Phosphorus Metabolism Disorders
Does this patient have hyperphosphatemia?
Does this patient have hypophosphatemia?
- What tests to perform?
- How should patients with phosphorus metabolism disorders be managed?
- What happens to patients with phosphorus metabolism disorders?
- How to utilize team care?
Are there clinical practice guidelines to inform decision making?
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, 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
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|
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.
Patients with increased phosphorus absorption. This includes patients who have ingested large amounts of phosphorus in the diet (more than 4000 mg/day) 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.
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.
Endocrinopathies. Since PTH is a key hormone in promoting renal excretion of phosphorus, hypoparathyroidism or resistance to PTH can cause hyperphosphatemia. Vitamin D toxicity may also cause this by the decrease in PTH in the setting of hypercalcemia and high vitamin D.
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.
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.
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 (the FGF-23 co-receptor) 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).
Patients at risk of developing hypophosphatemia can be divided into the following categories (see
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)|
Decreased intake or intestinal absorption of phosphorus. This occurs in malnutrition (including chronic alcoholism), use of oral phosphate binders including calcium, 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. This 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 nd 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. 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, this can occur.
Genetic disorders causing renal phosphate wasting are a rare cause of hypophosphatemia. 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, and vitamin D 1,25.
In hyperphosphatemia serum phosphorous will be > 4.5 mg/dl. Corrected serum calcium (serum calcium corrected for albumin such that for every 1g/dl drop in serum albumin serum calcium drops by 0.8 mg/dl) is often normal but may be low if hyperphosphatemia is severe enough to cause calcium phosphorous precipitation or in some cases of renal dysfunction. 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 or in cases of acidosis.
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, and vitamin D 1,25 can also be high in sarcoidosis and certain cancers. 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 and the severity of the hyperphosphatemia (e.g., tumor lysis syndrome versus rhabdomyolysis versus chronic kidney disease). 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 phosphorus which is given by the following formula: [(Uphos* PCr)/(Pphos* UCr)] * 100 where Uphosand Pphosindicate urine and serum phosphorus respectively and PCrand UCrindicate 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. However, in patients with renal disease and secondary hyperparathyroidism the decreased renal phosphorus excretion may counteract this.
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. There are calcium-based binders and non-calcium based binders. Calcium-based binders are much cheaper but in meta-analyses and non-randomized trials seem to be associated with a higher risk of all-cause mortality and potentially cardiovascular mortality as well but the effect was not significant. Calcium-based binders are also associated with an increase in hypercalcemia, adynamic bone disease and vascular calcification.
Calcium-based phosphate binders include calcium carbonate (TUMS, Os-Cal, Caltrate) and calcium acetate (Phoslo, Eliphos). Both of these binders have the potential to cause hypercalcemia and must be used with caution in patients with renal insufficiency with regular monitoring of serum calcium. Calcium acetate appears to be more effective than calcium carbonate.
Sevelamer chloride (Renagel) and sevelamer carbonate (Renvela) are non-calcium–containing anion exchange resins. Given concerns about metabolic acidosis, sevelamer carbonate is more commonly prescribed. Sevelamer and calcium-containing phosphate binders appear to have similar efficacy in lowering serum.
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.
Sucroferric oxyhydroxide (Velphoro) is a newer iron-based phosphate binder that has been compared to sevelamer and is considered to be non-inferior. It has a lower pill burden but a higher rate of GI adverse events causing patients to stop the medication. Ferric citrate (Auryxia) is another iron-based phosphate binder. It has been found to be as effective as calcium acetate and sevelamer in lowering phosphorus, and also has the added benefit of increasing iron levels.
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 at least every 6 hours during repletion. 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 phosphorus 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 although may complain of significant pruritis. 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, arrhythmias 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 one patient had progressed to end-stage renal disease, one 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, symptoms of 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 arrhythmias 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, as many foods are high in phosphorus and therefore implementation of a low phosphorus diet is key. Hyperphosphatemia in these patients is a chronic problem that requires continual management.
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.
Disorders of phosphorus metabolism
DRG E83.3 Disorders of phosphorus metabolism and phosphatases
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