Hyperphosphatemia in Emergency Medicine
- Author: Leigh A Patterson, MD; Chief Editor: Erik D Schraga, MD more...
Background
Phosphorus is the sixth most abundant element in the human body. It is critical for bone mineralization, cellular structure, genetic coding, and energy metabolism. Many organic and inorganic forms exist. The adult body contains approximately 1000 g of phosphorus, of which 80-90% is in bone. An additional 10-14% is intracellular and the remaining 1% is extracellular.
The phosphorus in plasma is 12-17% protein bound. Free serum compounds represent much less than 1% of the total body phosphorus content. This fraction also varies with shifts between the intracellular and extracellular compartments. Thus, serum phosphorus levels may not reflect accurately the total body phosphorus content.
Levels are expressed in terms of serum phosphorus mass (mg/dL). One mg/dL of phosphorus is equal to 0.32 mmol of phosphate. The normal adult range is 2.5-4.5 mg/dL (0.81-1.45 mmol/L). Levels are 50% higher in infants and 30% higher in children because of growth hormone effects.
Hyperphosphatemia is considered significant when levels are greater than 5 mg/dL in adults or 7 mg/dL in children or adolescents.
Pathophysiology
Phosphorus homeostasis is normally maintained through several mechanisms. GI absorption must be matched by renal excretion, and cellular release is balanced by uptake in other tissues. Hormonal control is provided mainly by parathyroid hormone.
Hyperphosphatemia occurs when the phosphorus load (from GI absorption, exogenous administration, or cellular release) exceeds renal excretion and tissue uptake.
GI absorption
Phosphorus is present in nearly all foods, and GI absorption of dietary forms is very efficient. With low dietary intake, 80-90% is absorbed. When intake is greater than 10 mg/kg/d, 70% is absorbed. Normal daily dietary intake varies from 800-1500 mg.
Absorption mainly occurs in the jejunum, although some absorption occurs throughout the intestinal tract. A small amount of phosphorus is secreted into the GI tract.
Serum phosphorus levels
Serum phosphorus levels rise after a large meal. Antacids decrease absorption because calcium, aluminum, and magnesium bind phosphorus into insoluble complexes. Aluminum is the most efficient binder found in antacids.
Renal excretion and reabsorption
To maintain homeostasis, renal phosphorus excretion normally matches the amount of daily GI absorption. Excretion occurs in the proximal tubule and largely depends on the filtered phosphorus load. As the filtered load increases, a higher fraction of excreted phosphorus is reabsorbed.
Reabsorption also depends on concurrent sodium transport. However, although sodium that is not reabsorbed at the proximal tubule may be reabsorbed distally, this is not true for phosphorus. Proximal diuretics, which decrease sodium reabsorption, also increase phosphorus excretion. The usual load excreted is 5-15% of the filtered load or 600-800 mg/d in the normal net steady state. This amount may markedly increase in hyperphosphatemia. Marked hyperphosphatemia is unusual in chronic renal insufficiency unless the glomerular filtration rate (GFR) is less than 25 mL/min. Secretion plays an insignificant role in renal phosphorus excretion.
Hyperphosphatemia occurs most often in patients with renal insufficiency. Most patients with acute or chronic renal failure have hyperphosphatemia to some degree. To avoid hyperphosphatemia, patients with end-stage renal disease and a GFR of less than 30 must restrict their intake of dietary phosphorus.[1] If dietary restriction alone does not reduce serum phosphate levels into the reference range, oral phosphate binders should be added to reduce absorption.
Illustrations of phosphate homeostasis and renal regulation of phosphate are depicted in the images below.
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. 
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. Sequelae of hyperphosphatemia
Hyperphosphatemia causes hypocalcemia by precipitating calcium, decreasing vitamin D production, and interfering with parathyroid hormone-mediated bone resorption. Severe life-threatening hypocalcemia may result. Signs and symptoms of acute hyperphosphatemia are due to the effects of hypocalcemia.
Prolonged hyperphosphatemia promotes metastatic calcification, an abnormal deposition of calcium phosphate in previously healthy connective tissues such as cardiac valves and in solid organs such as muscles. The calcium-phosphate product predicts the risk of metastatic calcification.
Excess free serum phosphorus is taken up into vascular smooth muscle via a sodium-phosphate cotransporter. The increased cellular phosphate activates a gene, cbfa-1, that promotes calcium deposition in the vascular cell, making smooth muscle cells engage in osteogenesis. Vascular walls become calcified and arteriosclerotic, leading to increased systolic blood pressure, widened pulse pressure, and subsequent left ventricular hypertrophy.
Hyperphosphatemia is an independent risk factor contributing to the increased incidence of aortic and mitral stenosis and other cardiovascular disease among patients who are dependent on dialysis. A peripheral form known as calcific uremic arteriolopathy (calciphylaxis) can induce necrotic ulceration and gangrene in affected extremities.
Hyperphosphatemia-induced resistance to parathyroid hormone contributes to secondary hyperparathyroidism and renal osteodystrophy.[2]
An image depicting the body's defense against hyperphosphatemia is 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 increases 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. Epidemiology
Frequency
United States
Patients with end-stage renal disease make up the bulk of patients with hyperphosphatemia. Approximately 250,000 persons are affected.
Mortality/Morbidity
Prolonged hyperphosphatemia is an independent risk factor for cardiovascular disease in patients with renal failure. Patients with chronic phosphate levels above 6.5 have an 18-39% higher mortality compared with patients with renal failure with near-normal serum phosphate levels.
Sex
Although women have physiologic elevation of serum phosphate levels after menopause, this has no known clinical significance.
Age
Phosphorus levels are naturally higher in infants, children, and postmenopausal women. A phosphate-driven rise of erythrocyte 2,3-diphosphoglycerate and ATP in children may account for the physiologic anemia of childhood.
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