Phosphate Homeostasis

Derangements in the metabolism of phosphate are common in the intensive care unit (ICU) and can be clinically significant. Phosphate serves a number of crucial functions. It is an essential component of the main energy “currency” of the cell, adenosine triphosphate; it is a component of phospholipids in cell membranes; it is a component of hydroxyapatite, the structural matrix of bone; and it serves as a buffer against acid-base derangements.

An important distinction must be made between low serum phosphate concentration, referred to as hypophosphatemia, and low total body phosphorus stores, referred to as phosphate depletion. Serum phosphate may not reflect total body phosphorus stores because: (1) the vast majority of total body phosphorus is in the form of hydroxyapatite; (2) phosphate is primarily intracellular, and extracellular phosphate accounts for only a small fraction of total body phosphorus stores; and (3) shifts between the intracellular and extracellular compartments occur. There is no common laboratory test to accurately measure total body phosphate stores.

Phosphate homeostasis is a function of bone metabolism, intestinal absorption, and kidney resorption. Bone metabolism is linked to calcium homeostasis. In the setting of hypocalcemia, increased parathyroid hormone levels cause phosphate and calcium to be released from the bone. Intestinal absorption of phosphate occurs in the small bowel, primarily in the jejunum. Vitamin D, produced by the kidney in increased amounts when serum phosphate levels are low, increases the intestinal absorption of both calcium and phosphate. Phosphate in the circulation is filtered by the kidneys, but most of the phosphate in the glomerular filtrate undergoes resorption in the proximal tubule. Parathyroid hormone increases phosphate excretion by inhibiting phosphate resorption in the kidney; resorption increases in the setting of phosphate deficiency. Newer research on phosphate homeostasis has focused on fibroblast growth factor 23 and klotho, which may result in new therapeutics for phosphate imbalances.¹

Hypophosphatemia

Hypophosphatemia is typically classified as mild (serum phosphate concentration 2.5-3 mg/dL), moderate (1-2.5 mg/dL), or severe (<1 mg/dL). Although mild to moderate hypophosphatemia is often subclinical, severe hypophosphatemia can be associated with significant morbidity. All-cause mortality in patients with serum phosphate concentrations less than 1 mg/dL is as high as 30%.²

Common causes of hypophosphatemia are summarized in Table 15-1. Respiratory alkalosis (of any cause) can induce transcellular shifts of phosphate and cause hypophosphatemia. Renal losses of phosphate occur with osmotic diuresis or excessive diuretic therapy. Therapies instituted in the ICU, including overly aggressive renal replacement therapy³ and erythropoietin therapy,⁴ can increase the risk of hypophosphatemia. Hyperparathyroidism (either primary or secondary) causes hypophosphatemia by decreasing urinary resorption of phosphate. Proximal renal tubular disorders also impair phosphate resorption and cause hypophosphatemia. Total body phosphate depletion also occurs in extreme catabolic states such as burns or sepsis.

TABLE 15-1 Common Causes of Hypophosphatemia

Hypophosphatemia should be anticipated when nutritional support is initiated in chronically malnourished patients, such as those with a long history of alcohol abuse or elderly patients with oropharyngeal dysphagia,⁵ who may already have low phosphate levels and are in a catabolic state. A carbohydrate load administered in the setting of chronic malnutrition rapidly switches the body to anabolism and causes a spike in insulin release. High circulating insulin levels promote cellular uptake of phosphate and can induce a precipitous decrease in serum phosphate concentration. This phenomenon has been termed the refeeding syndrome.⁶ Profound hypophosphatemia in the refeeding syndrome can produce severe clinical manifestations including death. Concurrent hypokalemia and hypomagnesemia are common. In chronically malnourished patients, the refeeding syndrome can be avoided by cautiously ramping up nutritional support (especially administration of carbohydrates), careful monitoring of serum phosphorus levels, and appropriate phosphate supplementation when indicated.⁶

Patients with diabetic ketoacidosis often have phosphate depletion because hyperglycemia induces increased urinary losses of phosphate via osmotic diuresis. The serum phosphate concentration may be normal in the initial phase of therapy because severe acidosis causes a shift of phosphate into the extracellular space from the intracellular compartment. As acidosis is corrected, however, phosphate shifts back into the intracellular compartment, leading to a precipitous decrease in serum phosphate concentration.⁷ Although common, the clinical significance of moderate hypophosphatemia in diabetic ketoacidosis is unclear. Therapy for hypophosphatemia in diabetic ketoacidosis is typically warranted only if the serum phosphate level is less than 1.0 mg/dL or if hypophosphatemia is associated with clinical manifestations such as central nervous system (CNS) or left ventricular (LV) dysfunction.⁷

Clinical manifestations due to hypophosphatemia are rare unless the serum phosphate concentration is below 1 mg/dL. The clinical findings are summarized in Table 15-2. Diffuse skeletal muscle weakness can be profound. Respiratory failure secondary to diaphragmatic weakness can occur.^8–10 Respiratory failure can be primary, or it can manifest as inability to liberate the patient from mechanical ventilation. CNS dysfunction can include confusion, lethargy, and gait disturbances. Hematologic manifestations, including acute hemolytic anemia and leukocyte dysfunction (impaired phagocytosis and chemotaxis), have been reported. Cardiovascular manifestations can include acute LV dysfunction and development of reversible dilated cardiomyopathy that typically responds only to phosphate repletion. Rhabdomyolysis also can occur.¹¹

TABLE 15-2 Clinical Manifestations of Severe Hypophosphatemia

Hypophosphatemia also can cause disorders of oxygen transport. Profound hypophosphatemia can impair oxygen delivery to the tissues because of decreased production of 2,3-diphosphoglycerate, a key molecule found in erythrocytes that facilitates the release of oxygen from hemoglobin (hb). Decreased intracellular levels of 2,3-diphosphoglycerate cause a leftward shift of the oxyhemoglobin dissociation curve.

Because phosphate serves as a buffer against acid-base derangements, hypophosphatemia influences the interpretation of acid-base status. Phosphate and proteins (albumin) are measured anions. Unmeasured anions are accounted for in acid-base interpretation by calculation of the anion gap. Although there is no true “normal” value for the anion gap, the value is typically lower for a patient with low measurable anions (i.e., either hypophosphatemia or hypoalbuminemia, or both). Therefore, the presence of a “normal” value for the calculated anion gap in the setting of profound hypophosphatemia can actually represent the presence of unmeasured anions (i.e., the presence of a wide anion gap). As a rule, the expected anion gap (in mEq/L) equals twice the serum albumin concentration (in g/dL) plus half the serum phosphate concentration (in mM/L). Thus, a patient with hypophosphatemia and hypoalbuminemia can have significant levels of unmeasured anions even if the measured anion gap is less than the commonly used threshold of 10 to 12.

Severe hypophosphatemia (phosphate concentration <1 mg/dL) mandates intravenous (IV) phosphate replacement. Phosphate should not be administered by the IV route to patients with renal failure; it should also be avoided in patients with hypercalcemia, because metastatic calcification can occur. For moderate hypophosphatemia (phosphate concentration 1-2.5 mg/dL), oral supplementation is adequate for patients who are able to take medications by mouth or via an enteral feeding tube. It is impossible to accurately predict the exact amount of phosphate supplementation required to replenish phosphate stores because most phosphate is intracellular.

Hyperphosphatemia

Hyperphosphatemia is defined as a serum phosphate level above 4.5 mg/dL; it may be clinically significant at levels over 5 mg/dL. Causes of hyperphosphatemia are summarized in Table 15-3. The most common cause of hyperphosphatemia is renal failure. Renal insufficiency causes hyperphosphatemia because phosphate excretion by the kidneys is impaired; however, the serum phosphate level is usually normal until the creatinine clearance is less than 30 mL/min. Any insult causing extensive cell damage, including rhabdomyolysis, hemolysis, or tumor lysis syndrome,¹² can release phosphorus into the extracellular space. Hyperphosphatemia has been reported in patients using some bisphosphonate medications; the phosphate increase is due to decreased renal phosphate clearance.¹³ There are numerous reports in the literature about hyperphosphatemia in patients using phosphate-containing laxatives or bowel preparations.¹⁴

TABLE 15-3 Common Causes of Hyperphosphatemia

The most frequent clinical findings in acute hyperphosphatemia are signs and symptoms of hypocalcemia. Hyperphosphatemia produces hypocalcemia by three mechanisms: (1) precipitation of calcium (formation of calcium-phosphorus complexes), (2) interference with parathyroid hormone–mediated resorption of bone, and (3) decreased vitamin D levels.¹⁵ Clinical signs and symptoms of hypocalcemia such as muscle cramping, tetany, hyperreflexia, and seizures, as well as cardiovascular manifestations, can be evident.

Management of acute hyperphosphatemia includes limiting phosphate intake and enhancing urinary phosphate excretion. In the absence of end-stage renal disease, phosphate excretion can be optimized with saline infusion (volume diuresis) and diuretic administration. Diuretics that work in the proximal tubule (e.g., acetazolamide) are especially effective for enhancing phosphate excretion. Any patient with life-threatening hyperphosphatemia should be considered for dialysis.

Oral phosphate binders decrease the absorption of phosphate in the gut and are a mainstay for preventing and treating hyperphosphatemia in patients with chronic renal failure. Calcium and aluminum salts are widely used. However, calcium salts can produce hypercalcemia and metastatic calcification from a high calcium-phosphorus (Ca × PO₄) product, and aluminum salts can be toxic. For patients requiring renal replacement therapy, chronic management of hyperphosphatemia with calcium-free phosphate binders (e.g., sevelamer hydrochloride [Renagel]) may reduce long-term mortality by preventing cardiovascular complications associated with a high Ca × PO₄ product.¹⁶ It should be noted that these investigations have been observational in nature, and to date, data are lacking to convincingly show that normalization of phosphate in chronic hyperphosphatemia decreases morbidity of chronic kidney disease. Sevelamer is highly effective for increasing fecal elimination of phosphate without producing hypercalcemia or aluminum toxicity.¹⁷ In the acute management of patients with hyperphosphatemia accompanied by hypocalcemia, the likelihood (and clinical significance) of metastatic calcification with acute calcium administration is unclear.