Renal handling of phosphorus and magnesium.
Phosphorus and its Functions
Phosphorus is located primarily within body cells in combination with hydrogen and oxygen, as a major intracellular anion. It is found in the plasma and interstitial fluid in two forms at pH 7.4: the divalent or alkaline form, known as sodium monohydrogen phosphate (NaHP[O.sub.4.sup.--]), and the monovalent or acid form, sodium dihydrogen phosphate (Na[H.sub.2]P[O.sub.4.sup.-]), in a ratio of 4:1. Because of their ability to pick up and release hydrogen, both of these forms play important roles as acid-base buffers. In acidosis, Na[H.sub.2]P[O.sub.4.sup.-] shows a relative increase, while NaHP[O.sub.4.sup.--] decreases. The opposite occurs when the extracellular fluid becomes alkaline.
The total quantity of phosphate in the body includes both forms and is expressed in milligrams per deciliter of blood. In the plasma, phosphate ranges from 2.0-4.5 mg/dl in adults, with concentrations slightly higher in children. Approximately 5%-10% of plasma phosphate is protein-bound and is, therefore, not filterable at the renal glomerulus. Within the cells, phosphates are also found combined with lipids (phospholipids) as part or the lipid bilayer of the cell membrane, with nucleic acids in DNA and RNA, and as part of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and cyclic adenosine monophosphate (cAMP), providing the energy currency of the cell. Lastly, the major crystalline salt found in bone, hydroxyapatite, is composed of phosphate and calcium.
The effects of hypophosphatemia and hyperphosphatemia illustrate the importance of phosphate homeostasis. Hypophosphatemia produces consequences secondary to the red blood cells' reduced capacity for oxygen transport and to disturbed energy metabolism. Reduced levels of 2,3-diphosphoglycerate and ATP may lead to hypoxia, while the derangement in energy metabolism may lead to nerve and muscle dysfunction, as manifested by irritability, confusion, numbness, coma, convulsions, muscle weakness, and respiratory and cardiac failure. Alternatively, hyperphosphatemia may lower calcium levels because increased amounts of phosphate mad calcium are deposited in bone and soft tissues. Thus, symptoms of hyperphosphatemia are primarily those of hypocalcemia, such as confusion, muscle spasms, hyperreflexia, intestinal cramping, mad may progress to convulsions, tetany, and respiratory failure.
Phosphates are found in meats, cereals, and dairy products. When these foods are ingested, they are hydrolyzed in the gastrointestinal tract to form inorganic phosphate and are readily absorbed through the intestinal mucosa. Under normal conditions, the intestinal absorption of phosphate is unregulated in that the net absorption is directly proportional to the amount ingested.
The amount of phosphate released during bone resorption and taken up during bone formation depends primarily on the same mechanisms that govern calcium homeostasis. That is, when serum calcium level drops, bone is absorbed, releasing both phosphate and calcium into the extracellular fluids. When serum calcium level rises, bone is formed, withdrawing both phosphate and calcium from body fluids. Thus, neither the intestines nor the bone have a specific way to control phosphorus levels that are based on the body's needs. This is the role of the kidneys.
Renal Handling of Phosphorus
Phosphate is regulated within the normal range primarily by renal excretion. More than 90% of plasma phosphate is filterable at the glomerulus, and 70%-80% of this is reabsorbed by the proximal tubule, as shown in Figure 1. Under normal conditions, the renal tubules reabsorb phosphate at a maximum rate of about 0.1 mmol/min. When less phosphate is present in the glomerular filtrate, all of it is reabsorbed. When more is present, the excess is excreted. Because phosphate is not secreted by the tubules, its renal excretion may be described by the following equation:
Phosphate excreted = Phosphate filtered - Phosphate reabsorbed.
[FIGURE 1 OMITTED]
Accordingly, phosphate excretion may be altered by changing the amount filtered and/or the amount reabsorbed. Because the maximum amount of phosphorus that can be reabsorbed is close to the normal filtered amount, even relatively small increases in plasma phosphate concentration can produce relatively large increases in phosphate excretion. Thus, when plasma phosphate concentration increases due to an increase in phosphate intake, the amount filtered increases and the amount excreted increases.
Most of the filtered phosphate is actively reabsorbed in the proximal tubule in co-transport with sodium. Distal nephron segments have shown some capacity for reabsorbing additional phosphate, but that capacity is very limited and has been demonstrated only in the acute absence of parathyroid hormone (PTH) (such as post parathyroidectomy) or with severe dietary phosphate restriction.
The cellular mechanisms for phosphate reabsorption in the proximal tubule are shown in Figure 2. Phosphate enters the cells across the luminal membrane by way of type I and II sodium/phosphate ([Na.sup.+]/Pi) co-transporters. Type II co-transporters facilitate the majority of tubular phosphate reabsorption and are the main target for regulating phosphate by PTH and dietary phosphate content. Most of the phosphate enters the proximal tubule cell as divalent phosphate (NaHP[O.sub.4.sup.--]) along with two sodium ions and is, therefore, electroneutral. In contrast, the smaller transport volume of monovalent phosphate (Na[H.sub.2]P[O.sub.4.sup.-]) is electrogenic. A hallmark of these [Na.sup.+]/Pi co-transporter mechanisms is dependency on pH in that HP[O.sub.4.sup.--] (divalent) is reabsorbed at physiologic pH, while [H.sub.2]P[O.sub.4.sup.-] (monovalent) is only reabsorbed at low pH. Hydrogen in the luminal fluid alters this transport by inhibiting the sodium site and decreasing the availability of divalent phosphate. It is thought that basolateral phosphate exit is controlled so that intracellular phosphate concentration remains high enough to sustain cellular metabolism. Phosphate exit probably occurs via [Na.sup.+] co-transport and an anion-exchange mechanism, in addition to passive diffusion along its electrochemical gradient. The rate limiting event in phosphate reabsorption appears to be phosphate entry at the luminal membrane, which is determined by the number of phosphate co-transporters located in the luminal membrane and the intensity of the inward-directed sodium gradient. Mechanisms that modify existing transporters insert new co-transporters into the luminal membrane or delete existing co-transporters, change the number and velocity of phosphate co-transporters, and are thought to provide the physiological basis by which phosphate excretion is regulated.
[FIGURE 2 OMITTED]
Regulation of Phosphate Excretion
Two major factors regulate urinary phosphate excretion: dietary adaptation and PTH. Over time, a diet low in phosphate increases the amount of phosphate reabsorbed in the tubules; whereas a diet high in phosphate reduces the amount reabsorbed. Because dietary adaptation changes the velocity of phosphate transport, dietary-induced changes in reabsorption are likely to remove existing co-transporters or insert new co-transporters into the luminal membrane. For example, if co-transporters are removed due to a high phosphate diet, phosphate reabsorption decreases and excretion increases.
PTH also affects phosphate excretion. Increases or decreases in PTH due to changes in calcium concentration inhibit or stimulate tubular phosphate reabsorption, respectively. This phenomenon is explained if one remembers that in hypocalcemia, the parathyroid gland releases PTH, which induces bone resorption, thereby increasing blood levels of both calcium and phosphate. Similarly, hypocalcemia stimulates activation of Vitamin D3, which enhances the intestinal absorption of both calcium and phosphate. Therefore, through its adaptive mechanisms, low calcium produces a rise in plasma phosphate. The ability of PTH to inhibit phosphate reabsorption in the kidney prevents this rise, thus increasing phosphate excretion. The mechanism by which PTH does this is, however, unclear. It may stimulate a rapid endocytosis of type II [Na.sup.+]/Pi co-transporters on the luminal membrane, thereby decreasing reabsorption.
Urinary phosphate excretion is also affected by other hormonal and nonhormonal factors. Vitamin D increases excretion of phosphate, perhaps by enhancing the effects of PTH. The thyroid hormone thyroxine also increases phosphate reabsorption, probably by inserting new phosphate co-transporters into the luminal membrane. Other hormones that increase phosphate reabsorption and, thus, decrease excretion include: somatotropin (human growth hormone), serotonin, insulin, and norepinephrine. Dopamine inhibits reabsorption of phosphate, and controversy remains over whether or not glucocorticoids are similarly phosphaturic. Nonhormonal factors such as metabolic acidosis, respiratory acidosis, hypercapnia, and extracellular volume expansion also decrease reabsorption, thereby increasing excretion of phosphate. In contrast, phosphate excretion is decreased in respiratory alkalosis.
Magnesium and its Functions
Magnesium is the second most abundant and important intracellular cation. It is found mostly within bone (55%) and other intracellular fluids (44%). Only about 1% of the body's magnesium is found in plasma and other extracellular fluids. Plasma concentration is 1.8-2.5 mEq/L or 1.8-2.4 mg/dl, with about 20% of this bound to proteins.
Magnesium functions as a cofactor in many intracellular enzymatic reactions. It helps to regulate potassium and calcium cell membrane channels, is vital for protein synthesis, and also helps to fuel energy production in the mitochondria. While rare, hypomagnesemia increases neuromuscular excitability, producing symptoms such as behavioral changes, irritability, hyperreflexia, ventricular arrhythmias, muscle weakness, tetany, and convulsions. Excess magnesium depresses skeletal muscle contraction and nerve function producing nausea and vomiting, muscle weakness, hypotension, bradycardia, and respiratory depression.
Magnesium is ubiquitous in our diet, being abundant in green vegetables, seafood, grains, nuts, and meats. About 30%-40% of our dietary intake of magnesium is absorbed in the small intestine via saturable and passive transport processes. This absorption varies inversely with dietary intake and does not seem to be affected by Vitamin D or PTH. Magnesium concentrations in the intracellular and extracellular fluid are primarily regulated by the gastrointestinal tract, the kidney, and the bone, although these processes are not well understood.
Renal Handling of Magnesium
With a normal dietary intake of magnesium, urinary excretion averages 100-150 mg per day. This may decrease to 10 mg per day with dietary restriction or may increase to 600 mg per day in patients receiving magnesium-containing antacids. Thus, the kidney is very adept at conserving or excreting magnesium as necessary. Control of magnesium occurs primarily by filtration and tubular reabsorption, although the mechanisms involved are not yet well defined.
Seventy to 80% of the plasma magnesium is filterable; the remainder is bound to protein and is not filterable. As shown in Figure 1, 10%-25% of the filtered magnesium is reabsorbed along the length of the proximal tubule. In contrast to sodium and calcium, which are reabsorbed along the proximal tubule in equivalent concentrations to plasma, the ratio of the magnesium concentration (Mg) in tubule fluid relative to the plasma ultrafiltrate ([[TF/UF].sub.Mg]) rises as a function of water absorption along the length of the proximal tubule to a value as high as 2.0. This indicates that the proximal tubule is comparatively impermeable to magnesium. Although the orientation of the electrochemical gradient along most of the proximal tubule favors diffusion of magnesium from the lumen to blood through the paracellular pathway, this has not been demonstrated.
The thick ascending limb of the loop of Henle is the principle site of magnesium reabsorption, where 50%-65% of the filtered load is reabsorbed. Here, as depicted in Figure 3, sodium chloride transport is coupled to potassium, probably via an electroneutral [Na.sup.+]/2[Cl.sup.-]/[K.sup.+] co transport. The selective movement of potassium back across the luminal membrane and the preferential transfer of chloride across the basolateral membrane accounts for the lumen-positive voltage in the thick ascending limb. The lumen-positive voltage allows for magnesium to move passively between the cells (through the paracellular pathway).
The distal tubule and collecting duct have a very limited role in renal magnesium conservation, reabsorbing only about 5%-10% of the filtered load. This reabsorption appears to be load dependent, but again the cellular mechanisms involved are not well understood. There is some evidence that magnesium moves passively into the cell across the luminal membrane, driven by the transmembrane voltage difference (i.e., -10mV in the lumen vs. -70mV in the cell). Magnesium then leaves the cell against both electrical and concentration gradients, perhaps via [Na.sup.+]/[Mg.sup.+] exchange.
Regulation of Magnesium Excretion
The amount of magnesium excreted is primarily dependent on the amount reabsorbed. No single hormone appears to regulate urinary magnesium reabsorption directly. Rather, excretion varies according to many factors, such as those affecting reabsorption in the thick ascending limb, dietary magnesium intake, calcium concentration, pH balance, and certain hormones. Since transport in the thick ascending limb depends on sodium chloride transport and on the electrical potential, factors that alter these (e.g., loop diuretics such as furosemide) also alter magnesium reabsorption.
Excretion also varies with dietary magnesium intake. A high dietary intake decreases reabsorption in the proximal tubule and ascending limb markedly. In contrast, hypomagnesemia reduces reabsorption in the proximal tubule corresponding to the reduction in filtered load. At the same time, the reabsorption in the thick ascending limb is enhanced leading to excellent conservation of magnesium.
Hypercalcemia markedly increases magnesium excretion by reducing both magnesium and calcium reabsorprion in the thick ascending limb. In contrast, hypocalcemia decreases magnesium excretion. These effects of calcium are thought to be due to a [Ca.sup.++]/[Mg.sup.++]-sensing receptor located in glomeruli, proximal tubules, thick ascending limbs, and distal tubules. Binding of [Ca.sup.++] or [Mg.sup.++] to this sensor initiates intracellular signals that alter reabsorprion.
Metabolic acidosis is associated with increased magnesium excretion, and metabolic alkalosis is associated with decreased excretion, probably through changes in transport in the loop of Henle and distal tubule. In addition, a number of hormones, including PTH, calcitonin, and vasopressin, enhance magnesium reabsorption in the thick ascending limb and distal tubule, thereby decreasing excretion.
In contrast to renal homeostasis of calcium, much less is known about renal homeostasis of phosphate and especially of magnesium. New information about renal regulation of these elements is being discovered on a regular basis. Many genetic products associated with phosphorus reabsorption have been identified. Mutational alterations of these and other proteins are associated with familial hypo- and hyper-phosphatemias. Scientists are beginning to describe age-related reductions of co-transporter molecules that, coupled with new information on age-related changes in cholesterol (and concomitantly the membrane fluidity), may lead to better understanding of the changes in renal function that occur with age.
Drueke, T., & Lacour, B. (2000). Disorders of calcium, phosphate, and magnesium metabolism. In R.J. Johnson & J. Freehally (Eds.), Comprehensive clinical nephrology (pp. 3.11.1-3.11.16). London: Mosby.
Guyton, A.C. & Hall, J.E. (2000). Textbook of medical physiology (10th ed.). Philadelphia: W.B. Saunders.
Koeppen, B.M., & Stanton, B.A. (2003). Renal physiology (3rd ed.). St. Louis: Mosby, Inc.
Lote, C.J. (2000). Principles of renal physiology (4th ed.). Boston, MA: Klewer Academic Publishers.
Murer, H., Kaissling, B., Forster, I., & Biber, J. (2000). Cellular mechanisms in proximal tubular handling of phosphate. In, D.W. Seldin & G. Giebisch (Eds.), The kidney: Physiology and pathophysiology (pp. 1869-1884) (3rd ed.) (Vol. 2). Philadelphia: Lippincott.
Quamme, G.A., & Rouffignac, C. (2000). Renal magnesium handling. In D.W. Seldin & G. Giebisch (Eds.), The kidney: Physiology and pathophysiology (pp. 1711-1729) (3rd ed.) (Vol. 2). Philadelphia: Lippincott.
Silve, C., & Friedlander, G. (2000). Renal regulation of phosphate excretion. In D.W. Seldin & G. Giebisch (Eds.), The kidney: Physiology and pathophysiology (pp. 1885-1904) (3rd ed.) (Vol. 2). Philadelphia: Lippincott.
Renal Control of Phosphate and Magnesium
Carolyn Yucha, PhD, RN and Jennifer Dungan, MSN, RN, ARNP
Posttest--1.2 Contact Hours
(See posttest instructions on the answer form, on page 39.)
1. What percentage of the phosphate in plasma is filtered at the glomerulus?
2. You are assessing a patient in the intensive care unit. You note that your patient is confused with hyperreflexia. What electrolyte abnormalities would you expect to be treating?
A. Hypophosphatemia and hypercalcemia
B. Hypocalcemia and hyperphosphatemia
C. Hypomagnesemia and hypercalcemia
D. Hypophosphaemia and hypermagnesium
3. You are in the dialysis unit discussing Mr. Jones's latest lab results. His phosphorous is 8.0 mg/dl. Mr. Jones states, "I use to have better control of my phosphorus when I first started dialysis 6 months ago. Why has my phosphorus increased if my diet contains the same amount?" Your best explanation would be:
A. "When larger amounts of phosphate are ingested (in meats and dairy products), the intestine absorbs more phosphate."
B. "You have lost more of your residual kidney function since starting dialysis and the kidney is primarily responsible for regulating phosphorus levels in the body."
C. "You have bone disease and your high phosphorus is because of increased PTH."
D. "You are not taking your phosphate binders correctly."
4. Most of the filtered phosphate is reabsorbed in the
A. thick ascending limb, along with calcium.
B. thick ascending limb, along with bicarbonate.
C. proximal tubule, along with calcium.
D. proximal tubule, along with sodium.
5. Phosphate reabsorption in the proximal tubule is sped up by
A. decreased production of cyclic AMP in the luminal membrane.
B. insertion of transporters into the luminal membrane.
C. removal of transporters in the luminal membrane.
D. increased production of cyclic AMP in the luminal membrane.
6. As the serum calcium levels falls, PTH is secreted from the parathyroid gland. PTH
A. increases renal reabsorption of phosphate.
B. decreases renal excretion of phosphate.
C. induces bone resorption, increasing serum phosphate.
D. decreases phosphate through bone remodeling.
7. Most of the magnesium in the body is found in the
A. extracellular fluid.
8. Your patient with end stage renal disease is taking a magnesium containing binder to help control his phosphorus. You should assess the patient for what sign or symptom?
B. Muscle weakness
C. Premature ventricular contractions
D. Behavior change
9. Magnesium reabsorption in the thick ascending limb is driven by
B. concentration gradient.
C. lumen-negative voltage.
D. lumen-positive voltage.
10. You note on Mrs. Sing's labs that she has a low magnesium level. Based on this finding, the patient is most likely to have which of the following?
A. Hypocalcemia only
B. Hypocalcemia and use of loop diuretics only
C. Hypocalcemia, use of loop diuretics and metabolic acidosis only
D. Hypocalcemia, use of loop diuretics, metabolic acidosis, and hyperparthyrodism
Carolyn Yucha, PhD, RN, is Professor and Associate Dean for Research, University of Florida College of Nursing, Gainesville, FL.
Jennifer Dungan, MSN, RN, ARNP, is PhD Student, University of Florida College of Nursing Gainesville, FL.
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|Author:||Yucha, Carolyn; Dungan, Jennifer|
|Publication:||Nephrology Nursing Journal|
|Date:||Jan 1, 2004|
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