eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Hypophosphatemia

Author: Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine; Interim Chief of Nephrology; Director of Nephrology Training Program; Director, Metabolic Stone Clinic; Director of Outpatient Clinics, Kidney Disease Program, University of Louisville School of Medicine
Coauthor(s): Rosemary Ouseph, MD, Professor of Medicine, Director of Kidney Transplant, University of Louisville School of Medicine
Contributor Information and Disclosures

Updated: Aug 7, 2009

Introduction

Background

Hypophosphatemia is defined as a phosphate level of less than 2.5 mg/dL (0.8 mmol/L). Phosphate is critical for an incredible array of cellular processes. It is one of the major components of the skeleton, providing mineral strength to bone. Phosphate is an integral component of the nucleic acids that comprise DNA and RNA. Phosphate bonds of ATP carry the energy required for all cellular functions. It also 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, the fact that phosphate homeostasis is a highly regulated process is not surprising.

Phosphate in the body

The bulk of total body phosphate resides in bone as part of the mineralized extracellular matrix. This phosphate pool is accessible, although in a somewhat limited fashion. Approximately 300 mg of phosphate per day enters and exits bone tissue. 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 and 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, 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 the kidneys, bones, and intestines. In epithelial cells, these transporters are responsible for transepithelial transport, ie, absorption of phosphate from intestine and reabsorption of phosphate from renal tubular fluid. 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.^1,2

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 2c transporters, initially described as growth-related phosphate transporters, are a third member of the type 2 sodium phosphate cotransporter family. They are expressed exclusively on the S1 segment of the proximal tubule and together with Type 2a transporters are essential for normal phosphate homeostasis.³  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.⁴

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 also participate in the regulation of renal and intestinal transepithelial transport^5,6 and in the regulation of bone mineralization.⁷

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, as discussed in the next section. Importantly, because phosphate enters and exits 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 concentration. 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 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.

Regulation of intestinal phosphate transport overall is poorly understood. Although studies had suggested that the majority of small intestine phosphate uptake is accomplished through sodium-independent, unregulated 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.⁸

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 loses approximately 300 mg of phosphate per day, but that 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.

PTH and vitamin D were previously the only recognized regulators of phosphate metabolism. However, several novel regulators of mineral homeostasis have been 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 of FGF23 in the regulation of phosphate homeostasis is still under investigation. FGF23 is produced in several types of tissue, 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.^9,10  FGF23 production by osteoblasts is stimulated by 1,25 vitamin D.⁹ 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. Klotho, a transmembrane protein, is an essential cofactor for the effects of FGF23 on renal proximal tubule cells.¹¹  Inactivation or deletion of Klotho expression results in hyperphosphatemia and accelerated aging. The relationship between these 2 functions of Klotho remains unknown.

A study also demonstrated that FGF23 levels rapidly decreased after kidney transplantation suggesting that FGF23 is cleared by the kidney.¹² 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.¹³

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 with either the PTH-vitamin D axis or with the phosphatonin-PHEX system.

Pathophysiology

Any of 3 pathogenic mechanisms can cause hypophosphatemia.

Inadequate intake

Inadequate phosphate intake alone is an uncommon cause of hypophosphatemia. The ease of intestinal absorption of phosphate coupled with the ubiquitous presence of phosphate in almost all ingested food substances ensures that daily phosphate requirements are more than met by even a less-than-ideal diet.

Hypophosphatemia is most often caused by long-term, relatively low phosphate intake in the setting of a sudden increase in intracellular phosphate requirements such as occurs with refeeding. Intestinal malabsorption can contribute to inadequate phosphate intake, especially if coupled with a poor diet. Although generally not essential for adequate phosphate absorption, vitamin D deficiency can contribute to hypophosphatemia by failing to stimulate phosphate absorption in cases of poor dietary ingestion. Case reports also document patients developing hypophosphatemia due to excessive use of antacids, particularly calcium-, magnesium-, or aluminum-containing antacids.

Increased excretion

Increased excretion of phosphate is a more common mechanism for the development of hypophosphatemia. The most common cause of increased renal phosphate excretion is hyperparathyroidism due to the ability of PTH to inhibit proximal renal tubule phosphate transport. However, frank hypophosphatemia is not universal and is most often mild.

Increased excretion of phosphate can also be induced by forced saline diuresis due to the inhibitory effect of saline diuresis on all proximal renal tubule transport processes. Again, the degree of hypophosphatemia is generally minimal. Vitamin D deficiency not only impairs intestinal absorption, but also decreases renal absorption of phosphate. Several genetic and acquired syndromes of phosphate wasting and associated skeletal abnormalities have been described.

Shift from extracellular to intracellular space

This pathogenetic mechanism alone is an uncommon cause of hypophosphatemia, but it can exacerbate hypophosphatemia produced by other mechanisms. Clinical situations in which this mechanism is the major cause of hypophosphatemia are the treatment of diabetic ketoacidosis, refeeding, short-term increases in cellular demand (eg, hungry bones syndrome), and acute respiratory alkalosis.

Frequency

United States

Exact figures are difficult to determine, mainly because phosphate measurements are often not obtained with routine laboratory studies and are determined only when the care provider has a high index of suspicion for hypophosphatemia. In the general population of hospitalized patients, hypophosphatemia is observed in 1-5% of individuals and is usually mild and asymptomatic. The percentage rises steeply in patients with alcoholism, diabetic ketoacidosis, or sepsis, in whom studies have reported frequency rates of up to 40-80%.

Hypophosphatemia has been reported in a significant number of patients following partial hepatectomy for transplantation (up to 55%) and in acute hepatic failure, attributed to an increase in cell utilization due to regeneration of liver tissue. Hypophosphatemia in this setting is associated with a favorable prognosis. Hypophosphatemia is also seen in approximately one third of hematopoietic cell transplantation, but, in this setting, it correlates highly with mortality.

Hypophosphatemia occurs in a significant percentage of kidney transplant recipients (50-80%), in particular immediately after transplantation. In many patients it can persist for the life of the transplant. Hypophosphatemia has also been reported in association with the metabolic syndrome.

Mortality/Morbidity

The morbidity of hypophosphatemia is highly dependent on cause, duration, and severity.

• Mild and transient hypophosphatemia is generally asymptomatic and is not accompanied by long-term complications.
• Chronic hypophosphatemia that accompanies chronic phosphate deficiency can result in significant bone disease. This is seen most commonly in osteomalacia due to vitamin D deficiency, long-term antacid abuse, hereditary phosphate wasting syndromes, malnutrition, and tumor-induced osteomalacia. Frequently in these conditions, the hypophosphatemia is accompanied by significant bone pain, fracture rate, nephrocalcinosis, and renal insufficiency. In childhood phosphate wasting syndromes, long-term treatment with phosphate replacement frequently results in renal insufficiency and hyperparathyroidism.
• Acute severe hypophosphatemia can manifest as widespread organ dysfunction. Hypophosphatemia in the ICU setting is associated with respiratory insufficiency due to impaired diaphragmatic contractility and depressed cardiac output due to decreased myocardial contractility that reverse with correction of the electrolyte abnormality. Severe hypophosphatemia is also associated with rhabdomyolysis, cardiac arrhythmias, altered mental status, seizures, hemolysis, impaired hepatic function, and depressed white cell function. The newest recommendation for the use of aggressive insulin therapy in the ICU setting has the potential for increasing the frequency and severity of and the morbidity of hypophosphatemia. Another factor increasing the frequency and severity of hypophosphatemia is the widespread use of continuous therapies for the treatment of acute renal failure.

Race

Hypophosphatemia has no race predilection except for the syndrome of X-linked hypophosphatemic rickets, which predominates in Caucasian populations.

Sex

Hypophosphatemia has no sex predilection except for the syndrome of X-linked hypophosphatemic rickets, which is seen in male children.

Age

Hypophosphatemia can occur in persons of any age. Acquired hypophosphatemia tends to occur in late adolescence to adulthood. Cases occurring in late adolescence are often related to eating disorders. With aging, hypophosphatemia is often related to alcoholism, tumors, malabsorption, or vitamin D deficiency.

• The genetic syndromes of phosphate wasting manifest in infancy or childhood. These syndromes include X-linked hypophosphatemic rickets, vitamin D resistant rickets, autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemia with hypercalciuria, and congenital Fanconi syndrome.
• Acquired hypophosphatemia tends to occur in late adolescence to adulthood. Cases occurring in late adolescence are often related to eating disorders. With aging, hypophosphatemia is often related to alcoholism, tumors, malabsorption, malnutrition, or vitamin D deficiency. Hypophosphatemia has been reported in up to 15% of geriatric patients undergoing refeeding. Hypophosphatemia has also been reported in up to 35% of adult patients undergoing open heart surgery and is associated with prolonged mechanical ventilation, increased use of cardiovascular drugs, and prolonged hospitalization.

Clinical

History

Most patients with hypophosphatemia are asymptomatic. History alone rarely alerts the physician to the possibility of hypophosphatemia. In cases of oncogenic osteomalacia or in some of the genetic causes of phosphate wasting, patients complain of bone pain and fractures. Otherwise, physicians must have a high index of suspicion and must be aware of the clinical conditions that might be complicated by hypophosphatemia.

Symptoms of hypophosphatemia are nonspecific and highly dependent on cause, duration, and severity.

• Mild hypophosphatemia (ie, 2-2.5 mg/dL), whether acute or chronic, is generally asymptomatic. Occasionally, patients may complain of weakness, but whether the weakness is secondary to hypophosphatemia or is due to the underlying disorder causing the hypophosphatemia is not clear.
• Acute mild hypophosphatemia commonly occurs with the treatment of diabetic ketoacidosis because of the sudden large doses of insulin used to treat the uncontrolled diabetes. However, mild hypophosphatemia is asymptomatic and rapidly reversed.
  • Mild hypophosphatemia can also occur after renal transplantation and can last years without any discernible symptoms.
  • Primary hyperparathyroidism is also associated with mild hypophosphatemia; however, the symptoms of hypercalcemia appear to be more prominent than those of mild hypophosphatemia.
• Patients with severe and/or chronic hypophosphatemia are more likely to be symptomatic.
  • Moderate degrees of hypophosphatemia are commonly observed in patients with the refeeding syndromes. Most commonly, these individuals have a history of long-standing alcohol use and chronic malnutrition, resulting in the development of total body phosphate depletion.
  • When these patients are admitted to the hospital, their serum phosphate level is most often within the reference range. However, feeding stimulates insulin release, leading to a shift of phosphate from the extracellular to the intracellular compartment.
  • At times, the ensuing hypophosphatemia can be profound. Depending on the severity of the hypophosphatemia, the patient may complain of muscle weakness and generalized weakness or may develop the full-blown hypophosphatemic syndrome. In this particular clinical situation, if the practitioner does not have a high index of suspicion, the delirious state can be misinterpreted as delirium tremens.
  • The acute hypophosphatemic syndrome occurs most commonly in persons with chronic alcoholism, but it can also be observed in refeeding of patients who have eating disorders, patients who have been starved for any reason, or patients who are receiving parenteral nutrition with inadequate quantities of phosphate replacement.
• Patients with chronic phosphate wasting syndromes frequently present with bone pain, muscle weakness, and skeletal disorders. In the genetic syndromes of renal phosphate wasting or acquired oncogenic osteomalacia, the serum phosphate level is generally moderately depressed. Symptoms are predominantly muscle weakness and bone pain or fractures.
• In short, symptoms alone rarely alert the physician to the possibility of hypophosphatemia. Recognizing that hypophosphatemia can complicate specific clinical conditions allows the physician to make this diagnosis.
  • Weakness, bone pain, rhabdomyolysis, and altered mental status are the most common presenting features of persons with symptomatic hypophosphatemia.
  • If considering the diagnosis of hypophosphatemia, the physician should attempt to elicit the following clinical clues to conditions associated with hypophosphatemia:
    • Poor nutrition
    • Symptoms of malabsorption
    • Excessive antacid use
    • Bone pain or fractures
    • Symptoms suggestive of multiple myeloma or other paraproteinemia
    • Treatment with parenteral nutrition
    • Exposure to heavy metals
    • Use of drugs such as glucocorticoids, cisplatin, or pamidronate
    • Treatment of diabetic ketoacidosis
    • Extensive burns
    • Use of growth factors
    • Bone marrow transplant
    • Intensive care unit (ICU) setting

Physical

No physical signs are specific for hypophosphatemia. In fact, physical signs of mild hypophosphatemia are generally absent.

• Chronic hypophosphatemia can be associated with short stature and evidence of rickets, with bowing of the legs, when caused by one of the genetically transmitted phosphate wasting disorders. In adults, chronic hypophosphatemia is more commonly associated with bone pain upon palpation.
• Severe acute hypophosphatemia can have a variety of signs, including disorientation, seizures, focal neurologic findings, evidence of heart failure, and muscle pain.
• Myocardial contractility may be impaired with ATP depletion, and respiratory failure due to weakness of the diaphragm has been described. The reduction in cardiac output may become clinically significant, leading to congestive heart failure, when the plasma phosphate concentration falls to 1.0 mg/dL (0.32 mmol/L).¹⁴ Acute hypophosphatemia superimposed upon preexisting severe phosphate depletion can lead to rhabdomyolysis. Although CPK elevations are fairly common in hypophosphatemia, clinically significant rhabdomyolysis has been described almost exclusively in alcoholics and in patients receiving hyperalimentation without phosphate supplementation.

Causes

The differential diagnosis of hypophosphatemia is most easily considered according to pathogenetic mechanisms. The following discussion conforms to this approach, but note that hypophosphatemia is frequently the result of more than one mechanism.

• Inadequate intake
  • Hypophosphatemia due to inadequate intake is uncommon but should be strongly considered in certain patient populations. Inadequate ingestion can result from phosphate deficiency in the diet or from poor intestinal absorption. Patients who have had prolonged poor intake of phosphate develop true phosphate deficiency.
  • Persons with alcoholism who ingest an inadequate diet comprise one population at risk for this clinical scenario. Serum phosphate levels may be within reference ranges upon admission to the hospital, but refeeding stimulates cellular uptake and results in profound hypophosphatemia.
  • Similarly, critically ill patients receiving a parenteral diet deficient in phosphate may suddenly become hypophosphatemic as their catabolic condition resolves and they become more anabolic.
  • People with eating disorders or dietary deficiencies due to socioeconomic, dental, or swallowing difficulties may also become hypophosphatemic when fed an adequate diet.
  • Malabsorption of intestinal phosphate can be severe enough to produce phosphate deficiency and hypophosphatemia.
  • Individuals who ingest large quantities of antacids can become hypophosphatemic because of phosphate binding by the antacids, resulting in poor intestinal absorption.
  • Primary intestinal disorders, such as Crohn disease or celiac sprue, can limit phosphate absorption, leading to hypophosphatemia.
  • Similarly, steatorrhea or chronic diarrhea can cause mild-to-moderate hypophosphatemia due to decreased phosphate absorption from the gut and renal phosphate wasting; the latter is caused by secondary hyperparathyroidism induced by concomitant vitamin D deficiency.
  • Vitamin D deficiency causes hypophosphatemia by limiting intestinal and renal phosphate absorption.
• Excessive losses
  • Phosphate wasting can result from genetic or acquired renal disorders. The genetic disorders generally manifest in infancy, when the children exhibit short stature and bone deformities.
    • X-linked hypophosphatemic rickets is characterized by short stature, radiographic evidence of rickets, and bone pain. Patients with this condition also may have calcification of tendons, cranial abnormalities, and spinal stenosis. In addition to hypophosphatemia, these patients have relatively low levels of 1,25 dihydroxyvitamin D-3, levels that are inappropriately low for the degree of hypophosphatemia. The defective gene is PHEX, which encodes for a membrane-bound neutral endopeptidase. Present understanding of this disorder is that the inactive neutral endopeptidase is unable to cleave a circulating phosphaturic substance. Data suggest that this circulating substance might be FGF23. This results in impaired phosphate reabsorption by decreasing the sodium-phosphate cotransporter in the kidneys.
    • Autosomal dominant hypophosphatemic rickets has similar manifestations, with hypophosphatemia, clinical rickets, and inappropriately low levels of 1,25 dihydroxyvitamin D-3. The cause of this disorder is thought to be mutations of FGF23 that result in resistance to degradation, persistently high circulating levels of FGF23, and subsequent phosphaturia.
    • Hereditary hypophosphatemic rickets with hypercalciuria is a rare disorder characterized by hypophosphatemia, phosphate wasting, hypercalciuria, bone pain, muscle weakness, and high levels of 1,25 dihydroxyvitamin D-3. The cause of this disorder is an inactivating mutation in the type 2c sodium-phosphate cotransporter.
    • Vitamin D–resistant rickets is an autosomal recessive disorder. In type I, the defect is in renal 1-alpha-hydroxylation. Type II is characterized by end organ resistance to the effects of 1,25 dihydroxyvitamin D-3. These patients present in childhood with hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, bone pain, muscle weakness, and alopecia. The disease is caused by mutations in the vitamin D receptor that prevent normal responsiveness to circulating vitamin D-3.
    • Mutations in the type 2a sodium-phosphate cotransporter have been reported in some patients with hypophosphatemia and inappropriate urinary phosphate wasting associated with nephrolithiasis and/or osteoporosis.^1,15
    • Rarely, significant renal phosphate wasting is observed in patients with fibrous dysplasia/McCune-Albright syndrome, disorders that result from mutations in the alpha subunit of the stimulatory G protein. Excess production of FGF23 has been found in some of these patients.¹⁶
  • Acquired phosphate wasting syndromes are of diverse etiologies.
    • Simple vitamin D deficiency results in hypophosphatemia, at least in part, from renal wasting. Vitamin D deficiency can result from several mechanisms, including poor oral intake, lack of sun exposure, drug-induced hypermetabolism of vitamin D precursors in the liver, or loss of vitamin D binding protein in the urine in persons with nephrotic syndrome. The loss of normal bone mineralization produces rickets in children and osteomalacia in adults.
    • Primary hyperparathyroidism is another cause of renal phosphate wasting.
    • Heavy metal intoxication and paraproteinemias can cause global proximal renal tubule dysfunction. These patients have hypophosphatemia along with type II renal tubular acidosis, renal glycosuria, aminoaciduria, and hypouricemia, ie, the condition referred to as Fanconi syndrome. Serum calcitriol concentrations can be either low or inappropriately normal. In children, cystinosis, Wilson disease, and hereditary fructose intolerance are the most common of the syndrome.
    • Drugs that can produce renal phosphate wasting include loop diuretics; acetazolamide; bisphosphonates, including pamidronate and zoledronate; and multiple chemotherapeutic and biologic agents, including cisplatinum; bevacizumab plus irinotecan¹⁷ ; everolimus plus octreotide LAR¹⁸ ; imatinib mesylate, a drug used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors^19,20 ; sorafenib²¹ ; carmustine²² ; and ifosfamide.²³  In some circumstances, renal phosphate wasting is part of a more generalized, drug-induced Fanconi syndrome.²⁴
    • Extracellular volume expansion or the administration of bicarbonate can cause loss of phosphate through the kidneys.
    • Oncogenic osteomalacia is a paraneoplastic syndrome characterized by osteomalacia, hypophosphatemia, renal phosphate wasting, bone pain, and muscle weakness. Several tumors that cause this syndrome have been described, most of which are benign tumors of mesenchymal origin.
    • Other factors that can increase urinary phosphate excretion are osmotic diuresis (most often due to glucosuria), proximally acting diuretics (acetazolamide and some thiazide diuretics that also have carbonic anhydrase inhibitory activity, such as metolazone), and acute volume expansion (which diminishes proximal sodium reabsorption).
• Intracellular shift of phosphate
  • Several physiologic agents stimulate phosphate uptake from the extracellular environment into the cell. This phenomenon can exacerbate the hypophosphatemia caused by the previously described mechanisms and can result in profound hypophosphatemia. However, in some circumstances, the shift alone may be enough to produce hypophosphatemia, albeit of a milder degree.
  • Acute respiratory alkalosis or hyperventilation produces hypophosphatemia by stimulating a shift of phosphate into the cells. This mechanism is responsible for the hypophosphatemia observed with salicylate overdose, panic attacks, and sepsis. Extreme hyperventilation in normal subjects can lower serum phosphate concentrations to below 1.0 mg/dL (0.32 mmol/L), and it is probably the most common cause of marked hypophosphatemia in hospitalized patients. Less pronounced hypophosphatemia may occur during the increase in ventilation after the successful treatment of severe asthma. The effects of respiratory alkalosis are exacerbated by concomitant glucose infusions and may persist after hyperventilation ceases. Respiratory alkalosis also may be the precipitating factor in the hypophosphatemia-induced acute rhabdomyolysis that can occur in alcoholic patients.²⁵
  • Insulin increases cell phosphate uptake and causes hypophosphatemia during treatment of diabetic ketoacidosis, refeeding, and parenteral nutrition therapy.
  • Exogenous epinephrine also stimulates cellular phosphate uptake.
  • Several cytokines reportedly stimulate intracellular phosphate shifts. This mechanism is perhaps responsible for the hypophosphatemia observed in the ICU setting of trauma, extensive burns, and bone marrow transplantation.
  • In hungry bone syndrome, rapid uptake of phosphate into bone occurs after the initial treatment of osteomalacia or rickets or postparathyroidectomy.
  • Hypophosphatemia is a common complication of kidney transplantation. Tertiary hyperparathyroidism has long been thought to be the etiology, but hypophosphatemia can occur despite low PTH levels and can persist after high PTH levels normalize. Furthermore, even in the setting of normal allograft function, hypophosphatemia, and hyperparathyroidism, calcitriol levels remain inappropriately low following transplantation, suggesting that mechanisms other than PTH contribute to phosphate homeostasis.
    
    FGF23 induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. This factor has been suggested as a possible mediator of posttransplantation hypophosphatemia. Dipyridamole enhances renal tubular phosphate reabsorption and has been shown to be effective in posttransplant hypophosphatemia in small studies.

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