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 (as depicted in the image below) is understandably a highly regulated process.
Approximately 60-70% of dietary phosphate, 1000-1500 mg/d, is absorbed in the small intestine. Although vitamin D can enhance the absorption, especially under conditions of dietary phosphate depletion, intestinal phosphate absorption is generally unregulated. Specifically, high serum phosphate and high dietary phosphate intake do not significantly impair intestinal uptake. The movement of phosphate in and out of bone, the reservoir containing most of the total body phosphate, is generally balanced. Renal excretion of excess dietary phosphate intake ensures maintenance of phosphate homeostasis, maintaining serum phosphate at a level of approximately 4.5 mg/dL in the serum. 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. 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 kidneys, bone, 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] Renal regulation of phosphate is depicted in the image below.
The vast majority of filtered phosphate is reabsorbed by type 2a sodium phosphate cotransporters located on the apical membrane of the renal proximal tubule. The expression of these cotransporters is increased by low dietary phosphate intake and several growth factors to enhance phosphate absorption. The expression is decreased by high dietary phosphate intake, parathyroid hormone, and dopamine. Phosphate absorption in the remainder of the nephron is generally mediated by type 1 or 3 sodium phosphate cotransporters. No direct evidence related to regulation of these transporters in renal cells under physiologic conditions has been found. The absorption in the proximal tubule is regulated such that the final excretion matches the dietary excess in order to maintain homeostasis. Type 2b transporters are very similar but not identical to type 2a transporters. They are expressed in the small intestine and are also up-regulated under conditions of dietary phosphate deprivation. Type 2c transporters, a third member of the Type 2 sodium phosphate cotransporter family, were initially described as growth-related phosphate transporters. They are expressed exclusively on the S1 segment of the proximal tubule and together with Type 2a transporters are essential for normal phosphate homeostasis. Similarly to type 2a transporters, type 2c transporters are also regulated by diet and PTH. Loss of type 2c function results in hereditary hypophosphatemic rickets with hypercalciuria.[2]
Type 3 transporters were initially identified as viral transport proteins. Almost all cells express type 3 sodium phosphate cotransporters; therefore, these transporters presumably play a housekeeping role in ensuring adequate phosphate for all cells. The factors that regulate the activity of these transporter proteins are not completely understood. Evidence suggests, however, that these transporters may also participate in regulation of renal and intestinal transepithelial transport[3, 4] and in regulation of bone mineralization.[5]
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. 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 was 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.[6]
Absorption of phosphate can be blocked by commonly used over-the-counter aluminum-, calcium-, and magnesium-containing antacids. Mild-to-moderate use of such phosphate binders generally poses no threat to phosphate homeostasis because dietary ingestion greatly exceeds body needs. However, very heavy use of these antacids can cause significant phosphate deficits. Stool losses of phosphate are minor, ie, 100-300 mg/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. Defense against hyperphosphatemia is depicted in the image below.
Hyperphosphatemia inhibits 1-alpha hydroxylase in the proximal tubule, thus inhibiting the conversion of 25-hydroxy vitamin D3 to the active metabolite, 1,25 dihydroxyvitamin D3. The decrease in active vitamin D production is somewhat offset by the ability of hyperphosphatemia to stimulate the secretion of parathyroid hormone (PTH), which will increase the activity of 1-alpha hydroxylase. The result is generally a neutral effect on intestinal phosphate absorption. Hyperphosphatemia-stimulated PTH secretion is mediated through an as yet unidentified pathway. With normal renal function, the transient increase in PTH and decrease in vitamin D serve to inhibit renal and intestinal absorption of phosphate, resulting in resolution of the hyperphosphatemia. In contrast, under conditions of renal failure, sustained hyperphosphatemia results in sustained hyperparathyroidism. The hyperparathyroidism enhances renal phosphate excretion but also enhances bone resorption, releasing more phosphate into the serum. As renal failure progresses and the ability of the kidney to excrete phosphate continues to diminish, the action of PTH on the bone can exacerbate the already present hyperphosphatemia. Conversely, low dietary phosphate intake, low PTH levels, and high vitamin D levels enhance renal proximal tubule phosphate absorption. To some extent, phosphate regulates its own regulators. High phosphate concentrations in the blood down-regulate the expression of some phosphate transporters, decrease vitamin D production, and increase PTH secretion by the parathyroid gland. Distal tubule phosphate handling is less well understood. PTH increases phosphate absorption in the distal tubule, but the mechanisms by which this occurs are unknown. Renal phosphate excretion can also be increased by the administration of loop diuretics.
PTH and vitamin D were the only recognized regulators of phosphate metabolism until the discovery several novel regulators of mineral homeostasis, identified through studies of serum factors associated with phosphate wasting syndromes, such as oncogenic osteomalacia and the hereditary forms of hypophosphatemic rickets.
The first to be discovered was a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), a neutral endopeptidase mutated in the syndrome of X-linked hypophosphatemic rickets. The characteristics of this syndrome (ie, hypophosphatemia, renal phosphate wasting, low 1,25-dihydroxyvitamin D levels) 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 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.[7, 8]
FGF23 production by osteoblasts is stimulated by 1,25 vitamin D.[8] Conversely, individuals with X-linked hypophosphatemic rickets show inappropriately depressed levels of 1,25 vitamin D due to FGF23-mediated suppression of 1-alpha hydroxylase activity. Studies in patients with end-stage renal disease found that FGF23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels. Klotho, a transmembrane protein, is an essential cofactor for the effects of FGF23 on renal proximal tubule cells.[9] Inactivation or deletion of Klotho expression results in hyperphosphatemia and accelerated aging. The relationship between these 2 functions of Klotho remains unknown.
A study also demonstrated that FGF23 levels rapidly decreased after kidney transplantation suggesting that FGF23 is cleared by the kidney.[10] Thus, residual FGF23 could contribute to the hypophosphatemia frequently seen in posttransplant patients. In healthy young men without renal disease, phosphate intake did not significantly increase FGF23 levels, suggesting that FGF23 may not play a role in acute phosphate homeostasis.[11]
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.
The syndromes of tumoral calcinosis produced by inactivating mutations of the phosphaturic hormone FGF23; GALNT3, an enzyme that controls FGF23 glycosylation and function; or Klotho, an essential cofactor for the phosphaturic effect of FGF23 in the renal tubule, also are characterized by decreased renal excretion of phosphate, resulting in hyperphosphatemia.[12, 13, 14, 15, 16] 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.
Epidemiology
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. Acute hyperphosphatemia caused by excessive phospho-soda ingestion may cause acute renal failure and, at times, chronic kidney disease.[17, 18, 19, 20]
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 recommended targets of the Kidney Disease Outcome Quality Initiative (KDOQI) were robust predictors of higher death risk.
Hyperphosphatemia is a risk factor for mortality in multiple populations, including kidney transplant recipients,[21] patients with end-stage renal disease,[22] and patients with chronic kidney disease.[23] Serum phosphate level is associated with cardiovascular risk even in individuals without kidney disease where the serum phosphate is within the "normal" range.[24] Interestingly, whether treatment to lower phosphate levels in patients with chronic kidney disease or end stage renal disease results in lower morbidity and mortality has not really been definitively demonstrated. A study showed that patients treated with phosphate binders had a decrease in 1-year mortality, but the effect did not correlate with the degree of hyperphosphatemia.[14, 25]
Some experimental evidence indicates that high phosphate levels are toxic to some cells. Specifically, a high ambient phosphate level causes apoptosis of chondrocytes and osteoblasts in cell culture. During growth, high phosphate-stimulated apoptosis is critical for normal bone development.[26] However, the effect of chronic hyperphosphatemia per se on bone and cartilage metabolism after closure of the growth plates is unknown. Studies have shown that acute phosphate loads obtained through dietary ingestion cause endothelial cell dysfunction, manifested as a decrease in flow-mediated dilation, in healthy men. This finding raises the possibility that prolonged and chronic hyperphosphatemia, as is seen with chronic kidney disease, could play a direct role in the enhanced cardiovascular morbidity and mortality seen in patients with chronic kidney disease.[27]
- 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. This effect is most likely a result of hyperphosphatemia-stimulated increase in FGF23 levels. The decrease in active vitamin D results in impaired gastrointestinal absorption of calcium, decreased renal reabsorption of calcium and phosphate, and impaired bone mineralization. Over months to years, bone density decreases. Additionally, the PTH and vitamin D derangements result in abnormal bone architecture. Clinically, the skeletal manifestations of chronic hyperphosphatemia include bone pain and fractures.
- 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 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 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. Multiple investigators have suggested that the acute and chronic kidney disease resulting from the use of phosphate-containing bowel cleansing agents is far more prevalent in the elderly population. This observation may be due to the higher prevalence of chronic kidney disease in this population.
Prie D, Huart V, Bakouh N, Planelles G, Dellis O, Gerard B, et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mujtations in the type 2a sodium-phosphate cotransporter. N Engl J Med. 2002;347:98991. [Medline].
Segawa H, Onitsuka A, Kuwahata M, Hanabusa E, Furutani J, Kaneko I, et al. Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J Amn Soc Nephrol. 2009;20:104-113. [Medline].
Collins JF, Bai L, Ghishan FK. The SLC20 family of proteins: dual functions as sodium-phosphate cotransporters and viral receptors. Pflugers Arch. 2004;447:647-652. [Medline].
Nowik M, Picard N, Stange G, et al. Renal phosphaturia during metabolic acidosis revisited: molecular mechanisms for decreased renal phosphate reabsorption. Pflugers Arch. Nov 2008;457(2):539-49. [Medline].
Virkki LV, Biber J, Murer H, Forster IC. Phosphate transporters: a tale of two solute carrier families. Am J Physiol Renal Physiol. 2007;293:F643-F654. [Medline].
Shaikh A, Berndt T, Kumar R. Regulation of phospahte homeostasis by the phosphatonins and other novel mediators. Pediatr Nephrol. 2008;23:1203-1210. [Medline].
Mirams M, Robinson BG, Mason RS, Nelson AE. Bone as a source of FGF23: regulation by phosphate?. Bone. Nov 2004;35(5):1192-9. [Medline].
Liu S, Zhou J, Tang W, et al. Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab. Jul 2006;291(1):E38-49. [Medline].
Razzaque MS. FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player. Am J Physiol Renal Physiol. 2009;296:F470-F476. [Medline].
Pande S, Ritter CS, Rothstein M, et al. FGF-23 and sFRP-4 in chronic kidney disease and post-renal transplantation. Nephron Physiol. 2006;104(1):p23-32. [Medline].
Nishida Y, Taketani Y, Yamanaka-Okumura H, et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int. Dec 2006;70(12):2141-7. [Medline].
Prie D, Beck L, Urena P, Friedlander G. Recent findings in phosphate homeostasis. Curr Opin Nephrol Hypertens. 2005;14:318-324. [Medline].
Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin INvest. 2007;117:2684-2691. [Medline].
Ichikawa S, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A, et al. Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology. 2009;150:2543-2550. [Medline].
Lammoglia JJ, Mericq V. Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer. Horm Res. 2009;71:178-184. [Medline].
Barbieri AM, Filopanti M, Bua G, Beck-Peccoz P. Two novel nonsense mutations in GALNT3 gene are responsible for familial tumoral calcinosis. J Hum Genet. 2007;52:464-468. [Medline].
Beloosesky Y, Grinblat J, Weiss A, Grosman B, Gafter U, Chagnac A. Electrolyte disorders following oral sodium phospahte administration for bowel cleansing in elderly patients. Arch Intern Med. 2003;163:803-808. [Medline].
Gumurdulu Y, Serin E, Ozer B, Gokcel A, Boyacioglu S. Age as a predictor of hyperphosphatemia after oral phosphosoda administration for colon preparation. J Gastroenterol Hepatol. 2004;19:68-72. [Medline].
Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol. 2005;16:3389-3396. [Medline].
Markowitz GS, Nasr SH, Klein P, Anderson H, Stack JI, Alterman L, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol. 2004;35:675-684. [Medline].
Connolly GM, Cunningham R, McNamee PT, Young IS, Maxwell AP. Elevated serum phosphate predicts mortality in renal transplant recipients. Transplantation. 2009;87:1041-1044. [Medline].
Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2008;52:519-530. [Medline].
Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney International. 2008;74:148-157. [Medline].
Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G, Cholesterol and Recurrent Events Trial Investigators. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005;112:2627-2633. [Medline].
Cannata-Andia JB, Naves-Diaz M. Phosphorus and Survival: Key Questions That Need Answers. J Am Soc Nephrol. 2009;20:234-236. [Medline].
Sabbagh Y, Carpenter TO, Demay MB. Hypophospphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci USA. 2005;102:9637-9642. [Medline].
Shuto E, Taketani Y, Tanaka R, Harada N, Isshiki M, Sato M, et al. Dietary phosphorus acutely impairs endothelial function. J Am Soc Nephrol. 2009;20:1504-1512. [Medline].
Ball CL, Tobler K, Ross BC, Connors MR, Lyon ME. Spurious hyperphosphatemia due to sample contamination with heparinized saline from an indwelling catheter. Clin Chem Lab Med. Jan 2004;42(1):107-8. [Medline].
Cachat F, Bardy D, Durussel C, Di Paolo E. Spurious hyperphosphatemia in a patient with alteplase-locked central venous catheter. Pediatr Nephrol. Feb 2006;21(2):301-2. [Medline].
Marcu CB, Hotchkiss M. Pseudohyperphosphatemia in a patient with multiple myeloma. Conn Med. Feb 2004;68(2):71-2. [Medline].
Larner AJ. Pseudohyperphosphatemia. Clin Biochem. Aug 1995;28(4):391-3. [Medline].
Leehey DJ, Daugirdas JT, Ing TS, Reid RW. Spurious hyperphosphatemia due to hyperlipidemia. Arch Intern Med. Apr 1985;145(4):743-4. [Medline].
Ketteler M. Phosphate Metabolism in CKD Stages 3-5: Dietary and Pharmacological Control. Int J Nephrol. 2011;2011:970245. [Medline]. [Full Text].
Spaia S. Phosphate binders: Sevelamer in the prevention and treatment of hyperphosphataemia in chronic renal failure. Hippokratia. Jan 2011;15:22-6. [Medline]. [Full Text].
Vemuri N, Michelis MF, Matalon A. Conversion to lanthanum carbonate monotherapy effectively controls serum phosphorus with a reduced tablet burden: a multicenter open-label study. BMC Nephrol. Sep 30 2011;12:49. [Medline]. [Full Text].
Frazao JM, Adragao T. Treatment of hyperphosphatemia with sevelamer hydrochloride in dialoysis patients: effects on vascular calcification, bone and a close look into the survival data. Kidney Int Suppl. 2008;111:S38-S43. [Medline].
Sprague SM. A comparative review of the efficacy and safety of established phospahte binders: calcium, sevelamer, and lanthanum carbonate. Curr Med Res Opin. 2007;23:3167-3175. [Medline].
Marangon N, Lindholm B, Stenvinkel P. Nonphosphate-binding effects of sevelamer--are they of clinical relevance?. Semin Dial. 2008;21:385-389. [Medline].
Takei T, Otsubo S, Uchida K, Matsugami K, Mimuro T, Kabaya T, et al. Effects of sevelamer on the progression of vacular calcification in pateints on chronic hemodialysis. Nephron Clin Pract. 2008;108:c278-283. [Medline].
Connor A. Novel therapeutic agents and strategies for the management of chronic kidney disease mineral and bone disorder. Postgrad Med J. 2009;85:274-279.
Barreto DV, Barreto FdeC, de Carvalho AB, Cuppari L, Draibe SA, Dalboni MA, et al. Phosphate binder impact on bone remodeling and coronary calcification -- results from the BRIC study. Nephron Clin Pract. 2008;110:c278-c283. [Medline].
Hansen D, Rasmussen K, Danielsen H, et al. No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized crossover trial. Kidney Int. Oct 2011;80(8):841-50. [Medline].
Ahmed S, O'Neill KD, Hood AF, et al. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis. Jun 2001;37(6):1267-76. [Medline].
Bastepe M, Juppner H. Pseudohypoparathyroidism. New insights into an old disease. Endocrinol Metab Clin North Am. Sep 2000;29(3):569-89. [Medline].
Berndt T, Craig TA, Bowe AE, et al. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest. Sep 2003;112(5):785-94. [Medline].
Biarent D, Brumagne C, Steppe M, Bouton JM. Acute phosphate intoxication in seven infants under parenteral nutrition. JPEN J Parenter Enteral Nutr. Nov-Dec 1992;16(6):558-60. [Medline].
Blay P, Fernandez-Martinez JM, Diaz-Lopez B. Vertebral involvement in hyperphosphatemic tumoral calcinosis. Bone. Mar 2001;28(3):316-8. [Medline].
Block GA. Control of serum phosphorus: implications for coronary artery calcification and calcific uremic arteriolopathy (calciphylaxis). Curr Opin Nephrol Hypertens. Nov 2001;10(6):741-7. [Medline].
Burke SK, Amin NS, Incerti C, et al. Sevelamer hydrochloride (Renagel), a phosphate-binding polymer, does not alter the pharmacokinetics of two commonly used antihypertensives in healthy volunteers. J Clin Pharmacol. Feb 2001;41(2):199-205. [Medline].
Carpenter TO. Oncogenic osteomalacia--a complex dance of factors. N Engl J Med. Apr 24 2003;348(17):1705-8. [Medline].
Carvalho AB, Lobao RR, Cuppari L, et al. Does hypophosphataemia induce hypoparathyroidism in pre-dialysis patients?. Nephrol Dial Transplant. 1998;13 Suppl 3:12-4. [Medline].
Chen NX, Moe SM. Vascular calcification in chronic kidney disease. Semin Nephrol. Jan 2004;24(1):61-8. [Medline].
Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant. Dec 1999;14(12):2907-14. [Medline].
Chertow GM, Burke SK, Raggi P; Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. Jul 2002;62(1):245-52. [Medline].
Connor A. Novel therapeutic agents and strategies for the management of chronic kidney disease mineral and bone disorder. Postgrad Med J. 2009;85:274-278. [Medline].
Cozzolino M, Dusso AS, Slatopolsky E. Role of calcium-phosphate product and bone-associated proteins on vascular calcification in renal failure. J Am Soc Nephrol. 2001;12(11):2511-6. [Medline].
Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int. 2001;60(2):472-9. [Medline].
DiMeglio LA, White KE, Econs MJ. Disorders of phosphate metabolism. Endocrinol Metab Clin North Am. Sep 2000;29(3):591-609. [Medline].
Drezner MK. PHEX gene and hypophosphatemia. Kidney Int. Jan 2000;57(1):9-18. [Medline].
Fine A, Patterson J. Severe hyperphosphatemia following phosphate administration for bowel preparation in patients with renal failure: two cases and a review of the literature. Am J Kidney Dis. Jan 1997;29(1):103-5. [Medline].
Finn WF, Joy MS, Hladik G; Lanthanum Study Group. Efficacy and safety of lanthanum carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving hemodialysis. Clin Nephrol. Sep 2004;62(3):193-201. [Medline].
Fiorino AS. Hypercalcemia and alkalosis due to the milk-alkali syndrome: a case report and review. Yale J Biol Med. Nov-Dec 1996;69(6):517-23. [Medline].
Fournier A, Oprisiu R, Albu AT, et al. The crossover comparative trial of calcium acetate versus sevelamer hydrochloride (Renagel) as phosphate binders in dialysis patients. Am J Kidney Dis. Jun 2000;35(6):1248-50. [Medline].
Gallieni M, Cozzolino M, Carpani P, et al. Sevelamer reduces calcium load and maintains a low calcium-phosphorus ion product in dialysis patients. J Nephrol. May-Jun 2001;14(3):176-83. [Medline].
Ganesh SK, Stack AG, Levin NW, et al. Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol. Oct 2001;12(10):2131-8. [Medline].
Garfield N, Karaplis AC. Genetics and animal models of hypoparathyroidism. Trends Endocrinol Metab. Sep 2001;12(7):288-94. [Medline].
Goldsmith D, Ritz E, Covic A. Vascular calcification: a stiff challenge for the nephrologist: does preventing bone disease cause arterial disease?. Kidney Int. 66(4):1315-33. [Medline].
Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. May 18 2000;342(20):1478-83. [Medline].
Gupta D, Brietzke S, Hayden MR, Kurukulasuriya LR, Sowers JR. Phosphate Metabolism in Cardiorenal Metabolic Disease. Cardiorenal Med. 2011;1(4):261-270. [Medline]. [Full Text].
Isakova T, Gutierrez OM, Chang Y, Shah A, Tamez H, Smith K, et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol. 2009;20:386-396. [Medline].
Ishibashi K, Imai M. Prospect of a stanniocalcin endocrine/paracrine system in mammals. Am J Physiol Renal Physiol. Mar 2002;282(3):F367-75. [Medline].
Jeha S. Tumor lysis syndrome. Semin Hematol. 2001;38(4 Suppl 10):4-8. [Medline].
Jonsson KB, Mannstadt M, Miyauchi A, et al. Extracts from tumors causing oncogenic osteomalacia inhibit phosphate uptake in opossum kidney cells. J Endocrinol. Jun 2001;169(3):613-20. [Medline].
Jonsson KB, Zahradnik R, Larsson T, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. Apr 24 2003;348(17):1656-63. [Medline].
Joy MS, Finn WF, LAM-302 Study Group. Randomized, double-blind, placebo-controlled, dose-titration, phase III study assessing the efficacy and tolerability of lanthanum carbonate: a new phosphate binder for the treatment of hyperphosphatemia. Am J Kidney Dis. 42(1):96-107. [Medline].
Kalemkerian GP, Darwish B, Varterasian ML. Tumor lysis syndrome in small cell carcinoma and other solid tumors. Am J Med. Nov 1997;103(5):363-7. [Medline].
Kirschbaum B. The acidosis of exogenous phosphate intoxication. Arch Intern Med. Feb 23 1998;158(4):405-8. [Medline].
Kumar R. New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia. Curr Opin Nephrol Hypertens. Sep 2002;11(5):547-53. [Medline].
Kumar R. Tumor-induced osteomalacia and the regulation of phosphate homeostasis. Bone. Sep 2000;27(3):333-8. [Medline].
Lania A, Mantovani G, Spada A. G protein mutations in endocrine diseases. Eur J Endocrinol. Nov 2001;145(5):543-59. [Medline].
Larsson T, Nisbeth U, Ljunggren O, et al. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. Dec 2003;64(6):2272-9. [Medline].
Lee KW, Cohen KL, Walters JB, Federman DG. Iatrogenic vitamin D intoxication: report of a case and review of vitamin D physiology. Conn Med. Jul 1999;63(7):399-403. [Medline].
Levi M. Novel NaPi-2c mutations that cause mistargeting of NaPi-2c protein and uncoupling of Na-Pi cotransport cause HHRH. Am J Physiol Renal Physiol. 2008;295:F369-370. [Medline].
Levin NW, Hoenich NA. Consequences of hyperphosphatemia and elevated levels of the calcium-phosphorus product in dialysis patients. Curr Opin Nephrol Hypertens. Sep 2001;10(5):563-8. [Medline].
Levine MA. Clinical spectrum and pathogenesis of pseudohypoparathyroidism. Rev Endocr Metab Disord. Nov 2000;1(4):265-74. [Medline].
Liu YL, Lin HH, Yu CC, Kuo HL, Yang YF, Chou CY. A comparison of sevelamer hydrochloride with calcium acetate on biomarkers of bone turnover in hemodialysis patients. Ren Fail. 2006;28(8):701-7. [Medline].
Llach F. Hyperphosphatemia in end-stage renal disease patients: pathophysiological consequences. Kidney Int Suppl. Dec 1999;73:S31-7. [Medline].
Locatelli F, Cannata-Andia JB, Drueke TB, et al. Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant. 2002;17(5):723-31. [Medline].
Loghman-Adham M. Phosphate binders for control of phosphate retention in chronic renal failure. Pediatr Nephrol. Oct 1999;13(8):701-8. [Medline].
London GM, Guerin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 18(9):1731-40. [Medline].
Malluche HH, Monier-Faugere MC. Hyperphosphatemia: pharmacologic intervention yesterday, today and tomorrow. Clin Nephrol. Oct 2000;54(4):309-17. [Medline].
Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med. Dec 21 2000;343(25):1863-75. [Medline].
Masi L, Gozzini A, Franchi A, Campanacci D, Amedei A, Falchetti A, et al. A novel recessive mutation of fibroblast growth factor-23 in tumoral calcinosis. J Bone Joint Surg Am. 2009;91:1190-8. [Medline].
Mauro LS, Kuhl DA, Kirchhoff JR, et al. Impact of oral bases on aluminum absorption. Am J Ther. Jan-Feb 2001;8(1):21-5. [Medline].
Moe SM, O'Neill KD, Duan D, et al. Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int. Feb 2002;61(2):638-47. [Medline].
Narchi H. Hyperostosis with hyperphosphatemia: evidence of familial occurrence and association with tumoral calcinosis. Pediatrics. May 1997;99(5):745-8. [Medline].
Nelson AE, Bligh RC, Mirams M, et al. Clinical case seminar: Fibroblast growth factor 23: a new clinical marker for oncogenic osteomalacia. J Clin Endocrinol Metab. Sep 2003;88(9):4088-94. [Medline].
Nelson AE, Hogan JJ, Holm IA, et al. Phosphate wasting in oncogenic osteomalacia: PHEX is normal and the tumor-derived factor has unique properties. Bone. Apr 2001;28(4):430-9. [Medline].
Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann Clin Biochem. Mar 1998;35 ( Pt 2):201-6. [Medline].
Quarles LD. Evidence for a bone-kidney axis regulating phosphate homeostasis. J Clin Invest. Sep 2003;112(5):642-6. [Medline].
Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab. Jul 2003;285(1):E1-9. [Medline].
Raggi P. Effects of excess calcium load on the cardiovascular system measured with electron beam tomography in end-stage renal disease. Nephrol Dial Transplant. 2002;17(2):332-5. [Medline].
Ribeiro S, Ramos A, Brandao A, et al. Cardiac valve calcification in haemodialysis patients: role of calcium- phosphate metabolism. Nephrol Dial Transplant. Aug 1998;13(8):2037-40. [Medline].
Rowe PS, Kumagai Y, Gutierrez G, et al. MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone. Feb 2004;34(2):303-19. [Medline].
Savaci N, Avunduk MC, Tosun Z, Hosnuter M. Hyperphosphatemic tumoral calcinosis. Plast Reconstr Surg. Jan 2000;105(1):162-5. [Medline].
Savica V, Calo LA, Monardo P, Davis PA, Granata A, Santoro D, et al. Salivary phosphate-binding chewing gum reduces hyperphospahtemia in dialysis pateints. J Am Soc Nephrol. 2009;20:639-644. [Medline].
Schiavi SC, Kumar R. The phosphatonin pathway: new insights in phosphate homeostasis. Kidney Int. Jan 2004;65(1):1-14. [Medline].
Schoenhagen P, Tuzcu EM. Coronary artery calcification and end-stage renal disease: vascular biology and clinical implications. Cleve Clin J Med. 2002;69 Suppl 3:S12-20. [Medline].
Segawa H, Kawakami E, Kaneko I, et al. Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter. Pflugers Arch. Aug 2003;446(5):585-92. [Medline].
Shaoul R, Wolff R, Seligmann H, et al. Symptoms of hyperphosphatemia, hypocalcemia, and hypomagnesemia in an adolescent after the oral administration of sodium phosphate in preparation for a colonoscopy. Gastrointest Endosc. May 2001;53(6):650-2. [Medline].
Shioi A, Taniwaki H, Jono S, et al. Monckeberg's medial sclerosis and inorganic phosphate in uremia. Am J Kidney Dis. Oct 2001;38(4 Suppl 1):S47-9. [Medline].
Slatopolsky E, Brown A, Dusso A. Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis. 2001;37(1 Suppl 2):S54-7. [Medline].
Uhlig K, Sarnak MJ, Singh AK. New approaches to the treatment of calcium and phosphorus abnormalities in patients on hemodialysis. Curr Opin Nephrol Hypertens. Nov 2001;10(6):793-8. [Medline].
Weinstein LS, Yu S, Warner DR, Liu J. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev. Oct 2001;22(5):675-705. [Medline].
White KE, Carn G, Lorenz-Depiereux B, et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. Dec 2001;60(6):2079-86. [Medline].
Yasuda T, Niimi H. Hypoparathyroidism and pseudohypoparathyroidism. Acta Paediatr Jpn. Aug 1997;39(4):485-90. [Medline].
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