AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Phosphate is critical for a vast array of cellular processes. Phosphate is one of the major components of the skeleton, providing mineral strength to bone. Phosphate is an integral component of the nucleic acids that make up DNA and RNA. The phosphate bonds of ATP carry the energy required for all cellular functions. Phosphate functions as a buffer in bone, serum, and urine. The addition and deletion of phosphate groups to enzymes and proteins are common mechanisms for the regulation of their activity. In view of the sheer breadth of influence of this mineral, phosphate homeostasis is understandably a highly regulated process.

Phosphate in the body

The bulk of total body phosphate (85%) 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.

Phosphate is a predominantly intracellular anion 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. Although the intracellular supply of phosphate is essential for most, if not all, cellular processes, 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, possibly, the distal tubule cells. 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, and intestines. 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. Type 2b transporters are very similar but not identical to type 2a transporters. They are expressed in the small intestine and are also up-regulated under conditions of dietary phosphate deprivation.

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.

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 univalent species is 4 times as prevalent as the divalent 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 3-4.5 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. Furthermore, intestinal absorption of phosphate is virtually unregulated. A normal diet provides approximately 1000 mg of phosphate, two thirds of which is absorbed, predominantly in the proximal small intestine. The 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.

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/d from sloughed intestinal cells and gastrointestinal secretions. However, these losses can be increased dramatically in persons with diseases that cause severe diarrhea or intestinal malabsorption.

Bone losses are approximately 300 mg 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 generalized inflammation.

The 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.

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, 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.

Until quite recently, PTH and vitamin D were the only recognized regulators of phosphate metabolism. In the last decade, however, 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, have been discovered.

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) and 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, 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 the heart, liver, thyroid/parathyroid, small intestine, and bone.  The source of circulating FGF23 has not been conclusively established; however, the highest mRNA expression for FGF23 in mice is in bone (Mirams et al, 2004; Liu et al, 2006).  FGF production by osteoblasts is stimulated by 1,25 vitamin D (Liu et al, 2006).  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. Recent studies in patients with end-stage renal disease found that FGF23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels.

A recent study also demonstrated that FGF23 levels rapidly decreased after kidney transplantation suggesting that FGF23 is cleared by the kidney (Pande et al, 2006). 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 (Nishida et al, 2006). 

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. However, in mammals, 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 either with the PTH-vitamin D axis or with the phosphatonin-PHEX system.

Pathophysiology

Hyperphosphatemia can occur because of 1 of 3 pathogenetic mechanisms.

The first is excessive 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. 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 patients have developed hyperphosphatemia because of excessive use of phosphate-containing laxatives or enemas. Short-term administration of large quantities of phosphate parenterally can also produce hyperphosphatemia but, again, most often in the setting of impaired renal function.

The second is decreased excretion. 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 renal failure, acute or chronic, of any cause. 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.

Hypoparathyroidism causes hyperphosphatemia through a failure 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. Vitamin D intoxication, in addition to increasing gastrointestinal phosphate absorption, increases renal phosphate reabsorption, thus enhancing the hyperphosphatemic effect.

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

Regardless of the cause, hyperphosphatemia produces similar signs and symptoms. Because phosphate is predominantly an intracellular cation 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.

Frequency

United States

Hyperphosphatemia is rare in the general population; however, in patients with renal insufficiency or renal failure, the rate of hyperphosphatemia is at least 70%. Almost all patients with renal failure experience hyperphosphatemia at some time during the course of their disease. This is true for both acute and chronic renal failure.

International

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

Mortality/Morbidity

Hyperphosphatemia, even of a quite severe degree, is largely a clinically asymptomatic condition. The morbidity of hyperphosphatemia is more commonly associated with the underlying condition than with the actual hyperphosphatemia.

The short-term complications of hyperphosphatemia include acute hypocalcemia with possible tetany and, more rarely, acute deposition of calcium/phosphate complexes into joints, subcutaneous tissue, or other soft tissue areas.

The long-term complications of chronic hyperphosphatemia can be devastating and can affect any organ system. Organs most commonly affected include the vascular system and the bones, skin, joints, and heart. Changes in baseline phosphorus values beyond the Kidney Disease Outcome Quality Initiative (KDOQI) recommended targets were robust predictors of higher death risk.

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. The clinical significance of these findings and the extent to which this might occur throughout the body are unknown.

• Phosphate is a major mineral component of bone; therefore, not surprisingly, chronic excess of phosphate results in bone pathology due to several different mechanisms.
  
  
  • 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, releasing calcium to normalize the serum calcium level at the expense of bone calcium.
  
  
  
  • High phosphate levels also inhibit the renal enzyme 1-alpha hydroxylase, which produces active vitamin D by adding a hydroxyl group to circulating 25-hydroxycholecalciferol. 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.
     
• Patients with renal failure who have chronically uncontrolled hyperphosphatemia develop progressively extensive soft tissue calcifications.
  
  
  • Hyperphosphatemia is ultimately responsible for the increase in vascular calcifications, but recent studies have also suggested that the process may additionally be influenced by 1,25 vitamin and an elevated calcium-phosphate product.
  
  
  
  • Deposition of calcium/phosphate into skin causes a papular rash and may contribute to uremic pruritus and ischemic ulcers.
  
  
  
  • Large deposits can develop within joints, leading to pain and limitation of movement.
  
  
  
  • Calcium deposition in tendons and ligaments results in a high frequency of spontaneous rupture.
  
  
  
  • Eye deposits have also been well described, producing the syndrome of band-shaped keratopathy and red eye or conjunctivitis.
     
• Undoubtedly the most significant long-term complication of chronic uncontrolled hyperphosphatemia is the development of vascular calcifications. Although the syndrome of calciphylaxis has been recognized and reported for many years in patients with renal failure, the full extent of vascular involvement, the widespread prevalence in the renal failure population, and the ominous significance of this complication have been appreciated only in the past decade. Vascular calcifications can assume 3 basic forms: capillary and small arteriole, medial arterial, and cardiac.
  
  
  • Capillary and small arteriole deposition of calcium is generally the pathology detected in classic calciphylaxis. Blood supply distal to the calcified vessels is impaired, leading to the development of necrotic skin lesions and hemorrhagic subcutaneous lesions. Many case reports have been published describing the syndrome, but only in a few series of more than several patients. The 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. However, most have a history of uncontrolled phosphate levels, implicating hyperphosphatemia as a particularly important pathogenetic 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 recent 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 comparing coronary calcification in patients with renal failure versus patients without renal failure uniformly show a higher degree of calcification at a younger age. 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.

Race

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

Sex

Susceptibility to hyperphosphatemia favors neither sex.

Age

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 renal failure and because renal failure most commonly occurs in elderly persons, the incidence of hyperphosphatemia increases with age, proportionate to the increase in the incidence of renal failure.

CLINICAL

Section 3 of 11  

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• Multimedia
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History

Typically, most patients with hyperphosphatemia are asymptomatic. However, patients occasionally report hypocalcemic symptoms such as muscle cramps, tetany, and perioral numbness or tingling. Other symptoms include bone and joint pain, pruritus, or 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, important information to obtain is related to 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.

Physical

No aspects of the physical examination are specific to or pathognomonic of hyperphosphatemia. If the hyperphosphatemia is acute, especially if 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.

Causes

The most common cause of hyperphosphatemia is renal failure. Less common causes can be classified according to pathogenesis, ie, increased intake, decreased output, or shift 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
• • Excessive oral or rectal use of an oral saline laxative (Phospho-soda)
  
  
  
  • Excessive parenteral administration of phosphate
  
  
  
  • Milk-alkali syndrome
  
  
  
  • Vitamin D intoxication
• Decreased excretion
• • Renal failure, acute or chronic
  
  
  
  • Hypoparathyroidism
  
  
  
  • Pseudohypoparathyroidism
  
  
  
  • Severe hypomagnesemia
  
  
  
  • Tumoral calcinosis
  
  
  
  • Bisphosphonate therapy
• Shift of phosphate from intracellular to extracellular space
  • Rhabdomyolysis
  
  
  
  • Tumor lysis
  
  
  
  • Acute hemolysis
  
  
  
  • Acute metabolic or respiratory acidosis

• Spurious

• Blood sample taken from line containing heparin or alteplase (Cachat et al, 2006; Ball et al, 2004)
  
  
• High concentrations of paraproteins (Marcu and Hotchkiss, 2004)
  
  
• Hyperbilirubinemia (Larner, 1995)
  
  
• In vitro hemolysis

• Hyperlipidemia (Leehey et al, 1985)

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

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

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Full chemistry profile
  • In particular, serum calcium, magnesium, BUN, and creatinine are of critical importance. The levels of calcium and magnesium yield information concerning 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 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 unusual disorders, such as vitamin D intoxication, laxative (Phospho-soda) abuse, tumor lysis, rhabdomyolysis, or isolated hypoparathyroidism, may be the cause.
  
  
  
  • Urine studies are rarely indicated. If renal function is normal and if PTH levels are high or normal, then a 24-hour urine measurement for cyclic adenosine monophosphate can be obtained. Patients with pseudohypoparathyroidism have abnormally low levels. However, note 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.

Imaging Studies

• Imaging studies are not generally indicated in the evaluation of hyperphosphatemia.
• If renal failure is discovered, then renal imaging studies (eg, ultrasound) are indicated.
• If significant secondary hyperparathyroidism due to renal failure is found, then long-bone studies may help assess for the presence of hyperparathyroid bone disease. Likewise, bone densitometry might 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 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 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 ultrasound, bone studies, and coronary calcification studies yield data on the chronicity of the process and the patient's prognosis. Shrinkage of kidneys due to renal failure, changes in hyperparathyroidism based on bone survey results, and coronary calcification are highly suggestive of chronic processes.

Other Tests

• Rarely, if the cause of hyperphosphatemia is not clear, 24-hour urine measurement of phosphate can be performed. 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.

Procedures

• No specific procedures are indicated to evaluate hyperphosphatemia.
• Bone biopsy findings may be helpful to differentiate parathyroid bone disease and osteomalacia.

TREATMENT

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Medical Care

The major strategies in treating hyperphosphatemia are (1) to diagnose the cause in order to initiate specific therapy, (2) to limit intake, and (3) to enhance renal excretion.

• If the cause of hyperphosphatemia can be determined, then specific treatment can be provided in some cases. For example, excessive ingestion of phosphate-containing purgatives or the administration of excessive quantities of parenteral phosphate is easily treatable by decreasing or discontinuing the supplements. Hyperphosphatemia due to renal failure is predominantly treated by limiting ingested quantities and by dialysis. Hyperphosphatemia due to tumor lysis responds to forced saline diuresis to enhance urinary losses.



• The clinical condition most often requiring curtailment of ingestion is renal failure. Because intestinal absorption of phosphate is unregulated and phosphate content in a typical diet is high, maintenance of phosphate homeostasis is dependent on renal excretion of the ingested excess. Therefore, when renal failure develops and hyperphosphatemia ensues, the sole means of controlling it is limitation of intake.
• • Instruct patients with renal insufficiency and renal failure to avoid foods especially high in phosphate, such as dairy products.
  
  
  
  • Dietary restriction alone may suffice for control of hyperphosphatemia in persons with mild renal insufficiency but is inadequate for control in those with advanced renal insufficiency or complete renal failure. These latter patients require the addition of phosphate binders to inhibit gastrointestinal absorption of phosphate. Phosphate binders are taken concomitantly with meals and work by directly interacting with the phosphate in the food, preventing intestinal absorption. Three classes of phosphate binders are widely used.
    
    
    • The aluminum-containing binders were the first, 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; however, with long-term use, many patients developed a constellation of clinical symptoms attributable to aluminum. These included 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.

     

    • The next class of phosphate binders introduced and still used extensively today are the calcium-containing binders such as calcium carbonate and calcium citrate. These drugs have the advantage of providing a needed mineral, calcium, along with inhibiting phosphate absorption. The disadvantage of these drugs is the relatively high incidence of hypercalcemia and the more recent 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 CARE study, have shown that calcium acetate is more cost-effective than sevelamer 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 KDOQI guidelines.

     

    • These concerns have led to the development of another class of phosphate binders that contain no aluminum or calcium. At present, 2 drugs of this class are in clinical use: sevelamer (Renagel) and lanthanum carbonate (Fosrenol). For patients with demonstrable extraskeletal calcification or recurrent hypercalcemia with calcium-containing phosphate binders, sevelamer is an excellent alternative. Sevelamer hydrochloride is well tolerated in the control of serum phosphorus in dialysis patients. Furthermore, sevelamer has been shown to improve the lipid profile in these patients. 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 human beings can comply with for extended periods.

     

    • A recent 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.  Lanthanum has also recently been shown to be a safe and equally efficacious agent in short-term studies, but concerns of long-term administration and toxicity exist. Furthermore, these agents are significantly more expensive than calcium salts, which may also contribute to patient noncompliance.
       
  • An alternative therapy 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.
  
  
  
  • Just as better control of hyperphosphatemia in renal failure patients helps prevent the nearly universal development of secondary hyperparathyroidism, better control of hyperphosphatemia is also achieved through control of secondary hyperparathyroidism. The agents commonly used to control secondary hyperparathyroidism are vitamin D metabolites and, more recently, the calcium-sensing receptor agonists.
  
  
  
• The strategy for treatment of hyperphosphatemia for patients with normal renal function and hyperphosphatemia is to enhance renal excretion. This can be accomplished most effectively by a combination of 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.
  
  
  
• For the rare cases of hypoparathyroidism, calcium and vitamin D are prescribed. PTH injections or infusions could be considered but are impractical and not used in clinical practice.

Surgical Care

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

Consultations

Consultation with an endocrinologist may be required for determining if the patient has hypoparathyroidism or one of the various forms of pseudohypoparathyroidism. Consultation with a nephrologist may be required for evaluating and treating hyperphosphatemia associated with renal failure.

Diet

When dietary phosphate intake is a significant contributor to hyperphosphatemia, such as with renal failure, dietary phosphate restriction is appropriate. Foods high in phosphate include dairy products, meats, nuts, and other high-protein foods.

Activity

Hyperphosphatemia does not mandate any alteration in physical activity; however, deposition of calcium deposits in joints may limit certain activities.

MEDICATION

Section 7 of 11  

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The goals of pharmacotherapy are to reduce phosphate levels and morbidity and to prevent complications.

Drug Category: Diuretics

Lower phosphate serum levels by enhancing renal excretion.

Drug Category: Phosphate binders

Bind to phosphate contained in food in intestine, thus limiting intestinal absorption.

Drug Name	Calcium carbonate (Oystercal, Caltrate)
Description	Successfully normalizes phosphate concentrations in patients on dialysis. Combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces. Marketed in a variety of dosage forms and is relatively inexpensive. Available by tab for chewing or swallowing in many sizes (250-1000 mg). Used also as antacid or calcium supplement.
Adult Dose	250-1500 mg PO with meals and snacks; titrate dose depending on level of serum phosphate
Pediatric Dose	45-65 mg/kg/d PO divided qid
Contraindications	Renal calculi, hypercalcemia, hypophosphatemia, renal or cardiac disease, patients with digitalis toxicity; hypercalcemia, renal stones
Interactions	May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; IV administration antagonizes effects of verapamil; high intake of dietary fiber may decrease absorption and levels
Pregnancy	A - Safe in pregnancy
Precautions	Hypercalcemia or hypercalcuria may occur at therapeutic doses; ensure patient is taking with meals to gain phosphate-binding effect; monitor serum calcium closely

Drug Name	Calcium acetate (Calphron, PhosLo)
Description	Combines with dietary phosphorus to form insoluble calcium phosphate, which is excreted in feces.
Adult Dose	2 tab PO with each meal; increase to bring serum phosphate value to 4 mg/dL as long as hypercalcemia does not develop; may require up to 4 tab
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypercalcemia, hypophosphatemia, renal calculi
Interactions	May increase effect of quinidine; may decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; IV administration antagonizes effects of verapamil; high intake of dietary fiber may decrease absorption and levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypercalcemia or hypercalcuria may occur when therapeutic amounts are administered

Drug Name	Magnesium hydroxide (Phillips Milk of Magnesia)
Description	Reduces absorption of dietary phosphate.
Adult Dose	5-15 mL or 650-mg to 1.3-g tab PO up to qid with meals; titrate dose depending on serum phosphate concentrations
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; colostomy, ileostomy, renal failure, fecal impaction, appendicitis
Interactions	Decreases effects of tetracyclines, digoxin, indomethacin, and iron salts
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in severe renal impairment because of potential for magnesium intoxication

Drug Name	Sevelamer hydrochloride (Renagel)
Description	Polymeric phosphate binder for PO administration. Does not contain aluminum; thus, aluminum intoxication not a concern.
Adult Dose	2-4 cap PO pc; adjust based on serum phosphorus concentrations to lower serum phosphorus level to 4 mg/dL
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bowel obstruction, hypophosphatemia
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with dysphagia, severe GI motility disorders, or swallowing disorders

Drug Name	Lanthanum carbonate (Fosrenol)
Description	Noncalcium, nonaluminum phosphate binder indicated for reduction of high phosphorus levels in patients with end-stage renal disease. Directly binds dietary phosphorus in upper GI tract, thereby inhibiting phosphorus absorption.
Adult Dose	Initial: 250-500 mg PO tid pc (chewable tabs); adjust dose q2-3wk to target serum phosphorus level Maintenance: 500-1000 mg PO tid pc
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bowel obstruction; hypophosphatemia
Interactions	Drugs known to interact with antacids (eg, alendronate, amprenavir, ciprofloxacin, itraconazole, tetracycline, thyroid hormones) should not be administered within 2 h
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Deposited into developing bone, including growth plate (long-term effects unknown); common adverse effects typically diminish over time but include headache, abdominal pain, nausea, diarrhea, constipation, and vomiting; in clinical trials, dialysis graft occlusion occurred more frequently than with placebo; caution with GI motility diseases (eg, Crohn disease, ulcerative colitis) or recent GI surgery

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Hyperphosphatemia is generally not an indication for hospitalization unless complicated by hypocalcemic tetany or massive extraosseous deposition of calcium phosphate crystals. Hospitalization may be required for treatment of the condition that led to the hyperphosphatemia (eg, renal failure, tumor lysis).

Further Outpatient Care

• Outpatient care should be directed toward the underlying cause of the hyperphosphatemia. Excessive ingestion, such as with Phospho-soda intoxication or milk-alkali syndrome, should be curtailed. Continued use of phosphate binders should be encouraged for individuals with chronic kidney failure. Calcium levels, phosphate levels, and renal function should be monitored at intervals consonant with the severity of the underlying disorder.

In/Out Patient Meds

• Phosphate binders are the only truly long-term therapy for chronic hyperphosphatemia due to renal failure. These medications should be administered with meals and snacks to ensure that they are present to bind the phosphate contained in food.

Transfer

• As a general rule, hyperphosphatemia is not an emergency. If the hyperphosphatemia is due to renal failure or severe tertiary hyperparathyroidism, transfer of the patient to a facility equipped to deal with these disorders is appropriate.

Deterrence/Prevention

• Methods of preventing hyperphosphatemia should be targeted at the clinical situation, whether the hyperphosphatemia is due to excessive ingestion, poor output, or release of massive intracellular quantities into the blood stream.
• • If due to excessive ingestion, then ingestion of Phospho-soda, vitamin D, and large quantities of alkali and milk should be discouraged.
  • If due to poor output, such as in renal failure, the use of phosphate binders and the avoidance of high-phosphate foods should be encouraged.
  • If due to predictable massive cell lysis, such as in the treatment of certain tumors, the patient should be admitted for hydration. This treatment should be continued until the crisis resolves.

Complications

• Hyperphosphatemia, especially for extended periods, leads to deposition of calcium phosphate in nonosseous sites. This process can result in severe complications that are predominantly chronic in development and chronic in duration.
• • Major sites of deposition include the eyes, joints, and vasculature. Joint deposits can become large and painful, necessitating surgical removal. Vascular deposits produce syndromes of accelerated coronary atherosclerosis, calciphylaxis, and medial arterial calcification.
  • All of these syndromes are associated with high morbidity and mortality rates.

Prognosis

• For acute hyperphosphatemia, the prognosis is excellent because the inciting cause can usually be successfully treated.



• For chronic hyperphosphatemia, the prognosis can be mixed.



• If started early in the course of renal failure, control of phosphate ingestion and phosphate absorption by appropriate changes in diet and the use of binders can successfully postpone the development of the previously mentioned complications. However, if hyperphosphatemia is not adequately addressed early in the course of renal failure, the changes that occur in bones, joints, and cardiovascular tissues can be very difficult, if not impossible, to eradicate.

• Optimal phosphate control in dialysis patients is extremely challenging. Despite the remarkable improvements in dialysis techniques over the years, phosphate control has not substantially improved.

Patient Education

• Patients must be educated about the phosphate content of food. This education is most effectively accomplished by a licensed dietitian who can provide lists of high- and low-phosphate foods and offer suggestions for substitution when needed.
• Patients also require education about how to take the phosphate binders and the importance of taking them consistently.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• No legal issues are prominent for this disorder. Control of phosphate is difficult in the chronic state and requires a concerted effort by the treatment team and the patient.
• Long-term use of aluminum-containing antacids as phosphate binders is no longer the first choice for prevention of hyperphosphatemia. These agents should only be used when others have failed to adequately control phosphate levels. Use of only aluminum-containing antacids that results in aluminum intoxication could be a potential liability for the physician.
• Similarly, failure to monitor calcium and phosphate levels, especially when treating with calcium-containing phosphate binders, can lead to severe life-threatening hypercalcemia. Calcium citrate and aluminum-containing binders should probably not be used together because the citrate might enhance aluminum absorption.

Special Concerns

• Aluminum-containing binders should probably be avoided in children.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Hyperphosphatemia. Approximately 60-70% of dietary phosphate, 1000-1500 mg/d, is absorbed in the small intestine. Although vitamin D can enhance the absorption, especially under conditions of dietary phosphate depletion, intestinal phosphate absorption is generally unregulated. 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 the excess dietary phosphate intake ensures maintenance of phosphate homeostasis, maintaining serum phosphate at a level of approximately 4.5 mg/dL in the serum.
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Media type:  Image

Media file 2:  Hyperphosphatemia. 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, and dopamine. Phosphate absorption in the remainder of the nephron is generally mediated by type 1 or 3 sodium phosphate cotransporters. No direct evidence related to regulation of these transporters in renal cells under physiologic conditions has been found. The absorption in the proximal tubule is regulated such that the final excretion matches the dietary excess to maintain homeostasis.
	View Full Size Image
Media type:  Image

Media file 3:  Hyperphosphatemia inhibits 1alpha hydroxylase in the proximal tubule, thus inhibiting the conversion of 25-hydroxy vitamin D3 to the active metabolite, 1,25 dihydroxyvitamin D3. The decrease in active vitamin D production is somewhat offset by the ability of hyperphosphatemia to stimulate the secretion of parathyroid hormone (PTH), which will increase the activity of 1alpha 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.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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