphate, enteral phosphate absorption unexplained by diet or vitamin D intake, and binder efficacy may account for hyperphosphatemia in dialysis patients, despite adherence to therapy.[12]

An alternative approach for dialysis-dependent patients that is presently being investigated is daily nocturnal dialysis. Dialysis performed in this manner, as opposed to intermittent thrice-weekly dialysis, seems to markedly decrease or even abolish the necessity for phosphate binders.[46]

Dey et al reported achieving phosphate control with thrice-weekly sessions by using hemodiafiltration, which combines diffusion and convection, rather than hemodialysis. Their program consisted of nocturnal sessions lasting a median of 8 hours. In the 14 patients in their study, pre-dialysis phosphate levels fell from a mean of 1.52 ± 0.4 to 1.06 ± 0.1 mmol/L (P< 0.05), and use of phosphate binders became unnecessary.[47]

Surgical care

Surgery may sometimes be required for removal of large calcium phosphate deposits in patients with tumoral calcinosis or long-standing CKD. Parathyroidectomy in patients with CKD who have tertiary (autonomous) hyperparathyroidism complicated by hypercalcemia, hyperphosphatemia, and severe bone disease.


The following consultations may be required:

  • Endocrinologist: To determine whether the patient has hypoparathyroidism or one of the various forms of pseudohypoparathyroidism
  • Nephrologist: To evaluate and treat hyperphosphatemia associated with CKD


Calcium levels, phosphate levels, and kidney function should be monitored at intervals consonant with the severity of the underlying disorder. KDIGO guidelines stress that in patients with CKD, the development of metabolic bone disease (MBD) involves a complex interaction of phosphate, calcium, and parathyroid hormone (PTH). Consequently in patients with stage G3a–G5D CKD, the KDIGO recommends serial assessments of all three parameters, considered together, in order to guide treatment of MBD.[37]

KDIGO recommends monitoring serum levels of calcium, phosphate, PTH, and alkaline phosphatase activity beginning in CKD stage G3a (in children, stage G2), at a frequency based on the presence and magnitude of abnormalities, and the rate of progression of CKD.[37] Reasonable monitoring intervals would be as follows:

  • CKD G3a–G3b – Serum phosphate and calcium, every 6–12 months; PTH, based on baseline level and CKD progression
  • CKD G4 – Serum phosphate and calcium, every 3–6 months; PTH, every 6–12 months
  • CKD G5, including G5D – Serum phosphate and calcium, every 1–3 months; PTH, every 3–6 months

Pharmacologic Therapies

Phosphate binders

Dietary restriction alone may suffice for control of hyperphosphatemia in persons with mild kidney insufficiency, but it is inadequate for patients with advanced kidney insufficiency or complete kidney failure. Such individuals require the addition of phosphate binders to inhibit gastrointestinal absorption of phosphate. These medications, which are taken concomitantly with meals, directly interact with the phosphate in the food, preventing intestinal absorption. The following classes of phosphate binders are widely used[48] :

  • Aluminum-containing phosphate binders
  • Calcium-containing phosphate binders
  • Phosphate binders that contain no aluminum or calcium

Administration of phosphate binders is the only truly long-term therapy for chronic hyperphosphatemia due to kidney failure. Monitor calcium and phosphate levels, especially when treating patients with calcium-containing phosphate binders, because of the possibility of severe, life-threatening hypercalcemia.[49]

Calcium citrate and aluminum-containing binders should probably not be used together, because the citrate may enhance aluminum absorption.

A systematic review by Sekercioglu et al of the comparative effectiveness of phosphate binders in patients with chronic kidney disease–mineral and bone disorder (CKD-MBD) found moderate-quality evidence that calcium-containing phosphate binders result in higher mortality than sevelamer in particular and non–calcium-based phosphate binders in general. These authors concluded that their results “raise questions about whether administration of calcium as an intervention for CKD-MBD remains ethical.”[50]

Aluminum-containing phosphate binders

The aluminum-containing binders were the first to be used to treat hyperphosphatemia, but they have largely been abandoned because of the toxic effects of absorbed aluminum. Initially, the amount of aluminum absorbed was thought to be trivial; with long-term use, however, many patients developed a constellation of clinical symptoms attributable to aluminum, including dementia, severe osteomalacia, and anemia.

Bone biopsies performed on patients with aluminum intoxication revealed deposition of aluminum along the mineralizing front of bone, preventing normal mineralization. Aluminum levels in the fasting state and after a challenge with desferrioxamine confirmed the increased total body aluminum load. Aluminum-containing phosphate binders should be used only when other agents have failed to adequately control phosphate levels.

Calcium-containing phosphate binders

The next phosphate binders to be introduced were the calcium-containing binders, such as calcium carbonate and calcium citrate. These drugs, which are still used extensively, have the advantage of inhibiting phosphate absorption while providing the patient with a required mineral, calcium. The disadvantage of these drugs has been the relatively high incidence of hypercalcemia occurring in patients. There have also been concerns about the contribution of large exogenous calcium loads to the occurrence of soft tissue calcification in end-stage renal disease.

Several studies, including the Calcium Acetate Renagel Evaluation (CARE) study, have shown that calcium acetate is more cost-effective than sevelamer (discussed below) as a phosphate binder. Although concern has been raised about its purported link to cardiovascular calcification, calcium acetate can be used effectively with doses of elemental calcium that meet the Kidney Disease Outcome Quality Initiative (KDOQI) guidelines.

Phosphate binders with no aluminum or calcium

The above concerns about calcium-containing binders led to the development of a class of phosphate binders that contain neither aluminum nor calcium. At present, several drugs in this class, including the following, are in clinical use:

Sucroferric oxyhydroxide and ferric citrate are iron-based phosphate binders that reduce serum phosphorus comparably to calcium-based binders and sevelamer. These agents may offer the advantages of providing iron supplementation, low pill burden, and high efficacy, but their place in therapy requires further evaluation.[51, 52]

For patients taking calcium-containing phosphate binders who have had demonstrable extraskeletal calcification or recurrent hypercalcemia, sevelamer and sucroferric oxyhydroxide are excellent alternatives and are well tolerated in the control of serum phosphorus in dialysis patients.

Sucroferric oxyhydroxide

Sucroferric oxyhydroxide is an iron-based phosphate binder that when taken with meals adsorbs dietary phosphate in the GI tract.

Approval for sucroferric oxyhydroxide (1-3 g/day) was based on the results of a phase 3 study that compared the drug’s dose titration and maintenance phases with those of sevelamer (2.4-14.4 g/day). Sucroferric oxyhydroxide and sevelamer efficacy were maintained during long-term use, with no notable difference in safety observed between the treatment groups. Moreover, sucroferric oxyhydroxide had a lower pill burden than did sevelamer.[53, 54]

In an open-label phase 3 extension study that compared sucroferric oxyhydroxide with sevelamer in 644 dialysis patients with hyperphosphatemia, sucroferric oxyhydroxide maintained its serum phosphorus-lowering effect over 1 year. Sucroferric oxyhydroxide was generally well tolerated over the long term, and patients showed no evidence of iron accumulation.[55]  

Increased ferritin levels have been reported after long-term sucroferric oxyhydroxide treatment in patients undergoing hemodialysis.[56] However, a 1-year study reported that transferrin saturation, iron, and hemoglobin concentrations generally remained stable.[57]


Sevelamer and calcium-containing phosphate binders can be used in combination to minimize adverse effects; however, the major barrier to their use is patient noncompliance. The patient is required to ingest 3-6 large capsules with every meal, which is more than most patients can comply with for extended periods. A study, however, demonstrated that once-daily sevelamer was as effective as thrice-daily sevelamer in the control of serum phosphorus, which may improve patient compliance.[58]

In addition to its effects as a phosphate binder, sevelamer has also been shown to improve the lipid profile in patients with hyperphosphatemia.

Lanthanum carbonate

Lanthanum has been shown to be a safe and equally efficacious agent in short-term studies, but concerns about long-term administration and toxicity exist. Furthermore, these agents are significantly more expensive than calcium salts, which may contribute to patient noncompliance. A 16-week, phase 4 study conducted by Vemuri et al found that patients who converted from other phosphate-binder medications to lanthanum carbonate maintained productive serum phosphorus levels with much satisfaction and lessened tablet burden.[59]

Ferric citrate

Oral ferric citrate was approved in 2014 for the control of serum phosphorus levels in patients with CKD who are on dialysis. Approval was based on a randomized trial in 441 adults with end-stage renal disease who were receiving hemodialysis or peritoneal dialysis 3 times per week for at least 3 months. Participants were treated either with ferric citrate or with active control (calcium acetate or sevelamer carbonate) for 52 weeks.

Phosphorus levels were similar in the ferric citrate and active control groups, as were adverse events, which occurred in 39.1% of patients receiving ferric citrate and 49.0% of patients receiving active control. Patients receiving ferric citrate had significantly higher mean ferritin levels (899 ng/mL vs 628 ngmL; P < 0.001), transferrin saturation (39% vs 30%; P < 0.001), and less need for IV iron (12.95 mg/week vs 26.88 mg/week; P < 0.001) compared with active control.[60]

Cardiovascular considerations

Although long-term ingestion of aluminum-containing binders has known toxic effects, no definitive studies suggest that the long-term use of any of the other binders confers either a benefit or a disadvantage in terms of mortality.

Theoretically, the high calcium load of a calcium-containing phosphate binder could perpetuate or worsen vascular calcification, which does correlate with cardiovascular mortality in CKD patients, when compared with non–calcium-containing phosphate binders. In fact, the use of non–calcium-containing binders does result in less vascular calcification; however, a beneficial effect on mortality has not been consistently demonstrated.[61, 62, 63, 64, 65, 66, 67]  

Sodium/hydrogen exchanger 3 (NHE3) inhibitors 

The sodium/hydrogen exchanger isoform 3 (NHE3) acts locally in the gut to reduce absorption of sodium and phosphate.[68] Tenapanor (Xphozah), an NHE3 inhibitor, was approved by the US Food and Drug Administration (FDA) in 2023 to reduce serum phosphorus concentrations in adults with CKD who are on dialysis. It is also indicated 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. Tenapanor had previously been approved for treatment of irritable bowel syndrome with constipation in adults.

In the PHREEDOM study, mean serum phosphate concentrations fell from 7.7 mg/dL to 5.1 mg/dL in patients randomized to tenapanor.[69] The AMPLIFY study reported a larger mean decrease in serum phosphorus concentration from baseline to week 4 in patients treated with tenapanor plus binder, compared with those receiving placebo plus binder (−0.84 versus −0.19 mg/dL, P < 0.001).[70]  

In a phase 3 randomized, double-blind trial of tenapanor, 219 patients with hyperphosphatemia receiving maintenance hemodialysis were given oral tenapanor (3, 10, or 30 mg twice-daily) for 8 weeks. All three groups had significant decreases in serum phosphate (reductions of 1, 1.02, and 1.19 mg/dL, respectively). Patients were then rerandomized 1:1 to continue receiving their assigned dose or placebo for a 4-week period. The placebo group experienced a mean increase of 0.85 mg/dL versus a mean increase of 0.02 mg/dL across the three groups continuing to receive tenapanor.[71]

In another phase 3 trial of tenapanor in 236 patients on maintenance hemodialysis who had hyperphosphatemia despite receiving phosphate binders, 116 were randomly assigned to receive 30 mg oral tenapanor twice daily for 4 weeks while 119 patients received a placebo. Both groups continued to receive phosphate binders. Mean decrease in serum phosphorus concentration over that period was significantly greater in patients treated with tenapanor than in patients taking the placebo (0.84 versus 0.19 mg/dL, P < 0.001).[72]

A preclinical study of the effects of tenapanor and sevelamer carbonate on urinary phosphorus excretion reported that combined tenapanor and sevelamer decreased urinary phosphorus excretion in rats significantly more than either agent administered alone. This result was consistent across varying sevelamer dose levels.[73]

Increased Renal Excretion

The strategy for treatment of hyperphosphatemia in patients with normal kidney function is to enhance renal excretion. This can be accomplished most effectively by volume repletion with saline coupled with forced diuresis with a loop diuretic such as furosemide or bumetanide.

The marked increase in intravascular volume with saline globally inhibits proximal renal tubule absorption of solutes, in this specific case, phosphate, thus promoting phosphaturia.

The increased distal tubule delivery of phosphate overwhelms the ability of that portion of the nephron to absorb phosphate, leading to a negative phosphate balance.

Management of Secondary Hyperparathyroidism

Just as better control of hyperphosphatemia in patients with kidney failure helps to prevent the nearly universal development of secondary hyperparathyroidism, better control of hyperphosphatemia is achieved through control of secondary hyperparathyroidism. The agents commonly used to control secondary hyperparathyroidism are vitamin D metabolites and the calcium-sensing receptor agonists.

A study by Hansen et al found that alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in patients on hemodialysis.[74]

Management of Hypoparathyroidism

For the rare cases of hypoparathyroidism, calcium and vitamin D are prescribed, predominantly for treatment of the hypocalcemia. Given with meals, the oral calcium can ameliorate the hyperphosphatemia of hypoparathyroidism, although this effect has to be carefully balanced against the phosphate absorption–promoting effects of the vitamin D. Over the long term, this therapy may result in nephrocalcinosis. Recombinant PTH injections can be considered but are not commonly used in clinical practice, because of the efficacy of calcium and vitamin D, as well as the cost and inconvenience of injected PTH.



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.


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.


Questions & Answers


What causes hyperphosphatemia?

What are the signs and symptoms of hyperphosphatemia?

What are the signs and symptoms of acute hyperphosphatemia?

What is the role of a full chemistry profile in the evaluation of hyperphosphatemia?

What may cause hyperphosphatemia if renal function is normal?

What is the role of urinary phosphate measurement in the evaluation of hyperphosphatemia?

How is hyperphosphatemia treated?

What is the clinical background of hyperphosphatemia?

What is the role of phosphate in hyperphosphatemia?

What is the role of intracellular phosphate in hyperphosphatemia?

What is the role of type 1 sodium-phosphate transporters in hyperphosphatemia?

Where are type 2 sodium-phosphate transporters expressed in hyperphosphatemia?

Where are type 2a sodium-phosphate transporters expressed in hyperphosphatemia?

Where are type 2b sodium-phosphate transporters expressed in hyperphosphatemia?

Where are type 2c sodium-phosphate transporters expressed in hyperphosphatemia?

What is the role of type 3 sodium-phosphate transporters in hyperphosphatemia?

Which factors affect serum phosphate concentration in hyperphosphatemia?

What is phosphate homeostasis?

What is the role of parathyroid hormone (PTH) and vitamin D in hyperphosphatemia?

What is the role of genetics in hyperphosphatemia?

What is the role of fibroblast growth factor 23 (FGF23) in hyperphosphatemia?

What is the role of stanniocalcins (STC1 and STC2) in hyperphosphatemia?

What is the role of hypoparathyroidism in the pathophysiology of hyperphosphatemia?

What are the pathogenic mechanisms in hyperphosphatemia?

What is the role of excessive phosphate intake in the pathogenesis of hyperphosphatemia?

What is the role of renal failure in the pathogenesis of hyperphosphatemia?

What is the role of tumoral calcinosis in the pathophysiology of hyperphosphatemia?

What is the role of vitamin D intoxication in the pathophysiology of hyperphosphatemia?

What causes a shift from intracellular to extracellular space in the pathogenesis of hyperphosphatemia?

How does hyperphosphatemia cause hypocalcemia?

Hyperphosphatemia increases the risk for which disorders?

What are the cardiovascular effects of hyperphosphatemia?

What are the osseocartilaginous effects of hyperphosphatemia?

How does hyperphosphatemia cause soft-tissue calcification?

What is the role of vascular calcification in the pathophysiology of hyperphosphatemia?

What causes hyperphosphatemia?

What causes an increased intake pathogenesis of hyperphosphatemia?

What causes a decreased excretion pathogenesis of hyperphosphatemia?

What causes the shift of phosphate from intracellular to extracellular space in hyperphosphatemia?

What causes false-positive indication of hyperphosphatemia?

What is the prevalence of hyperphosphatemia in the US?

What is the global prevalence of hyperphosphatemia?

What are the racial predilections of hyperphosphatemia?

How does the prevalence of hyperphosphatemia vary by sex?

How does the prevalence of hyperphosphatemia vary by age?

What is the prognosis of hyperphosphatemia?

What is the prognosis of hyperphosphatemia in renal disease?

What is included in patient education for hyperphosphatemia?


What should be the focus of medication history in the evaluation for hyperphosphatemia?

What are the signs and symptoms of hyperphosphatemia?

What should be the focus of history in the evaluation of hyperphosphatemia?

What are the physical findings characteristic of hyperphosphatemia?


What should be included in the differential diagnoses for hyperphosphatemia?

What are the differential diagnoses for Hyperphosphatemia?


Which studies should be performed in the evaluation of hyperphosphatemia?

What is the role of a full chemistry profile in the workup of hyperphosphatemia?

What is the role of urinalysis in the evaluation of hyperphosphatemia?

What is the role of imaging studies in the workup of hyperphosphatemia?


What is the focus of treatment for hyperphosphatemia?

How is hyperphosphatemia managed in patients on dialysis?

What is the role of surgery in the treatment of hyperphosphatemia?

Which specialist consultations may be beneficial in the treatment of hyperphosphatemia?

How are patients with hyperphosphatemia monitored?

What is the role of tenapanor in the treatment of hyperphosphatemia?

How is hyperphosphatemia managed in patients with normal renal function?

How is secondary hyperparathyroidism managed in hyperphosphatemia?

How is hypoparathyroidism managed in hyperphosphatemia?

What is the role of phosphate binders in the treatment of hyperphosphatemia?

What is the role of aluminum-containing binders in the treatment of hyperphosphatemia?

What is the role of calcium-containing binders in the treatment of hyperphosphatemia?

Which phosphate binders are used in the treatment of hyperphosphatemia?

What is the role of sucroferric oxyhydroxide (Velphoro) in the treatment of hyperphosphatemia?

What is the role of sevelamer for the treatment of hyperphosphatemia?

What is the role of lanthanum in the treatment of hyperphosphatemia?

What is the role of ferric citrate in the treatment of hyperphosphatemia?

What are the benefits of non-calcium phosphate binders for treatment of hyperphosphatemia?


What is the role of drug treatment for hyperphosphatemia?

Which medications in the drug class Phosphate Binders are used in the treatment of Hyperphosphatemia?

Which medications in the drug class Diuretics are used in the treatment of Hyperphosphatemia?