Regulation of Potassium Balance





Objectives


Upon completion of this chapter, the student should be able to answer the following questions:




  • How does the body maintain K + homeostasis?



  • What is the distribution of K + within the body compartments? Why is this distribution important?



  • What are the hormones and factors that regulate plasma K + levels? Why is this regulation important?



  • How do the various segments of the nephron transport K + , and how does the mechanism of K + transport by these segments determine how much K + is excreted in the urine?



  • Why are the distal tubule and collecting duct so important in regulating K + excretion?



  • How do plasma K + levels, aldosterone, vasopressin, tubular fluid flow rate, and acid-base balance influence K + excretion?





Key Terms


Hyperkalemia


Hypokalemia


Pseudohyperkalemia


Cardiac arrhythmias


Epinephrine


Insulin


Aldosterone


Tumor lysis syndrome


Rhabdomyolysis


ASDN


AVP


Chronic hypokalemia


Chronic hyperkalemia


Prostatin


ROMK


Glucocorticoids


K + homeostasis


Potassium (K + ) is one of the most abundant cations in the body and is critical for many cell functions, including cell volume regulation, intracellular pH regulation, DNA and protein synthesis, 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 the [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 K + excretion.




Overview of K + Homeostasis


Total body K + is 50 mEq/kg of body weight, or 3500 mEq for a person weighing 70 kg. A total of 98% of the K + in the body is located within cells, where its average [K + ] is 150 mEq/L. A high intracellular [K + ] is required for many cell functions, including cell growth and division and volume regulation. Only 2% of total body K + is in the ECF, where its normal concentration is approximately 4 mEq/L. [K + ] in the ECF that exceeds ∼5.0 mEq/L constitutes hyperkalemia . Conversely, [K + ] in the 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 common causes of hypokalemia include administration of diuretic drugs (see Chapter 10 ), surreptitious vomiting (i.e., bulimia), and severe diarrhea. Gitelman syndrome (a genetic defect in the Na + -Cl symporter in the apical membrane of distal tubule cells) also causes hypokalemia (see Chapter 4 , Table 4.3 ). Hyperkalemia also is a common electrolyte disorder and is seen in 1%–10% of hospitalized patients. Hyperkalemia often is seen in patients with renal failure, in persons taking drugs such as angiotensin-converting enzyme inhibitors and K + -sparing diuretics (see Chapter 10 ), in persons 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 while blood is being drawn. Red blood cells, like all cells, contain K + , and lysis of red blood cells releases K + into the plasma, artificially elevating the plasma [K + ].


The large concentration difference of K + across cell membranes (approximately 146 mEq/L) is maintained by the Na + -K + -adenosine triphosphatase (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 and for the contractility of cardiac, skeletal, and smooth muscle cells ( Fig. 7.1 ).




Fig. 7.1


The effects of variations in plasma K + concentration on the resting membrane potential of skeletal muscle. Hyperkalemia causes the membrane potential to become less negative and decreases the excitability by inactivating fast Na + channels, which are responsible for the depolarizing phase of the action potential. Hypokalemia hyperpolarizes the membrane potential and thereby reduces excitability, because a larger stimulus is required to depolarize the membrane potential to the threshold potential. Resting indicates the “normal” resting membrane potential. Normal threshold indicates the membrane threshold potential.



In the Clinic


Cardiac arrhythmias are produced by both hypokalemia and hyperkalemia. The electrocardiogram (ECG; Fig. 7.2 ) monitors the electrical activity of the heart and is a quick and easy way to determine whether changes in plasma [K + ] influence the heart and other excitable cells. In contrast, measurements of the plasma [K + ] by the clinical laboratory require a blood sample, and values often are not immediately available. The first sign of hyperkalemia is the appearance of tall, thin T waves on the ECG. Further increases in the plasma [K + ] prolong the PR interval, depress the ST segment, and lengthen the QRS interval on the ECG. Finally, as the 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 on the ECG.




Fig. 7.2


Electrocardiograms from individuals with varying plasma K + concentrations. See the text for details.

Modified from Barker L, Burton J, Zieve P: Principles of ambulatory medicine, ed 5, Baltimore, 1999, Williams & Wilkins.



After a meal, the K + absorbed by the gastrointestinal tract enters the ECF within minutes ( Fig. 7.3 ). If the K + ingested during a normal meal (≈33 mEq) were to remain in the ECF compartment (14 L), the plasma [K + ] would increase by 2.4 mEq/L (33 mEq added to 14 L of ECF):


<SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='33mEq/14L=2.4mEq/L’>33mEq/14L=2.4mEq/L33mEq/14L=2.4mEq/L
33mEq/14L=2.4mEq/L



Fig. 7.3


Overview of potassium homeostasis. An increase in plasma insulin, epinephrine, or aldosterone stimulates K + movement into cells and decreases plasma K + concentration ([K + ]), whereas a decrease in the plasma concentration of these hormones has the opposite effect and 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. The excretion of K + by the kidneys is regulated by plasma [K + ], aldosterone, and arginine vasopressin (AVP) .


This rise in the plasma [K + ], which could have deleterious effects on the electrical activity of the heart and other excitable tissues, is prevented by the rapid uptake (within minutes) of K + into cells. Because the excretion of K + by the kidneys after a meal is relatively slow (within hours), the uptake of K + by cells is essential to prevent life-threatening hyperkalemia. Maintaining total body K + constant requires all the K + absorbed by the gastrointestinal tract to eventually be excreted by the kidneys. This process requires about 6 hours.





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 common causes of hypokalemia include administration of diuretic drugs (see Chapter 10 ), surreptitious vomiting (i.e., bulimia), and severe diarrhea. Gitelman syndrome (a genetic defect in the Na + -Cl symporter in the apical membrane of distal tubule cells) also causes hypokalemia (see Chapter 4 , Table 4.3 ). Hyperkalemia also is a common electrolyte disorder and is seen in 1%–10% of hospitalized patients. Hyperkalemia often is seen in patients with renal failure, in persons taking drugs such as angiotensin-converting enzyme inhibitors and K + -sparing diuretics (see Chapter 10 ), in persons 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 while blood is being drawn. Red blood cells, like all cells, contain K + , and lysis of red blood cells releases K + into the plasma, artificially elevating the plasma [K + ].


The large concentration difference of K + across cell membranes (approximately 146 mEq/L) is maintained by the Na + -K + -adenosine triphosphatase (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 and for the contractility of cardiac, skeletal, and smooth muscle cells ( Fig. 7.1 ).




Fig. 7.1


The effects of variations in plasma K + concentration on the resting membrane potential of skeletal muscle. Hyperkalemia causes the membrane potential to become less negative and decreases the excitability by inactivating fast Na + channels, which are responsible for the depolarizing phase of the action potential. Hypokalemia hyperpolarizes the membrane potential and thereby reduces excitability, because a larger stimulus is required to depolarize the membrane potential to the threshold potential. Resting indicates the “normal” resting membrane potential. Normal threshold indicates the membrane threshold potential.





In the Clinic


Cardiac arrhythmias are produced by both hypokalemia and hyperkalemia. The electrocardiogram (ECG; Fig. 7.2 ) monitors the electrical activity of the heart and is a quick and easy way to determine whether changes in plasma [K + ] influence the heart and other excitable cells. In contrast, measurements of the plasma [K + ] by the clinical laboratory require a blood sample, and values often are not immediately available. The first sign of hyperkalemia is the appearance of tall, thin T waves on the ECG. Further increases in the plasma [K + ] prolong the PR interval, depress the ST segment, and lengthen the QRS interval on the ECG. Finally, as the 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 on the ECG.




Fig. 7.2


Electrocardiograms from individuals with varying plasma K + concentrations. See the text for details.

Modified from Barker L, Burton J, Zieve P: Principles of ambulatory medicine, ed 5, Baltimore, 1999, Williams & Wilkins.




Regulation of Plasma [K + ]


Several hormones, including epinephrine , insulin , and aldosterone , increase K + uptake into skeletal muscle, liver, bone, and red blood cells by stimulating Na + -K + -ATPase, the Na + -K + -2Cl symporter, and the Na + -Cl symporter in these cells ( Box 7.1 ; see Fig. 7.3 ). Acute stimulation of K + uptake (i.e., within minutes) is mediated by an increase in the activity of existing Na + -K + -ATPase, Na + -K + -2Cl , and Na + -Cl transporters, whereas the chronic increase in K + uptake (i.e., within hours to days) is mediated by an increase in the quantity of Na + -K + -ATPase. A rise in the plasma [K + ] that follows K + absorption by the gastrointestinal tract stimulates insulin secretion from the pancreas, aldosterone release from the adrenal cortex, and epinephrine secretion from the adrenal medulla. In contrast, a decrease in the plasma [K + ] inhibits the release of these hormones. Whereas insulin and epinephrine act within a few minutes, aldosterone requires about 1 hour to stimulate K + uptake into cells.



BOX 7.1

Major Factors, Hormones, and Drugs Influencing the Distribution of K + Between the Intracellular and Extracellular Fluid Compartments


Physiologic: Keep Plasma [K + ] Constant





  • Adrenergic receptor agonists



  • Insulin



  • Aldosterone



Pathophysiologic: Displace Plasma [K + ] From Normal





  • Acid-base disorders



  • Plasma osmolality



  • Cell lysis



  • Vigorous exercise



Drugs That Induce Hyperkalemia





  • Dietary potassium supplements



  • Angiotensin-converting enzyme inhibitors



  • K + -sparing diuretics (see Chapter 10 )



  • Heparin




Epinephrine


Catecholamines affect the distribution of K + across cell membranes by activating α- and β 2 -adrenergic receptors. The stimulation of α-adrenoceptors releases K + from cells, especially in the liver, whereas the stimulation of β 2 -adrenceptors promotes K + uptake by cells. For example, the activation of β 2 -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 β 2 -adrenoceptor antagonist. Furthermore, the release of epinephrine during stress (e.g., myocardial ischemia) can lower the plasma [K + ] rapidly.


Insulin


Insulin also stimulates K + uptake 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 healthy 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. Although insulin-stimulated glucose uptake into cells is impaired in patients with chronic kidney disease (CKD), insulin stimulation of K + uptake into cells is normal.


Aldosterone


Aldosterone, like catecholamines and insulin, also promotes K + uptake into cells. A rise in aldosterone levels (e.g., primary aldosteronism) causes hypokalemia, whereas a fall in aldosterone levels (e.g., in persons with Addison disease) causes hyperkalemia. As discussed later and illustrated in Fig. 7.3 , aldosterone also stimulates urinary K + excretion. Thus aldosterone alters the plasma [K + ] by acting on K + uptake into cells and by altering urinary K + excretion.




Epinephrine


Catecholamines affect the distribution of K + across cell membranes by activating α- and β 2 -adrenergic receptors. The stimulation of α-adrenoceptors releases K + from cells, especially in the liver, whereas the stimulation of β 2 -adrenceptors promotes K + uptake by cells. For example, the activation of β 2 -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 β 2 -adrenoceptor antagonist. Furthermore, the release of epinephrine during stress (e.g., myocardial ischemia) can lower the plasma [K + ] rapidly.




Insulin


Insulin also stimulates K + uptake 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 healthy 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. Although insulin-stimulated glucose uptake into cells is impaired in patients with chronic kidney disease (CKD), insulin stimulation of K + uptake into cells is normal.




Aldosterone


Aldosterone, like catecholamines and insulin, also promotes K + uptake into cells. A rise in aldosterone levels (e.g., primary aldosteronism) causes hypokalemia, whereas a fall in aldosterone levels (e.g., in persons with Addison disease) causes hyperkalemia. As discussed later and illustrated in Fig. 7.3 , aldosterone also stimulates urinary K + excretion. Thus aldosterone alters the plasma [K + ] by acting on K + uptake into cells and by altering urinary K + excretion.




Alterations of Plasma [K + ]


Several factors can alter the plasma [K + ] (see Box 7.1 ). These factors are not involved in the regulation of the plasma [K + ], but rather alter the movement of K + between the intracellular fluid and ECF and thus cause the development of hypokalemia or hyperkalemia.


Acid-Base Balance


Metabolic acidosis increases the plasma [K + ], whereas metabolic alkalosis decreases it. Respiratory alkalosis causes hypokalemia. 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 and H 2 SO 4 ) increases the plasma [K + ] much more than an equivalent acidosis produced by the accumulation of organic acids (e.g., lactic acid, acetic acid, and keto acids). The reduced pH—that is, 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 the Na + -K + -ATPase and the Na + -K + -2Cl symporter. In addition, the movement of H + into cells occurs as the cells buffer changes in the [H + ] of the ECF (see Chapter 8 ). As H + moves across the cell membranes, K + moves in the opposite direction; thus cations are neither gained nor lost across cell membranes. Metabolic alkalosis has the opposite effect; the 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 the plasma also influences the distribution of K + across cell membranes. An increase in the osmolality of the ECF enhances K + release by cells and thus increases extracellular [K + ]. The plasma [K + ] may increase by 0.4 to 0.8 mEq/L for an elevation of 10 mOsm/kg H 2 O in plasma osmolality. In patients with diabetes mellitus who do not take insulin, plasma K + often is elevated, in part because of the lack of insulin and in part because of the increase in the concentration of glucose in plasma (i.e., from a normal value of ∼100 mg/dL to as high as ∼1200 mg/dL in some cases), 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 the cell [K + ] 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, which results from 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 the 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, the plasma [K + ] increases by 0.3 mEq/L. With vigorous exercise the plasma [K + ] may increase by 2.0 mEq/L or more.



In the Clinic


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


Because acid-base balance, plasma osmolality, cell lysis, and exercise do not maintain the plasma [K + ] at a normal value, they do not contribute to K + homeostasis (see Box 7.1 ). The extent to which these pathophysiologic states alter the plasma [K + ] depends on the integrity of the homeostatic mechanisms that regulate plasma [K + ] (e.g., the secretion of epinephrine, insulin, and aldosterone).





Acid-Base Balance


Metabolic acidosis increases the plasma [K + ], whereas metabolic alkalosis decreases it. Respiratory alkalosis causes hypokalemia. 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 and H 2 SO 4 ) increases the plasma [K + ] much more than an equivalent acidosis produced by the accumulation of organic acids (e.g., lactic acid, acetic acid, and keto acids). The reduced pH—that is, 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 the Na + -K + -ATPase and the Na + -K + -2Cl symporter. In addition, the movement of H + into cells occurs as the cells buffer changes in the [H + ] of the ECF (see Chapter 8 ). As H + moves across the cell membranes, K + moves in the opposite direction; thus cations are neither gained nor lost across cell membranes. Metabolic alkalosis has the opposite effect; the 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 the plasma also influences the distribution of K + across cell membranes. An increase in the osmolality of the ECF enhances K + release by cells and thus increases extracellular [K + ]. The plasma [K + ] may increase by 0.4 to 0.8 mEq/L for an elevation of 10 mOsm/kg H 2 O in plasma osmolality. In patients with diabetes mellitus who do not take insulin, plasma K + often is elevated, in part because of the lack of insulin and in part because of the increase in the concentration of glucose in plasma (i.e., from a normal value of ∼100 mg/dL to as high as ∼1200 mg/dL in some cases), 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 the cell [K + ] 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, which results from 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 the 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, the plasma [K + ] increases by 0.3 mEq/L. With vigorous exercise the plasma [K + ] may increase by 2.0 mEq/L or more.



In the Clinic


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


Because acid-base balance, plasma osmolality, cell lysis, and exercise do not maintain the plasma [K + ] at a normal value, they do not contribute to K + homeostasis (see Box 7.1 ). The extent to which these pathophysiologic states alter the plasma [K + ] depends on the integrity of the homeostatic mechanisms that regulate plasma [K + ] (e.g., the secretion of epinephrine, insulin, and aldosterone).

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Oct 10, 2019 | Posted by in NEPHROLOGY | Comments Off on Regulation of Potassium Balance
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