Hypophosphatemia: Practice Essentials, Background, Pathophysiology and Etiology (original) (raw)

Overview

Practice Essentials

Hypophosphatemia is defined as a serum phosphate level of less than 2.5 mg/dL (0.8 mmol/L) in adults. [1] The normal level for serum phosphate in neonates and children is considerably higher, up to 7 mg/dL for infants_._

Hypophosphatemia can result from inadequate phosphate intake; increased excretion of phosphate, which can be a genetic or acquired condition; or a shift of phosphate from the extracellular to the intracellular space. Most often it is caused by long-term, relatively low phosphate intake in the setting of a sudden increase in intracellular phosphate requirements. [2] (See Pathophysiology.)

Most patients with hypophosphatemia are asymptomatic. Occasionally, patients with mild hypophosphatemia may complain of weakness. Severe acute hypophosphatemia can have a variety of signs and symptoms, including the following:

In addition to serum phosphate studies, serum calcium and magnesium studies can be helpful for identifying underlying causes. Parathyroid hormone (PTH) and vitamin D assays can identify primary hyperparathyroidism (common in the elderly) and vitamin D deficiency (common in the elderly and the chronically ill). Other studies (eg, imaging studies to detect skeletal effects) may be useful, depending on the setting (see Workup).

Medical care for hypophosphatemia is highly dependent on the cause, severity, and duration of the condition, as follows (see Treatment and Medication):

Burosumab, an IgG1 monoclonal antibody that binds excess fibroblast growth factor 23 (FGF23), is approved for treatment of X-linked hypophosphatemia and of FGF23-related hypophosphatemia in tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized, in adults and pediatric patients aged 2 years or older.

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Background

Phosphate is critical for a remarkably wide 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 adenosine triphosphate (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 conductance of chloride 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. Three subtypes exist: types 2a, 2b, and 2c.

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, vitamin D, and dietary phosphate. Currently, these transporters are believed (predominantly on the basis of animal studies) to be most critical for maintenance of renal phosphate homeostasis. Impaired expression or function of these transporters is associated with nephrolithiasis. [3, 4]

Type 2b transporters are very similar, but not identical, to type 2a transporters. They are expressed in the small intestine and are up-regulated under conditions of dietary phosphate deprivation and by vitamin D.

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. [5] 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 in human beings, suggesting that these transporters may actually play a significantly more prominent role in regulation of phosphate homeostasis in human beings than in rodents. [6]

Type 3 transporters (Pit1 and Pit2) were initially identified as viral transport proteins. Almost all cells express type 3 sodium phosphate cotransporters; therefore, these transporters were presumed to play a housekeeping role in ensuring adequate phosphate for all cells. Subsequent studies, however, have pointed toward a more specific role for Pit1 and Pit2, as Pit1 has been implicated in the development of vascular calcifications, and abnormalities in Pit2 are associated with the development of choroid plexus calcifications. [7] 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 [8, 9] and in the regulation of bone mineralization. [10]

Circulating phosphate exists as either the univalent or divalent hydrogenated species. Because the ionization constant of acid (pK) of phosphate is 6.8, at the normal ambient serum pH of 7.4 the divalent species is 4 times as prevalent as the monovalent species. Serum phosphate concentration varies with age, time of day, fasting state, and season. Serum phosphate concentration is higher in children than adults; the reference range is 4-7 mg/dL in children compared with 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_-_2000 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 increases expression ofsodium-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. [11] Studies have confirmed that the ability of intestinal phosphate transport to influence renal phosphate transport is PTH-dependent; however, the signal to the parathyroid gland remains unknown_._ [12]

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. The major site of renal regulation of phosphate excretion is the early proximal renal tubule, with some contribution by the distal convoluted tubule. [13] 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.

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. [14] 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. [15, 16] FGF23 production by osteoblasts is stimulated by 1,25 vitamin D. [15] 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 chronic kidney disease and end-stage renal disease found that FGF23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels,long before elevations in serum PTH levels are detected. Klotho, a transmembrane protein synthesized in the kidney (predominantly in the distal nephron), is an essential cofactor for the effects of FGF23 on renal proximal tubule cells. [17] Inactivation or deletion of Klotho expression results in hyperphosphatemia and accelerated aging.

The relationship between these 2 functions of Klotho remains unknown. However, Klotho has demonstrable antioxidant, antifibrotic, and pro-survival effects throughout the body. [18]

A study also demonstrated that FGF23 levels rapidly decreased after kidney transplantation, suggesting that FGF23 is cleared by the kidney. [19] Thus, residual FGF23 could contribute to the hypophosphatemia frequently seen in posttransplant patients. In healthy young men without kidney disease, phosphate intake did not significantly increase FGF23 levels, suggesting that FGF23 may not play a role in acute phosphate homeostasis. [20]

Intravenous iron formulations (especially ferric carboxymaltose) can significantly increase FGF23 levels. This can result in hypophosphatemia due to increased urinary phosphate excretion. [21]

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.

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Pathophysiology and Etiology

Any of the following three pathogenic mechanisms can cause hypophosphatemia:

The following discussion conforms to this approach, but note that hypophosphatemia is frequently the result of more than one mechanism.

Inadequate intake

Inadequate intake can result from phosphate deficiency in the diet or from poor intestinal absorption. However, 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 a sudden increase in intracellular phosphate requirements, such as occurs with refeeding, in the setting of long-term, relatively low phosphate intake. 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.

Hypophosphatemia due to inadequate intake should be strongly considered in certain patient populations, as follows:

Excessive losses

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 parathyroid hormone (PTH) to inhibit proximal renal tubule phosphate transport. However, frank hypophosphatemia is not universal and is most often mild.

Phosphate wasting can result from genetic or acquired renal disorders. Several genetic and acquired syndromes of phosphate wasting and associated skeletal abnormalities have been described. These include syndromes characterized by isolated proximal tubule phosphate wasting, such as the congenital or acquired rickets syndromes described previously, and Fanconi syndrome, in which phosphate wasting represents one component of a generalized proximal tubule dysfunction.

Congenital Fanconi syndromes include Wilson disease and cystinosis, while acquired Fanconi syndrome can be seen with several medications, paraproteinemias, connective tissue disorders, and heavy metals. [22, 23, 24] The genetic disorders generally manifest in infancy, when the children exhibit short stature and bone deformities.

Genetic disorders

Genetic disorders that cause phosphate wasting include the following:

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 D3, levels that are inappropriately low for the degree of hypophosphatemia.

The defective gene is PHEX, which encodes for a membrane-bound neutral endopeptidase. [28, 29] 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 D3. 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 D3. 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 D3. 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 D3. Impaired absorption of dietary calcium and consequent calcium deficiency increases PTH levels, resulting in renal phosphate wasting and hypophosphatemia. [27]

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. [3, 30]

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. [31]

Acquired phosphate-wasting syndromes

Acquired phosphate wasting syndromes are of diverse etiologies, as follows:

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.

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 bone syndrome), and acute respiratory alkalosis.

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. [43]

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. [44]

Other mechanisms are as follows:

Hypophosphatemia is a common complication of kidney transplantation. [46] Tertiary hyperparathyroidism has long been thought to be the etiology, but hypophosphatemia can occur in patients with 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. [47] Dipyridamole enhances renal tubular phosphate reabsorption and has been shown to be effective in posttransplant hypophosphatemia in small studies.

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Epidemiology

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%.

A study from a tertiary medical referral center found that the incidence of hospital-acquired hypophosphatemia was 35%. Hospital-acquired hypophosphatemia was associated with odds ratio (OR) of 1.56 for in-hospital mortality. [48]

Hypophosphatemia has been reported in a significant number of patients following partial hepatectomy for transplantation (up to 55%), attributed to an increase in cell utilization due to regeneration of liver tissue. [49] 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. [50]

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. [51]

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 kidney injury.

Because it has been theorized that hypophosphatemia in the early stages of sepsis may contribute to the development of new arrhythmias, Schwartz et al hypothesized that intravenous phosphorus replacement may reduce the incidence of arrhythmias in critically ill patients. In a study of 34 adult septic patients with hypophosphatemia, IV phosphorus replacement was associated with a significantly reduced incidence of arrhythmias when compared with 16 patients from previously published data (38% vs. 63%, P = 0.04). [52]

Saito et al noted that hypophosphatemia is a common complication in severely disabled individuals, related to frequent bacterial infections, refeeding following malnutrition, and valproate treatment for epilepsy. Because severe hypophosphatemia is life-threatening, serum phosphate levels should be closely monitored, according to the authors. In a study of 19 severely disabled patients, there were 25 episodes of hypophosphatemia. The causes included febrile illnesses (N = 17), refeeding syndrome (N = 4), and Fanconi syndrome (N = 3); one episode was not identifiable. Significantly increased C-reactive protein levels and reduced sodium levels were present during hypophosphatemia episodes. [53]

Race- and sex-related demographics

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

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. The genetic syndromes of phosphate wasting manifest in infancy or childhood. These syndromes include the following:

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. [54] 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. [55]

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Prognosis

The prognosis for patients with a treatable and usually transient cause of hypophosphatemia is excellent. Discontinuation of antacids in cases of antacid abuse, ingestion of a normal diet in patients with eating disorders, or parathyroidectomy for patients with hyperparathyroidism are all examples of curable hypophosphatemia. In patients with acute liver failure, hypophosphatemia is associated with a good prognosis, as it may represent cellular use of phosphorus during hepatocyte regeneration. [56, 57]

The prognosis for phosphate wasting syndromes is also largely dependent on the underlying cause. For hyperparathyroidism, parathyroidectomy is curative. For X-linked hypophosphatemic rickets, the advent of the FGF23 antibody burosumab offers the promise of improved prognosis. [58] For vitamin D deficiency (a combination of poor absorption and renal wasting), replacement of vitamin D is curative. On the other hand, some cases of vitamin D–resistant rickets are only partially treatable with present medications and result in lifelong skeletal deformities. [59]

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Patient Education

Patients with inadequate ingestion of phosphate-containing foods or with excessive antacid ingestion benefit from dietary education.

Patients with vitamin D deficiency should be educated on the importance of maintaining a normal vitamin D balance.

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Author

Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology
Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc.

Coauthor(s)

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Christie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division of Nephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, Royal College of Physicians

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Acknowledgements

Datinder Deo, MD Chief Fellow, Department of Nephrology, University of Louisville Hospitals

Disclosure: Nothing to disclose.

Deepak Mittal, MD Fellow, Department of Nephrology, University of Louisville School of Medicine

Disclosure: Nothing to disclose.

Snehal Patel, MD Fellow, Department of Nephrology, University of Louisville School of Medicine

Snehal Patel, MD is a member of the following medical societies: American College of Physicians, American Society of Nephrology, Kentucky Medical Association, and Renal Physicians Association

Disclosure: Nothing to disclose.