Nephrology Hypertension

Phosphorus Metabolism Disorders

Does this patient have a phosphorus metabolism disorder?

Does this patient have hyperphosphatemia?

Normal serum phosphorus is defined as serum phosphorus levels between 2.5 and 4.5 mg/dl (0.81-1.45 mmol/L). Phosphorus homeostasis is a complex interplay between several organs and hormones. The regulatory organ systems are bone, intestines and kidneys, while the regulatory hormones include parathyroid hormone (PTH), vitamin D 25 and vitamin D 1,25, and fibroblast growth factor 23 (FGF-23).

Dietary phosphorus is absorbed predominantly in the small intestine. This process, which is increased by vitamin D 25 is essentially unregulated (ie, hyperphosphatemia does not significantly decrease intestinal phosphate absorption). Excess serum phosphorus is excreted by the kidneys under the influence of parathyroid hormone and FGF-23. Bone is the principal reservoir of phosphorus in the body. For a complete review of phosphate homeostasis please see the recent (2011) study by Blaine et al (see What is the Evidence? section below).

Patients at risk of developing hyperphosphatemia can be divided into the following categories (see Table I):

Table I.

Factors that cause hyperphosphatemia
Impaired Excretion Increased Absorption Release from Stores Endocrinopathies Shift Genetic Diseases Pseudohyperphosphatemia
Renal impairment Increased dietary intake Rhabdomyolysis Hypoparathyroidism Metabolic acidosis Familial tumoral calcinosis Hyperbilirubinemia
Ingestion of phosphorus containing supplements or bowel preparations Tumor lysis syndrome Resistance to parathyroid hormone Lactic acidosis Hyperglobulinemia
Impaired colonic motility Malignant hyperthermia Diabetic ketoacidosis Hyperlipidemia
Hematologic malignancies Treatment with liposomal amphotericin B
  1. Patients with impaired phosphorus excretion. These patients always have some degree of impaired renal function as the kidney is the principal organ via which phosphorus is removed from the body.

  2. Patients with increased phosphorus absorption. This includes patients who have ingested large amounts of phosphorus in the diet or those who have used phosphorus containing bowel preparations. Also in this category are patients with impaired colonic motility which, allows for increased phosphorus absorption. Approximately 80% of the absorption of phosphate via enteral sources occurs in the small intestine.

  3. Release from intracellular stores. This includes patients with hematologic malignancies, those with the tumor lysis syndrome , rhabdomyolysis or malignant hyperthermia. Massive hemolysis can cause hyperphosphatemia as can bowel ischemia.

  4. Endocrinopathies. Since PTH is a key hormone in promoting renal excretion of phosphorus, hypoparathyroidism or resistance to PTH can cause hyperphosphatemia.

  5. Shift from intracellular to extracellular compartments. Metabolic acidosis causes phosphorus to shift out of cells. In lactic acidosis glycolysis is decreased, which decreases intracellular utilization of phosphate in the generation of adenosine triphosphate (ATP). In diabetic ketoacidosis, glycolysis is impaired and hyperglycemia can shift phosphate out of cells via osmotic drag.

  6. Pseudohyperphosphatemia: Falsely elevated measurements of serum phosphate can be obtained when another substance interferes with the accurate measurement of phosphate. This can be seen in patients with hyperbilirubinemia, hyperglobulinemia, or hyperlipidemia. Prolonged treatment with liposomal amphotericin B can also cause false elevations in serum phosphorus.

  7. Genetic diseases: Familial tumoral calcinosis is a rare autosomal recessive disease in which hyperphosphatemia is due to increased renal proximal tubule reabsorption of phosphate and increased vitamin D 1,25 production, Mutations in the GALNT3 gene (which encodes a glycosyltransferase) as well as fibroblast growth factor 23 (FGF-23) and Klotho genes have been described in this disorder.

Does this patient have hypophosphatemia?

Hypophosphatemia is defined as serum phosphorus < 2.5 mg/dl (0.81 mmol/L) and severe hypophosphatemia is defined as serum phosphorus < 1 mg/dl (0.32 mmol/L).

Hypophosphatemia can be caused by (1) decreased intake of phosphorus or decreased intestinal absorption of phosphorus, (2) increased renal excretion of phosphorus, (3) shift of phosphorus from extracellular to intracellular compartments or (4) genetic disorders (see Table II).

Table II.

Factors that cause hypophosphatemia
Decreased Intake or Absorption Increased Renal Excretion Shift Genetic Disorders
Malnutrition Hyperparathyroidism Elevated serum insulin or glucose levels Autosomal dominant hereditary hypophosphatemic rickets (ADHR)
Vitamin D deficiency or resistance Elevated PTHrp levels Metabolic alkalosis X-linked hypophosphatemic rickets (XHR)
Use of oral phosphate binders Metabolic acidosis Rapid cellular proliferation Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)
Diarrhea Excess glucocorticoids Elevated catecholamine levels
Steatorrhea Fanconi syndrome (from a variety of causes)
Tumor-induced osteomalacia

Decreased intake or intestinal absorption of phosphorus occurs in malnutrition (including chronic alcoholism), use of oral phosphate binders, vitamin D deficiency or resistance, steatorrhea (which decreases absorption of fat soluble vitamins such as vitamin D), diarrhea and nasogastric suctioning.

Increased renal excretion of phosphorus occurs in patients with hyperparathyroidism, increased levels of parathyroid hormone related protein (PTHrp), metabolic acidosis, and increased glucocorticoid levels. Since the majority of renal phosphate absorption occurs in the renal proximal tubule, diseases or drugs that affect the proximal tubule can also cause renal phosphate wasting.

Widespread proximal tubular dysfunction characterized by glucosuria, aminoaciduria, bicarbonaturia and phosphaturia is also known as the Fanconi syndrome and can be caused by multiple myeloma (due to filtered light chain toxicity), Wilson's disease , cystinosis, systemic lupus erythematosus and drugs such as cisplatin, ifosfamide and heavy metals. Tumor-induced osteomalacia is a less common form of renal phosphate wasting in which a tumor secretes a phosphatonin that induces renal phosphate loss.

Shift of phosphorus into cells occurs in patients with elevated levels of serum glucose or insulin, in those with metabolic alkalosis, in patients with rapid cell proliferation (eg, hematologic malignancies or hungry bone syndrome), and in those with elevated circulating catecholamines.

Genetic disorders are a rare cause of hypophosphatemia and all cause renal phosphate wasting. In autosomal dominant hereditary hypophosphatemic rickets (ADHR) there is a mutation in the FGF-23 gene which causes a gain of function in FGF-23 leading to loss of phosphorus in the urine. In X-linked hypophosphatemic rickets (XHR) a mutation in the PHEX gene causes an increase in FGF-23 levels. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by an inactivating mutation in one of the renal phosphate transporters. For a complete review of the subject please see the paper by Alizadeh Naderi and Reilly (see What is the Evidence? section, below).

What tests to perform?


For evaluation of hyperphosphatemia the following lab tests should be ordered: serum phosphorus, serum calcium, serum albumin, creatinine and electrolytes (sodium, potassium, bicarbonate), complete blood count (CBC), parathyroid hormone (PTH), vitamin D 25, vitamin D 1,25.

In hyperphosphatemia serum phosphorous will be > 4.5 mg/dl. Corrected serum calcium (serum calcium corrected for albumin) is often normal but may be low if hyperphosphatemia is severe enough to cause calcium phosphorous precipitation. Creatinine will be normal if the patient's renal function is unaffected but will be high in those with impaired renal function. Electrolytes are generally normal unless renal impairment is severe.

The CBC is usually normal unless the patient has a hematologic malignancy. PTH is usually normal in those with normal renal function but is elevated in those with chronic kidney disease or those with resistance to parathyroid hormone. Vitamin D 25 and vitamin D 1,25 will be high in those with vitamin D intoxication or the milk-alkali syndrome. Elevated vitamin D 1,25 will increase intestinal phosphate reabsorption thereby contributing to hyperphosphatemia.

The frequency with which lab tests should be ordered depends on the underlying cause of hyperphosphatemia (eg, tumor lysis syndrome versus rhabdomyolysis versus chronic kidney disease). For those with relatively normal renal function, serum phosphorus and corrected serum calcium should be followed daily to monitor the effectiveness of treatment. For patients with chronic kidney disease phosphorus, corrected serum calcium, PTH, vitamin D 25 and vitamin D 1, 25 are measured monthly or every 3 to 6 months depending on the severity of renal disease.

Imaging is usually not indicated for evaluation of hyperphosphatemia.

The only situation in which a kidney biopsy is necessary in the evaluation of hyperphosphatemia is if acute phosphate nephropathy (see above) is suspected. In this case, renal biopsy will show evidence of renal tubular damage and widespread deposition of calcium phosphate crystals. If renal biopsy is performed further out in time from the time of insult, chronic tubular damage and interstitial fibrosis may also be present.


For evaluation of hypophosphatemia the following lab tests should be ordered: serum phosphorus, serum calcium, serum albumin, serum creatinine, parathyroid hormone (PTH), vitamin D 25, vitamin D 1,25. Urinary phosphate excretion can be measured in a 24-hour urine collection or a spot urine. A serum and urine creatinine should be obtained simultaneously to evaluate the fractional excretion of potassium which is given by the following formula: [(Uphos * PCr)/(Pphos * UCr)] * 100 where Uphos and Pphos indicate urine and serum phosphorus respectively and PCr and UCr indicate serum and urine creatinine respectively. In hypophosphatemic states in which the kidneys are functioning appropriately, there should be maximal reabsorption of urinary phosphate and the fractional excretion of phosphorus should be less than 5%.

In primary hyperparathyroidism, PTH levels will be high, serum phosphorus levels are often low, and serum calcium levels are elevated. In contrast, in secondary hyperparathyroidism serum calcium levels are low, which stimulates PTH release causing renal phosphate wasting.

In patients who are malnourished or who have intestinal malabsorption syndromes vitamin D levels are low, which impairs intestinal absorption of phosphorus and promotes renal phosphorus wasting.

Imaging is usually not indicated for the evaluation of hypophosphatemia and neither is renal biopsy.

How should patients with phosphorus metabolism disorders be managed?


Patients with severe symptomatic hyperphosphatemia causing severe hypocalcemia and renal failure may need dialysis to correct the hypocalcemia and lower the serum phosphorus.

Patients with advanced kidney disease (estimated glomerular filtration rate < 25 ) and hyperphosphatemia need to be placed on a low phosphorus diet and will also often need oral phosphate binders. There are several different formulations of oral phosphate binders available. At present, all of the commonly prescribed oral phosphorus binders need to be taken in substantial amounts to be effective, which often hinders patient compliance.

Calcium-based phosphate binders include calcium carbonate (TUMS, Os-Cal, Caltrate) and calcium acetate (Phoslo, Eliphos). Calcium carbonate and calcium acetate appear equally effective in lowering serum phosphorus and both have the potential to cause hypercalcemia.

Sevelamer (RenaGel) is a non-calcium–containing anion exchange resin that was initially released as sevelamer hydrochloride but, given concerns about metabolic acidosis is now sold as sevelamer carbonate. Sevelamer and calcium-containing phosphate binders appear to have similar efficacy in lowering serum phosphorus and several meta-analyses have not revealed any differences between calcium and non-calcium–containing binders with regard to overall mortality and cardiovascular outcomes.

Sevelamer is significantly more expensive than calcium-containing formulations but also appears to lower serum low density lipoprotein (LDL) via an unknown mechanism. In addition, the risk of hypercalcemia is much lower with sevelamer compared to calcium-containing binders.

Lanthanum carbonate (Fosrenol) is a non-calcium , non-aluminum containing phosphate binder that appears to have similar efficacy to calcium-containing binders although it is significantly more expensive. It also appears to be less well tolerated than calcium-containing binders. In trials comparing lanthanum to calcium-containing binders there was a significantly higher dropout rate in the lanthanum groups.

While aluminum-containing phosphate binders (Amphojel) are highly effective, their use is discouraged due to concerns about aluminum deposition in the brain leading to dementia, as well as their potential to cause anemia and osteomalacia. In general, aluminum containing binders should not be used for periods of longer than a week and repeat courses should not be given. Amphojel is generally used acutely as "salvage" therapy in patients with severe hyperphosphatemia.

While magnesium-based phosphate binders (Milk of Magnesia) are effective in lowering serum phosphorus, their use among dialysis patients and those with severely impaired renal function is limited because of the risk of hypermagnesemia and respiratory depression.

Treatment of hyperphosphatemia due due to excessive release of intracellular phosphorus (such as tumor lysis syndrome or rhabdomyolysis) involve vigorous intravenous hydration to maintain adequate renal function or dialysis if renal function is severely compromised.


The primary goal of treatment of hypophosphatemia should be to correct the underlying cause if possible (especially in cases of malnutrition, vitamin D deficiency).

Phosphate repletion can occur by oral or intravenous (IV) routes. Oral repletion is safer, as rapid intravenous repletion can cause hypocalcemia, hypotension, and/or acute kidney injury. Intravenous repletion is advised if the serum phosphorus is less than or equal to 1.0 mg/dl and/or if the patient is unable to take anything by mouth.

When ordering IV phosphate it is best to specify the number of mmol of elemental phosphorus desired (1 mmol phosphate = 31 mg phosphorus) as well as whether the sodium phosphate or potassium phosphate is required. In general 0.16 - 0.24 mmol/kg ideal body weight of elemental phosphorus can be infused over 4-6 hours and then the serum phosphorus should be rechecked. If hyperkalemia is of concern then sodium phosphate should be ordered, as potassium phosphate contains ~ 1.5 mEq potassium for every mmol of phosphorus.

If the patient can take medication orally, then IV phosphate repletion is usually stopped when the serum phosphorus reaches 1.5 mg/dl and the patient can be switched to an oral formulation. It should be remembered that serum phosphorus is not reflective of total body phosphorus stores and in cases of chronic phoshphorus depletion such as alcoholism or prolonged malnutrition substantial amounts of phosphate will be required for repletion.

Oral phosphorus preparations can also be obtained as the sodium or potassium salt. Usually 1 mmol/kg ideal body weight up to a maximum of 80 mmol per day is given orally in 2 -3 divided doses. If the patient is taking adequate nutrition and does not have chronic urinary losses or problems with malabsorption then oral supplementation can be stopped when the serum phosphorus reaches 2.0 mg/dl.

The above dosing regimens assume that the patient has normal renal function. If the patient has impaired renal function, the starting dose should be half that suggested above and the serum phosphorus should be checked frequently.

Chronic urinary wasting of phosphorus (such as can be seen in the Fanconi syndrome or with genetic disorders of phosphate wasting) can be challenging to treat. Small studies have shown that dipyridamole (up to 75 mg four times daily) can decrease urinary phosphate wasting and increase serum phosphorus levels but further studies need to be done before this can routinely be recommended.

What happens to patients with phosphorus metabolism disorders?


Patients with increased serum phosphorus levels are generally asymptomatic. However, severe hyperphosphatemia (generally considered to be serum phosphorus greater than 8 mg/dl) can cause hypocalcemia acutely by precipitating with calcium and forming an insoluble product. The symptoms of severe hyperphosphatemia are due to hypocalcemia, which most often causes muscle cramps but can also lead to altered mental status or seizures, arrythmias and hypotension.

Hyperphosphatemia with advanced renal disease (estimated GFR < 30) is common. This is often a chronic problem that must be managed with the use of oral phosphate binders (see above).

Chronically elevated phosphorus levels are associated with an increased risk of cardiovascular death and elevated phosphorus levels contribute to an increased serum calcium phosphorus product. Dialysis patients with a calcium phosphorus product greater than 55 mg2/dl2 are at increased risk of developing calcific uremic arteriolopathy (calciphylaxis) which is characterized by widespread medial calcification of arterioles leading to subcutaneous necrosis and skin ulceration. This is a devastating condition that can often be fatal.

Acute phosphate nephropathy is a complication of ingestion of phosphate containing bowel purgatives (such as Fleets Phosphosoda, Visicol or Osmoprep) in preparation for colonoscopy. The intake of large amounts of phosphate causes an acute rise in serum phosphorus levels (as much as a 4.1 mg/dl increase within 24 hours). This. together with the associated volume depletion from colonic purgatives, is thought to cause renal damage. Risk factors for acute phosphate nephropathy include concurrent renal disease, advanced age, female gender and use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers.

Acute phosphate nephropathy is characterized by acute kidney injury and a renal biopsy showing evidence of acute tubular injury with widespread calcium phosphate deposits. Acute phosphate nephropathy has been estimated to occur at a frequency of 1 in every thousand doses of oral sodium phosphate solution sold. Patients who develop acute phosphate nephropathy generally have a poor renal outcome.

In one study of acute phosphate nephropathy, at a mean follow-up of 16.7 months, 4 out of 21 patients were on hemodialysis and the remaining 17 patients had chronic kidney disease with a mean serum creatinine of 2.4 mg/dl. In another study performed in Iceland, of 15 patients with documented acute phosphate nephropathy after a mean follow up of 26.6 months 1 patient had progressed to end-stage renal disease, 1 patient had died of progressive renal failure and none of the other 13 patients had returned to their baseline renal function.

Hyperphosphatemia due to acute kidney injury (AKI) will improve as renal function improves and if due to isolated AKI has no long term sequelae.


It should be noted that serum phosphate levels often do not reflect total body phosphate stores. Thus, symptomsof hypophosphatemia do not always correlate with the serum phosphorus level. In general symptoms are related to the critical role phosphorus plays in energy metabolism (in the generation of ATP), in the maintenance of 2,3 diphosphoglycerate (2,3-DPG) levels in red blood cells, or in bone homeostasis.

Severe hypophosphatemia (serum phosphorus < 1 mg/dl) can lead to respiratory depression or difficulty in weaning from the ventilator in intubated patients. In addition, depletion of red blood cell 2,3 diphosphoglycerate stores shifts the oxygen dissociation curve to the left and decreases oxygen delivery to tissues increasing tissue ischemia. Severe hypophosphatemia can also cause arrythmias and decrease myocardial contractility. In addition low serum phosphorus can cause rhabdomyolysis.

The release of large quantities of phosphorus from damaged muscle can mask the underlying hypophosphatemia. Critically low phosphorus levels can also cause central pontine myelinolysis via an unknown mechanism. Other effects of hypophosphatemia include hemolysis, leukocyte dysfunction and insulin resistance.

Acute hypophosphatemia usually has no lasting sequelae provided rhabdomyolysis, central pontine myelinolysis, or other sequelae with severe morbidity have not occurred.

Chronic hypophosphatemia causes hypercalciuria via an unknown mechanism. In addition, chronic hypophosphatemia results in rickets and osteomalacia as phosphate is mobilized from skeletal stores. This predisposes to fractures and can be particularly devastating in the pediatric population. Children have an increased requirement for phosphorus compared to adults due to skeletal growth.

How to utilize team care?


If the patient has hyperphosphatemia due to acute or chronic kidney injury, then consultation with a nephrologist can be helpful.

Assistance from a dietician is especially useful in patients with chronic kidney failure and hyperphosphatemia. Hyperphosphatemia in these patients is a chronic problem that requires continual management . Since many foods are high in phosphorus, consultation with a dietician is very useful in the implementation of a low phosphorus diet.


Assistance from a dietician may be helpful in those patients with hypophosphatemia due to chronic malnourishment or malabsorption.

A pharmacist may be helpful in ensuring that the correct formulation and amount of phosphorus is given for hypophosphatemia. As mentioned above, when ordering or prescribing phosphorus for repletion it is best to specify the number of mmol of elemental phosphorus to be given as well as whether the sodium or potassium salt is desired.

Are there clinical practice guidelines to inform decision making?

The National Kidney Foundation has created a set of guidelines for management of hyperphosphatemia in patients with chronic kidney disease. These are known as the Kidney Disease Outcomes Quality Initiative or KDOQI. Kidney Disease: Improving Global Outcomes (KDIGO) is another global foundation that has released a set of guidelines for managing phosphorus homeostasis in patients with chronic kidney disease.

A limitation to both the KDOQI and KDIGO guidelines is that several of their recommendations are consensus opinion and are not evidence-based, as there are not many clinical trials that address phosphorus homeostasis.

Other considerations

  • ICD-10 275.3 Disorders of phosphorus metabolism

  • DRG E83.3 Disorders of phosphorus metabolism and phosphatases

What is the evidence?

Alizadeh Naderi, AS, Reilly, RF. "Hereditary disorders of renal phosphate wasting". Nat Rev Nephrol. vol. 6. 2010. pp. 657-665.

(This article reviews genetic disorders of renal phosphate wasting and describes the cloning and characterization of the genes involved in these disorders.)

Blaine, J, Weinman, EJ, Cunningham, R. "The regulation of renal phosphate transport". Adv Chronic Kidney Dis. vol. 18. 2011. pp. 77-84.

(This article described the molecular mechanisms that control phosphorus handling by the kidney.)

Geerse DA, BA, Kuiper, MA, Roos, AN, Spronk, PE, Schultz, MJ. "Treatment of hypophosphatemia in the intensive care unit: a review". Crit Care. vol. 14. 2010. pp. R147.

(This article reviews the incidence, etiologies, symptoms and management of hypophosphatemia in the intensive care unit.)

Kendrick, J, Kestenbaum, B, Chonchol, M. "Phosphate and cardiovascular disease". Adv Chronic Kidney Dis. vol. 18. 2011. pp. 113-119.

(This article reviews the epidemiological evidence linking hyperphosphatemia to cardiovascular disease and explores some of the mechanisms by which phosphate excess may increase vascular calcification.)

Markowitz, GS, Perazella, MA. "Acute phosphate nephropathy". Kidney Int. vol. 76. 2009. pp. 1027-1034.

(This article defines acute phosphate nephropathy, describes the risk factors for and pathophysiology of this condition and gives recommendations on how to avoid acute phosphate nephropathy.)]

Martin, KJ, González, EA. "Prevention and control of phosphate retention/hyperphosphatemia in CKD-MBD: What Is normal, when to Start, and how to treat?". Clin J Am Soc Nephrol. vol. 6. 2011. pp. 440-446.

(This article reviews the epidemiological evidence underlying goal serum phosphorus levels in chronic kidney disease (CKD) and discusses management of hyperphosphatemia in individuals with CKD.)

Tonelli, M, Pannu, N, Manns, B. "Oral phosphate binders in patients with kidney failure". New Engl J Med. vol. 362. 2010. pp. 1312-1324.

(This article is a comprehensive review of the types of oral phosphate binders available and summarizes the clincal trials that have been conducted using these binders.)
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