Approach Considerations
The following measurements are indicated in patients with hyperphosphatemia:
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Serum phosphate level [42] : Reference range in adults, 2.5-4.5 mg/dL; reference range in children, 3-6 mg/dL; hemolysis or hyperlipidemia of the serum sample may lead to falsely elevated phosphorus levels
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Serum calcium level
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Electrolytes
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Blood urea nitrogen (BUN) and creatinine levels
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Serum magnesium level (may be low)
No specific procedures are indicated to evaluate hyperphosphatemia. Bone biopsy findings, however, may help in differentiating parathyroid bone disease and osteomalacia in patients with chronic or end-stage renal disease.
Full Chemistry Profile
Measures of serum calcium, magnesium, BUN, and creatinine are of critical importance. The levels of calcium and magnesium, for example, yield information on the status of all divalent ion metabolism.
Low serum calcium levels along with high phosphate levels are observed with renal failure, hypoparathyroidism, and pseudohypoparathyroidism. BUN and creatinine values help to determine whether renal failure is the cause of hyperphosphatemia. Patients with renal failure are also more likely to have elevated intact PTH levels. On the other hand, patients with hypoparathyroidism, either primary or acquired, will have relatively low levels of intact PTH and normal renal function.
High serum calcium and high phosphate levels are observed with vitamin D intoxication and milk-alkali syndrome. Patients with vitamin D intoxication should show relatively low levels of intact PTH and high 25 and 1,25 vitamin D. Patients with milk-alkali syndrome should show low levels of both PTH and vitamin D.
If renal function is normal, then more a unusual disorder, such as one of the following, may be the cause:
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Vitamin D intoxication
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Laxative (Phospho-soda) abuse
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Tumor lysis
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Rhabdomyolysis
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Isolated hypoparathyroidism
Urinalysis
Urine studies are rarely indicated, but if renal function is normal and PTH levels are high or normal, then a 24-hour urine measurement of cyclic adenosine monophosphate (cAMP) levels can be obtained. Patients with pseudohypoparathyroidism have abnormally low cAMP levels.
Note, however, that most cases of pseudohypoparathyroidism are diagnosed based on clinical grounds, ie, characteristic physical features of Albright hereditary osteodystrophy (eg, short phalanges, short stature, obesity, round face, mental retardation) accompanied by low calcium levels, high phosphate levels, and positive findings from the family history.
In a patient with hyperphosphatemia, the fractional renal excretion of phosphate should be well in excess of 15%. If not, this suggests that renal excretion is impaired either because of renal failure or hypoparathyroidism. If the fractional renal excretion exceeds 15%, this suggests either massive ingestion (eg, laxative [Phospho-soda] abuse) or lysis of tissue with release of intracellular phosphate.
Imaging Studies
Imaging studies are not generally indicated in the evaluation of hyperphosphatemia. If, however, renal failure is discovered, then renal imaging studies (eg, ultrasonography) are indicated.
If significant secondary hyperparathyroidism due to renal failure is found, then long-bone studies may help to assess for the presence of hyperparathyroid bone disease. Likewise, bone densitometry may be desirable for individuals in whom significant bone loss is suggested. Bone biopsy findings may be helpful to differentiate parathyroid bone disease and osteomalacia.
Evaluation of vascular calcification in coronary arteries and peripheral vasculature is being used increasingly, although it is still not in widespread use. Electron beam computed tomography (CT) scanning is the most commonly used modality for imaging and quantitation of coronary artery calcification. The presence of coronary artery and valvular calcification in patients with renal failure and in those on dialysis indicates a poor outcome in some studies. Some investigators suggest that these patients should take sevelamer and not calcium-containing phosphate binders for control of serum phosphorus.
Renal ultrasonography, bone studies, and coronary calcification studies yield data on the chronicity of the process and the patient's prognosis. Shrinkage of the kidneys due to renal failure; changes associated with hyperparathyroidism, based on bone survey results; and coronary calcification are highly suggestive of chronic processes.
Radiography is not necessary for the workup of hyperphosphatemia, but it may reveal evidence of metastatic calcifications (eg, bilateral, symmetrical calcifications of the basal ganglia; periarticular calcifications around large joints; soft tissue calcifications at pressure point areas).
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Approximately 60-70% of dietary phosphate, 1000-1500 mg/day, is absorbed in the small intestine. Although vitamin D can enhance the absorption, especially under conditions of dietary phosphate depletion, intestinal phosphate absorption does not require the presence of active vitamin D. 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 3-4 mg/dL in the serum.
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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 (PTH), FGF23, and dopamine. Phosphate absorption in the remainder of the nephron is generally mediated by type 3 sodium phosphate cotransporters. No direct evidence has been found related to the regulation of these transporters in renal cells under physiologic conditions. The absorption in the proximal tubule is regulated such that the final excretion matches the dietary excess in order to maintain homeostasis.
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Hyperphosphatemia inhibits 1-alpha hydroxylase in the proximal tubule directly and indirectly through stimulation of FGF23, thus inhibiting the conversion of 25-hydroxy vitamin D3 to the active metabolite, 1,25 dihydroxyvitamin D3. FGF23 additionally increases the expression of 24-hydroxylase, leading to inactivation of active 1,25 dihydroxyvitamin D3. The decrease in active vitamin D production with high phosphate 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.
