CHAPTER 35 Potassium, Calcium, and Phosphate Homeostasis

K⁺ HOMEOSTASIS

Potassium (K⁺) is one of the most abundant cations in the body, and it is critical for many cell functions, including regulation of cell volume, regulation of intracellular pH, synthesis of DNA and protein, growth, enzyme function, resting membrane potential, and cardiac and neuromuscular activity. Despite wide fluctuations in dietary K⁺ intake, [K⁺] in cells and extracellular fluid (ECF) remains remarkably constant. Two sets of regulatory mechanisms safeguard K⁺ homeostasis. First, several mechanisms regulate [K⁺] in the ECF. Second, other mechanisms maintain the amount of K⁺ in the body constant by adjusting renal K⁺ excretion to match dietary K⁺ intake. It is the kidneys that regulate excretion of K⁺.

Total body [K⁺] is 50 mEq/kg of body weight, or 3500 mEq for a 70-kg individual. Ninety-eight percent of the K⁺ in the body is located within cells, where the average [K⁺] is 150 mEq/L. High intracellular [K⁺] is required for many cell functions, including cell growth and division and volume regulation. Only 2% of total body [K⁺] is located in the ECF, where its normal concentration is approximately 4 mEq/L. A [K⁺] in ECF that exceeds 5.0 mEq/L constitutes hyperkalemia. Conversely, a [K⁺] in ECF of less than 3.5 mEq/L constitutes hypokalemia.

IN THE CLINIC

Hypokalemia is one of the most common electrolyte disorders in clinical practice and can be observed in as many as 20% of hospitalized patients. The most frequent causes of hypokalemia include administration of diuretic drugs, surreptitious vomiting (e.g., bulimia), and severe diarrhea. Gitelman’s syndrome (a genetic defect in the Na⁺-Cl⁻ symporter in the apical membrane of distal tubule cells) also causes hypokalemia (see Chapter 33, Table 33-3). Hyperkalemia is also a common electrolyte disorder and is seen in 1% to 10% of hospitalized patients. Hyperkalemia often occurs in patients with renal failure, in patients taking drugs, including angiotensin-converting enzyme (ACE) inhibitors and K⁺-sparing diuretics, in patients with hyperglycemia (i.e., high blood sugar), and in the elderly. Pseudohyperkalemia, a falsely high plasma [K⁺], is caused by traumatic lysis of red blood cells during blood drawing. Red blood cells, like all cells, contain K⁺, and lysis of red blood cells releases K⁺ into plasma, thereby artificially elevating plasma [K⁺].

The large concentration difference of K⁺ across cell membranes (approximately 146 mEq/L) is maintained by the operation of Na⁺,K⁺-ATPase. This [K⁺] gradient is important in maintaining the potential difference across cell membranes. Thus, K⁺ is critical for the excitability of nerve and muscle cells, as well as for the contractility of cardiac, skeletal, and smooth muscle cells (Fig. 35-1).

Figure 35-1 The effects of variations in plasma [K⁺] on the resting membrane potential of skeletal muscle. Hyperkalemia causes the membrane potential to become less negative, which decreases excitability by inactivating the fast Na⁺ channels responsible for the depolarizing phase of the action potential. Hypokalemia hyperpolarizes the membrane potential and thereby reduces excitability.

After a meal, the K⁺ absorbed by the gastrointestinal tract enters the ECF within minutes (see Fig. 35-3). If the K⁺ ingested during a normal meal (≈33 mEq) were to remain in the ECF compartment (14 L), plasma [K⁺] would increase by a potentially lethal 2.4 mEq/L (33 mEq added to 14 L of ECF):

Figure 35-3 Overview of K⁺ homeostasis. An increase in plasma insulin, epinephrine, or aldosterone stimulates movement of K⁺ into cells and decreases plasma [K⁺], whereas a fall in the plasma concentration of these hormones increases plasma [K⁺]. The amount of K⁺ in the body is determined by the kidneys. An individual is in K⁺ balance when dietary intake and urinary output (plus output by the gastrointestinal tract) are equal. Excretion of K⁺ by the kidneys is regulated by plasma [K⁺], aldosterone, and ADH.

Equation 35-1

This rise in plasma [K⁺] is prevented by the rapid (minutes) uptake of K⁺ into cells. Because excretion of K⁺ by the kidneys after a meal is relatively slow (hours), uptake of K⁺ by cells is essential to prevent lifethreatening hyperkalemia. Maintaining total body [K⁺] constant requires that all the K⁺ absorbed by the gastrointestinal tract eventually be excreted by the kidneys. This process requires about 6 hours.

IN THE CLINIC

Cardiac arrhythmias are produced by both hypokalemia and hyperkalemia. The electrocardiogram (ECG; see Fig. 35-2 and Chapter 16) monitors the electrical activity of the heart and is a fast and easy way to determine whether changes in plasma [K⁺] influence the heart and other excitable cells. In contrast, measurement of plasma [K⁺] by the clinical laboratory requires a blood sample, and values are often not immediately available. The first sign of hyperkalemia is the appearance of tall, thin T waves on the ECG. Further increases in plasma [K⁺] prolong the PR interval, depress the ST segment, and lengthen the QRS interval of the ECG. Finally, as plasma [K⁺] approaches 10 mEq/L, the P wave disappears, the QRS interval broadens, the ECG appears as a sine wave, and the ventricles fibrillate (i.e., manifest rapid, uncoordinated contractions of muscle fibers). Hypokalemia prolongs the QT interval, inverts the T wave, and lowers the ST segment of the ECG.

Figure 35-2 Electrocardiographs from individuals with varying plasma [K⁺]. Hyperkalemia increases the height of the T wave, and hypokalemia inverts the T wave. See text for details.

(Modified from Barker L et al: Principles of Ambulatory Medicine, 5th ed. Baltimore, Williams & Wilkins, 1999.)

REGULATION OF PLASMA [K⁺]

As illustrated in Figure 35-3 and Table 35-1, several hormones, including epinephrine, insulin, and aldosterone, increase uptake of K⁺ into skeletal muscle, liver, bone, and red blood cells by stimulating Na⁺,K⁺-ATPase, the 1Na⁺-1K⁺-2Cl⁻ symporter, and the Na⁺-Cl⁻ symporter in these cells. Acute stimulation of K⁺ uptake (i.e., within minutes) is mediated by an increased turnover rate of existing Na⁺,K⁺-ATPase, 1Na⁺-1K⁺-2Cl⁻, and Na⁺-Cl⁻ transporters, whereas a chronic increase in K⁺ uptake (i.e., within hours to days) is mediated by an increase in the quantity of Na⁺,K⁺-ATPase. The rise in plasma [K⁺] that follows K⁺ absorption by the gastrointestinal tract stimulates secretion of insulin from the pancreas, release of aldosterone from the adrenal cortex, and secretion of epinephrine from the adrenal medulla. In contrast, a decrease in plasma [K⁺] inhibits the release of these hormones. Whereas insulin and epinephrine act within a few minutes, aldosterone requires about an hour to stimulate uptake of K⁺ into cells.

Table 35-1 Major Factors, Hormones, and Drugs Influencing the Distribution of K⁺ between the Intracellular and Extracellular Fluid Compartments

Epinephrine

Catecholamines affect the distribution of K⁺ across cell membranes by activating α- and β₂-adrenergic receptors. Stimulation of α-adrenoceptors releases K⁺ from cells, especially in the liver, whereas stimulation of β₂-adrenoceptors promotes K⁺ uptake by cells.

For example, activation of β₂-adrenoceptors after exercise is important in preventing hyperkalemia. The rise in plasma [K⁺] after a K⁺-rich meal is greater if the patient has been pretreated with propranolol, a β₂-adrenoceptor antagonist. Furthermore, the release of epinephrine during stress (e.g., myocardial ischemia) can rapidly lower plasma [K⁺].

Insulin

Insulin also stimulates uptake of K⁺ into cells. The importance of insulin is illustrated by two observations. First, the rise in plasma [K⁺] after a K⁺-rich meal is greater in patients with diabetes mellitus (i.e., insulin deficiency) than in normal people. Second, insulin (and glucose to prevent insulin-induced hypoglycemia) can be infused to correct hyperkalemia. Insulin is the most important hormone that shifts K⁺ into cells after the ingestion of K⁺ in a meal.

Aldosterone

Aldosterone, like catecholamines and insulin, also promotes uptake of K⁺ into cells. A rise in aldosterone levels (e.g., primary aldosteronism) causes hypokalemia, whereas a fall in aldosterone levels (e.g., Addison’s disease) causes hyperkalemia. As discussed later, aldosterone also stimulates urinary K⁺ excretion. Thus, aldosterone alters plasma [K⁺] by acting on uptake of K⁺ into cells and altering urinary K⁺ excretion.

ALTERATIONS IN PLASMA [K⁺]

Several factors can alter plasma [K⁺] (Table 35-1). These factors are not involved in the regulation of plasma [K⁺] but rather alter the movement of K⁺ between the intracellular fluid (ICF) and ECF and thus cause the development of hypokalemia or hyperkalemia.

Acid-Base Balance

Metabolic acidosis increases the plasma [K⁺], whereas metabolic alkalosis and respiratory alkalosis decreases it. In contrast, respiratory acidosis has little or no effect on the plasma [K⁺]. Metabolic acidosis produced by the addition of inorganic acids (e.g., HCl, H₂SO₄) increases plasma [K⁺] much more than an equivalent acidosis produced by the accumulation of organic acids (e.g., lactic acid, acetic acid, keto acids). The reduced pH (i.e., increased [H⁺]) promotes the movement of H⁺ into cells and the reciprocal movement of K⁺ out of cells to maintain electroneutrality. This effect of acidosis occurs in part because acidosis inhibits the transporters that accumulate K⁺ inside cells, including Na⁺,K⁺-ATPase and the 1Na⁺-1K⁺-2Cl⁻ symporter. In addition, movement of H⁺ into cells occurs as the cells buffer changes in [H⁺] of the ECF (see Chapter 36). As H⁺ moves across the cell membranes, K⁺ moves in the opposite direction, and thus cations are neither gained nor lost across cell membranes. Metabolic alkalosis has the opposite effect; plasma [K⁺] decreases as K⁺ moves into cells and H⁺ exits.

Although organic acids produce a metabolic acidosis, they do not cause significant hyperkalemia. Two explanations have been suggested for the reduced ability of organic acids to cause hyperkalemia. First, the organic anion may enter the cell with H⁺ and thereby eliminate the need for K⁺-H⁺ exchange across the membrane. Second, organic anions may stimulate insulin secretion, which moves K⁺ into cells. This movement may counteract the direct effect of the acidosis, which moves K⁺ out of cells.

Plasma Osmolality

The osmolality of plasma also influences the distribution of K⁺ across cell membranes. An increase in the osmolality of ECF enhances the release of K⁺ by cells and thus increases extracellular [K⁺]. Plasma [K⁺] may increase by 0.4 to 0.8 mEq/L with a 10 mOsm/kg H₂O elevation in plasma osmolality. In patients with diabetes mellitus who do not take insulin, plasma [K⁺] is often elevated, in part because of the lack of insulin and in part because of the increase in plasma [glucose] (i.e., from a normal value of ≈100 mg/dL to as high as ≈1200 mg/dL), which increases plasma osmolality. Hypoosmolality has the opposite action. The alterations in plasma [K⁺] associated with changes in osmolality are related to changes in cell volume. For example, as plasma osmolality increases, water leaves cells because of the osmotic gradient across the plasma membrane (see Chapter 1). Water leaves cells until the intracellular osmolality equals that of the ECF. This loss of water shrinks cells and causes [K⁺] in cells to rise. The rise in intracellular [K⁺] provides a driving force for the exit of K⁺ from cells. This sequence increases plasma [K⁺]. A fall in plasma osmolality has the opposite effect.

Cell Lysis

Cell lysis causes hyperkalemia as a result of the addition of intracellular K⁺ to the ECF. Severe trauma (e.g., burns) and some conditions such as tumor lysis syndrome (i.e., chemotherapy-induced destruction of tumor cells) and rhabdomyolysis (i.e., destruction of skeletal muscle) destroy cells and release K⁺ and other cell solutes into the ECF. In addition, gastric ulcers may cause seepage of red blood cells into the gastrointestinal tract. The blood cells are digested, and the K⁺ released from the cells is absorbed and can cause hyperkalemia.

Exercise

More K⁺ is released from skeletal muscle cells during exercise than during rest. The ensuing hyperkalemia depends on the degree of exercise. In people walking slowly, plasma [K⁺] increases by 0.3 mEq/L. With vigorous exercise, plasma [K⁺] may increase by 2.0 mEq/L.

K⁺ EXCRETION BY THE KIDNEYS

The kidneys play a major role in maintaining K⁺ balance. As illustrated in Figure 35-3, the kidneys excrete 90% to 95% of the K⁺ ingested in the diet. Excretion equals intake even when intake increases by as much as 10-fold. This balance in urinary excretion and dietary intake underscores the importance of the kidneys in maintaining K⁺ homeostasis. Although small amounts of K⁺ are lost each day in feces and sweat (approximately 5% to 10% of the K⁺ ingested in the diet), this amount is essentially constant, is not regulated, and therefore is relatively less important than the K⁺ excreted by the kidneys. K⁺ secretion from blood into tubular fluid by cells of the distal tubule and collecting duct system is the key factor in determining urinary K⁺ excretion (Fig. 35-4).

Figure 35-4 K⁺ transport along the nephron. Excretion of K⁺ depends on the rate and direction of K⁺ transport by the distal tubule and collecting duct. Percentages refer to the amount of filtered K⁺ reabsorbed or secreted by each nephron segment. Left, Dietary K⁺ depletion. An amount of K⁺ equal to 1% of the filtered load of K⁺ is excreted. Right, Normal and increased dietary K⁺ intake. An amount of K⁺ equal to 15% to 80% of the filtered load is excreted. CCD, cortical collecting duct; DT, distal tubule; IMCD, inner medullary collecting duct; PT, proximal tubule; TAL, thick ascending limb.

IN THE CLINIC

Exercise-induced changes in plasma [K⁺] do not usually produce symptoms and are reversed after several minutes of rest. However, exercise can lead to life-threatening hyperkalemia in individuals (1) who have endocrine disorders that affect the release of insulin, epinephrine, or aldosterone; (2) whose ability to excrete K⁺ is impaired (e.g., renal failure); or (3) who take certain medications, such as β₂-adrenergic blockers. For example, during exercise, plasma [K⁺] may increase by at least 2 to 4 mEq/L in individuals who take β₂adrenergic receptor antagonists for hypertension.

Because acid-base balance, plasma osmolality, cell lysis, and exercise do not maintain plasma [K⁺] at a normal value, they do not contribute to K⁺ homeostasis (Table 35-1). The extent to which these pathophysiological states alter plasma [K⁺] depends on the integrity of the homeostatic mechanisms that regulate plasma [K⁺] (e.g., secretion of epinephrine, insulin, and aldosterone).

Because K⁺ is not bound to plasma proteins, it is freely filtered by the glomerulus. When individuals ingest 100 mEq of K⁺ per day, urinary K⁺ excretion is about 15% of the amount filtered. Accordingly, K⁺ must be reabsorbed along the nephron. When dietary K⁺ intake increases, however, K⁺ excretion can exceed the amount filtered. Thus, K⁺ can also be secreted.

The proximal tubule reabsorbs about 67% of the filtered K⁺ under most conditions. Approximately 20% of the filtered K⁺ is reabsorbed by the loop of Henle, and as with the proximal tubule, the amount reabsorbed is a constant fraction of the amount filtered. In contrast to these segments, which can only reabsorb K⁺, the distal tubule and collecting duct are able to reabsorb or secrete K⁺. The rate of K⁺ reabsorption or secretion by the distal tubule and collecting duct depends on a variety of hormones and factors. When 100 mEq/day of K⁺ is ingested, it is secreted by these nephron segments. A rise in dietary K⁺ intake increases K⁺ secretion. K⁺ secretion can increase the amount of K⁺ that appears in urine so that it approaches 80% of the amount filtered (Fig. 35-4). In contrast, a low-K⁺ diet activates K⁺ reabsorption along the distal tubule and collecting duct so that urinary excretion falls to about 1% of the K⁺ filtered by the glomerulus (Fig. 35-4). The kidneys cannot reduce K⁺ excretion to the same low levels as they can for Na⁺ (i.e., 0.2%). Therefore, hypokalemia can develop in individuals placed on a K⁺-deficient diet. Because the magnitude and direction of K⁺ transport by the distal tubule and collecting duct are variable, the overall rate of urinary K⁺ excretion is determined by these tubular segments.

IN THE CLINIC

In individuals with advanced renal disease, the kidneys are unable to eliminate K⁺ from the body. Therefore, plasma [K⁺] rises. The resulting hyperkalemia reduces the resting membrane potential (i.e., the voltage becomes less negative), and this reduced potential decreases the excitability of neurons, cardiac cells, and muscle cells by inactivating fast Na⁺ channels, which are critical for the depolarization phase of the action potential (Fig. 35-1). Severe, rapid increases in plasma [K⁺] can lead to cardiac arrest and death. In contrast, in patients taking diuretic drugs for hypertension, urinary K⁺ excretion often exceeds dietary K⁺ intake. Accordingly, K⁺ balance is negative, and hypokalemia develops. This decline in extracellular [K⁺] hyperpolarizes the resting cell membrane (i.e., the voltage becomes more negative) and reduces the excitability of neurons, cardiac cells, and muscle cells. Severe hypokalemia can lead to paralysis, cardiac arrhythmias, and death. Hypokalemia can also impair the ability of the kidneys to concentrate the urine and can stimulate the renal production of NH₄⁺, which affects acid-base balance (see Chapter 36). Therefore, maintenance of high intracellular [K⁺], low extracellular [K⁺], and a high [K⁺] gradient across cell membranes is essential for a number of cellular functions.

CELLULAR MECHANISM OF K⁺ SECRETION BY PRINCIPAL CELLS IN THE DISTAL TUBULE AND COLLECTING DUCT

Figure 35-5 illustrates the cellular mechanisms of K⁺ secretion by principal cells in the distal tubule and collecting duct. Secretion from blood into the tubule lumen is a two-step process: (1) uptake of K⁺ from blood across the basolateral membrane by Na⁺,K⁺-ATPase and (2) diffusion of K⁺ from the cell into tubular fluid via K⁺ channels. Na⁺,K⁺-ATPase creates a high intracellular [K⁺] that provides the chemical driving force for exit of K⁺ across the apical membrane through K⁺ channels. Although K⁺ channels are also present in the basolateral membrane, K⁺ preferentially leaves the cell across the apical membrane and enters the tubular fluid. K⁺ transport follows this route for two reasons. First, the electrochemical gradient of K⁺ across the apical membrane favors its downhill movement into tubular fluid. Second, the permeability of the apical membrane to K⁺ is greater than that of the basolateral membrane. Therefore K⁺ preferentially diffuses across the apical membrane into tubular fluid. The three major factors that control the rate of K⁺ secretion by the distal tubule and the collecting duct are

1. The activity of Na⁺,K⁺-ATPase

2. The driving force (electrochemical gradient) for movement of K⁺ across the apical membrane

3. The permeability of the apical membrane to K⁺

Figure 35-5 Cellular mechanism of K⁺ secretion by a principal cell in the distal tubule and collecting duct. The numbers indicate the sites where K⁺ secretion is regulated. 1, Na⁺,K⁺-ATPase; 2, electrochemical gradient of K⁺ across the apical membrane; 3, permeability of the apical membrane to K⁺.

Every change in K⁺ secretion results from an alteration in one or more of these factors.

Intercalated cells reabsorb K⁺ via an H⁺,K⁺-ATPase transport mechanism located in the apical membrane (see Chapter 36). This transporter mediates uptake of K⁺ in exchange for H⁺. The pathway for exit of K⁺ from intercalated cells into blood is unknown. Reabsorption of K⁺ is activated by a low K⁺-diet.