eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders
Hyperphosphatemia
Updated: Apr 5, 2007
Introduction
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
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)
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Further Reading
Keywords
high phosphate, phosphate homeostasis, sodium-phosphate cotransporters, parathyroid hormone, PTH, dopamine, dietary phosphate, renal proximal tubule phosphate reabsorption, pseudohypoparathyroidism, hypomagnesemia, rhabdomyolysis, tumor lysis, renal failure, vascular calcifications, calciphylaxis, chronic renal failure, CRF, acute renal failure, ARF, kidney failure, renal disease, kidney disease, excessive phosphate intake, excessive phosphate ingestion, decreased phosphate excretion, vitamin D intoxication, hypoparathyroidism, pseudo-hypoparathyroidism
