Who is at risk for hyperphosphatemia?

Hyperphosphatemia

Serum phosphate levels are controlled primarily by the rate of proximal renal tubular phosphate reabsorption, which is due, in turn, to the integrated activity of the major sodium-dependent cotransporters (NaPi-IIa and NaPi-IIc). The latter are strongly downregulated by parathyroid hormone and FGF23, both of which are stimulated by phosphate. Thus absent extraordinary filtered loads of phosphate, the capacity of normal kidneys to excrete phosphate is not easily exceeded. Consequently, the occurrence of hyperphosphatemia usually signifies impaired renal functon, hypoparathyroidism, defective FGF23 action, a huge flux of phosphate into the extracellular fluid, or some combination of these factors (Table 29.7).

The most common cause of hyperphosphatemia is acute or chronic renal failure in which GFR is so reduced that the usual daily load of phosphate cannot be excreted at a normal level of serum phosphate, despite maximal inhibition of phosphate reabsorption in the remaining functional nephrons. In hypoparathyroidism (or PHP), serum phosphate may rise to levels as high as 6 to 8 mg/dL because of loss of the tonic inhibitory effect of PTH on phosphate reabsorption, although elevated FGF23 levels may prevent even further increases in serum phosphate.572 The hyperphosphatemia of hypoparathyroidism is only partly due to the absence of PTH per se. Hypocalcemia may further impair phosphate clearance in this setting, and correction of hypocalcemia by treatment with vitamin D metabolites and oral calcium may reduce serum phosphate, for example, even though PTH levels remain low.573

Other circumstances in which renal tubular phosphate excretion is decreased, in the absence of renal failure, include acromegaly,574 chronic therapy with heparin, and familial tumoral calcinosis.575 Familial tumoral calcinosis can result from inactivating mutations in either FGF23 or theO-linked glycosyl transferase GalNAc-T3, which glycosylates FGF23 at its cleavage site targeted by furin-like proteases, thereby suppressing this cleavage.576 In the absence of GalNAc-T3, FGF23 is cleaved at an accelerated rate.577–579 The choice of FGF23 assay is important therefore for diagnosing tumoral calcinosis. The responsible FGF23 and GalNac-T3 mutations may render the molecule more susceptible to proteolyic degradation, such that the blood levels of (inactive) carboxyl fragments may be quite high in contrast to low levels of (bioactive) intact FGF23.578 Affected patients may display focal hyperostosis; large, lobulated periarticular ectopic calcifications, especially around shoulders or hips; hyperphosphatemia due to increased renal tubular reabsorption of phosphate; increased serum 1,25(OH)2D despite normal or low serum PTH; and increased intestinal calcium absorption, consistent with the elevated serum 1,25(OH)2D concentration. The disorder may present in childhood or adulthood, is more common in African Americans, and is lifelong, with a tendency for the tumoral calcifications to progress at affected sites. In contrast to the elevated serum 1,25(OH)2D, hyperphosphatemia is not a constant feature of tumoral calcinosis, although it tends to be most severe in those with prominent calcifications. Despite their chronic hyperphosphatemia, secondary hyperparathyroidism does not develop in these patients, presumably because of the high 1,25(OH)2D levels and intestinal hyperabsorption of calcium. Treatment is problematic, although some success has been reported with phosphate-binding antacids, calcium deprivation, calcitonin, and acetazolamide therapy.580

Causes of Hyperphosphatemia

There are a number of causes of hyperphosphatemia. For example, hereditary or acquired hypoparathyroidism, in which circulating levels of PTH are low or absent, results in the development of hyperphosphatemia, most likely due to increased renal reabsorption of phosphate. Elevated levels of growth hormone, as seen in acromegaly, are also associated with elevated plasma phosphate levels due to increased renal absorption. Other causes of hyperphosphatemia include the release of phosphate from the large intracellular pool as a result of cell injury or cell death as occurs in tumor lysis syndrome or rhabdomyolysis.

However, perhaps the most common cause of chronic hyperphosphatemia, and the one with the most dire consequences for the patient, is that associated with chronic renal disease. When renal function is compromised either experimentally or by disease, there is a compensatory enlargement of the remaining nephrons and an increased rate of filtration per nephron. To remain in balance, the phosphate excretion per nephron must also increase. Increased levels of PTH appear to mediate the increased excretion of phosphate per nephron in early renal disease. Thus, normal plasma phosphate levels are maintained, but at the expense of elevated PTH levels. As renal function progressively declines, increasingly higher levels of PTH are needed to maintain phosphate homeostasis. In advanced stages of renal disease in which the kidney's excretory function is markedly reduced, the elevated levels of PTH are unable to maintain normal phosphate levels and hyperphosphatemia becomes evident. The consequences of hyperphosphatemia are numerous, with the most important being the development of secondary hyperparathyroidism, uremic bone disease, and the promotion of vascular and visceral calcifications (Fig. 1).

Secondary hyperparathyroidism is a common complication in renal failure patients. Hyperphosphatemia contributes to elevated levels of PTH by at least three mechanisms. First, phosphate by itself appears to increase PTH synthesis by the parathyroid gland by posttranslational mechanisms. Second, high levels of plasma phosphate can lead to the precipitation of calcium phosphate in soft tissues, resulting in a decrease in plasma calcium, which is a major signal for PTH release. Finally, vitamin D3 is a major inhibitor of PTH gene transcription and also promotes intestinal calcium absorption. The kidney is the major source of the enzyme 1α-hydroxylase, which is responsible for converting 25(OH)-vitamin D to the active form, 1,25(OH)2-vitamin D3. Not only is 1α-hydroxylase activity deceased in renal disease because of the reduction in renal mass, but high levels of phosphate can also inhibit the enzyme activity. Therefore, hyperphosphatemia, either directly or indirectly, can attenuate major negative feedback mechanisms aimed at reducing circulating PTH. Furthermore, with low levels of vitamin D3, intestinal calcium absorption is impaired, and this can also contribute to the hypocalcemia. All of these abnormalities related to phosphate, calcium, PTH, and vitamin D3 metabolism in chronic renal disease patients result in nearly all such patients having some degree of abnormal bone metabolism, generally known as uremic bone disease or renal osteodystrophy.

As mentioned previously, high levels of plasma phosphate can complex with calcium, resulting in the deposition of calcium–phosphate crystals in soft tissues. Recent attention has been directed toward the consequences of soft tissue calcification. It is now clear that hyperphosphatemia and an elevated calcium–phosphorus product (Ca × P) can promote visceral and vascular calcification and are linked to increased cardiovascular mortality. Cardiovascular disease accounts for nearly 50% of all deaths in dialysis patients, a percentage that is markedly higher than that in the general population. A recent analysis of dialysis patients revealed that the relative risk of death increased in proportion to elevations in the Ca × P product. In another study of dialysis patients, the prevalences of mitral and aortic valve calcification were markedly higher (44.5 and 54.0%, respectively) than those in the control populations (10.0 and 4.3%, respectively). There is also evidence that elevated PTH levels may contribute to cardiovascular morbidity and mortality through their effects on arteriolar wall thickening and myocardial interstitial fibrosis. All of these recent findings have led to recommendations for the tighter control of plasma phosphate, calcium, and PTH levels in patients with chronic renal disease, especially in the dialysis population.

Hypocalcemia Associated With Hyperphosphatemia

CKD leads to diminished calcitriol production and subsequently a low-normal SCa. In parallel, declining glomerular filtration of phosphate leads to a progressive rise in serum phosphate once the glomerular filtration rate (GFR) falls below approximately 35 ml/min/1.73 m2. AKI may cause hypocalcemia and hyperphosphatemia through the same mechanisms, as well as specific mechanisms in rhabdomyolysis or pancreatitis.

Hypoparathyroidism may be caused by surgical removal of the parathyroid glands (post-thyroidectomy or parathyroidectomy), radiation, autoimmune destruction of parathyroid tissue, or infiltrative diseases. Sporadic cases of hypoparathyroidism are occasionally seen in patients with pernicious anemia or adrenal insufficiency. Pseudohypoparathyroidism (Albright hereditary osteodystrophy) has a characteristic phenotype including short neck, round face, and short metacarpals, with end-organ resistance to PTH.

In addition, massive oral phosphate administration, such as that used in bowel preparations, also can lead to hypocalcemia with hyperphosphatemia, often with AKI.22

Treatment

Hyperphosphatemia is best managed by treating the underlying disorder (i.e., administering intravenous fluids for rhabdomyolysis). No treatment is usually needed in the setting of normal renal function as hyperphosphatemia is self-resolving. Limiting dietary phosphate intake (by reducing protein intake) and blocking intestinal phosphate absorption with phosphate binders is indicated in mild persistent asymptomatic hyperphosphatemia in the setting of mild to moderate renal failure. Common oral phosphate binders include calcium carbonate, calcium acetate, and sevelamer (Moe, 2008). Hemodialysis may be required for severe hyperphosphatemia with symptomatic hypocalcemia (Shiber and Mattu, 2002).

Hyperphosphatemia

As discussed earlier in this chapter, the normal range for serum phosphate changes with age, and hyperphosphatemia thus refers to a serum concentration above the age-appropriate reference range. The clinical features of hyperphosphatemia are related to hypocalcemia. In view of the reverse interrelationship between these divalent ions, a high serum phosphate concentration is chemically linked to a low serum ionized calcium concentration, and vice versa. Thus, hyperphosphatemia becomes symptomatic from the hypocalcemia (e.g., tetany and other symptoms, discussed earlier in the section on hypocalcemia).Table 73.18 lists the causes of hyperphosphatemia.

Hyperphosphatemia

Hyperphosphatemia can result from increased intestinal absorption, from cellular release or rapid shifts of phosphorus from the intracellular to the extracellular compartment, or from decreased renal excretion. Persistent hyperphosphatemia (>12 hours) occurs almost exclusively in the setting of impaired kidney function. Increased intestinal absorption is usually caused either by the use of phosphate-containing oral purgatives or enemas, or by vitamin D overdoses. Increased tissue release of phosphorus is commonly seen in acute tumor lysis syndrome, rhabdomyolysis, hemolysis, hyperthermia, profound catabolic stress, or acute leukemia. These disorders can also lead to acute kidney injury, limiting renal phosphate excretion and further exacerbating the hyperphosphatemia. Rarely, thyrotoxicosis or acromegaly leads to hyperphosphatemia. Acute hyperphosphatemia usually does not cause symptoms unless there is a significant reciprocal reduction of serum calcium. The treatment of acute hyperphosphatemia includes volume expansion, dialysis, and administration of phosphate binders. In the setting of normal kidney function, or even mild to moderate kidney disease, hyperphosphatemia is usually self limited because of the capacity of the kidney to excrete a phosphorus load. Sequelae and treatment of hyperphosphatemia related to CKD, including bone disease and cardiovascular disease, is discussed in detail in Chapter 56.

Causes of Hyperphosphatemia

Hyperphosphatemia may be caused by (1) redistribution of phosphorus from the intracellular to the extracellular space, (2) increased phosphorus intake, and (3) decreased renal excretion of phosphorus (Table 58-8). Importantly, most hyperphosphatemia is multifactorial.

Hyperphosphatemia

Pathogenesis

Hyperphosphatemia occurs when the phosphate load exceeds renal excretion and tissue uptake; patients at highest risk for hyperphosphatemia are those with preexisting chronic or superimposed acute renal failure.

Hyperphosphatemia can be related to an increase in endogenous sources (because of either cell lysis or a shift from the intracellular to the extracellular compartment), to increased exogenous sources, or to reduced urinary excretion (Table 100-4).

The emergency physician must be aware of the pre-sence of pseudohyperphosphatemia, which can be due to interference with biochemical assay results in patients with hyperglobulinemia, extreme hypertriglyceridemia, or hyperbilirubinemia, or because of in vitro hemolysis.27

12 INGESTION AND/OR ADMINISTRATION OF SALTS CONTAINING PHOSPHATE

Hyperphosphatemia has been observed in adults ingesting laxative-containing phosphate salts or after administration of enemas containing large amounts of phosphate.208,209 Intravenous phosphate administration has been used in the treatment of hypercalcemia of malignancy. The administration of 1 to 2 g of phosphate intravenously decreases the concentration of serum calcium. Unfortunately, the severe hyperphosphatemia induced by administration of large amounts of phosphorus intravenously may lead to calcium precipitation in important organs such as the heart and kidney, and several deaths have been reported as a consequence of this form of therapy. Hyperphosphatemia may develop in newborn infants fed cow’s milk, which is higher in phosphorus content than human milk. This may be an important factor in the genesis of neonatal tetany.