Renal homeostasis of calcium.
Functions and Forms of Calcium
Calcium is a necessary ion for many metabolic processes. Due to its structural features, which make it well suited for its diverse biological roles, calcium can be rapidly bound and released from many different proteins. This enhances calcium's ability to regulate ion channels mad promote activation of enzymes. It is the major cation within the structure of bone and teeth. The following processes depend on calcium:
Neuromuscular excitability. Normal membrane excitability depends on a consistent calcium level. When extracellular calcium falls, membrane permeability increases nonselectively. This increase in permeability increases neuromuscular excitability. If left unchecked, a decreasing serum calcium level will result in spontaneous muscle contractions (tetany). On the other hand, hypercalcemia has the opposite effect and may lead to decreased neuromuscular activity, cardiac arrhythmias, lethargy, muscle weakness, and disorientation.
Secretion. Calcium is essential for secretion of many hormones and neurotransmitters. When serum calcium levels drop, both hormone and neurotransmitter secretion is impaired. Enzymes activated by calcium binding regulate critical intracellular functions such as DNA formation, glycogen metabolism, actin/myosin muscular filament contraction, and mitosis.
Alveolar surfactant. In the setting of reduced calcium, surfactant spreads so slowly that its role in reducing alveolar surface tension is impaired.
Coagulation. Calcium is required for blood clotting to occur. It promotes several reactions along the coagulation cascade, most notably the conversion of prothrombin to thrombin and the conversion of fibrinogen to fibrin. Fortunately, calcium ion concentration rarely falls low enough to significantly affect clotting. However, with severe blood loss requiring multiple red blood cell transfusions, calcium ion concentration is lowered because the citrate ion (present in transfusion preparations) reacts with and lowers the total body calcium ion concentration.
The total body calcium is about 1,200 g, 99% of which is located within bone as hydroxyapatite. The remainder is in the plasma and body cells. The total plasma calcium reflects the extracellular calcium level, which is less than the intracellular calcium level. The phosphate level is normally higher intracellularly (due to its role in ATP); keeping a low intracellular calcium level prevents precipitation of calcium phosphate within the cell. The total plasma calcium (normally 4.5-5.5 mEq/L or 8.6-10.5 mg/dl) exists in three general forms.
Ionized. Approximately 45% (4.5 mg/dl) is in the free or ionized form ([Ca.sup.++]). This is the only biologically active form in nerve, muscle, and other target organs and is the form that is regulated. This form of calcium is diffusible across cell membranes and can be filtered at the glomerulus of the nephron.
Bound. About 40% (4.0 mg/dl) is reversibly bound to plasma proteins, with albumin accounting for 90% of this. When the serum protein level is reduced, more calcium is in the ionized state; when serum proteins are elevated, more calcium is in the bound form. Protein binding is also influenced by plasma pH. During alkalosis, hydrogen ions are released from protein exposing more negatively charged binding sites. Tiffs increases the sites available for calcium binding and reduces the amount of free calcium in the plasma. Thus, a patient with alkalosis is susceptible to tetany. In con trash under acidotic conditions, proteins are saturated with hydrogen. Therefore, there are fewer sites on proteins available for calcium binding and more calcium remains in the plasma in its ionized form. Thus, an acidotic patient may not show tetany at calcium levels low enough to produce symptoms in other people. Bound calcium is not diffusible across cell membranes and is not filtered at the glomerulus.
Complexed. Approximately 15% of the calcium in plasma (1.5 mg/dl) is complexed to anions such as chloride, citrate, and phosphate. This form of calcium is diffusible and available for filtration at the glomerulus.
The importance of the control of calcium concentration can be illustrated by considering the consequences of abnormal concentrations of calcium. Hypercalcemia decreases the permeability of the cell membranes to sodium ions, preventing normal depolarization of nerve and muscle cells. This can lead to cardiac arrhythmias, fatigue, weakness, lethargy, anorexia, nausea, and constipation. Hypercalcemia also leads to the deposition of calcium carbonate salts in soft tissues, resulting in irritation and inflammation or in the development of kidney stones. In contrast, hypocalcemia increases the permeability of cell membranes to sodium ions such that nerve and muscle tissues undergo spontaneous action potential generation. This may lead to confusion, muscle spasms, hyperreflexia, intestinal cramping, and may progress to convulsions, tetany, and respiratory failure.
Calcium is regulated at three different sites, the bone, the intestine, and the kidney, as shown in Figure 1. Of the 1,000 mg ingested each day, approximately 300 mg is absorbed from the GI tract and enters the extracellular fluid. From here it may be stored in bone or excreted by the kidney, depending on the presence of parathyroid hormone, Vitamin D3, and calcitonin
[FIGURE 1 OMITTED]
Control of calcium concentration may be divided into daily control and long-term control. The calcium ion concentration in the extracellular fluid (ECF) remains within a few percent of 2.4 mEq/l and on a day-to-day basis is controlled principally by the effect of parathyroid hormone on bone absorption. Bone is not a fixed, dead tissue; rather, it is cellular and well supplied with blood. Bone is constantly broken down (absorbed) and simultaneously reformed under the influence of the bone cells, osteoclasts and osteoblasts, respectively. Thus, bone provides a huge source or storage area for the withdrawal or deposit of calcium. Typically 300 mg of calcium is used to build new bone and 300 mg is reabsorbed from bone each day.
The long-term control of calcium results from the reabsorption of calcium from the kidney tubules and from the gut through the intestinal mucosa. Under normal conditions, only part of the ingested calcium (approximately 300 mg) is absorbed from the intestine. Gastric secretions contain about 100 mg of calcium; thus, 800 mg is excreted in the feces. Accordingly, control of the active transport system that moves calcium from the intestinal lumen to file blood can result in large increases or decreases in net calcium absorption, thereby assisting in the regulation of total body calcium.
Renal Handling of Calcium
The kidneys control calcium by filtration and reabsorption. Only about 60% of the plasma calcium is filterable, the free calcium and that bound to anions. Protein-bound calcium is not filterable and remains in the plasma. Since calcium is both filtered at the glomerulus and reabsorbed by the tubules but is not secreted, the amount of calcium excreted can be described by the following equation:
Calcium Excreted = Calcium Filtered--Calcium Reabsorbed
The amount of calcium filtered can be calculated by multiplying the glomerular filtration rate (GFR) by the serum concentration of filterable calcium. To illustrate, if the GFR is 120 ml/min and the serum filterable calcium concentration is 5.0 mg/dl (0.5 mg/ml, the daily filtered load would be approximately 8,640 mg (see Table 1).
The filtered load may be altered by changes in the GFR or the serum calcium concentration. For example, the filtered load is reduced by a decreased GFR, such as occurs in chronic renal failure, or by a fall in the serum calcium concentration. Such alterations would lead to a reduction in the renal excretion of calcium if the amount reabsorbed were unchanged.
Changing the amount that is reabsorbed can also alter the amount of calcium excreted. In many situations, both the amount filtered and the amount reabsorbed change. For example, when calcium intake rises, the plasma calcium concentration increases. This increases the amount of calcium that is filtered. In addition, the rise in plasma calcium triggers hormonal changes that cause a diminished reabsorption. The net result is an increase in calcium excretion. Of the amount of calcium filtered, 98%99% is reabsorbed. Approximately 60%-70% of the filtered load is reabsorbed in the proximal tubule, 20% in the thick ascending limb of Henle's loop, and 5%-10% in the distal tubule.
Proximal tubule. The majority of the calcium filtered by the glomerulus is recovered by the proximal tubule along with sodium and chloride. Sodium is actively reabsorbed in the proximal tubule. It is followed passively by chloride and water. The ratio of the calcium concentration [Ca] in tubule fluid (TF) relative to the plasma ultrafiltrate (UF) is represented by the expression [[TF/UF].sub.Ca] This ratio remains near one along the proximal tubule, indicating that calcium reabsorption is paralleling sodium and fluid reabsorption. Changes in the rate of fluid reabsorption are accompanied by changes in calcium reabsorption. This suggests that calcium reabsorption in the proximal tubule occurs primarily through passive diffusion, probably by moving between the cells (i.e., a paracellular route), rather than through the cells (i.e., a transcellular route). A small amount of calcium is also absorbed via an active-transport pathway (requiring expenditure of energy in the form of ATP). This route requires transport proteins capable of moving calcium from the tubular cells across the basolateral membrane against its electrochemical gradient. Two such transporters are the plasma membrane [Ca.sup.++]-ATPase, which is an ATP-dependent pump, and the [Na.sup.+]-[Ca.sup.++]-exchanger, a carrier protein that derives its energy from the inwardly directed [Na.sup.+] gradient that is generated by the continuous activity of the [Na.sup.+]-[K.sup.+]-ATPase. By the end of the proximal tubule, 60% to 70% of the filtered calcium has been absorbed.
Loop of Henle. Calcium transport by thin descending and thin ascending limbs is minimal because of the low calcium permeability of these segments. In the thick ascending limb (where 20%-25% of filtered calcium is reabsorbed), calcium is reabsorbed by both passive and active mechanisms. In this segment, chloride is actively reabsorbed. Movement of a negatively charged ion out of the tubular fluid leaves behind a positive voltage in the lumen. Calcium reabsorption is driven passively, paracellularly, as the lumen-positive voltage repels the positively charged calcium ions. When the transepithelial voltage is manipulated experimentally, the direction and rate of calcium movement is changed. That is, when the voltage is zero, there is no net calcium movement, and when the voltage is negative, calcium secretion occurs. An active transport mechanism may also exist in this nephron segment, transcellularly, since under certain conditions calcium reabsorption occurs, even when the electrochemical driving forces are eliminated.
Distal tubule. Since more calcium than water is reabsorbed in the thick ascending limb, the calcium concentration in the fluid entering the distal tubule is less than that of plasma ultrafiltrate. The [[TF/UF].sub.Ca] ratio is about 0.6 at the beginning of the distal tubule and fails along the length of it to 0.3 or less. This information, taken together with the lumen-negative transepithelial voltage, provides evidence for an active calcium reabsorptive mechanism that proceeds against both electrical and chemical gradients. This is in contrast to proximal tubule calcium absorption, which is primarily passive and paracellular in nature.
A simplified model illustrating the mechanisms of transfer of calcium across the membranes of the distal tubule is shown in Figure 2. Calcium enters the distal tubule cell from the tubular lumen through a calcium channel. Its exit from the cell into the blood is mediated by a combination of [Na.sup.+] - [Ca.sup.++] exchange and [Ca.sup.++] ATPase. The first of these is driven by sodium gradients established by sodium entry across the luminal membrane and its extrusion from the cell across the basolateral membrane by the [3Na.sup.+] - [2K.sup.+] ATPase. Calcium reabsorption in the distal tubule is regulated by PTH, calcitonin, and vitamin D (1,25[(OH).sub.2]D3).
[FIGURE 2 OMITTED]
Collecting tubule. The contribution of the cortical collecting tubule to overall calcium reabsorption is small because the calcium permeability in the cortical collecting tubule is lower than in the thick ascending limb and proximal tubule. Calcium reabsorption in this segment varies with the magnitude and direction of the transepithelial voltage.
In summary, calcium is reabsorbed passively via the paracellular pathways, driven by a chemical gradient in the proximal tubule and by the lumen-positive transepithelial voltage in the thick ascending limb. In the distal tubule, calcium is actively reabsorbed. Calcium activity within the renal cells is about four tunes lower than that of the ECF. Calcium moves passively from the lumen into the renal epithelial cells driven by the chemical gradient. Calcium extrusion from the cell across the basolateral membrane occurs against an electrochemical gradient. This transport involves both an ATP-driven calcium transport pump and [Ca.sup.++]-[Na.sup.+] exchange.
Regulation of Calcium Excretion
The renal excretion of calcium may vary considerably. In normal subjects, an average of 200 mg/day is excreted, but may reach up to 300 mg/day for men and 2.50 mg/day for women. In severe states of calcium depletion, it may be reduced to 50 mg/day.
Tubular calcium reabsorption may be altered by many factors. In general, those maneuvers that alter sodium transport in the proximal tubule or chloride transport in the thick ascend tug limb cause parallel alterations in calcium transport by interfering with the passive driving forces (concentration gradient in the proximal tubule and lumen-positive voltage in the thick ascending limb). For example, as ECF volume expansion inhibits salt and water reabsorption, calcium reabsorption in the proximal tubule is diminished. Loop diuretics, such as furosemide, decrease the lumen-positive transepithelial voltage in the thick ascending limb. The usual passive driving force for calcium reabsorption is thereby eliminated, and sodium excretion is accompanied by calcium excretion.
The reabsorption that occurs in the distal tubule and collecting duct is very selective, depending upon the calcium ion concentration in the blood. In these segments of the nephron, sodium and calcium reabsorption can be dissociated from one another, suggesting that the reabsorptive mechanisms differ. This is supported by the observation that parathyroid hormone (PTH) reduces urinary excretion of calcium while enhancing urinary excretion of sodium. In addition, thiazide diuretics, acting in the early portion of the distal tubule induce a natriuresis, but cause urinary retention of calcium when administered on a chronic basis.
Phosphorus levels also affect calcium excretion. An increase in phosphorus may decrease urinary excretion of calcium. Presumably, this is due to deposition of calcium phosphate in the bone, thereby decreasing serum calcium levels and the filtered load. Although the mechanism has not been defined, phosphate depletion leads to an increased urinary excretion of calcium.
Acid-base disturbances, most notably metabolic in nature, also affect calcium excretion. Hydrogen ions, increased in acidosis, displace protein bound calcium resulting in more ionized calcium without affecting the total calcium concentration. This leads to a reduced distal tubule calcium reabsorption and increased calcium excretion. Conversely, metabolic alkalosis reduces ionized calcium levels through the mechanism of increased protein binding. Thus, an increased distal tubule reabsorption of calcium occurs and calcium excretion is reduced.
Parathormone (parathyroid hormone, PTH). Movement of calcium into and out of the bone, gastrointestinal tract mad kidney is under the control of a hormone called PTH. PTH is a single chain polypeptide, composed of 84 amino acids, produced by the chief cells of the parathyroid glands. Its production is controlled directly by the calcium concentration of the fluid bathing the cells of these glands. When the extracellular calcium concentration falls too low, the parathyroid glands are directly stimulated to increase their secretion of PTH. As shown in Figure 3, PTH increases the ECF concentration of calcium through effects on the bone, GI system, and the kidney.
[FIGURE 3 OMITTED]
1. PTH stimulates the absorption of bone salts (by increasing bone osteoclastic activity), thereby releasing large amounts of calcium into the ECF. (Related to this is the fact that PTH decreases renal bicarbonate reabsorption. Since renal bicarbonate reabsorption and renal chloride reabsorption are inversely related, this causes a rise in serum chloride concentration. This, in turn, produces hyperchloremic acidosis, which aids in bone demineralization).
2. PTH stimulates the renal mediated conversion of vitamin D3 to calcitriol. Calcitriol increases calcium and phosphate absorption in the intestine.
3. Since PTH increases serum calcium through its effects on the bone and GI system, a greater load of calcium passes through the glomerulus. This increases the reabsorption in the proximal tubule. However, PTH has also been reported to decrease or not to change proximal tubule calcium reabsorption. In fact, the primary action of PTH on proximal tubule transport is to inhibit phosphate reabsorption. This decreased reabsorption is so pronounced that it offsets the increase in GI phosphate absorption, thus resulting in a net decrease in serum phosphate concentrations. This is important because it decreases the likelihood of calcium-phosphate precipitates in the setting of rising serum calcium levels
PTH increases calcium reabsorption in the thick ascending limbs, the distal tubules, and the collecting ducts through activation of renal adenylate cyclase and generation of cyclic adenosine monophosphate (AMP) within the tubular cells. All of the effects of PTH on the bone, intestine and kidney result in a higher ECF calcium concentration. Ninety" percent of circulating PTH is degraded in the liver mad kidney, and the circulating half-life is short.
In contrast, when the calcium level becomes too great, PTH secretion falls and almost no bone absorption occurs. Since new bone continues to be formed by the osteoblastic system, calcium is removed from the ECF. In addition, without PTH, fecal and urinary calcium losses are increased and the ECF calcium level returns toward normal.
Vitamin D3 (calcitriol). A second hormone that effects calcium homeostasis is 1,25 dihydroxyvitamin D3 (also known as calcitriol). This hormone is metabolized from ingested vitamin D and from Vitamin D3 (cholecalciferol) formed by the action of ultraviolet radiation on 7-dehydrocholesterol in the skin. These precursors enter the blood and a hydroxyl group ([OH.sup.-]) is added in the 25 position by the liver. This chemical reaction is called hydroxylation and, in this case, involves the addition of a hydroxy group to the 25th carbon atom of Vitamin D3. When PTH is present, 2.5, hydroxyvitamin D3 is further hydroxylated in the 1 position within the proximal tubules of the kidney. The mitochondria of the proximal tubules contain the enzyme 1-alpha-hydroxylase, which is responsible for this conversion. The end result is the formation of 1,25 dihydroxyvitamin D3, the active form of vitamin D. One-alpha-hydroxylase activity is directly regulated by PTH (which stimulates renal synthesis of the enzyme) and serum phosphate levels (a decrease in serum phosphate stimulates enzymatic activity).
Calcitriol stimulates active absorption of calcium (and phosphate) by the intestine, enhances bone absorption, and stimulates the renal-tubular reabsorption of calcium. Throughout the cells of the body calcitriol regulates the synthesis of several proteins, most notably a family of proteins known as calbindin D. These proteins bind calcium with a high affinity and are widely found in the intestine, kidney, bone, as well as other organs. In the presence of calbindin D, there is an increase in transmembrane calcium pump activity within the membranes of the intestine and the distal tubule of the nephron. Tiffs increased pump activity combined with calbindin's greater affinity for calcium facilitates an influx of calcium into the ECF and the plasma.
Osteoclastic activity and bone turnover is increased when calcitriol works together with PTH. However, due to increases in intestinal and renal absorption of calcium, calcitriol ultimately provides the high ECF calcium levels necessary for bone mineralization. Finally, calcitriol decreases the synthesis of collagen and PTH, which also favors bone mineralization. In summary, calcitriol's actions on the bone, intestines, and kidney serve to increase the ECF calcium concentration.
Calcitonin. Calcitonin is a 24 amino acid polypeptide secreted by the parafollicular cells of the thyroid gland. It is secreted in response to hypercalcemia and tends to lower plasma calcium primarily by inhibiting osteoclastic bone absorption. Both osteoclast differentiation from precursor cells and activity of existing osteoclasts are reduced in the presence of calcitonin. Calcitonin also increases urinary excretion of calcium, but the mechanism for this is undefined. Its role is thought to be of minor significance in comparison to that of PTH mad 1,25 dihydroxyvitamin D3.
New information about the renal regulation of calcium is being discovered on a regular basis. Numerous genetic mutations have been identified that are associated with calcium imbalances. A calcium-sensing receptor located in the membranes of cells involved in regulating calcium homeostasis has been identified. Such receptors in the thick ascending limb and distal tubule respond directly to changes in plasma calcium and regulate calcium absorption by these nephron segments. Mutations in the gene coding for the calcium sensing receptors cause disorders in calcium homeostasis. A PTH related peptide (PTHrP) has been identified in proximal and distal convoluted tubules and cortical collecting ducts. While its actions have not been well delineated yet, its effects on renal calcium absorption appear to be significant in the hypercalcemia that occurs on some patients with cancer. Thus, we continue to enhance our understanding of the kidney's role in homeostasis.
This manuscript has reviewed the roles, homeostasis, and renal handling of calcium. The homeostasis of calcium is complex and involves the gastrointestinal tract, the bone, the kidney as well as interaction among these sites. The major sites of tubular reabsorption (the proximal tubule, thick ascending limb of Henle and the distal tubule) and the presumed cellular mechanisms involved have been described. In addition, the regulation of calcium by PTH, calcitonin, and vitamin D has been described.
Table 1 Calculating the Amount of Calcium Filtered Amount filtered per minute = GFR x [Ca] 120 ml/min x 0.05 mg/ml = 6 mg/min x 0.05 mg/ml = 6 mg/min Amount filtered per day = 6 mg/min x 60 min x 24 hours = 8,640 mg
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Editor's Note: This article is a continuation of a renal physiology series in the Nephrology Nursing Journal. The articles, which offer continuing education credits and are updates of manuscripts that previously appeared in the journal, are written by experts in nephrology and contain the most up-to-date information and research available.
Renal Homeostasis of Calcium Carolyn Yucha, PhD, RN, and David Guthrie, ARNP, MN Posttest--1.9 Contact Hours (See posttest instructions on the answer form, on page 628.)
1. Ninety-nine percent of the body calcium is found within
A. plasma, in its ionic form. B. plasma, bound to proteins. C. blood cells, bound to hemo globin. D. bone, as hydroxyapatite.
2. The calcium that is used during nerve conduction is
A. bound to anions, such as chloride. B. bound to cations, such as sodium. C. bound to plasma proteins. D. in the free or ionized form.
3. The amount of calcium that is bound to proteins in the plasma is
A. increased in acidosis. B. increased in alkalosis. C. not influenced by plasma pH. D. not affected by albumin level.
4. Which of the following is (are) involved in the regulation of calcium balance?
A. Bone only. B. Bone and kidney only. C. Bone, kidney and intestine only. D. Bone, kidney, intestine and liver only.
5. The day to day concentration of the extracellular fluid calcium is controlled principally by the effect of PTH on the
A. bone. B. intestine. C. kidney. D. liver.
6. The long-term control of calcium results from
A. reabsorption from the kidney tubules. B. secretion from the intestinal mucosa. C. oteoclast and osteoblast activity in the bone. D. ATP calcium driven pump.
7. In the distal tubule, calcium is
A. actively reabsorbed. B. passively reabsorbed, driven by the chemical gradient. C. passively reabsorbed, driven by the electrical gradient. D. not reabsorbed.
8. Renal calcium excretion is affected by
A. PTH only. B. PTH and hyperphosphatemia only. C. PTH, hyperphosphatemia and severe calcium depletion only. D. PTH, hyperphosphatemia, severe calcium depletion, and diuretics.
9. If the calcium concentration in the extracellular fluid drops, the calcium reabsorption in the distal nephron rises.
This is due to the action of
A. calcitonin. B. 7-dehydrocholesterol. C. 25, hydroxyvitamin D3. D. parathyroid hormone.
10. Vitamin D increases extracellular fluid calcium concentration by
A. increasing absorption of calcium by the intestine. B. decreasing calcium absorption form the bone. C. decreasing calcium reabsorption in the distal nephron. D. increasing calcium secretion in the proximal tubule.
11. Hypercalcemia decreases cell membrane permeability to sodium ions, thereby interfering with depolarization of nerve and muscle cells. Knowing this, the nurse should assess for
A. muscle spasms and hyperreflexia. B. convulsions and tetany. C. cardiac arrhythmias. D. respiratory failure.
12. What condition would make a patient susceptible to tetany?
A. Alkalosis. B. Acidosis. C. Hypecalcemia. D. Hypoalbuminemia.
13. You are reviewing your patient's labs. He has a plasma calcium of 7.5 mg/dl, with a normal albumin. What signs and symptoms might indicate increasing hypocalcemia?
A. Intestinal cramping only. B. Intestinal cramping and confusion only. C. Intestinal cramping, confusion, and muscle spasms only. D. Intestinal cramping, confusion, muscle spasms, and tetany.
Carolyn Yucha, PhD, RN, is Professor and Associate Dean for Research, University of Florida College of Nursing, Gainesville, FL.
David Guthrie, MN, ARNP, is Doctoral Student, University of Florida College of Nursing, Gainesville, FL.