CHAPTER 29 Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume
Regulation of Extracellular Fluid Potassium Concentration and Potassium Excretion (p. 361)
Extracellular fluid potassium concentration normally is regulated precisely at about 4.2 mEq/L, seldom rising or falling more than ±0.3 mEq/L. A special difficulty in regulating potassium concentration is the fact that about 98% of the total body potassium is contained in the cells and only 2% in the extracellular fluid. Failure to rapidly rid the extracellular fluid of the potassium ingested each day could result in life-threatening hyperkalemia (increased plasma potassium concentration). A small loss of potassium from the extracellular fluid could cause severe hypokalemia in the absence of rapid compensatory responses.
Internal Potassium Distribution Is Regulated
After ingestion of a large meal, the rise in extracellular fluid potassium concentration would be lethal if the ingested potassium did not move rapidly into the cells. For example, absorption of 40 mmol of potassium (the amount contained in a meal rich in vegetables and fruit) into an extracellular fluid volume of 14 L would increase the plasma potassium concentration by about 2.9 mmol/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, over time, eliminate the excess. Table 29–1 summarizes some of the factors that can influence the distribution of potassium between the intra- 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 | Insulin deficiency (diabetes mellitus) |
| Aldosterone | Aldosterone deficiency (Addison’s disease) |
| β-adrenergic stimulation | β-adrenergic blockade Cell lysis |
| Alkalosis | Strenuous exercise Increased extracellular fluid osmolarity Acidosis |
The most important hormone that increases cell potassium uptake after a meal is insulin. In people who have insulin deficiency resulting from diabetes mellitus, the rise in plasma potassium concentration after eating a meal is much greater than normal.
Increased potassium intake also stimulates secretion of aldosterone, which increases cell potassium uptake. Excess aldosterone secretion, as occurs in 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 significant hyperkalemia resulting from accumulation of potassium in the extracellular space as well as to renal retention of potassium.
Metabolic acidosis increases the extracellular potassium concentration in part by causing loss of potassium from the cells, whereas metabolic alkalosis decreases the extracellular fluid potassium concentration.
Cell injury can cause release of large amounts of potassium from the cells into the extracellular compartment. This can cause significant hyperkalemia if large amounts of tissue are destroyed, as occurs with severe muscle injury or red blood cell lysis.
Strenuous exercise can cause hyperkalemia by releasing potassium from skeletal muscle.
Increased extracellular fluid osmolarity causes cell dehydration, which in turn raises the intracellular potassium concentration and promotes diffusion of potassium from the cells to the extracellular fluid.
Daily Variations in Potassium Excretion Are Controlled Mainly by Changes in Secretion in Distal and Collecting Tubules
Maintaining potassium balance depends primarily on renal excretion because the amount of potassium in the feces is normally about 5% to 10% of the potassium intake. Renal potassium excretion is determined by the sum of three processes: (1) the rate of potassium filtration [the glomerular filtration rate (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. About 65% of the filtered potassium is reabsorbed in the proximal tubule and another 25% to 30% in the loop of Henle.
The normal day-to-day variation of potassium excretion, however, is regulated mainly by secretion in the distal and collecting tubules rather than by changes in glomerular filtration or tubular reabsorption. Potassium is sometimes reabsorbed in these tubular segments (e.g., during potassium depletion), and at other times it is secreted in large amounts depending on the needs of the body. With high potassium intake, the required extra excretion of potassium is achieved almost entirely through increased secretion of potassium in the distal and collecting tubules.
Potassium Secretion Occurs in the Principal Cells of the Late Distal Tubules and Cortical Collecting Tubules
Secretion of potassium from the peritubular capillary blood into the lumen of the distal and collecting tubules is a three-step process involving (1) passive diffusion of potassium from blood to the renal interstitium, (2) active transport of potassium from interstitium into tubular cells by the sodium-potassium ATPase pump at the basolateral membrane, and (3) passive diffusion of potassium from the cell interior to the tubular fluid. The primary factors that control potassium secretion by the principal cells include the following:
Aldosterone Is the Primary Hormonal Mechanism for Feedback Control of Extracellular Fluid Potassium Ion Concentration
There is direct feedback by which aldosterone and extracellular fluid potassium ion concentration are linked. This feedback mechanism operates as follows: Whenever the extracellular fluid potassium concentration increases above normal, aldosterone secretion is stimulated, which increases renal excretion of potassium, returning the extracellular potassium concentration toward normal. The opposite changes take place when the potassium concentration is too low.
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. Increased hydrogen ion concentration inhibits potassium secretion is by reducing the activity of the sodium-potassium ATPase pump.
Control of Renal Calcium Excretion and Extracellular Calcium Ion Concentration (p. 367)
As with other substances, 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. Only about 10% of the ingested calcium normally is reabsorbed in the intestinal tract, with the remainder excreted in the feces. Most of the calcium in the body (99%) is stored in the bones, with only about 1% in the intracellular fluid and 0.1% in the extracellular fluid. Bones therefore act as large reservoirs for storing calcium and as sources of calcium when the extracellular fluid calcium concentration tends to decrease (hypocalcemia).
Parathyroid Hormone (PTH) Is an Important Regulator of Bone Uptake and Release of Calcium
Decreased extracellular fluid calcium concentration promotes increased secretion of PTH, which acts directly on bones to increase the resorption of bone salts (release of bone salts from the bones) and therefore release of large amounts of calcium into the extracellular fluid. When the calcium ion concentration is elevated (hypercalcemia), PTH secretion decreases, and the excess calcium is deposited in the bones.
The bones, however, do not have an inexhaustible supply of calcium. Over the long term, the intake of calcium must be balanced with calcium excretion by the gastrointestinal tract and kidneys. The most important regulator of calcium reabsorption at both of these sites is PTH; thus PTH regulates the plasma calcium concentration through three main effects: (1) stimulating bone resorption; (2) stimulating activation of vitamin D, which increases intestinal absorption of calcium; and (3) directly increasing renal tubular calcium reabsorption. This is discussed in more detail in Chapter 79.
PTH Reduces Renal Calcium Excretion
Calcium is not secreted by the renal tubules, and its excretion rate is therefore determined by the rate of calcium filtration and tubular reabsorption. One of the primary controllers of renal tubular calcium reabsorption is PTH. With increased levels of PTH, there is increased calcium reabsorption through the thick ascending loop of Henle and distal tubule, which reduces urinary excretion of calcium. Conversely, decreased PTH promotes calcium excretion by reducing reabsorption in the loop of Henle and distal tubules.
Greater plasma phosphate concentration stimulates PTH, which increases calcium reabsorption by the renal tubules and decreases calcium excretion.
Calcium reabsorption is also stimulated by metabolic acidosis and inhibited by metabolic alkalosis.
Integration of Renal Mechanisms for Control of Extracellular Fluid Volume (p. 370)
When discussing control of extracellular fluid volume, we must consider factors that regulate the amount of sodium chloride in extracellular fluid because the sodium chloride content of the extracellular fluid usually parallels the extracellular fluid volume, provided the antidiuretic hormone (ADH)-thirst mechanisms are operative. In most cases, the burden of extracellular volume regulation is placed on the kidneys, which must adapt their excretion to match varying intakes of salt and water.
Sodium Excretion Is Precisely Matched with Sodium Intake Under Steady-State Conditions
An important consideration for overall control of sodium excretion—or excretion of any electrolyte—is that under steady-state conditions a person must excrete almost precisely the amount of sodium ingested. Even with disturbances that cause major changes in renal excretion of sodium, the balance between intake and excretion is usually restored within a few days.
Sodium Excretion Is Controlled by Altering Glomerular Filtration or Tubular Reabsorption Rates
The kidney alters sodium and water excretion by changing the rate of filtration, the rate of tubular reabsorption, or both, as follows:
As discussed previously, glomerular filtration and tubular reabsorption are both regulated by multiple factors, including hormones, sympathetic activity, and arterial pressure. Normally, the GFR is about 180 L/day, tubular reabsorption is 178.5 L/day, and urine excretion is 1.5 L/day. Small changes in either the GFR or tubular reabsorption have the potential to cause large changes in renal excretion.
Tubular reabsorption and GFR are usually regulated precisely, so excretion by the kidneys can be exactly matched to the intake of water and electrolytes. Even with disturbances that alter the GFR or tubular reabsorption, changes in urinary excretion are minimized by various buffering mechanisms. Two intrarenal buffering mechanisms are (1) glomerulotubular balance, which allows the renal tubules to increase their reabsorption rates in response to increased GFR and filtered sodium load, and (2) macula densa feedback, in which increased sodium chloride delivery to the distal tubules, resulting from an increased GFR or decreased proximal or loop of Henle sodium reabsorption, causes afferent arteriolar constriction and decreased GFR.
Because neither of these two intrarenal feedback mechanisms operates perfectly to restore urine output to normal, changes in the GFR or tubular reabsorption can lead to significant changes in sodium and water excretion. When this happens, systemic feedback mechanisms come into play—such as changes in blood pressure and changes in various hormones—that eventually return sodium excretion to equal intake.
Importance of Pressure Natriuresis and Pressure Diuresis for Maintaining Body Sodium and Fluid Balance (p. 371)
One of the most powerful mechanisms for controlling blood volume and extracellular fluid volume and for maintaining sodium and fluid balance is the effect of blood pressure on sodium and water excretion (pressure natriuresis and pressure diuresis, respectively). As discussed in Chapter 19, this feedback between the kidneys and circulation also plays a dominant role in long-term blood pressure regulation.
Pressure diuresis refers to the effect of increased arterial pressure to increase urinary volume excretion, whereas pressure natriuresis refers to the increased sodium excretion that occurs with increased arterial pressure. Because pressure diuresis and natriuresis usually occur in parallel, we often refer to these mechanisms simply as pressure natriuresis.
Pressure Natriuresis Is a Key Component of the Renal–Body Fluid Feedback Mechanism
During changes in sodium and fluid intake, this mechanism helps maintain fluid balance and minimizes changes in blood volume, extracellular fluid volume, and arterial pressure as follows:
The renal–body fluid feedback mechanism prevents continuous accumulation of salt and water in the body during increased salt and water intake. So long as kidney function is normal and pressure natriuresis is operating effectively, large increases in salt and water intake can be accommodated with only slight increases in blood volume, extracellular fluid volume, and arterial pressure. The opposite sequence of events occurs when fluid intake falls below normal.
As discussed later, there are nervous and hormonal systems, in addition to intrarenal mechanisms, that can raise salt and water excretion to match increased intake even without measurable increases in arterial pressure in many persons. Some individuals, however, are more “salt sensitive” and have significant increases in arterial pressure with even moderate increases in sodium intake. When blood pressure does rise, pressure natriuresis provides a critical means of maintaining balance between sodium intake and urinary sodium excretion.
Distribution of Extracellular Fluid Between the Interstitial Spaces and Vascular System (p. 373)
Ingested fluid and salt initially enter the blood but rapidly become distributed between the interstitial spaces and the plasma. Blood volume and extracellular fluid volume usually are controlled simultaneously and in parallel. There are conditions, however, that can markedly alter the distribution of extracellular fluid between the interstitial spaces and blood.
As discussed in Chapter 25, the principal factors that can cause loss of fluid from the plasma into the interstitial spaces (edema) include (1) increased capillary hydrostatic pressure, (2) decreased plasma colloid osmotic pressure, (3) increased permeability of the capillaries, and (4) obstruction of the lymphatic vessels.
Nervous and Hormonal Factors Increase the Effectiveness of Renal–Body Fluid Feedback (p. 373)
Nervous and hormonal mechanisms act in concert with pressure natriuresis to minimize the changes in blood volume, extracellular fluid volume, and arterial pressure that occur in response to day-to-day challenges. Abnormal kidney function or abnormal nervous and hormonal factors that influence the kidneys, however, can lead to serious changes in blood pressure and body fluid volumes (discussed later).
Sympathetic Nervous System Control of Renal Excretion by Arterial Baroreceptor and Low-Pressure Stretch Receptor Reflexes
The kidneys receive extensive sympathetic innervation, and under some conditions changes in sympathetic activity can alter renal sodium and water excretion and the extracellular fluid volume. For example, when blood volume is reduced by hemorrhage, reflex activation of the sympathetic nervous system occurs because of decreased pressure in the pulmonary blood vessels and other low-pressure regions of the thorax and because of low arterial pressure. The increased sympathetic activity in turn has several effects by which to reduce sodium and water excretion: (1) renal vasoconstriction, which decreases the GFR; (2) increased tubular reabsorption of salt and water; and (3) stimulation of renin release and increased formation of angiotensin II and aldosterone, both of which further elevate tubular reabsorption. All of these mechanisms together play an important role in the rapid restitution of the blood volume that occurs during acute conditions associated with reduced blood volume, low arterial pressure, or both.
Reflex decreases in renal sympathetic activity may contribute to rapid elimination of excess fluid in the circulation after ingestion of a meal that contains large amounts of salt and water.
Angiotensin II Is a Powerful Controller of Renal Excretion
When sodium intake is increased above normal, renin secretion decreases and causes reduced angiotensin II formation. Reduced angiotensin II levels have several effects on the kidney that decrease tubular sodium reabsorption (see Chapter 27). Conversely, when sodium intake is reduced, increased levels of angiotensin cause sodium and water retention and oppose decreases in arterial pressure that would otherwise occur. Changes in the activity of the renin-angiotensin system act as powerful amplifiers of the pressure natriuresis mechanism for maintaining stable blood pressure and body fluid volumes.
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 in persons with an otherwise normal cardiovascular system. The reason for this is that with large increases in angiotensin II levels, such as occurs with a renin-secreting tumor in the kidney, there is only transient sodium and water retention, which elevates the arterial pressure; this quickly increases kidney output of sodium and water, thereby overcoming the sodium-retaining effects of angiotensin II and reestablishing a balance between intake and output of sodium at a higher arterial pressure.
Conversely, blockade of angiotensin II formation with drugs, such as converting enzyme inhibitors and angiotensin II antagonists, greatly increases the ability of the kidneys to excrete salt and water but does not cause a major change in extracellular fluid volume. After blockade of angiotensin II, there is a transient increase in sodium and water excretion, but this reduces the arterial pressure, which helps re-establish the sodium balance. This effect of angiotensin II blockers has proved to be important for lowering blood pressure in hypertensive patients.
Aldosterone Has a Major Role in Controlling Renal Sodium Excretion
The function of aldosterone in regulating sodium balance is closely related to that described for angiotensin II; with decreased sodium intake, the increased angiotensin II levels stimulate aldosterone secretion, which contributes to decreased urinary sodium excretion and the maintenance of sodium balance. Conversely, with high sodium intake, suppression of aldosterone formation decreases tubular sodium reabsorption, allowing the kidneys to secrete large amounts of sodium. Changes in aldosterone formation also help the pressure natriuresis mechanism maintain sodium balance during variations in sodium intake.
However, when there is excess aldosterone formation, as occurs in patients with tumors of the adrenal gland, the increased sodium reabsorption and decreased sodium excretion usually last only a few days, and the extracellular fluid volume increases by only about 10% to 15%, causing increased arterial pressure. When the arterial pressure rises sufficiently, the kidneys “escape” from sodium and water retention (because of pressure natriuresis) and thereafter excrete amounts of sodium equal to the daily intake, despite continued high levels of aldosterone.
ADH Controls Renal Water Excretion
As explained previously, ADH plays an important role in allowing the kidneys to form a small volume of concentrated urine while excreting normal amounts of sodium. This effect is especially important during water deprivation. Conversely, when there is excess extracellular fluid volume, decreased ADH levels reduce reabsorption of water by the kidneys and help rid the body of excess volume.
Excessive levels of ADH, however, rarely cause large increases in arterial pressure or extracellular fluid volume. Infusion of large amounts of ADH into animals initially increases the extracellular fluid volume by only 10% to 15%. As the arterial pressure rises in response to this increased volume, much of the excess volume is excreted because of pressure diuresis; after several days, the blood volume and extracellular fluid volume are elevated by no more than 5% to 10%, and the arterial pressure is elevated by less than 10 mm Hg. High levels of ADH do not cause major increases in body fluid volume or arterial pressure, although high ADH levels can cause severe reductions in the extracellular sodium ion concentration.
Integrated Responses to Changes in Sodium Intake (p. 376)
Integration of the various control systems that regulate sodium and fluid excretion can be summarized by examining the homeostatic responses to increases in dietary sodium intake. As sodium intake is increased, sodium output initially lags behind intake. This causes slight increases in the cumulative sodium balance and the extracellular fluid volume. It is mainly the small increase in extracellular fluid volume that triggers various mechanisms in the body to increase the amount of sodium excretion. These mechanisms are as follows:
The combined activation of natriuretic systems and suppression of sodium- and water-retaining systems leads to increased excretion of sodium when sodium intake is increased. The opposite changes take place when sodium intake is reduced below normal levels.
Conditions That Cause Large Increases in Blood Volume and Extracellular Fluid Volume (p. 376)
Despite the powerful regulatory mechanisms that maintain blood volume and extracellular fluid volume at reasonably constant levels, there are abnormal conditions that can cause large increases in both of these variables. Almost all of these conditions result from circulatory abnormalities, including the following:
Conditions That Cause Large Increases in Extracellular Fluid Volume but with Normal Blood Volume (p. 377)
There are several pathophysiologic conditions in which the extracellular fluid volume becomes markedly increased but the blood volume remains normal or even slightly decreased. 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—the kidneys retain salt and water in an attempt to restore the blood volume toward normal. Two examples are as follows: