The maintenance of potassium (K+) balance is essential for the normal function of excitable tissues (e.g., nerve, skeletal muscle, cardiac muscle). Recall from Chapters 1 and 4 that the K+ concentration gradient across excitable cell membranes sets the resting membrane potential. Recall, also, that changes in resting membrane potential alter excitability by opening or closing gates on the Na+ channels, which are responsible for the upstroke of the action potential. Changes in either intracellular or extracellular K+ concentration alter the resting membrane potential and, as a consequence, alter the excitability of these tissues.
Most of the total body K+ is located in the ICF: 98% of the total K+ content is in the intracellular compartment and 2% is in the extracellular compartment. A consequence of this distribution is that the intracellular K+concentration (150 mEq/L) is much higher than the extracellular concentration (4.5 mEq/L). This large concentration gradient for K+ is maintained by the Na+-K+ ATPase that is present in all cell membranes.
One challenge to maintaining the low extracellular K+ concentration is the large amount of K+ present in the intracellular compartment. A small shift of K+ into or out of the cells can produce a large change in the extracellular K+concentration. The distribution of K+ across cell membranes is called internal K+ balance. Hormones, drugs, and various pathologic states alter this distribution and, as a consequence, can alter the extracellular K+ concentration.
Another challenge to maintaining the low extracellular K+ concentration is the variation in dietary K+ intake in humans: Dietary K+ can vary from as low as 50 mEq/day to as high as 150 mEq/day. To maintain K+ balance, urinary excretion of K+ must be equal to K+ intake. Thus, on a daily basis, urinary excretion of K+ must be capable of varying from 50 to 150 mEq/day. The renal mechanisms that allow for this variability are called external K+ balance.
Internal K+ Balance
Internal K+ balance is the distribution of K+ across cell membranes. To reemphasize, most K+ is present inside the cells and even small K+ shifts across cell membranes can cause large changes in K+concentrations in ECF and blood. The effects of hormones, drugs, and pathologic states that alter this distribution of K+ are summarized in Figure 6-30 and in Table 6-8. A shift of K+ out of cells produces an increase in the blood K+ concentration called hyperkalemia. A shift of K+ into cells produces a decrease in the blood K+ concentration called hypokalemia.
Figure 6–30 Agents affecting internal K+ balance. Arrows show directions of K+ movement into and out of cells. ECF, Extracellular fluid; ICF, intracellular fluid.
Table 6–8 Internal K+ Balance—Shifts across Cell Membranes
Causes of K+ Shift Out of Cells → Hyperkalemia
Causes of K+ Shift into Cells → Hypokalemia
Insulin stimulates K+ uptake into cells by increasing the activity of Na+-K+ ATPase. Physiologically, this effect of insulin is responsible for the uptake of dietary K+ into the cells following a meal. Thus, in response to food ingestion, insulin is secreted by the endocrine pancreas. One effect of this insulin (in addition to stimulation of glucose uptake into cells) is to stimulate K+ uptake into cells. This action ensures that ingested K+ does not remain in the ECF and produce hyperkalemia.
Deficiency of insulin, as occurs in type I diabetes mellitus, produces the opposite effect: decreased uptake of K+ into cells and hyperkalemia. When a person with untreated type I diabetes mellitus ingests a meal containing K+, the K+ remains in the ECF because insulin is not available to promote its uptake into cells. (Conversely, high levels of insulin can produce hypokalemia.)
Acid-base abnormalities often are associated with K+ disturbances. One of the mechanisms underlying internal K+ balance involves H+-K+ exchange across cell membranes. This exchange is useful because ICF has considerable buffering capacity for H+. In order to take advantage of these buffers, H+ must enter or leave the cells. To preserve electroneutrality, however, H+ cannot enter or leave cells by itself; either it must be accompanied by an anion, or it must be exchanged for another cation. When H+ is exchanged for another cation, that cation is K+.
In alkalemia, the H+ concentration in blood is decreased: H+ leaves the cells and K+ enters the cells, producing hypokalemia. On the other hand, in acidemia, the H+ concentration in blood is increased: H+enters the cells and K+leaves the cells, producing hyperkalemia.
Acid-base disturbances do not always produce a K+ shift across cell membranes, however, and it is important to note the following exceptions: First, respiratory acidosis and respiratory alkalosis typically do not cause a K+ shift because these conditions are caused by a primary disturbance in CO2. Because CO2 is lipid soluble, it freely crosses cell membranes and needs no exchange with K+ to preserve electroneutrality. Second, several forms of metabolic acidosis are caused by an excess of an organic acid (e.g., lactic acid, ketoacids, salicylic acid), which does not require a K+ shift. When an organic anion such as lactate is available to enter the cell with H+, electroneutrality is preserved. (Chapter 7 discusses the conditions under which an acid-base disturbance causes a K+ shift and when it does not.)
Adrenergic Agonists and Antagonists
Catecholamines alter the distribution of K+ across cell membranes by two separate receptors and mechanisms. Activation of β2-adrenergic receptors by β2 agonists (e.g., albuterol), by increasing the activity of the Na+-K+ ATPase, causes a shift of K+ into cells and may produce hypokalemia. On the other hand, activation of α-adrenergic receptors causes a shift of K+ out of cells and may produce hyperkalemia. The effects of adrenergic antagonists on the blood K+ concentration also are predictable: β2-adrenergic antagonists (e.g., propranolol) cause a shift of K+ out of cells, and α-adrenergic antagonists cause a shift of K+ into cells.
Hyperosmolarity (increased osmolarity of ECF) causes a shift of K+ out of cells. The mechanism involves water flow across cell membranes, which occurs in response to a change in ECF osmolarity. For example, if the osmolarity of ECF is increased, water will flow from ICF to ECF because of the osmotic gradient. As water leaves the cells, the intracellular K+ concentration increases, which then drives the diffusion of K+ from ICF to ECF. (A simpler way of visualizing the mechanism is to think of water flow from ICF to ECF as “dragging” K+ with it.)
Cell lysis (breakdown of cell membranes) releases a large amount of K+ from the ICF and produces hyperkalemia. Examples of cell lysis include burn, rhabdomyolysis (breakdown of skeletal muscle), and malignant cells being destroyed during cancer chemotherapy.
Exercise causes a K+ shift out of cells; the depletion of cellular ATP stores opens K+ channels in the muscle cell membranes and K+ moves out of the cells down its electrochemical gradient. Usually, the shift is small and produces only a slight increase in blood K+ concentration, which is reversed during a subsequent period of rest. However, in a person treated with a β2-adrenergic antagonist (which independently produces a K+ shift out of cells), or in those with impaired renal function (in which K+ cannot be adequately excreted), strenuous exercise can result in hyperkalemia.
As an aside, a K+ shift out of cells assists in the local control of blood flow to exercising skeletal muscle. Recall that blood flow in exercising muscle is controlled by vasodilator metabolites, one of which is K+. As K+ is released from cells during exercise, it acts directly on skeletal muscle arterioles, dilating them and increasing local blood flow.
External K+ Balance—Renal Mechanisms
On a daily basis, the urinary excretion of K+ is exactly equal to the dietary K+ (minus small amounts of K+ lost from the body via extrarenal routes such as the gastrointestinal tract or sweat). The physiologic concept of balance is now familiar. A person is in K+ balance when excretion of K+ equals intake of K+. If excretion of K+ is less than intake, then a person is in positive K+ balance and hyperkalemia can occur. If excretion of K+ is greater than intake, then a person is in negative K+ balance and hypokalemia can occur.
Maintaining K+ balance is a particular challenge because dietary K+ intake is so variable (50 to 150 mEq/day), both from one person to another and from day-to-day in the same person. Thus, the renal mechanisms responsible for external K+ balance must be flexible enough to ensure that K+ excretion matches K+ intake over a wide range. To accomplish this, K+ is handled in the kidneys by a combination offiltration, reabsorption, and secretionmechanisms (Fig. 6-31).
Figure 6–31 K+ handling in the nephron. Arrows show location of K+ reabsorption or secretion; numbers are percentages of the filtered load reabsorbed, secreted, or excreted.
Filtration. K+ is not bound to plasma proteins and is freely filtered across the glomerular capillaries.
The proximal convoluted tubule reabsorbs about 67% of the filtered load of K+ as part of the isosmotic fluid reabsorption.
The thick ascending limb reabsorbs an additional 20% of the filtered load of K+. Recall from the discussion of Na+ reabsorption that K+ enters the cells of the thick ascending limb via the Na+-K+-2Cl−cotransporter and then leaves the cell along either of two possible routes: K+ may diffuse across the basolateral membrane through K+ channels, to be reabsorbed, and K+ may diffuse back into the lumen, which does not result in reabsorption (but creates the lumen-positive potential difference across the thick ascending limb cells).
The distal tubule and collecting ducts are responsible for the adjustments in K+ excretion that occur when dietary K+ varies. These segments either reabsorb K+ or secrete K+, as dictated by the need to remain in K+ balance.
In the case of a person on a low K+ diet, there is further reabsorption of K+ by the α-intercalated cells of the late distal tubule and collecting ducts. On a low K+ diet, urinary excretion can be as low as 1% of the filtered load.
More commonly, though, in persons on a normal or high K+ diet, K+ is secreted by the principal cells of the late distal tubule and collecting duct. The magnitude of this K+ secretion is variable, depending on the amount of K+ingested in the diet and several other factors including mineralocorticoids, acid-base status, and flow rate. Urinary K+ excretion can be as high as 110% of the filtered load.
The greatest attention should be paid to the handling of K+ by the late distal tubule and collecting ducts because these segments perform the fine-tuning of K+ excretion to maintain K+ balance. (Reabsorption of K+ in the proximal convoluted tubule and in the thick ascending limb is constant under most conditions.)
K+ Reabsorption by α-Intercalated Cells
When a person is on a low K+ diet, K+ can be reabsorbed in the terminal nephron segments by the α-intercalated cells (Fig. 6-32A). Briefly, the luminal membrane of these cells contains an H+-K+ ATPase,similar to the H+-K+ATPase of the gastric parietal cells. The H+-K+ ATPase is a primary active transport mechanism that pumps H+ from the cell to the lumen and simultaneously pumps K+ from the lumen into the cell. K+ then diffuses from the cell into blood (is reabsorbed) via K+ channels. (In Figure 6-32A, another ATPase, the H+ ATPase, also is shown in the luminal membrane for completeness. It does not relate to the K+ reabsorptive function of the α-intercalated cells, but it will be discussed with acid-base balance in Chapter 7.)
Figure 6–32 Cellular mechanisms of K+ reabsorption in α-intercalated cells (A) and K+ secretion in principal cells (B) of the late distal tubule and collecting duct. ATP, Adenosine triphosphate.
K+ Secretion by Principal Cells
The function of the principal cells is to secrete, rather than to reabsorb, K+. Thus, the cellular mechanisms in the principal cells differ from those in the α-intercalated cells. The diagram of the principal cell inFigure 6-32B should be familiar because this cell type has been discussed previously in relation to Na+ reabsorption (see Fig. 6-27).
K+ secretion is net transfer of K+ from blood into the lumen. K+ is brought into the cell from the blood by the Na+-K+ ATPase, which is responsible for maintaining the high intracellular K+ concentration. Both the luminal and basolateral membranes have K+ channels, so, theoretically, K+ can diffuse into the lumen (secretion) or back into the blood. The K+ permeability and the size of the electrochemical gradient for K+ are higher in the luminal membrane; therefore, most of the K+ diffuses across the luminal membrane rather than being recycled across the basolateral membrane into the blood. (For simplicity, the basolateral K+ channels are omitted from the figure.)
The single most important principle for understanding the factors that alter K+ secretion is that the magnitude of K+ secretion is determined by the size of the electrochemical gradient for K+ across the luminal membrane. By employing this principle, it is then easy to predict the effects of aldosterone, acid-base disturbances, dietary K+, and flow rate (diuretics). Any factor that increases the magnitude of the electrochemical gradient for K+ across the luminal membrane will increase K+ secretion; conversely, any factor that decreases the size of the electrochemical gradient will decrease K+ secretion (Table 6-9).
Table 6–9 Regulation of K+ Secretion by the Principal Cells
Causes of Increased K+ Secretion
Causes of Decreased K+ Secretion
High K+ diet
Low K+ diet
Dietary K+. It has been emphasized that the fundamental mechanism for maintaining external K+ balance involves changes in K+ secretion by the principal cells. Knowing this, it is easy to understand the body’s response to a high K+ diet: The ingested K+ enters the cells (aided by the insulin response to a meal) and raises the intracellular K+ content and concentration. When the intracellular K+ concentration of the principal cells increases, the driving force for K+ secretion across the luminal membrane increases and the ingested K+ is excreted in urine. Conversely, when a person eats a low K+ diet, the principal cells are relatively depleted of K+; the intracellular K+ concentration decreases, which decreases the driving force for K+ secretion. On a low K+ diet, in addition to the decrease in K+ secretion by the principal cells, there is an increase in K+ reabsorption by the α-intercalated cells. Together, the two effects account for low rates of K+ excretion.
Aldosterone. Aldosterone increases K+ secretion by the principal cells. Recall the effect of aldosterone on Na+ reabsorption that was discussed previously: Aldosterone increases Na+ reabsorption in the principal cells by inducing synthesis of the luminal membrane Na+ channels and the basolateral membrane Na+-K+ ATPase. These actions on Na+ reabsorption are related to K+ secretion as follows: First, aldosterone induces the synthesis of more luminal membrane Na+ channels, which increases Na+ entry into the cell and provides more Na+ to the Na+-K+ ATPase. As more Na+ is pumped out of the cell, more K+ must be simultaneously pumped into the cell. Second, aldosterone increases the quantity of Na+-K+ ATPase, further increasing the amount of K+ pumped into the cell. Together, the two effects raise the intracellular K+ concentration, which increases the driving force for K+ secretion from the cell into the lumen. Finally, as a separate effect, aldosterone increases the number of K+ channels in the luminal membrane, which coordinates with the increased driving force to increase K+ secretion.
This discussion of the effects of aldosterone on Na+ reabsorption emphasizes the close relationship between Na+ reabsorption and K+ secretion in the principal cells. As described, much of the effect of aldosterone on K+ secretion is secondary to the effect of aldosterone on Na+ reabsorption. Other situations also demonstrate this relationship, and two examples are included here. The first example is of a person eating a high Na+ diet. This person will have increased Na+ excretion, as expected, to maintain Na+ balance, and also increased K+ excretion. The explanation for the increased K+ excretion is increased delivery of Na+ to the principal cells. As more Na+ is delivered to the principal cells, more Na+ enters the cells across the luminal membrane, more Na+ is extruded by the Na+-K+ ATPase, and more K+ is pumped into the cell, which increases the driving force for K+ secretion. The second example is a person treated with diuretics. Loop diuretics and thiazide diuretics inhibit Na+ reabsorption “upstream” to the principal cells, causing increased Na+ delivery to the principal cells. The mechanism discussed for a high Na+ diet can be applied again here: More Na+ is delivered to the principal cells, more Na+ is reabsorbed, and more K+ is secreted (Box 6-2).
BOX 6–2 Clinical Physiology: Primary Hyperaldosteronism
DESCRIPTION OF CASE. A 50-year-old man is referred to his physician for evaluation of weakness and hypertension. On physical examination, his systolic and diastolic blood pressures are elevated (160/110) in the supine position. The following blood and urine values are obtained:
[Na+], 142 mEq/L
[Na+], 60 mEq/L (normal)
[K+], 2.1 mEq/L
[K+], 55 mEq/L (high)
[Cl−], 98 mEq/L
Osmolarity, 520 mOsm/L
Osmolarity, 289 mOsm/L
EXPLANATION OF CASE. The man’s physical examination was notable for hypertension, which suggests ECF volume expansion. Increased ECF volume and increased blood volume explain his increased systolic and diastolic pressures. Because plasma [Na+] and osmolarity are normal, it can be concluded that the water content of his body is normal relative to solute content. Therefore, the man must have increased total body Na+ content with a proportionately increased water content. The combination of increased Na+ and water content in the body is responsible for his increased ECF volume.
The man has markedly decreased plasma [K+] concentration with increased urine K+ excretion. Although it would seem that renal K+ excretion should decrease in the face of such a low plasma [K+], these observations can be reconciled by concluding that the low plasma [K+] is caused by the increased urine K+ excretion.
All of the findings in this patient can be explained by the diagnosis of an aldosterone-secreting tumor of the zona glomerulosa of the adrenal gland, resulting in primary hyperaldosteronism (Conn syndrome). The high circulating levels of aldosterone have two effects on the principal cells of the late distal tubule and collecting ducts: increased Na+ reabsorption and increased K+ secretion. The consequences of the increased K+ secretion are straightforward: Increased K+ secretion by the principal cells causes the urinary K+ excretion to increase and the plasma [K+] to decrease. The observation of a normal urine Na+excretion is puzzling, however. The direct effect of aldosterone on the principal cells is to increase Na+ reabsorption, and urine Na+ should be decreased. The increased Na+ reabsorption then leads to increased ECF Na+ content and increased ECF volume. There is, however, a secondary effect of this ECF volume expansion on the proximal tubule: ECF volume expansion inhibits proximal tubule reabsorption, which is called “escape from aldosterone,” or mineralocorticoid escape. Thus, because of “escape from aldosterone,” the urine Na+ in this man is higher than if aldosterone had only a direct effect on the principal cells.
TREATMENT. The man’s hypertension is treatable by removal of the adrenal tumor. While awaiting surgery, he is placed on spironolactone, an aldosterone antagonist, and on a sodium-restricted diet. Spironolactone blocks all of the effects of aldosterone on the principal cells. Na+ reabsorption is reduced to normal (reducing his ECF volume) and K+ secretion also is reduced to normal (increasing his plasma [K+]). After surgery, his blood pressure returns to normal levels, and his blood and urine chemistries return to normal.
Acid-base disturbances. Acid-base disturbances can have profound effects on the blood K+ concentration, attributable to alterations in K+ secretion by the principal cells. Usually, alkalosis increases K+secretion, and acidosis decreases K+ secretion. The exchange of H+ and K+ ions across basolateral cell membranes underlies these effects as follows: In alkalosis, there is a deficit of H+ in the ECF. H+ leaves the cells to aid in buffering, and K+ enters the cells to maintain electroneutrality. The increased intracellular K+ concentration increases the driving force for K+ secretion, causing hypokalemia. In acidosis,there is an excess of H+ in the ECF. H+ enters the cells for buffering, and K+ leaves the cells to maintain electroneutrality. The intracellular K+ concentration decreases, which decreases the driving force for K+secretion, causing hyperkalemia.
Diuretics. The most commonly used diuretics, the loop diuretics and the thiazide diuretics, cause increased K+ excretion or kaliuresis. Therefore, an important side effect of diuretic therapy ishypokalemia. The basis for the diuretic-induced increase in K+ excretion is increased K+ secretion by the principal cells, by the mechanism explained in the previous section. Loop diuretics and thiazide diuretics inhibit Na+ reabsorption “upstream” to the site of K+ secretion (in the thick ascending limb and in the early distal tubule, respectively), thereby delivering more Na+ to the principal cells. When more Na+ is delivered to the principal cells, more Na+ enters the cells across the luminal membrane and more Na+ is extruded from the cells by the Na+-K+ ATPase. Simultaneously, more K+ is pumped into the cells, which increases the intracellular K+ concentration and increases the driving force for K+secretion.
A second factor contributing to the increased K+ secretion is the increased flow rate produced by these diuretics. When the flow rate through the late distal tubule and collecting duct increases, the luminal K+concentration is diluted, which increases the driving force for K+ secretion. (The driving force across the luminal membrane can be increased either by increasing the intracellular K+ concentration or by decreasing the luminal K+ concentration.)
Loop diuretics (but not thiazide diuretics) also cause increased K+ excretion by inhibiting Na+-K+-2Cl− cotransport and, as a result, K+ reabsorption in the thick ascending limb. This direct effect in the thick ascending limb, coupled with increased K+ secretion by the principal cells, predicts that loop diuretics will produce a profound kaliuresis and hypokalemia.
The K+-sparing diuretics (e.g., spironolactone, amiloride, triamterene) are the only diuretics that do not cause kaliuresis. As explained, these diuretics inhibit all of the actions of aldosterone on the principal cells and, therefore, inhibit K+ secretion. The major application of K+-sparing diuretics is in combination with the loop or thiazide diuretics to offset the kaliuresis and hypokalemia produced by those drugs.
Luminal anions. The presence of large anions (e.g., sulfate, HCO3−) in the lumen of the distal tubule and collecting duct increases K+ secretion. Such nonreabsorbable anions increase the electronegativity of the lumen, thereby increasing the electrochemical driving force for K+ secretion.