Introduction
Symptoms of phosphate depletion have been described through the years, from the times of the ancient Romans to observations by veterinarians on livestock. Phosphate compounds are in all cells and participate in numerous biochemical processes. Phosphate is a component of DNA and RNA, phospholipids, high-energy compounds such as ATP and creatine phosphate, and many coenzymes.
When both phosphate depletion and hypophosphatemia are present, serious biochemical abnormalities often result: impaired myocardial function, respiratory muscle paralysis, central nervous system disorders, and skeletal muscle degradation ( , ) . These may result from hypophosphatemia inhibiting mitochondrial respiration and ATP synthesis, processes that are vital to cellular survival. Furthermore, insulin resistance may be a consequence of hypophosphatemia ( ) .
More recently, several Na-coupled PO 4 transport proteins, called cotransporters, have been described that are key factors in PO 4 regulation. These cotransporters have been designated as Type 1, Type 2 (Npt2a, Npt2b, and Npt2c), and Type 3 cotransporters (PiT1 and PiT2) ( ) .
Distribution in cells and blood
About 80% of phosphate is in bone, mostly in the form of hydroxyapatite [Ca 10 (PO 4 ) 6 (OH) 2 ]. Phosphate in blood is either absorbed from dietary sources or resorbed from the bone. Most phosphate in the body outside of the bones is within cells, where the intracellular PO 4 concentration is about 100 mmol/L, most of which is either bound or complexed to proteins or lipids ( ) .
The total concentration of phosphate in the blood is ∼3.9 mmol/L (∼12 mg/dL), with most as organic phosphates. The concentration of inorganic PO 4 is about 1.0–1.3 mmol/L (3–4 mg/dL), all of which is completely ionized, circulating primarily as hydrogen phosphate HPO 4 −2 or dihydrogen phosphate H 2 PO 4 − in a ratio of 4:1 at plasma pH of 7.40 ( , ) .
Physiology and regulation
Cellular transport
Although cellular shifts of phosphate can affect phosphate concentrations in the blood and ECF, absorption from the intestine and excretion by the kidney are the dominant homeostatic mechanisms. Because absorption by the intestine fluctuates widely, the kidney is responsible for the precise regulation of phosphate concentrations in the blood ( ) .
Cotransporters are carrier proteins that are essential in PO 4 regulation. Cotransporters simultaneously transport two different molecules or ions from one side of the membrane to the other, amazingly at a rate of several thousand molecules per second. By using a favorable electrical or concentration gradient to transport one ion across a membrane, another ion may be transported against its concentration gradient. Because the intracellular concentration of phosphate is greater than the extracellular concentration, phosphate entry into cells requires a facilitated transport process. An example is the transport of a Na ion from high to low concentration provides the energy to transport a PO 4 ion intracellularly against a concentration gradient.
Several Na-coupled transport proteins enable intracellular uptake of PO 4 by taking advantage of the steep extracellular-to-intracellular Na gradient ( ) . The actions of these cotransporters in the nephron are shown in Fig. 7.1 .
Type 1 Na/PO 4 cotransporters are expressed predominantly in kidney proximal tubule cells, although their role in phosphate homeostasis is not clear.
Type 2a cotransporters (Npt2a) in the kidney proximal convoluted tubules (PCTs) are responsible for absorbing most of the filtered phosphate. To maintain PO 4 homeostasis, their expression is increased when PO 4 is needed and their expression is decreased by high dietary phosphate intake, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and dopamine.
Type 2b cotransporters (Npt2b) are similar to type 2a transporters, are expressed in the small intestine, and are also upregulated under conditions of dietary phosphate deprivation.
Type 2c Na/PO 4 cotransporters (Npt2c), together with Type 2a transporters, are essential for normal phosphate homeostasis, and are also regulated by diet and PTH. Loss of type 2c function can result in hypophosphatemic rickets ( ) .
Type 3 Na/PO 4 cotransporters (PiT1 and PiT2) are in almost all cells and presumably play a housekeeping role in ensuring adequate phosphate for all cells.
Serum levels of phosphate are affected by intestinal PO 4 absorption mediated by the Npt2b cotransporter. Npt2b is regulated by both dietary phosphate intake and 1,25(OH) 2 vitamin D, with most intestinal phosphate reabsorbed in the duodenum and the jejunum.
Maintenance of normal serum phosphorus levels is closely regulated by PO 4 reabsorption within the nephron, where approximately 85% of phosphate is reabsorbed within the proximal tubule. The remainder of the nephron plays a minor role in PO 4 regulation ( ) .
Within the PCT, PO 4 transport from the ultrafiltrate across the proximal tubule epithelium is an energy-dependent process that utilizes three Na/PO 4 cotransporters, Npt2a, Npt2c, and PiT-2 located in the PCT cells. Electrical potentials generated from the transport of Na ions facilitate the movement of PO 4 ions from the proximal tubular filtrate into the cells. The amount of PO 4 reabsorbed from the filtrate is determined by the number of these cotransporters expressed in the PCT cells and not by alterations in their ability to transport PO 4 .
Factors that affect renal absorption of PO 4
Several factors that affect PO 4 absorption in the kidney are listed in Table 7.1 .
| Factors that increase PO 4 absorption | Factors that decrease PO 4 absorption |
|---|---|
| Dietary deficiency of PO 4 | Parathyroid hormone |
| 1,25 (OH) 2 -Vitamin D | Fibroblast growth factor (FGF23) |
| Thyroid hormone (T3) | Dietary excess of PO 4 |
| Metabolic alkalosis | Metabolic acidosis |
| Glucocorticoids | |
| Dopamine | |
| Estrogens | |
| Hypertension |
Parathyroid hormone (PTH) . PTH decreases renal reabsorption of phosphate by decreasing the abundance of the Na/PO 4 cotransporters Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane. In response to PTH, the abundance of Npt2a cotransporters is diminished within minutes, whereas the decrease in the number of apical membrane Npt2c and PiT-2 cotransporters takes hours ( ) .
While PTH is primarily involved in the regulation of plasma calcium concentrations, PTH also acts on phosphate. As PTH concentrations increase, the bone releases calcium and phosphate-containing minerals into circulation. Because PTH increases renal tubular reabsorption of calcium and decreases phosphate reabsorption in the proximal tubules, the net effect is that PTH decreases serum phosphate concentrations. PTH also promotes formation in the kidneys of 1,25-dihydroxycholecalciferol (calcitriol), which enhances absorption of calcium and phosphate in the GI tract ( ) . The actions of these hormones and cotransporters in the nephron are shown in Fig. 7.1 .
Fibroblast growth factor-23 (FGF23) . FGF23, produced in osteoblasts in response to increases in serum PO 4 , has several hypophosphatemic actions. FGF23:
- •
Reduces the number of Na/PO 4 cotransporters in the renal proximal tubule,
- •
Reduces serum levels of calcitriol by decreasing the renal expression of 1α-hydroxylase, which is the rate-limiting step in calcitriol synthesis.
- •
Increases renal expression of 24-hydroxylase, which minimizes calcitriol production.
- •
Suppresses PTH synthesis in healthy kidneys ( ) .
Calcitriol (1,25(OH) 2 -vit D) . In response to hypophosphatemia, 25-hydroxycholecalciferol is converted by 1α-hydroxylase to 1,25-dihydroxycholecalciferol (calcitriol), which increases PO 4 reabsorption in the proximal. Calcitriol also regulates its own homeostasis by simultaneously suppressing 1α-hydroxylase and activating 24-hydroxylase, which makes inactive vitamin D ( ) . Calcitriol also regulates the Npt2b cotransporter in the intestine, and it increases the activity of the osteoblasts to lay down calcium into the bone matrix ( ) .
Glucocorticoids . Glucocorticoids decrease phosphate reabsorption by decreasing proximal tubule synthesis of Npt2a in membranes of the proximal tubules ( ) .
Estrogens . Estrogen causes phosphaturia by decreasing the number of Npt2a cotransporters in the proximal tubule. Estrogen also increases FGF23 synthesis ( ) .
Thyroid hormone . Thyroid hormone increases phosphate absorption by increasing proximal tubule expression of Npt2a. Npt2a gene transcription of mRNA is regulated by triiodothyronine ( ) .
Acid–base disorders . Metabolic acidosis stimulates phosphaturia by inhibiting Na/PO 4 cotransporter activity. Metabolic alkalosis increases renal phosphate absorption, possibly by increasing the abundance of Npt2a and Npt2c ( ) .
Hypophosphatemia
Causes of hypophosphatemia
The incidence of hypophosphatemia in hospitalized patients varies greatly, depending on the population studied ( , ) . For example, hypophosphatemia may occur in 1% of general patients upon admission. The percentage increases with length of stay, critical illness, and alcoholism.
Hypophosphatemia is commonly caused by transcellular shifts of phosphate, GI malabsorption, or renal loss. Dietary deficiency is rarely a cause of hypophosphatemia, both because PO 4 is present in most foods and because the intestines are highly efficient in absorbing PO 4 ( ) .
The mechanisms of hypophosphatemia are described as follows:
Transcellular shifts . Because the movement of glucose into cells is accompanied by phosphate, the administration of glucose or insulin will lead to an influx of phosphate into cells that may cause hypophosphatemia. Respiratory alkalosis also causes hypophosphatemia because CO 2 loss increases pH, which stimulates glycolysis which enhances phosphate uptake by cells ( ) .
Gl losses . As with many electrolyte disorders, diarrhea and vomiting can diminish GI absorption of phosphate. Because the divalent cations in antacids such as aluminum hydroxide, magnesium hydroxide, or aluminum carbonate bind phosphate and prevent its absorption in the gut, hypophosphatemia often results from chronic excessive use of such antacids ( ). These conditions are made worse if patients have vitamin D deficiency.
Renal losses . Renal loss of PO 4 is most commonly related to the use of diuretics. Other causes include primary hyperparathyroidism, hypomagnesemia, and defects in vitamin D metabolism ( ) .
Other causes . Hypophosphatemia can be caused by a mix of factors:
- •
In diabetic ketoacidosis, the combined effects of acidosis, glycosuria, ketonuria, and insulin therapy deplete PO 4 , both by renal loss and cellular uptake. Serum concentrations may decrease rapidly.
- •
Alcoholism leads to hypophosphatemia by increasing renal loss and decreasing GI absorption of PO 4 .
- •
During recovery from thermal burns, PO 4 is secreted into renal tubules, where it is lost in the urine.
- •
Cytokines have been associated with intracellular PO 4 shifts, which may be responsible for hypophosphatemia in trauma, burns, and sepsis ( , ) .
- •
Symptoms of hypophosphatemia
Severe hypophosphatemia usually results in decreased concentrations of phosphate-containing compounds, such as ATP and membrane phospholipids. These deficiencies are responsible for symptoms of hypophosphatemia, such as muscle weakness, seizures, respiratory and myocardial insufficiency, and hepatocellular damage ( , ) .
Hypophosphatemic patients have a marked increase in urinary calcium and magnesium excretion, caused by both increased bone loss and altered renal tubular handling of these ions. Phosphate depletion also suppresses PTH secretion, which further enhances the urinary loss of Mg and Ca ions.
Moderate hypophosphatemia can lead to weakness of pulmonary muscles ( , ) and can prolong the weaning of patients from a ventilator. These effects are usually reversed by phosphate repletion.
More severe hypophosphatemia is associated with life-threatening seizures, coma, and dysfunction of respiratory and myocardial muscles. Other undesirable cardiovascular effects include impaired mitochondrial oxygen consumption and decreased sensitivity to inotropic agents, such as epinephrine ( ) .
Phosphate depletion causes a reduction in 2,3-DPG in erythrocytes, which increases the affinity of Hb for oxygen. This can reduce oxygen release to tissues by 10%–15% in severe hypophosphatemia ( ) . If hypophosphatemia occurs suddenly, it can cause hemolysis.
Phosphate depletion causes a rapid breakdown of the bone matrix, even more so than that caused by either severe hypocalcemia or vitamin D depletion. These effects appear to be independent of vitamin D or PTH ( ) .
Evaluation of hypophosphatemia
When hypophosphatemia is confirmed, the sequence of laboratory tests that may be helpful is shown in Fig. 7.2 , and the interpretation of labortory test results in renal and non-renal causes of hypophosphatemia is shown in Table 7.2 .
| PO 4 | Ca | ALP | PTH | 1,25 vit D | Urine PO 4 or FeP | |
|---|---|---|---|---|---|---|
| Renal cause | ||||||
| Hyperparathyroidism | Dec | Inc | N-Inc | Inc | Inc | Inc |
| Rickets (HHRH) | Dec | N | Inc | Dec | Inc | Inc |
| Diuretics | Dec | N-Inc | N | N | N | Inc |
| Post liver Txp | Dec | N | N-Inc | N | N | Inc |
| Fanconi syndrome | Dec | N-Dec | N-Inc | N-Inc | N-Dec | Inc |
| Genetic cause: XLH, ADHR. TIO, postrenal Txp | Dec | N | Inc | N-Inc | N-Dec | Inc |
| Nonrenal cause | ||||||
| GI loss or dietary deficiency | Dec | N-Dec | N-Inc | N-Inc | – | Dec |
| Oral PO 4 binders in CKD | Dec | N-Inc | N-Inc | N | Inc | Dec |
| Intracellular uptake: insulin, alkalosis, refeeding; cytokines (sepsis) | Dec | N | N | N | – | Dec |
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