Regulation of Extracellular Fluid Potassium Concentration and Potassium Excretion
Extracellular fluid potassium concentration normally is regulated precisely at about 4.2 mEq/L, seldom rising or falling more than ±0.3 mEq/L. This precise control is necessary because many cell functions are very sensitive to changes in extracellular fluid potassium concentration. For instance, an increase in plasma potassium concentration of only 3 to 4 mEq/L can cause cardiac arrhythmias, and higher concentrations can lead to cardiac arrest or fibrillation.
A special difficulty in regulating extracellular potassium concentration is the fact that more than 98 percent of the total body potassium is contained in the cells and only 2 percent in the extracellular fluid (Figure 29-1). For a 70-kilogram adult, who has about 28 liters of intracellular fluid (40 percent of body weight) and 14 liters of extracellular fluid (20 percent of body weight), about 3920 mEq of potassium are inside the cells and only about 59 mEq are in the extracellular fluid. Also, the potassium contained in a single meal is often as high as 50 mEq, and the daily intake usually ranges between 50 and 200 mEq/day; therefore, failure to rapidly rid the extracellular fluid of the ingested potassium could cause life-threatening hyperkalemia (increased plasma potassium concentration). Likewise, a small loss of potassium from the extracellular fluid could cause severe hypokalemia (low plasma potassium concentration) in the absence of rapid and appropriate compensatory responses.
Figure 29-1 Normal potassium intake, distribution of potassium in the body fluids, and potassium output from the body.
Maintenance of balance between intake and output of potassium depends primarily on excretion by the kidneys because the amount excreted in the feces is only about 5 to 10 percent of the potassium intake. Thus, the maintenance of normal potassium balance requires the kidneys to adjust their potassium excretion rapidly and precisely in response to wide variations in intake, as is also true for most other electrolytes.
Control of potassium distribution between the extracellular and intracellular compartments also plays an important role in potassium homeostasis. Because more than 98 percent of the total body potassium is contained in the cells, they can serve as an overflow site for excess extracellular fluid potassium during hyperkalemia or as a source of potassium during hypokalemia. Thus, redistribution of potassium between the intracellular and extracellular fluid compartments provides a first line of defense against changes in extracellular fluid potassium concentration.
Regulation of Internal Potassium Distribution
After ingestion of a normal meal, extracellular fluid potassium concentration would rise to a lethal level if the ingested potassium did not rapidly move into the cells. For example, absorption of 40 mEq of potassium (the amount contained in a meal rich in vegetables and fruit) into an extracellular fluid volume of 14 liters would raise plasma potassium concentration by about 2.9 mEq/L if all the potassium remained in the extracellular compartment. Fortunately, most of the ingested potassium rapidly moves into the cells until the kidneys can eliminate the excess. Table 29-1 summarizes some of the factors that can influence the distribution of potassium between the intracellular and extracellular compartments.
Table 29-1 Factors That Can Alter Potassium Distribution Between the Intracellular and Extracellular Fluid
|
Factors That Shift K+ into Cells (Decrease Extracellular [K+]) |
Factors That Shift K+ Out of Cells (Increase Extracellular [K+]) |
|
• Insulin • Aldosterone • β-adrenergic stimulation • Alkalosis |
• Insulin deficiency (diabetes mellitus) • Aldosterone deficiency (Addison’s disease) • β-adrenergic blockade • Acidosis • Cell lysis • Strenuous exercise • Increased extracellular fluid osmolarity |
Insulin Stimulates Potassium Uptake into Cells
Insulin is important for increasing cell potassium uptake after a meal. In people who have insulin deficiency owing to diabetes mellitus, the rise in plasma potassium concentration after eating a meal is much greater than normal. Injections of insulin, however, can help to correct the hyperkalemia.
Aldosterone Increases Potassium Uptake into Cells
Increased potassium intake also stimulates secretion of aldosterone, which increases cell potassium uptake. Excess aldosterone secretion (Conn’s syndrome) is almost invariably associated with hypokalemia, due in part to movement of extracellular potassium into the cells. Conversely, patients with deficient aldosterone production (Addison’s disease) often have clinically significant hyperkalemia due to accumulation of potassium in the extracellular space, as well as to renal retention of potassium.
β-Adrenergic Stimulation Increases Cellular Uptake of Potassium
Increased secretion of catecholamines, especially epinephrine, can cause movement of potassium from the extracellular to the intracellular fluid, mainly by activation of β2-adrenergic receptors. Conversely, treatment of hypertension with β-adrenergic receptor blockers, such as propranolol, causes potassium to move out of the cells and creates a tendency toward hyperkalemia.
Acid-Base Abnormalities Can Cause Changes in Potassium Distribution
Metabolic acidosis increases extracellular potassium concentration, in part by causing loss of potassium from the cells, whereas metabolic alkalosis decreases extracellular fluid potassium concentration. Although the mechanisms responsible for the effect of hydrogen ion concentration on potassium internal distribution are not completely understood, one effect of increased hydrogen ion concentration is to reduce the activity of the sodium-potassium adenosine triphosphatase (ATPase) pump. This in turn decreases cellular uptake of potassium and raises extracellular potassium concentration.
Cell Lysis Causes Increased Extracellular Potassium Concentration
As cells are destroyed, the large amounts of potassium contained in the cells are released into the extracellular compartment. This can cause significant hyperkalemia if large amounts of tissue are destroyed, as occurs with severe muscle injury or with red blood cell lysis.
Strenuous Exercise Can Cause Hyperkalemia by Releasing Potassium from Skeletal Muscle
During prolonged exercise, potassium is released from skeletal muscle into the extracellular fluid. Usually the hyperkalemia is mild, but it may be clinically significant after heavy exercise, especially in patients treated with β-adrenergic blockers or in individuals with insulin deficiency. In rare instances, hyperkalemia after exercise may be severe enough to cause cardiac arrhythmias and sudden death.
Increased Extracellular Fluid Osmolarity Causes Redistribution of Potassium from the Cells to Extracellular Fluid
Increased extracellular fluid osmolarity causes osmotic flow of water out of the cells. The cellular dehydration increases intracellular potassium concentration, thereby promoting diffusion of potassium out of the cells and increasing extracellular fluid potassium concentration. Decreased extracellular fluid osmolarity has the opposite effect.
Overview of Renal Potassium Excretion
Renal potassium excretion is determined by the sum of three processes: (1) the rate of potassium filtration (GFR multiplied by the plasma potassium concentration), (2) the rate of potassium reabsorption by the tubules, and (3) the rate of potassium secretion by the tubules. The normal rate of potassium filtration by the glomerular capillaries is about 756 mEq/day (GFR, 180 L/day multiplied by plasma potassium, 4.2 mEq/L); this rate of filtration is relatively constant in healthy persons because of the autoregulatory mechanisms for GFR discussed previously and the precision with which plasma potassium concentration is regulated. Severe decreases in GFR in certain renal diseases, however, can cause serious potassium accumulation and hyperkalemia.
Figure 29-2 summarizes the tubular handling of potassium under normal conditions. About 65 percent of the filtered potassium is reabsorbed in the proximal tubule. Another 25 to 30 percent of the filtered potassium is reabsorbed in the loop of Henle, especially in the thick ascending part where potassium is actively co-transported along with sodium and chloride. In both the proximal tubule and the loop of Henle, a relatively constant fraction of the filtered potassium load is reabsorbed. Changes in potassium reabsorption in these segments can influence potassium excretion, but most of the day-to-day variation of potassium excretion is not due to changes in reabsorption in the proximal tubule or loop of Henle.
Figure 29-2 Renal tubular sites of potassium reabsorption and secretion. Potassium is reabsorbed in the proximal tubule and in the ascending loop of Henle, so only about 8 percent of the filtered load is delivered to the distal tubule. Secretion of potassium into the late distal tubules and collecting ducts adds to the amount delivered; therefore, the daily excretion is about 12 percent of the potassium filtered at the glomerular capillaries. The percentages indicate how much of the filtered load is reabsorbed or secreted into the different tubular segments.
Daily Variations in Potassium Excretion Are Caused Mainly by Changes in Potassium Secretion in Distal and Collecting Tubules
The most important sites for regulating potassium excretion are the principal cells of the late distal tubules and cortical collecting tubules. In these tubular segments, potassium can at times be reabsorbed or at other times be secreted, depending on the needs of the body. With a normal potassium intake of 100 mEq/day, the kidneys must excrete about 92 mEq/day (the remaining 8 mEq are lost in the feces). About 31 mEq/day of potassium are secreted into the distal and collecting tubules, accounting for about one third of the excreted potassium.
With high potassium intakes, the required extra excretion of potassium is achieved almost entirely by increasing the secretion of potassium into the distal and collecting tubules. In fact, with extremely high potassium diets, the rate of potassium excretion can exceed the amount of potassium in the glomerular filtrate, indicating a powerful mechanism for secreting potassium.
When potassium intake is low, the secretion rate of potassium in the distal and collecting tubules decreases, causing a reduction in urinary potassium secretion. With extreme reductions in potassium intake, there is net reabsorption of potassium in the distal segments of the nephron, and potassium excretion can fall to 1 percent of the potassium in the glomerular filtrate (to <10 mEq/day). With potassium intakes below this level, severe hypokalemia can develop.
Thus, most of the day-to-day regulation of potassium excretion occurs in the late distal and cortical collecting tubules, where potassium can be either reabsorbed or secreted, depending on the needs of the body. In the next section, we consider the basic mechanisms of potassium secretion and the factors that regulate this process.
Potassium Secretion by Principal Cells of Late Distal and Cortical Collecting Tubules
The cells in the late distal and cortical collecting tubules that secrete potassium are called principal cells and make up about 90 percent of the epithelial cells in these regions. Figure 29-3 shows the basic cellular mechanisms of potassium secretion by the principal cells.
Figure 29-3 Mechanisms of potassium secretion and sodium reabsorption by the principal cells of the late distal and collecting tubules.
Secretion of potassium from the blood into the tubular lumen is a two-step process, beginning with uptake from the interstitium into the cell by the sodium-potassium ATPase pump in the basolateral cell membrane; this pump moves sodium out of the cell into the interstitium and at the same time moves potassium to the interior of the cell.
The second step of the process is passive diffusion of potassium from the interior of the cell into the tubular fluid. The sodium-potassium ATPase pump creates a high intracellular potassium concentration, which provides the driving force for passive diffusion of potassium from the cell into the tubular lumen. The luminal membrane of the principal cells is highly permeable to potassium. One reason for this high permeability is that special channels are specifically permeable to potassium ions, thus allowing these ions to rapidly diffuse across the membrane.
Control of Potassium Secretion by Principal Cells
The primary factors that control potassium secretion by the principal cells of the late distal and cortical collecting tubules are (1) the activity of the sodium-potassium ATPase pump, (2) the electrochemical gradient for potassium secretion from the blood to the tubular lumen, and (3) the permeability of the luminal membrane for potassium. These three determinants of potassium secretion are in turn regulated by the factors discussed later.
Intercalated Cells Can Reabsorb Potassium During Potassium Depletion
In circumstances associated with severe potassium depletion, there is a cessation of potassium secretion and actually a net reabsorption of potassium in the late distal and collecting tubules. This reabsorption occurs through the intercalated cells; although this reabsorptive process is not completely understood, one mechanism believed to contribute is a hydrogen-potassium ATPase transport mechanism located in the luminal membrane. This transporter reabsorbs potassium in exchange for hydrogen ions secreted into the tubular lumen, and the potassium then diffuses through the basolateral membrane of the cell into the blood. This transporter is necessary to allow potassium reabsorption during extracellular fluid potassium depletion, but under normal conditions it plays only a small role in controlling potassium excretion.
Summary of Factors That Regulate Potassium Secretion: Plasma Potassium Concentration, Aldosterone, Tubular Flow Rate, and Hydrogen Ion Concentration
Because normal regulation of potassium excretion occurs mainly as a result of changes in potassium secretion by the principal cells of the late distal and collecting tubules, in this chapter we discuss the primary factors that influence secretion by these cells. The most important factors that stimulate potassium secretion by the principal cells include (1) increased extracellular fluid potassium concentration, (2) increased aldosterone, and (3) increased tubular flow rate.
One factor that decreases potassium secretion is increased hydrogen ion concentration (acidosis).
Increased Extracellular Fluid Potassium Concentration Stimulates Potassium Secretion
The rate of potassium secretion in the late distal and cortical collecting tubules is directly stimulated by increased extracellular fluid potassium concentration, leading to increases in potassium excretion, as shown in Figure 29-4. This effect is especially pronounced when extracellular fluid potassium concentration rises above about 4.1 mEq/L, slightly less than the normal concentration. Increased plasma potassium concentration, therefore, serves as one of the most important mechanisms for increasing potassium secretion and regulating extracellular fluid potassium ion concentration.
Figure 29-4 Effect of plasma aldosterone concentration (red line) and extracellular potassium ion concentration (black line) on the rate of urinary potassium excretion. These factors stimulate potassium secretion by the principal cells of the cortical collecting tubules.
(Drawn from data in Young DB, Paulsen AW: Interrelated effects of aldosterone and plasma potassium on potassium excretion. Am J Physiol 244:F28, 1983.)
Increased extracellular fluid potassium concentration raises potassium secretion by three mechanisms: (1) Increased extracellular fluid potassium concentration stimulates the sodium-potassium ATPase pump, thereby increasing potassium uptake across the basolateral membrane. This in turn increases intracellular potassium ion concentration, causing potassium to diffuse across the luminal membrane into the tubule. (2) Increased extracellular potassium concentration increases the potassium gradient from the renal interstitial fluid to the interior of the epithelial cell; this reduces back leakage of potassium ions from inside the cells through the basolateral membrane. (3) Increased potassium concentration stimulates aldosterone secretion by the adrenal cortex, which further stimulates potassium secretion, as discussed next.
Aldosterone Stimulates Potassium Secretion
Aldosterone stimulates active reabsorption of sodium ions by the principal cells of the late distal tubules and collecting ducts (see Chapter 27). This effect is mediated through a sodium-potassium ATPase pump that transports sodium outward through the basolateral membrane of the cell and into the blood at the same time that it pumps potassium into the cell. Thus, aldosterone also has a powerful effect to control the rate at which the principal cells secrete potassium.
A second effect of aldosterone is to increase the permeability of the luminal membrane for potassium, further adding to the effectiveness of aldosterone in stimulating potassium secretion. Therefore, aldosterone has a powerful effect to increase potassium excretion, as shown in Figure 29-4.
Increased Extracellular Potassium Ion Concentration Stimulates Aldosterone Secretion
In negative feedback control systems, the factor that is controlled usually has a feedback effect on the controller. In the case of the aldosterone-potassium control system, the rate of aldosterone secretion by the adrenal gland is controlled strongly by extracellular fluid potassium ion concentration. Figure 29-5 shows that an increase in plasma potassium concentration of about 3 mEq/L can increase plasma aldosterone concentration from nearly 0 to as high as 60 ng/100 ml, a concentration almost 10 times normal.
Figure 29-5 Effect of extracellular fluid potassium ion concentration on plasma aldosterone concentration. Note that small changes in potassium concentration cause large changes in aldosterone concentration.
The effect of potassium ion concentration to stimulate aldosterone secretion is part of a powerful feedback system for regulating potassium excretion, as shown in Figure 29-6. In this feedback system, an increase in plasma potassium concentration stimulates aldosterone secretion and, therefore, increases the blood level of aldosterone (block 1). The increase in blood aldosterone then causes a marked increase in potassium excretion by the kidneys (block 2). The increased potassium excretion then reduces the extracellular fluid potassium concentration back toward normal (blocks 3 and 4). Thus, this feedback mechanism acts synergistically with the direct effect of increased extracellular potassium concentration to elevate potassium excretion when potassium intake is raised (Figure 29-7).
Figure 29-6 Basic feedback mechanism for control of extracellular fluid potassium concentration by aldosterone (Ald.).
Figure 29-7 Primary mechanisms by which high potassium intake raises potassium excretion. Note that increased plasma potassium concentration directly raises potassium secretion by the cortical collecting tubules and indirectly increases potassium secretion by raising plasma aldosterone concentration.
Blockade of Aldosterone Feedback System Greatly Impairs Control of Potassium Concentration
In the absence of aldosterone secretion, as occurs in patients with Addison’s disease, renal secretion of potassium is impaired, thus causing extracellular fluid potassium concentration to rise to dangerously high levels. Conversely, with excess aldosterone secretion (primary aldosteronism), potassium secretion becomes greatly increased, causing potassium loss by the kidneys and thus leading to hypokalemia.
In addition to its stimulatory effect on renal secretion of potassium, aldosterone also increases cellular uptake of potassium, which contributes to the powerful aldosterone-potassium feedback system, as discussed previously.
The special quantitative importance of the aldosterone feedback system in controlling potassium concentration is shown in Figure 29-8. In this experiment, potassium intake was increased almost sevenfold in dogs under two conditions: (1) under normal conditions and (2) after the aldosterone feedback system had been blocked by removing the adrenal glands and placing the animals on a fixed rate of aldosterone infusion so that plasma aldosterone concentration could neither increase nor decrease.
Figure 29-8 Effect of large changes in potassium intake on extracellular fluid potassium concentration under normal conditions (red line) and after the aldosterone feedback had been blocked (blue line). Note that after blockade of the aldosterone system, regulation of potassium concentration was greatly impaired.
(Courtesy Dr. David B. Young.)
Note that in the normal animals, a sevenfold increase in potassium intake caused only a slight increase in potassium concentration, from 4.2 to 4.3 mEq/L. Thus, when the aldosterone feedback system is functioning normally, potassium concentration is precisely controlled, despite large changes in potassium intake.
When the aldosterone feedback system was blocked, the same increases in potassium intake caused a much larger increase in potassium concentration, from 3.8 to almost 4.7 mEq/L. Thus, control of potassium concentration is greatly impaired when the aldosterone feedback system is blocked. A similar impairment of potassium regulation is observed in humans with poorly functioning aldosterone feedback systems, such as occurs in patients with either primary aldosteronism (too much aldosterone) or Addison’s disease (too little aldosterone).
Increased Distal Tubular Flow Rate Stimulates Potassium Secretion
A rise in distal tubular flow rate, as occurs with volume expansion, high sodium intake, or treatment with some diuretics, stimulates potassium secretion (Figure 29-9). Conversely, a decrease in distal tubular flow rate, as caused by sodium depletion, reduces potassium secretion.
Figure 29-9 Relationship between flow rate in the cortical collecting tubules and potassium secretion and the effect of changes in potassium intake. Note that a high dietary potassium intake greatly enhances the effect of increased tubular flow rate to increase potassium secretion. The shaded bar shows the approximate normal tubular flow rate under most physiological conditions.
(Data from Malnic G, Berliner RW, Giebisch G. Am J Physiol 256:F932, 1989.)
The effect of tubular flow rate on potassium secretion in the distal and collecting tubules is strongly influenced by potassium intake. When potassium intake is high, increased tubular flow rate has a much greater effect to stimulate potassium secretion than when potassium intake is low (see Figure 29-9).
The mechanism for the effect of high-volume flow rate is as follows: When potassium is secreted into the tubular fluid, the luminal concentration of potassium increases, thereby reducing the driving force for potassium diffusion across the luminal membrane. With increased tubular flow rate, the secreted potassium is continuously flushed down the tubule, so the rise in tubular potassium concentration becomes minimized. Therefore, net potassium secretion is stimulated by increased tubular flow rate.
The effect of increased tubular flow rate is especially important in helping to preserve normal potassium excretion during changes in sodium intake. For example, with a high sodium intake, there is decreased aldosterone secretion, which by itself would tend to decrease the rate of potassium secretion and, therefore, reduce urinary excretion of potassium. However, the high distal tubular flow rate that occurs with a high sodium intake tends to increase potassium secretion (Figure 29-10), as discussed in the previous paragraph. Therefore, the two effects of high sodium intake, decreased aldosterone secretion and the high tubular flow rate, counterbalance each other, so there is little change in potassium excretion. Likewise, with a low sodium intake, there is little change in potassium excretion because of the counterbalancing effects of increased aldosterone secretion and decreased tubular flow rate on potassium secretion.
Figure 29-10 Effect of high sodium intake on renal excretion of potassium. Note that a high-sodium diet decreases plasma aldosterone, which tends to decrease potassium secretion by the cortical collecting tubules. However, the high-sodium diet simultaneously increases fluid delivery to the cortical collecting duct, which tends to increase potassium secretion. The opposing effects of a high-sodium diet counterbalance each other, so there is little change in potassium excretion.
Acute Acidosis Decreases Potassium Secretion
Acute increases in hydrogen ion concentration of the extracellular fluid (acidosis) reduce potassium secretion, whereas decreased hydrogen ion concentration (alkalosis) increases potassium secretion. The primary mechanism by which increased hydrogen ion concentration inhibits potassium secretion is by reducing the activity of the sodium-potassium ATPase pump. This in turn decreases intracellular potassium concentration and subsequent passive diffusion of potassium across the luminal membrane into the tubule.
With more prolonged acidosis, lasting over a period of several days, there is an increase in urinary potassium excretion. The mechanism for this effect is due in part to an effect of chronic acidosis to inhibit proximal tubular sodium chloride and water reabsorption, which increases distal volume delivery, thereby stimulating the secretion of potassium. This effect overrides the inhibitory effect of hydrogen ions on the sodium-potassium ATPase pump. Thus, chronic acidosis leads to a loss of potassium, whereas acute acidosis leads to decreased potassium excretion.
Beneficial Effects of a Diet High in Potassium and Low in Sodium Content
For most of human history, the typical diet has been one that is low in sodium and high in potassium content, compared with the typical modern diet. In isolated populations that have not experienced industrialization, such as the Yanomamo tribe living in the Amazon of Northern Brazil, sodium intake may be as low as 10 to 20 mmol/day while potassium intake may be as high as 200 mmol/day. This is due to their consumption of a diet containing large amounts of fruits and vegetables and no processed foods. Populations consuming this type of diet typically do not experience age-related increases in blood pressure and cardiovascular diseases.
With industrialization and increased consumption of processed foods, which often have high sodium and low potassium content, there have been dramatic increases in sodium intake and decreases in potassium intake. In most industrialized countries potassium consumption averages only 30 to 70 mmol/day while sodium intake averages 140 to 180 mmol/day.
Experimental and clinical studies have shown that the combination of high sodium and low potassium intake increases the risk for hypertension and associated cardiovascular and kidney diseases. A diet rich in potassium, however, seems to protect against the adverse effects of a high-sodium diet, reducing blood pressure and the risk for stroke, coronary artery disease, and kidney disease. The beneficial effects of increasing potassium intake are especially apparent when combined with a low-sodium diet.
Dietary guidelines published by U.S. National Academy of Sciences, the American Heart Association, and other organizations recommend reducing dietary intake sodium chloride to around 65 mmol/day (corresponding to 1.5 g/day of sodium or 3.8 g/day sodium chloride), while increasing potassium intake to 120 mmol/day (4.7 g/day) for healthy adults.
Control of Renal Calcium Excretion and Extracellular Calcium Ion Concentration
The mechanisms for regulating calcium ion concentration are discussed in detail in Chapter 79, along with the endocrinology of the calcium-regulating hormones, parathyroid hormone (PTH), and calcitonin. Therefore, calcium ion regulation is discussed only briefly in this chapter.
Extracellular fluid calcium ion concentration normally remains tightly controlled within a few percentage points of its normal level, 2.4 mEq/L. When calcium ion concentration falls to low levels (hypocalcemia), the excitability of nerve and muscle cells increases markedly and can in extreme cases result in hypocalcemic tetany. This is characterized by spastic skeletal muscle contractions. Hypercalcemia (increased calcium concentration) depresses neuromuscular excitability and can lead to cardiac arrhythmias.
About 50 percent of the total calcium in the plasma (5 mEq/L) exists in the ionized form, which is the form that has biological activity at cell membranes. The remainder is either bound to the plasma proteins (about 40 percent) or complexed in the non-ionized form with anions such as phosphate and citrate (about 10 percent).
Changes in plasma hydrogen ion concentration can influence the degree of calcium binding to plasma proteins. With acidosis, less calcium is bound to the plasma proteins. Conversely, in alkalosis, a greater amount of calcium is bound to the plasma proteins. Therefore, patients with alkalosis are more susceptible to hypocalcemic tetany.
As with other substances in the body, the intake of calcium must be balanced with the net loss of calcium over the long term. Unlike ions such as sodium and chloride, however, a large share of calcium excretion occurs in the feces. The usual rate of dietary calcium intake is about 1000 mg/day, with about 900 mg/day of calcium excreted in the feces. Under certain conditions, fecal calcium excretion can exceed calcium ingestion because calcium can also be secreted into the intestinal lumen. Therefore, the gastrointestinal tract and the regulatory mechanisms that influence intestinal calcium absorption and secretion play a major role in calcium homeostasis, as discussed in Chapter 79.
Almost all the calcium in the body (99 percent) is stored in the bone, with only about 0.1 percent in the extracellular fluid and 1.0 percent in the intracellular fluid and cell organelles. The bone, therefore, acts as a large reservoir for storing calcium and as a source of calcium when extracellular fluid calcium concentration tends to decrease.
One of the most important regulators of bone uptake and release of calcium is PTH. When extracellular fluid calcium concentration falls below normal, the parathyroid glands are directly stimulated by the low calcium levels to promote increased secretion of PTH. This hormone then acts directly on the bones to increase the resorption of bone salts (release of salts from the bones) and to release large amounts of calcium into the extracellular fluid, thereby returning calcium levels back toward normal. When calcium ion concentration is elevated, PTH secretion decreases, so almost no bone resorption occurs; instead, excess calcium is deposited in the bones. Thus, the day-to-day regulation of calcium ion concentration is mediated in large part by the effect of PTH on bone resorption.
The bones, however, do not have an inexhaustible supply of calcium. Therefore, over the long term, the intake of calcium must be balanced with calcium excretion by the gastrointestinal tract and the kidneys. The most important regulator of calcium reabsorption at both of these sites is PTH. Thus, PTH regulates plasma calcium concentration through three main effects: (1) by stimulating bone resorption; (2) by stimulating activation of vitamin D, which then increases intestinal reabsorption of calcium; and (3) by directly increasing renal tubular calcium reabsorption (Figure 29-11). The control of gastrointestinal calcium reabsorption and calcium exchange in the bones is discussed elsewhere, and the remainder of this section focuses on the mechanisms that control renal calcium excretion.
Figure 29-11 Compensatory responses to decreased plasma ionized calcium concentration mediated by parathyroid hormone (PTH) and vitamin D.
Control of Calcium Excretion by the Kidneys
Calcium is both filtered and reabsorbed in the kidneys but not secreted. Therefore, the rate of renal calcium excretion is calculated as
Only about 50 percent of the plasma calcium is ionized, with the remainder being bound to the plasma proteins or complexed with anions such as phosphate. Therefore, only about 50 percent of the plasma calcium can be filtered at the glomerulus. Normally, about 99 percent of the filtered calcium is reabsorbed by the tubules, with only about 1 percent of the filtered calcium being excreted. About 65 percent of the filtered calcium is reabsorbed in the proximal tubule, 25 to 30 percent is reabsorbed in the loop of Henle, and 4 to 9 percent is reabsorbed in the distal and collecting tubules. This pattern of reabsorption is similar to that for sodium.
As is true with the other ions, calcium excretion is adjusted to meet the body’s needs. With an increase in calcium intake, there is also increased renal calcium excretion, although much of the increase of calcium intake is eliminated in the feces. With calcium depletion, calcium excretion by the kidneys decreases as a result of enhanced tubular reabsorption.
Proximal Tubular Calcium Reabsorption
Most of the calcium reabsorption in the proximal tubule occurs through the paracellular pathway, dissolved in water and carried with the reabsorbed fluid as it flows between the cells. Only about 20% of proximal tubular calcium reabsorption occurs through the transcellular pathway in two steps: (1) calcium diffuses from the tubular lumen into the cell down an electrochemical gradient due to the much higher concentration of calcium in the tubular lumen, compared with the epithelial cell cytoplasm, and because the cell interior has a negative relative to the tubular lumen; (2) calcium exits the cell across the basolateral membrane by a calcium-ATPase pump and by sodium-calcium counter-transporter (Figure 29-12).
Figure 29-12 Mechanisms of calcium reabsorption by paracellular and transcellular pathways in the proximal tubular cells.
Loop of Henle and Distal Tubule Calcium Reabsorption
In the loop of Henle, calcium reabsorption is restricted to the thick ascending limb. Approximately 50% of calcium reabsorption in the thick ascending limb occurs through the paracellular route by passive diffusion due to the slight positive charge of the tubular lumen relative to the interstitial fluid. The remaining 50% of calcium reabsorption in the thick ascending limb occurs through the transcellular pathway, a process that is stimulated by PTH.
In the distal tubule, calcium reabsorption occurs almost entirely by active transport through the cell membrane. The mechanism for this active transport is similar to that in the proximal tubule and thick ascending limb and involves diffusion across the luminal membrane through calcium channels and exit across the basolateral membrane by a calcium-ATPase pump, as well as a sodium-calcium counter transport mechanism. In this segment, as well as in the loops of Henle, PTH stimulates calcium reabsorption. Vitamin D (Calcitrol) and calcitonin also stimulate calcium reabsorption in the thick ascending limb of Henle’s loop and in the distal tubule, although these hormones are not as important quantitatively as PTH in reducing renal calcium excretion.
Factors that Regulate Tubular Calcium Reabsorption
One of the primary controllers of renal tubular calcium reabsorption is PTH. Increased levels of PTH stimulate calcium reabsorption in the thick ascending loops of Henle and distal tubules, which reduces urinary excretion of calcium. Conversely, reduction of PTH promotes calcium excretion by decreasing reabsorption in the loops of Henle and distal tubules.
In the proximal tubule, calcium reabsorption usually parallels sodium and water reabsorption and is independent of PTH. Therefore, in instances of extracellular volume expansion or increased arterial pressure—both of which decrease proximal sodium and water reabsorption—there is also reduction in calcium reabsorption and, consequently, increased urinary excretion of calcium. Conversely, with extracellular volume contraction or decreased blood pressure, calcium excretion decreases primarily because of increased proximal tubular reabsorption.
Another factor that influences calcium reabsorption is the plasma concentration of phosphate. Increased plasma phosphate stimulates PTH, which increases calcium reabsorption by the renal tubules, thereby reducing calcium excretion. The opposite occurs with reduction in plasma phosphate concentration.
Calcium reabsorption is also stimulated by metabolic acidosis and inhibited by metabolic alkalosis. Most of the effect of hydrogen ion concentration on calcium excretion results from changes in calcium reabsorption in the distal tubule.
A summary of the factors that are known to influence calcium excretion by the renal tubules is shown in Table 29-2.
Table 29-2 Factors That Alter Renal Calcium Excretion
|
↓ Calcium Excretion |
↑ Calcium Excretion |
|
↑Parathyroid hormone (PTH) |
↓ PTH |
|
↓ Extracellular fluid volume |
↑ Extracellular fluid volume |
|
↓ Blood pressure |
↑ Blood pressure |
|
↑ Plasma phosphate |
↓ Plasma phosphate |
|
Metabolic acidosis |
Metabolic alkalosis |
|
Vitamin D3 |
Regulation of Renal Phosphate Excretion
Phosphate excretion by the kidneys is controlled primarily by an overflow mechanism that can be explained as follows: The renal tubules have a normal transport maximum for reabsorbing phosphate of about 0.1 mM/min. When less than this amount of phosphate is present in the glomerular filtrate, essentially all the filtered phosphate is reabsorbed. When more than this is present, the excess is excreted. Therefore, phosphate normally begins to spill into the urine when its concentration in the extracellular fluid rises above a threshold of about 0.8 mM/L, which gives a tubular load of phosphate of about 0.1 mM/min, assuming a GFR of 125 ml/min. Because most people ingest large quantities of phosphate in milk products and meat, the concentration of phosphate is usually maintained above 1 mM/L, a level at which there is continual excretion of phosphate into the urine.
The proximal tubule normally reabsorbs 75 to 80 percent of the filtered phosphate. The distal tubule reabsorbs about 10 percent of the filtered load, and only very small amounts are reabsorbed in the loop of Henle, collecting tubules, and collecting ducts. Approximately 10 percent of the filtered phosphate is excreted in the urine.
In the proximal tubule, phosphate reabsorption occurs mainly through the transcellular pathway. Phosphate enters the cell from the lumen by a sodium-phosphate co-transporter and exits the cell across the basolateral membrane by a process that is not well understood but may involve a counter transport mechanism in which phosphate is exchanged for an anion.
Changes in tubular phosphate reabsorptive capacity can also occur in different conditions and influence phosphate excretion. For instance, a diet low in phosphate can, over time, increase the reabsorptive transport maximum for phosphate, thereby reducing the tendency for phosphate to spill over into the urine.
PTH can play a significant role in regulating phosphate concentration through two effects: (1) PTH promotes bone resorption, thereby dumping large amounts of phosphate ions into the extracellular fluid from the bone salts, and (2) PTH decreases the transport maximum for phosphate by the renal tubules, so a greater proportion of the tubular phosphate is lost in the urine. Thus, whenever plasma PTH is increased, tubular phosphate reabsorption is decreased and more phosphate is excreted. These interrelations among phosphate, PTH, and calcium are discussed in more detail in Chapter 79.
Control of Renal Magnesium Excretion and Extracellular Magnesium Ion Concentration
More than one half of the body’s magnesium is stored in the bones. Most of the rest resides within the cells, with less than 1 percent located in the extracellular fluid. Although the total plasma magnesium concentration is about 1.8 mEq/L, more than one half of this is bound to plasma proteins. Therefore, the free ionized concentration of magnesium is only about 0.8 mEq/L.
The normal daily intake of magnesium is about 250 to 300 mg/day, but only about one half of this intake is absorbed by the gastrointestinal tract. To maintain magnesium balance, the kidneys must excrete this absorbed magnesium, about one half the daily intake of magnesium, or 125 to 150 mg/day. The kidneys normally excrete about 10 to 15 percent of the magnesium in the glomerular filtrate.
Renal excretion of magnesium can increase markedly during magnesium excess or decrease to almost nil during magnesium depletion. Because magnesium is involved in many biochemical processes in the body, including activation of many enzymes, its concentration must be closely regulated.
Regulation of magnesium excretion is achieved mainly by changing tubular reabsorption. The proximal tubule usually reabsorbs only about 25 percent of the filtered magnesium. The primary site of reabsorption is the loop of Henle, where about 65 percent of the filtered load of magnesium is reabsorbed. Only a small amount (usually <5 percent) of the filtered magnesium is reabsorbed in the distal and collecting tubules.
The mechanisms that regulate magnesium excretion are not well understood, but the following disturbances lead to increased magnesium excretion: (1) increased extracellular fluid magnesium concentration, (2) extracellular volume expansion, and (3) increased extracellular fluid calcium concentration.
Integration of Renal Mechanisms for Control of Extracellular Fluid
Extracellular fluid volume is determined mainly by the balance between intake and output of water and salt. In many instances, salt and fluid intakes are dictated by a person’s habits rather than by physiologic control mechanisms. Therefore, the burden of extracellular volume regulation is usually placed on the kidneys, which must adapt their excretion of salt and water to match intake of salt and water under steady-state conditions.
In discussing the regulation of extracellular fluid volume, we consider the factors that regulate the amount of sodium chloride in the extracellular fluid because changes in extracellular fluid sodium chloride content usually cause parallel changes in extracellular fluid volume, provided the antidiuretic hormone (ADH)-thirst mechanisms are operative. When the ADH-thirst mechanisms are functioning normally, a change in the amount of sodium chloride in the extracellular fluid is matched by a similar change in the amount of extracellular water, so osmolality and sodium concentration are maintained relatively constant.
Sodium Intake and Excretion Are Precisely Matched Under Steady-State Conditions
An important consideration in overall control of sodium excretion—or excretion of most electrolytes, for that matter—is that under steady-state conditions, excretion by the kidneys is determined by intake. To maintain life, a person must, over the long term, excrete almost precisely the amount of sodium ingested. Therefore, even with disturbances that cause major changes in kidney function, balance between intake and output of sodium usually is restored within a few days.
If disturbances of kidney function are not too severe, sodium balance may be achieved mainly by intrarenal adjustments with minimal changes in extracellular fluid volume or other systemic adjustments. But when perturbations to the kidneys are severe and intrarenal compensations are exhausted, systemic adjustments must be invoked, such as changes in blood pressure, changes in circulating hormones, and alterations of sympathetic nervous system activity.
These adjustments can be costly in terms of overall homeostasis because they cause other changes throughout the body that may, in the long run, be damaging. For example, impaired kidney function may lead to increased blood pressure that, in turn, helps to maintain normal sodium excretion. Over the long term the high blood pressure may cause injury to the blood vessels, heart, and other organs. These compensations, however, are necessary because a sustained imbalance between fluid and electrolyte intake and excretion would quickly lead to accumulation or loss of electrolytes and fluid, causing cardiovascular collapse within a few days. Thus, one can view the systemic adjustments that occur in response to abnormalities of kidney function as a necessary trade-off that brings electrolyte and fluid excretion back in balance with intake.
Sodium Excretion Is Controlled by Altering Glomerular Filtration or Tubular Sodium Reabsorption Rates
The two variables that influence sodium and water excretion are the rates of glomerular filtration and tubular reabsorption:
GFR normally is about 180 L/day, tubular reabsorption is 178.5 L/day, and urine excretion is 1.5 L/day. Thus, small changes in GFR or tubular reabsorption potentially can cause large changes in renal excretion. For example, a 5 percent increase in GFR (to 189 L/day) would cause a 9 L/day increase in urine volume, if tubular compensations did not occur; this would quickly cause catastrophic changes in body fluid volumes. Similarly, small changes in tubular reabsorption, in the absence of compensatory adjustments of GFR, would also lead to dramatic changes in urine volume and sodium excretion. Tubular reabsorption and GFR usually are regulated precisely, so excretion by the kidneys can be exactly matched to intake of water and electrolytes.
Even with disturbances that alter GFR or tubular reabsorption, changes in urinary excretion are minimized by various buffering mechanisms. For example, if the kidneys become greatly vasodilated and GFR increases (as can occur with certain drugs or high fever), this raises sodium chloride delivery to the tubules, which in turn leads to at least two intrarenal compensations: (1) increased tubular reabsorption of much of the extra sodium chloride filtered, called glomerulotubular balance, and (2) macula densa feedback, in which increased sodium chloride delivery to the distal tubule causes afferent arteriolar constriction and return of GFR toward normal. Likewise, abnormalities of tubular reabsorption in the proximal tubule or loop of Henle are partially compensated for by these same intrarenal feedbacks.
Because neither of these two mechanisms operates perfectly to restore distal sodium chloride delivery all the way back to normal, changes in either GFR or tubular reabsorption can lead to significant changes in urine sodium and water excretion. When this happens, other feedback mechanisms come into play, such as changes in blood pressure and changes in various hormones, and eventually return sodium excretion to equal sodium intake. In the next few sections, we review how these mechanisms operate together to control sodium and water balance and in so doing act also to control extracellular fluid volume. All these feedback mechanisms control renal excretion of sodium and water by altering either GFR or tubular reabsorption.
Importance of Pressure Natriuresis and Pressure Diuresis in Maintaining Body Sodium and Fluid Balance
One of the most basic and powerful mechanisms for the maintenance of sodium and fluid balance, as well as for controlling blood volume and extracellular fluid volume, is the effect of blood pressure on sodium and water excretion—called the pressure natriuresis and pressure diuresis mechanisms, respectively. As discussed in Chapter 19, this feedback between the kidneys and the circulatory system also plays a dominant role in long-term blood pressure regulation.
Pressure diuresis refers to the effect of increased blood pressure to raise urinary volume excretion, whereas pressure natriuresis refers to the rise in sodium excretion that occurs with elevated blood pressure. Because pressure diuresis and natriuresis usually occur in parallel, we refer to these mechanisms simply as “pressure natriuresis” in the following discussion.
Figure 29-13 shows the effect of arterial pressure on urinary sodium output. Note that acute increases in blood pressure of 30 to 50 mm Hg cause a twofold to threefold increase in urinary sodium output. This effect is independent of changes in activity of the sympathetic nervous system or of various hormones, such as angiotensin II, ADH, or aldosterone, because pressure natriuresis can be demonstrated in an isolated kidney that has been removed from the influence of these factors. With chronic increases in blood pressure, the effectiveness of pressure natriuresis is greatly enhanced because the increased blood pressure also, after a short time delay, suppresses renin release and, therefore, decreases formation of angiotensin II and aldosterone. As discussed previously, decreased levels of angiotensin II and aldosterone inhibit renal tubular reabsorption of sodium, thereby amplifying the direct effects of increased blood pressure to raise sodium and water excretion.
Figure 29-13 Acute and chronic effects of arterial pressure on sodium output by the kidneys (pressure natriuresis). Note that chronic increases in arterial pressure cause much greater increases in sodium output than those measured during acute increases in arterial pressure.
Pressure Natriuresis and Diuresis Are Key Components of a Renal-Body Fluid Feedback for Regulating Body Fluid Volumes and Arterial Pressure
The effect of increased blood pressure to raise urine output is part of a powerful feedback system that operates to maintain balance between fluid intake and output, as shown in Figure 29-14. This is the same mechanism that is discussed in Chapter 19 for arterial pressure control. The extracellular fluid volume, blood volume, cardiac output, arterial pressure, and urine output are all controlled at the same time as separate parts of this basic feedback mechanism.
Figure 29-14 Basic renal-body fluid feedback mechanism for control of blood volume, extracellular fluid volume, and arterial pressure. Solid lines indicate positive effects, and dashed lines indicate negative effects.
During changes in sodium and fluid intake, this feedback mechanism helps to maintain fluid balance and to minimize changes in blood volume, extracellular fluid volume, and arterial pressure as follows:
1. An increase in fluid intake (assuming that sodium accompanies the fluid intake) above the level of urine output causes a temporary accumulation of fluid in the body.
2. As long as fluid intake exceeds urine output, fluid accumulates in the blood and interstitial spaces, causing parallel increases in blood volume and extracellular fluid volume. As discussed later, the actual increases in these variables are usually small because of the effectiveness of this feedback.
3. An increase in blood volume raises mean circulatory filling pressure.
4. An increase in mean circulatory filling pressure raises the pressure gradient for venous return.
5. An increased pressure gradient for venous return elevates cardiac output.
6. An increased cardiac output raises arterial pressure.
7. An increased arterial pressure increases urine output by way of pressure diuresis. The steepness of the normal pressure natriuresis relation indicates that only a slight increase in blood pressure is required to raise urinary excretion severalfold.
8. The increased fluid excretion balances the increased intake, and further accumulation of fluid is prevented.
Thus, the renal-body fluid feedback mechanism operates to prevent continuous accumulation of salt and water in the body during increased salt and water intake. As long as kidney function is normal and the pressure diuresis mechanism is operating effectively, large changes in salt and water intake can be accommodated with only slight changes in blood volume, extracellular fluid volume, cardiac output, and arterial pressure.
The opposite sequence of events occurs when fluid intake falls below normal. In this case, there is a tendency toward decreased blood volume and extracellular fluid volume, as well as reduced arterial pressure. Even a small decrease in blood pressure causes a large decrease in urine output, thereby allowing fluid balance to be maintained with minimal changes in blood pressure, blood volume, or extracellular fluid volume. The effectiveness of this mechanism in preventing large changes in blood volume is demonstrated in Figure 29-15, which shows that changes in blood volume are almost imperceptible despite large variations in daily intake of water and electrolytes, except when intake becomes so low that it is not sufficient to make up for fluid losses caused by evaporation or other inescapable losses.
Figure 29-15 Approximate effect of changes in daily fluid intake on blood volume. Note that blood volume remains relatively constant in the normal range of daily fluid intakes.
As discussed later, there are nervous and hormonal systems, in addition to intrarenal mechanisms, that can raise sodium excretion to match increased sodium intake even without measureable increases in arterial pressure in many persons. Other individuals who are more “salt sensitive” have significant increases in arterial pressure with even moderate increases in sodium intake. With prolonged high-sodium intake, lasting over several years, high blood pressure may occur even in those persons who are not initially salt sensitive. When blood pressure does rise, pressure natriuresis provides a critical means of maintaining balance between sodium intake and urinary sodium excretion.
Precision of Blood Volume and Extracellular Fluid Volume Regulation
By studying Figure 29-14, one can see why the blood volume remains almost exactly constant despite extreme changes in daily fluid intake. The reason for this is the following: (1) A slight change in blood volume causes a marked change in cardiac output, (2) a slight change in cardiac output causes a large change in blood pressure, and (3) a slight change in blood pressure causes a large change in urine output. These factors work together to provide effective feedback control of blood volume.
The same control mechanisms operate whenever there is a blood loss because of hemorrhage. In this case, a fall in blood pressure along with nervous and hormonal factors discussed later cause fluid retention by the kidneys. Other parallel processes occur to reconstitute the red blood cells and plasma proteins in the blood. If abnormalities of red blood cell volume remain, such as occurs when there is deficiency of erythropoietin or other factors needed to stimulate red blood cell production, the plasma volume will simply make up the difference, and the overall blood volume will return essentially to normal despite the low red blood cell mass.
Distribution of Extracellular Fluid Between the Interstitial Spaces and Vascular System
From Figure 29-14 it is apparent that blood volume and extracellular fluid volume are usually controlled in parallel with each other. Ingested fluid initially goes into the blood, but it rapidly becomes distributed between the interstitial spaces and the plasma. Therefore, blood volume and extracellular fluid volume usually are controlled simultaneously.
There are circumstances, however, in which the distribution of extracellular fluid between the interstitial spaces and blood can vary greatly. As discussed in Chapter 25, the principal factors that can cause accumulation of fluid in the interstitial spaces include (1) increased capillary hydrostatic pressure, (2) decreased plasma colloid osmotic pressure, (3) increased permeability of the capillaries, and (4) obstruction of lymphatic vessels. In all these conditions, an unusually high proportion of the extracellular fluid becomes distributed to the interstitial spaces.
Figure 29-16 shows the normal distribution of fluid between the interstitial spaces and the vascular system and the distribution that occurs in edema states. When small amounts of fluid accumulate in the blood as a result of either too much fluid intake or a decrease in renal output of fluid, about 20 to 30 percent of it stays in the blood and increases the blood volume. The remainder is distributed to the interstitial spaces. When the extracellular fluid volume rises more than 30 to 50 percent above normal, almost all the additional fluid goes into the interstitial spaces and little remains in the blood. This occurs because once the interstitial fluid pressure rises from its normally negative value to become positive, the tissue interstitial spaces become compliant and large amounts of fluid then pour into the tissues without interstitial fluid pressure rising much more. In other words, the safety factor against edema, owing to a rising interstitial fluid pressure that counteracts fluid accumulation in the tissues, is lost once the tissues become highly compliant.
Figure 29-16 Approximate relation between extracellular fluid volume and blood volume, showing a nearly linear relation in the normal range but also showing the failure of blood volume to continue rising when the extracellular fluid volume becomes excessive. When this occurs, the additional extracellular fluid volume resides in the interstitial spaces and edema results.
Thus, under normal conditions, the interstitial spaces act as an “overflow” reservoir for excess fluid, sometimes increasing in volume 10 to 30 liters. This causes edema, as explained in Chapter 25, but it also acts as an important overflow release valve for the circulation, protecting the cardiovascular system against dangerous overload that could lead to pulmonary edema and cardiac failure.
To summarize, extracellular fluid volume and blood volume are controlled simultaneously, but the quantitative amounts of fluid distribution between the interstitium and the blood depend on the physical properties of the circulation and the interstitial spaces, as well as on the dynamics of fluid exchange through the capillary membranes.
Nervous and Hormonal Factors Increase the Effectiveness of Renal-Body Fluid Feedback Control
In Chapter 27, we discuss the nervous and hormonal factors that influence GFR and tubular reabsorption and, therefore, renal excretion of salt and water. These nervous and hormonal mechanisms usually act in concert with the pressure natriuresis and pressure diuresis mechanisms, making them more effective in minimizing the changes in blood volume, extracellular fluid volume, and arterial pressure that occur in response to day-to-day challenges. However, abnormalities of kidney function or of the various nervous and hormonal factors that influence the kidneys can lead to serious changes in blood pressure and body fluid volumes, as discussed later.
Sympathetic Nervous System Control of Renal Excretion: Arterial Baroreceptor and Low-Pressure Stretch Receptor Reflexes
Because the kidneys receive extensive sympathetic innervation, changes in sympathetic activity can alter renal sodium and water excretion, as well as regulation of extracellular fluid volume under some conditions. For example, when blood volume is reduced by hemorrhage, pressures in the pulmonary blood vessels and other low-pressure regions of the thorax decrease, causing reflex activation of the sympathetic nervous system. This in turn increases renal sympathetic nerve activity, which has several effects to decrease sodium and water excretion: (1) constriction of the renal arterioles, with resultant decreased GFR of the sympathetic activation if severe; (2) increased tubular reabsorption of salt and water; and (3) stimulation of renin release and increased angiotensin II and aldosterone formation, both of which further increase tubular reabsorption. And if the reduction in blood volume is great enough to lower systemic arterial pressure, further activation of the sympathetic nervous system occurs because of decreased stretch of the arterial baroreceptors located in the carotid sinus and aortic arch. All these reflexes together play an important role in the rapid restitution of blood volume that occurs in acute conditions such as hemorrhage. Also, reflex inhibition of renal sympathetic activity may contribute to the rapid elimination of excess fluid in the circulation that occurs after eating a meal that contains large amounts of salt and water.
Role of Angiotensin II in Controlling Renal Excretion
One of the body’s most powerful controllers of sodium excretion is angiotensin II. Changes in sodium and fluid intake are associated with reciprocal changes in angiotensin II formation, and this in turn contributes greatly to the maintenance of body sodium and fluid balances. That is, when sodium intake is elevated above normal, renin secretion is decreased, causing decreased angiotensin II formation. Because angiotensin II has several important effects in increasing tubular reabsorption of sodium, as explained in Chapter 27, a reduced level of angiotensin II decreases tubular reabsorption of sodium and water, thus increasing the kidneys’ excretion of sodium and water. The net result is to minimize the rise in extracellular fluid volume and arterial pressure that would otherwise occur when sodium intake increases.
Conversely, when sodium intake is reduced below normal, increased levels of angiotensin II cause sodium and water retention and oppose reductions in arterial blood pressure that would otherwise occur. Thus, changes in activity of the renin-angiotensin system act as a powerful amplifier of the pressure natriuresis mechanism for maintaining stable blood pressures and body fluid volumes.
Importance of Changes in Angiotensin II in Altering Pressure Natriuresis
The importance of angiotensin II in making the pressure natriuresis mechanism more effective is shown in Figure 29-17. Note that when the angiotensin control of natriuresis is fully functional, the pressure natriuresis curve is steep (normal curve), indicating that only minor changes in blood pressure are necessary to increase sodium excretion when sodium intake is raised.
Figure 29-17 Effects of excessive angiotensin II formation and blocking angiotensin II formation on the renal-pressure natriuresis curve. Note that high levels of angiotensin II formation decrease the slope of pressure natriuresis, making blood pressure very sensitive to changes in sodium intake. Blockade of angiotensin II formation shifts pressure natriuresis to lower blood pressures.
In contrast, when angiotensin levels cannot be decreased in response to increased sodium intake (high angiotensin II curve), as occurs in some hypertensive patients who have impaired ability to decrease renin secretion, the pressure natriuresis curve is not nearly as steep. Therefore, when sodium intake is raised, much greater increases in arterial pressure are necessary to increase sodium excretion and maintain sodium balance. For example, in most people, a 10-fold increase in sodium intake causes an increase of only a few millimeters of mercury in arterial pressure, whereas in subjects who cannot suppress angiotensin II formation appropriately in response to excess sodium, the same rise in sodium intake causes blood pressure to rise as much as 50 mm Hg. Thus, the inability to suppress angiotensin II formation when there is excess sodium reduces the slope of pressure natriuresis and makes arterial pressure very salt sensitive, as discussed in Chapter 19.
The use of drugs to block the effects of angiotensin II has proved to be important clinically for improving the kidneys’ ability to excrete salt and water. When angiotensin II formation is blocked with an angiotensin-converting enzyme inhibitor (see Figure 29-17) or an angiotensin II receptor antagonist, the renal-pressure natriuresis curve is shifted to lower pressures; this indicates an enhanced ability of the kidneys to excrete sodium because normal levels of sodium excretion can now be maintained at reduced arterial pressures. This shift of pressure natriuresis provides the basis for the chronic blood pressure–lowering effects in hypertensive patients of the angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists.
Excessive Angiotensin II Does Not Usually Cause Large Increases in Extracellular Fluid Volume Because Increased Arterial Pressure Counterbalances Angiotensin-Mediated Sodium Retention
Although angiotensin II is one of the most powerful sodium- and water-retaining hormones in the body, neither a decrease nor an increase in circulating angiotensin II has a large effect on extracellular fluid volume or blood volume as long as heart failure or kidney failure does not occur. The reason for this is that with large increases in angiotensin II levels, as occurs with a renin-secreting tumor of the kidney, the high angiotensin II levels initially cause sodium and water retention by the kidneys and a small increase in extracellular fluid volume. This also initiates a rise in arterial pressure that quickly increases kidney output of sodium and water, thereby overcoming the sodium- and water-retaining effects of the angiotensin II and re-establishing a balance between intake and output of sodium at a higher blood pressure. Conversely, after blockade of angiotensin II formation, as occurs when an angiotensin-converting enzyme inhibitor is administered, there is initial loss of sodium and water, but the fall in blood pressure offsets this effect and sodium excretion is once again restored to normal.
If the heart is weakened or there is underlying heart disease, cardiac pumping ability may not be great enough to raise arterial pressure enough to overcome the sodium retaining effects of high levels of angiotensin II; in these instances angiotensin II may cause large amounts of sodium and water retention that may progress to congestive heart failure. Blockade of angiotensin II formation may, in these cases, relieve some of the sodium and water retention and attenuate the large expansion of extracellular fluid volume associated with heart failure.
Role of Aldosterone in Controlling Renal Excretion
Aldosterone increases sodium reabsorption, especially in the cortical collecting tubules. The increased sodium reabsorption is also associated with increased water reabsorption and potassium secretion. Therefore, the net effect of aldosterone is to make the kidneys retain sodium and water but also to increase potassium excretion in the urine.
The function of aldosterone in regulating sodium balance is closely related to that described for angiotensin II. That is, with reduction in sodium intake, the increased angiotensin II levels that occur stimulate aldosterone secretion, which in turn contributes to the reduction in urinary sodium excretion and, therefore, to the maintenance of sodium balance. Conversely, with high sodium intake, suppression of aldosterone formation decreases tubular reabsorption, allowing the kidneys to excrete larger amounts of sodium. Thus, changes in aldosterone formation also aid the pressure natriuresis mechanism in maintaining sodium balance during variations in salt intake.
During Chronic Oversecretion of Aldosterone, the Kidneys “Escape” from Sodium Retention as Arterial Pressure Rises
Although aldosterone has powerful effects on sodium reabsorption, when there is excessive infusion of aldosterone or excessive formation of aldosterone, as occurs in patients with tumors of the adrenal gland (Conn’s syndrome), the increased sodium reabsorption and decreased sodium excretion by the kidneys are transient. After 1 to 3 days of sodium and water retention, the extracellular fluid volume rises by about 10 to 15 percent and there is a simultaneous increase in arterial blood pressure. When the arterial pressure rises sufficiently, the kidneys “escape” from the sodium and water retention and thereafter excrete amounts of sodium equal to the daily intake, despite continued presence of high levels of aldosterone. The primary reason for the escape is the pressure natriuresis and diuresis that occur when the arterial pressure rises.
In patients with adrenal insufficiency who do not secrete enough aldosterone (Addison’s disease), there is increased excretion of sodium and water, reduction in extracellular fluid volume, and a tendency toward low blood pressure. In the complete absence of aldosterone, the volume depletion may be severe unless the person is allowed to eat large amounts of salt and drink large amounts of water to balance the increased urine output of salt and water.
Role of ADH in Controlling Renal Water Excretion
As discussed in Chapter 28, ADH plays an important role in allowing the kidneys to form a small volume of concentrated urine while excreting normal amounts of salt. This effect is especially important during water deprivation, which strongly elevates plasma levels of ADH that in turn increase water reabsorption by the kidneys and help to minimize the decreases in extracellular fluid volume and arterial pressure that would otherwise occur. Water deprivation for 24 to 48 hours normally causes only a small decrease in extracellular fluid volume and arterial pressure. However, if the effects of ADH are blocked with a drug that antagonizes the action of ADH to promote water reabsorption in the distal and collecting tubules, the same period of water deprivation causes a substantial fall in both extracellular fluid volume and arterial pressure. Conversely, when there is excess extracellular volume, decreasedADH levels reduce reabsorption of water by the kidneys, thus helping to rid the body of the excess volume.
Excess ADH Secretion Usually Causes Only Small Increases in Extracellular Fluid Volume but Large Decreases in Sodium Concentration
Although ADH is important in regulating extracellular fluid volume, excessive levels of ADH seldom cause large increases in arterial pressure or extracellular fluid volume. Infusion of large amounts of ADH into animals initially causes renal retention of water and a 10 to 15 percent increase in extracellular fluid volume. As the arterial pressure rises in response to this increased volume, much of the excess volume is excreted because of the pressure diuresis mechanism. Also, the rise in blood pressure causes pressure natriuresis and loss of sodium from the extracellular fluid. After several days of ADH infusion, the blood volume and extracellular fluid volume are elevated no more than 5 to 10 percent and the arterial pressure is also elevated by less than 10 mm Hg. The same is true for patients with inappropriate ADH syndrome, in which ADH levels may be elevated severalfold.
Thus, high levels of ADH do not cause major increases of either body fluid volume or arterial pressure, although high ADH levels can cause severe reductions in extracellular sodium ion concentration. The reason for this is that increased water reabsorption by the kidneys dilutes the extracellular sodium, and at the same time, the small increase in blood pressure that does occur causes loss of sodium from the extracellular fluid in the urine through pressure natriuresis.
In patients who have lost their ability to secrete ADH because of destruction of the supraoptic nuclei, the urine volume may become 5 to 10 times normal. This is almost always compensated for by ingestion of enough water to maintain fluid balance. If free access to water is prevented, the inability to secrete ADH may lead to marked reductions in blood volume and arterial pressure.
Role of Atrial Natriuretic Peptide in Controlling Renal Excretion
Thus far, we have discussed mainly the role of sodium- and water-retaining hormones in controlling extracellular fluid volume. However, several different natriuretic hormones may also contribute to volume regulation. One of the most important of the natriuretic hormones is a peptide referred to as atrial natriuretic peptide (ANP), released by the cardiac atrial muscle fibers. The stimulus for release of this peptide appears to be increased stretch of the atria, which can result from excess blood volume. Once released by the cardiac atria, ANP enters the circulation and acts on the kidneys to cause small increases in GFR and decreases in sodium reabsorption by the collecting ducts. These combined actions of ANP lead to increased excretion of salt and water, which helps to compensate for the excess blood volume.
Changes in ANP levels probably help to minimize changes in blood volume during various disturbances, such as increased salt and water intake. However, excessive production of ANP or even complete lack of ANP does not cause major changes in blood volume because these effects can easily be overcome by small changes in blood pressure, acting through pressure natriuresis. For example, infusions of large amounts of ANP initially raise urine output of salt and water and cause slight decreases in blood volume. In less than 24 hours, this effect is overcome by a slight decrease in blood pressure that returns urine output toward normal, despite continued excess of ANP.
Integrated Responses to Changes in Sodium Intake
The integration of the different control systems that regulate sodium and fluid excretion under normal conditions can be summarized by examining the homeostatic responses to progressive increases in dietary sodium intake. As discussed previously, the kidneys have an amazing capability to match their excretion of salt and water to intakes that can range from as low as one tenth of normal to as high as 10 times normal.
High Sodium Intake Suppresses Antinatriuretic Systems and Activates Natriuretic Systems
As sodium intake is increased, sodium output initially lags slightly behind intake. The time delay results in a small increase in the cumulative sodium balance, which causes a slight increase in extracellular fluid volume. It is mainly this small increase in extracellular fluid volume that triggers various mechanisms in the body to increase sodium excretion. These mechanisms include the following:
1. Activation of low-pressure receptor reflexes that originate from the stretch receptors of the right atrium and the pulmonary blood vessels. Signals from the stretch receptors go to the brain stem and there inhibit sympathetic nerve activity to the kidneys to decrease tubular sodium reabsorption. This mechanism is most important in the first few hours—or perhaps the first day—after a large increase in salt and water intake.
2. Suppression of angiotensin II formation, caused by increased arterial pressure and extracellular fluid volume expansion, decreases tubular sodium reabsorption by eliminating the normal effect of angiotensin II to increase sodium reabsorption. Also, reduced angiotensin II decreases aldosterone secretion, thus further reducing tubular sodium reabsorption.
3. Stimulation of natriuretic systems, especially ANP, contributes further to increased sodium excretion. Thus, the combined activation of natriuretic systems and suppression of sodium- and water-retaining systems leads to an increase in sodium excretion when sodium intake is increased. The opposite changes take place when sodium intake is reduced below normal levels.
4. Small increases in arterial pressure, caused by volume expansion, may occur with large increases in sodium intake; this raises sodium excretion through pressure natriuresis. As discussed previously, if the nervous, hormonal, and intrarenal mechanisms are operating effectively, measurable increases in blood pressure may not occur even with large increases in sodium intake over several days. However, when high sodium intake is sustained for months or years, the kidneys may become damaged and less effective in excreting sodium, necessitating increased blood pressure to maintain sodium balance through the pressure natriuresis mechanism.
Conditions That Cause Large Increases in Blood Volume and Extracellular Fluid Volume
Despite the powerful regulatory mechanisms that maintain blood volume and extracellular fluid volume reasonably constant, there are abnormal conditions that can cause large increases in both of these variables. Almost all of these conditions result from circulatory abnormalities.
Increased Blood Volume and Extracellular Fluid Volume Caused by Heart Diseases
In congestive heart failure, blood volume may increase 15 to 20 percent and extracellular fluid volume sometimes increases by 200 percent or more. The reason for this can be understood by re-examination of Figure 29-14. Initially, heart failure reduces cardiac output and, consequently, decreases arterial pressure. This in turn activates multiple sodium-retaining systems, especially the renin-angiotensin, aldosterone, and sympathetic nervous systems. In addition, the low blood pressure itself causes the kidneys to retain salt and water. Therefore, the kidneys retain volume in an attempt to return the arterial pressure and cardiac output toward normal.
If the heart failure is not too severe, the rise in blood volume can often return cardiac output and arterial pressure virtually all the way to normal and sodium excretion will eventually increase back to normal, although there will remain increased extracellular fluid volume and blood volume to keep the weakened heart pumping adequately. However, if the heart is greatly weakened, arterial pressure may not be able to increase enough to restore urine output to normal. When this occurs, the kidneys continue to retain volume until the person develops severe circulatory congestion and may eventually die of pulmonary edema.
In myocardial failure, heart valvular disease, and congenital abnormalities of the heart, increased blood volume serves as an important circulatory compensation, which helps to return cardiac output and blood pressure toward normal. This allows even the weakened heart to maintain a life-sustaining level of cardiac output.
Increased Blood Volume Caused by Increased Capacity of Circulation
Any condition that increases vascular capacity will also cause the blood volume to increase to fill this extra capacity. An increase in vascular capacity initially reduces mean circulatory filling pressure (see Figure 29-14), which leads to decreased cardiac output and decreased arterial pressure. The fall in pressure causes salt and water retention by the kidneys until the blood volume increases sufficiently to fill the extra capacity.
In pregnancy the increased vascular capacity of the uterus, placenta, and other enlarged organs of the woman’s body regularly increases the blood volume 15 to 25 percent. Similarly, in patients who have large varicose veins of the legs, which in rare instances may hold up to an extra liter of blood, the blood volume simply increases to fill the extra vascular capacity. In these cases, salt and water are retained by the kidneys until the total vascular bed is filled enough to raise blood pressure to the level required to balance renal output of fluid with daily intake of fluid.
Conditions That Cause Large Increases in Extracellular Fluid Volume but with Normal Blood Volume
In several conditions extracellular fluid volume becomes markedly increased but blood volume remains normal or even slightly reduced. These conditions are usually initiated by leakage of fluid and protein into the interstitium, which tends to decrease the blood volume. The kidneys’ response to these conditions is similar to the response after hemorrhage. That is, the kidneys retain salt and water in an attempt to restore blood volume toward normal. Much of the extra fluid, however, leaks into the interstitium, causing further edema.
Nephrotic Syndrome—Loss of Plasma Proteins in Urine and Sodium Retention by the Kidneys
The general mechanisms that lead to extracellular edema are reviewed in Chapter 25. One of the most important clinical causes of edema is the so-called nephrotic syndrome. In nephrotic syndrome, the glomerular capillaries leak large amounts of protein into the filtrate and the urine because of increased glomerular capillary permeability. Thirty to 50 grams of plasma protein can be lost in the urine each day, sometimes causing the plasma protein concentration to fall to less than one-third normal. As a consequence of the decreased plasma protein concentration, the plasma colloid osmotic pressure falls to low levels. This causes the capillaries all over the body to filter large amounts of fluid into the various tissues, which in turn causes edema and decreases the plasma volume.
Renal sodium retention in nephrotic syndrome occurs through multiple mechanisms activated by leakage of protein and fluid from the plasma into the interstitial fluid, including stimulation of various sodium-retaining systems such as the renin-angiotensin system, aldosterone, and the sympathetic nervous system. The kidneys continue to retain sodium and water until plasma volume is restored nearly to normal. However, because of the large amount of sodium and water retention, the plasma protein concentration becomes further diluted, causing still more fluid to leak into the tissues of the body. The net result is massive fluid retention by the kidneys until tremendous extracellular edema occurs unless treatment is instituted to restore the plasma proteins.
Liver Cirrhosis—Decreased Synthesis of Plasma Proteins by the Liver and Sodium Retention by the Kidneys
A similar sequence of events occurs in cirrhosis of the liver as in nephrotic syndrome, except that in liver cirrhosis, the reduction in plasma protein concentration results from destruction of liver cells, thus reducing the ability of the liver to synthesize enough plasma proteins. Cirrhosis is also associated with large amounts of fibrous tissue in the liver structure, which greatly impedes the flow of portal blood through the liver. This in turn raises capillary pressure throughout the portal vascular bed, which also contributes to the leakage of fluid and proteins into the peritoneal cavity, a condition called ascites.
Once fluid and protein are lost from the circulation, the renal responses are similar to those observed in other conditions associated with decreased plasma volume. That is, the kidneys continue to retain salt and water until plasma volume and arterial pressure are restored to normal. In some cases, plasma volume may actually increase above normal because of increased vascular capacity in cirrhosis; the high pressures in the portal circulation can greatly distend veins and therefore increase vascular capacity.
Bibliography
Appel L.J., Brands M.W., Daniels S.R., et al. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension. 2006;47:296.
Antunes-Rodrigues J., de Castro M., Elias L.L., et al. Neuroendocrine control of body fluid metabolism. Physiol Rev. 2004;84:169.
Cowley A.W.Jr. Long-term control of arterial pressure. Physiol Rev. 1992;72:231.
Giebisch G., Hebert S.C., Wang W.H. New aspects of renal potassium transport. Pflugers Arch. 2003;446:289.
Guyton A.C. Blood pressure control—special role of the kidneys and body fluids. Science. 1991;252:1813.
Granger J.P., Hall J.E. Role of the kidney in hypertension. In: Lip G.Y.H., Hall J.E., editors. Comprehensive Hypertension. Philadelphia: Mosby-Elsevier; 2008:241-264.
Hall J.E., Granger J.P., Hall M.E., et al. Pathophysiology of hypertension. In Hurst’s The Heart, ed 12, New York: McGraw-Hill Medical; 2008:1570-1609.
Hall J.E., Brands M.W. The renin-angiotensin-aldosterone system: renal mechanisms and circulatory homeostasis. In: Seldin D.W., Giebisch G., editors. The Kidney—Physiology and Pathophysiology. ed 3. New York: Raven Press; 2000:1009-1046.
Hall J.E. Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney. J Am Soc Nephrol. 1999;10(Suppl 12):s258.
Hebert S.C., Desir G., Giebisch G., et al. Molecular diversity and regulation of renal potassium channels. Physiol Rev. 2005;85:319.
Hoenderop J.G., Bindels R.J. Epithelial Ca2+ and Mg2+ channels in health and disease. J Am Soc Nephrol. 2005;16:15.
Huang C.L., Kuo E. Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol. 2007;18:2649.
Murer H., Hernando N., Forster I., et al. Regulation of Na/Pi transporter in the proximal tubule. Annu Rev Physiol. 2003;65:531.
Schrier R.W. Decreased effective blood volume in edematous disorders: what does this mean? J Am Soc Nephrol. 2007;18:2028.
Suki W.N., Lederer E.D., Rouse D. Renal transport of calcium magnesium and phosphate. In: Brenner B.M., editor. The Kidney. ed 6. Philadelphia: WB Saunders; 2000:520-574.
Suzuki Y., Landowski C.P., Hediger M.A. Mechanisms and regulation of epithelial Ca2+ absorption in health and disease. Annu Rev Physiol. 2008;70:257.
Wall S.M. Recent advances in our understanding of intercalated cells. Curr Opin Nephrol Hypertens. 2005;14:480.
Warnock D.G. Renal genetic disorders related to K+ and Mg2+. Annu Rev Physiol. 2002;64:845.
Worcester E.M., Coe F.L. New insights into the pathogenesis of idiopathic hypercalciuria. Semin Nephrol. 2008;28:120.
Young D.B. Quantitative analysis of aldosterone’s role in potassium regulation. Am J Physiol. 1988;255:F811.
Young D.B. Analysis of long-term potassium regulation. Endocr Rev. 1985;6:24.