Table 37-2 summarizes factors that modulate K+ secretion. These may be grouped into luminal and peritubular (i.e., bathing basolateral membrane) factors.
Luminal and Peritubular Factors that Modulate K+ Secretion by the Distal K+-Secretory System*
↑ Flow rate
↑ K+ intake
*ICT and CCT, and proximal portion of MCD.
Increased luminal flow increases K+ secretion
One of the most potent stimuli of K+ secretion is the rate of fluid flow along the distal K+-secretory system (i.e., ICT and CCT). Under almost all circumstances, an increase in luminal flow increases K+ secretion (Fig. 37-8) and a similar relationship holds between final urine flow and K+ excretion. Accordingly, the increased urine flow that occurs with extracellular volume expansion, osmotic diuresis, or administration of several diuretic agents (e.g., acetazolamide, furosemide, thiazides) leads to enhanced K+ excretion—kaliuresis.
FIGURE 37-8 Effect of flow (i.e., Na+ delivery) on K+ excretion. (Data from Stanton BA, Giebisch G: Renal potassium transport. In Windhager EE [ed]: Handbook of Physiology, Section 8: Renal Physiology. New York, Oxford University Press, 1992, pp 813–874.)
The strong flow dependence of distal K+ secretion is a consequence of enhancements in both the cell-to-lumen K+ gradient and apical K+ permeability of α-intercalated cells (see Fig. 37-7D), β-intercalated cells, and principal cells (see Fig. 37-7C). When luminal flow is low, the movement of K+ from cell to lumen causes luminal [K+] to rise, which opposes further K+ diffusion from the cell and limits total K+ secretion. When luminal flow increases and sweeps newly secreted K+ downstream, the resulting fall in luminal [K+] steepens the K+ gradient across the apical membrane and consequently increases passive K+ flux from cell to lumen. In addition to producing this enhanced gradient, increased luminal flow activates apical BKCa channels, which enhances apical K+ permeability, as noted above (p. 799).
Increased luminal flow also increases the Na+ delivery to tubule cells, thus raising luminal [Na+] and enhancing Na+ uptake by principal cells (p. 765). This incremental supply of Na+ to the principal cell stimulates its Na-K pump, increases basolateral K+ uptake, and further increases K+ secretion. The Na+ sensitivity of K+ secretion is most pronounced when luminal [Na+] is <35 mM, as is often the case in the CCT. Almost uniformly, increased urinary flow is associated with increased Na+ excretion (natriuresis), so that the urinary excretion of both K+ and Na+ increases.
An increased lumen-negative transepithelial potential increases K+ secretion
The apical step of K+ secretion in the ICT and CCT occurs by diffusion of K+ from the principal cell to the lumen, a process that depends on the apical electrochemical K+ gradient (see Fig. 37-7C). Increases in luminal [Na+]—enhancing apical Na+ entry through epithelial Na+ channels (ENaCs) (pp. 758–759)—depolarize the apical membrane, favoring the exit of K+ from cell to lumen (i.e., K+ secretion). Conversely, a fall in luminal [Na+] hyperpolarizes the apical membrane, thereby inhibiting K+ secretion.
The diuretic amiloride (pp. 758–759) has the same effect on K+ secretion as decreasing luminal [Na+]. By blocking apical ENaCs, amiloride hyperpolarizes the apical membrane and reduces the electrochemical gradient for K+ secretion. Moreover, by inhibiting apical Na+ entry, amiloride lowers intracellular Na+ and reduces the activity of the basolateral Na-K pump. Thus, amiloride is a K+-sparing diuretic.
Low luminal [Cl−] enhances K+ secretion
Lowering luminal Cl−—replacing it with an anion (e.g., or ) that the tubule reabsorbs poorly—promotes K+ loss into the urine, independent of changes in the lumen-negative Vte. Underlying this effect may be a KCC in the apical membrane of the principal cell of the ICT and CCT (see Fig. 37-7C). Lowering luminal [Cl−] increases the cell-to-lumen Cl− gradient, which presumably stimulates K/Cl cotransport, and thus K+ secretion. N37-6
Paradoxical Inhibition of K+ Secretion by Thiazide Diuretics in Low-Cl− States
Contributed by Erich Windhager, Gerhard Giebisch
As noted on pages 799–800, K+ secretion in the distal nephron is strongly flow dependent as a result of the high K+ permeability of the apical membrane. Figure 37-8 illustrates this effect. Accordingly, all diuretics (e.g., furosemide, thiazides, and acetazolamide) that act proximal to the collecting duct—and thus increase the luminal flow at the level of the collecting duct—enhance K+ secretion by the collecting duct. Thus, these diuretics enhance K+ excretion and are termed kaliuretic agents (i.e., they are not “K+-sparing” diuretics).
An exception to this general rule is the administration of thiazide diuretics in low-Cl− states (hypochloremia), in which the diuretic inhibits K+ secretion. The basis of this paradox is that because luminal [Cl−] is low all along the nephron—including the CCT—the apical K/Cl cotransporter (KCC) in the CCT (see Fig. 37-7C) makes an unusually large contribution to K+ secretion in a low-Cl− state. When a patient with hypochloremia takes a thiazide diuretic, the drug inhibits the Na/Cl cotransporter (NCC) in the apical membrane of the DCT, which is illustrated in Figure 35-4C. As a result, luminal [Cl−] is higher than it otherwise would be in the DCT and also downstream in the CCT. In the CCT, the higher-than-otherwise luminal [Cl−] now acts as a brake on the apical KCC, thereby decreasing K+ secretion.
Aldosterone increases K+ secretion
Both mineralocorticoids (p. 1026) and glucocorticoids (pp. 1018–1019) cause kaliuresis. Primary hyperaldosteronism leads to K+ wasting and hypokalemia, whereas adrenocortical insufficiency (i.e., deficiency of both mineralocorticoids and glucocorticoids) leads to K+ retention and hyperkalemia.
Aldosterone, the main native mineralocorticoid, induces K+ secretion in the ICT and CCT, N37-7 particularly when its effects are prolonged. Aldosterone and desoxycorticosterone acetate (DOCA), a powerful synthetic mineralocorticoid, increase the transcription of genes that enhance Na+ reabsorption and, secondarily, K+ secretion in the principal cells of the ICT and CCT (p. 766). Three factors act in concert to promote K+ secretion. First, over a period of a few hours, aldosterone increases the basolateral K+ uptake by stimulating the Na-K pump. Over a few days, elevated aldosterone levels also lead to a marked amplification of the area of the basolateral membrane of principal cells, as well as to a corresponding increase in the number of Na-K pump molecules. Conversely, adrenalectomy causes a significant reduction in basolateral surface area and Na-K pumps in principal cells. Second, mineralocorticoids stimulate apical ENaCs (p. 766), thus depolarizing the apical membrane and increasing the driving force for K+ diffusion from cell to lumen. Third, aldosterone increases the K+ conductance of the apical membrane.
Acute Effects of Intravenous Aldosterone
Contributed by Erich Windhager, Gerhard Giebisch
eFigure 37-1 shows the renal effects of intravenously administered aldosterone. The acute effects include significant decreases in Na+ and Cl− excretion, as well as increases in K+ and excretion. The reverse changes occur in adrenalectomy, and the administration of mineralocorticoids (e.g., aldosterone) promptly reverses these deficiencies.
EFIGURE 37-1 Acute effects of intravenously administered aldosterone on electrolyte excretion in humans. (Data from Liddle GW: Aldosterone antagonists. Arch Intern Med 102:998–1005, 1958.)
Given aldosterone's mechanisms of action, one would think that the renal excretion of K+ and Na+ should always be inversely related. However, the extent to which aldosterone increases K+ excretion depends strongly on Na+ excretion. For example, when Na+ intake and excretion are low, the Na+ retention induced by aldosterone reduces luminal flow and Na+ delivery to such low levels that K+ excretion fails to increase. In contrast, under high-flow conditions (e.g., with a high Na+ load or following administration of diuretics that act on the TAL or the DCT), aldosterone increases K+ excretion.
Simultaneous elevation of both aldosterone and angiotensin II (ANG II) is another example of a case in which K+ and Na+ excretion are not inversely related. In hypovolemia, when both ANG II and aldosterone levels are high, intracellular kinases, including WNK4 and SPAK, cause activation of ENaC but inhibition of ROMK, so that Na+ reabsorption is enhanced without a large increase in K+ secretion—an appropriate adaptive response that tends to restore Na+ content with minimal K+ loss. In contrast, when it is hyperkalemia rather than hypovolemia that increases aldosterone secretion (pp. 1027–1029), ANG II levels do not rise. Here, cell-signaling mechanisms activate both ENaC and ROMK, and appropriately enhance K+ secretion.
Long-term administration of mineralocorticoids or untreated primary hyperaldosteronism leads to a sequence of events known as aldosterone escape. Aldosterone leads to Na+ retention and hence volume expansion. Eventually, the volume expansion causes proximal Na+ reabsorption to fall (see Fig. 34-10), which increases Na+ delivery to the ICT and CCT, and ultimately raises Na+ excretion toward prealdosterone levels. Thus, the kidney can escape the Na+-retaining effect of aldosterone, albeit at the price of expanding the extracellular volume and causing hypertension. However, the increased Na+ delivery to the principal cells continues to stimulate K+ secretion. Once the body has become depleted of K+, the aldosterone-stimulated K+ secretion eventually wanes, and the distal nephron may return to net K+reabsorption, but at the price of continued hypokalemia.
Under physiological conditions, glucocorticoids enhance K+ excretion (Fig. 37-9). Corticosterone and dexamethasone, a synthetic glucocorticoid, produce this effect largely by increasing flow along the distal K+-secretory system (i.e., ICT and CCT). Because glucocorticoids increase the glomerular filtration rate and probably lower the water permeability of the distal K+-secretory system, they increase the amounts of fluid and Na+ remaining in these segments. These two flow effects, by themselves, increase K+ secretion. Indeed, when one perfuses the distal K+- secretory system at a constant rate, glucocorticoids have no effect on K+transport.
FIGURE 37-9 Effect of changes in plasma [K+] on the electrocardiogram (ECG). These five traces show ECG recordings from the precordial V4 lead.
In addition, administering unphysiologically high doses of glucocorticoids may stimulate K+ transport directly as glucocorticoids bind to mineralocorticoid receptors, despite the presence of 11β-hydroxysteroid dehydrogenase 2 in aldosterone target cells (p. 766).
Hyperkalemia and the Heart
An electrocardiogram (ECG)—a measure of the electrical activity of the myocardial cells (pp. 493–496)—can be clinically useful for detecting rising plasma [K+].
As plasma [K+] begins to rise (Fig. 37-9, ECG tracing for 6 mM), the T wave becomes tall and peaked, assuming a symmetric, “tented” shape. The PR interval becomes prolonged, and the P wave gradually flattens. Eventually, the P wave disappears (see Fig. 37-9, tracing for 8 mM). Moreover, the QRS complex, which represents depolarization of the ventricles, widens and merges with the T wave, forming a sine-wave pattern. At higher concentrations, ventricular fibrillation, a lethal arrhythmia, may develop (see Fig. 37-9, tracing for 10 mM). These ECG changes do not always occur in this precise order, and some patients with hyperkalemia may progress very rapidly to ventricular fibrillation. Any change in the ECG resulting from hyperkalemia requires immediate clinical attention.
Decreases in plasma [K+] also affect the ECG. For example, moderate decreases in [K+] to ~3 mM cause the QT interval to lengthen and the T wave to flatten. Lower values of [K+] lead to the appearance of a U wave (see Fig. 37-9, tracing for 1.5 mM), which represents the delayed repolarization of the ventricles. The most severe manifestation of hypokalemia is ventricular tachycardia or fibrillation (not shown).
Evaluating Hypokalemia and Hyperkalemia in the Patient
We can directly apply the physiological principles discussed in this chapter to understanding the common causes and treatment of hypokalemia and hyperkalemia.
The body can lose K+ from three sites: the kidneys, the GI tract, and the skin. Renal losses occur most commonly in patients taking diuretics (e.g., furosemide and thiazides) that act at sites upstream to the distal K+-secretory system (i.e., ICT, CCT, and proximal portion of MCD). K+ losses can also occur in individuals with renal tubule disorders or alterations in the renin-angiotensin-aldosterone system (e.g., hyperaldosteronism). Because intestinal secretions have a high [K+], severe diarrhea is a common cause of hypokalemia. Significant K+ depletion through the skin can occur in two situations: (1) strenuous exercise on a hot, humid day can cause dehydration and hypokalemia from the loss of many liters of perspiration; and (2) severe and extensive burns can result in the transudation of vast amounts of K+-containing fluid through the skin. In both cases, the lost fluid is K+ rich compared with plasma.
Low plasma [K+] can also develop as the result of altered K+ distribution within the body without any net loss of whole-body K+. Common causes include alkalosis, a catecholamine surge (e.g., as during any acute stress to the body, such as an acute myocardial infarction), and insulin administration without K+ repletion during the treatment of diabetic ketoacidosis.
Patients may develop hypokalemia because of inadequate dietary K+ intake. Patients receiving large amounts of intravenous saline (which lacks K+) may also waste K+. Some persons in rural areas ingest clay (a behavior called pica), which binds K+ in the GI tract and prevents K+ absorption.
Probably the most common cause of a high laboratory value for plasma [K+] is pseudohyperkalemia, a falsely elevated value that results from traumatic hemolysis of red blood cells during blood drawing. Red blood cells release their intracellular stores of K+ in the blood sample, and the laboratory reports a falsely elevated plasma [K+]. Patients with myeloproliferative disorders associated with greatly increased numbers of platelets or white blood cells can also show a falsely elevated [K+] because of K+ released during clot formation within the blood-sample tube.
Excessive intake of K+ rarely causes hyperkalemia in persons with healthy kidneys. However, even in these individuals, a large K+ bolus can cause transient hyperkalemia (see Fig. 37-2, top panel), often from ill-advised use of an inappropriate intravenous fluid. Altered distribution of K+ can lead to elevated plasma levels in patients with acidosis and, rarely, as a result of β-adrenergic blockade. Intoxication with digitalis, a cardiac glycoside that inhibits the Na-K pump (p. 117), is another rare cause of hyperkalemia resulting from K+ redistribution. Massive breakdown of cells can release large amounts of K+ into the extracellular space. This release can occur in patients with intravascular hemolysis (e.g., from a mismatched blood transfusion), burns, crush injuries, rhabdomyolysis (massive muscle destruction such as can be seen with trauma or sepsis), GI bleeding with subsequent intestinal absorption of K+-rich fluid, or destruction of tumor tissue or leukemic blood cells by chemotherapy.
Impaired renal excretion of K+ is the primary cause of a sustained increase in plasma [K+]. Hypoaldosteronism N37-8 and high doses of amiloride can be responsible, but advanced renal failure itself, from any myriad of disorders, is the most common cause.
The treatment of hyperkalemia depends on the severity of the problem. For severe hyperkalemia (i.e., [K+] > 8 mM) with accompanying ECG changes, the physician immediately infuses calcium gluconate intravenously to counter the electrophysiological effects of the hyperkalemia. (Ca2+ raises the threshold for action potentials and lessens membrane excitability). The simultaneous administration of glucose and insulin leads to the uptake of some of the K+ from the extracellular to the intracellular space. In addition, if the patient is acidotic, administration of NaHCO3 can promote cellular uptake of K+. These are all temporizing measures. To remove the excess K+ from the body, the physician administers an oral nonabsorbable Na-K cation exchange resin (e.g., sodium polystyrene sulfonate). The resin binds the K+ and carries it out of the body via the GI tract. However, the resin takes several hours to work. Thus, for patients with hyperkalemia and ECG changes, the temporizing measures buy time for the resin to act. For patients with renal failure, dialysis is often necessary to return the plasma [K+] to normal.
High K+ intake promotes renal K+ secretion
Dietary K+ Loading
An increase in dietary K+ intake causes, after some delay, an increase in urinary K+ excretion (see Fig. 37-5B). If the period of high-K+ intake is prolonged, a condition of tolerance (K+ adaptation) develops in which the kidneys become able to excrete large doses of K+—even previously lethal doses—with only a small rise in plasma [K+].
The kaliuresis following an acute or chronic K+ load is the result of increased K+ secretion in the ICT and CCT (compare the three curves in Fig. 37-8 at a single flow), a process that occurs by three mechanisms. First, a transient rise in plasma [K+], even if maintained for only short periods, is an effective stimulus for K+ excretion. The mechanism is increased K+ uptake across the basolateral membrane of principal cells by the Na-K pump, a response shared by most of the cells of the body. As is the case with mineralocorticoid stimulation, the ultrastructure of the ICT and CCT correlates with changes in the rate of K+ transport induced by high dietary K+. Therefore, a high-K+ diet—independent of the effects of aldosterone—causes surface amplification of the basolateral membrane of principal cells. Second, the increased plasma [K+] stimulates glomerulosa cells in the adrenal cortex to synthesize and release aldosterone (p. 1028). This mineralocorticoid is a potent stimulus for K+ secretion both in the kidney by principal cells (p. 799) and in the colon (p. 909). Third, acute K+ loading inhibits proximal Na+ and fluid reabsorption and increases flow and Na+ delivery to the distal K+-secretory system, processes that stimulate K+ secretion. In addition, independent of a rise in plasma K+ or aldosterone, dietary K+ ingestion can stimulate renal K+ excretion, which suggests a feed-forward mechanism, perhaps involving the sensing of ingested K+ by the gut, and the release of humoral factors.
Dietary K+ Deprivation
In response to K+ restriction, the kidneys retain K+ (see Fig. 37-5A). The rate of urinary K+ excretion may fall to 1% to 3% of the filtered load, via three mechanisms.
First, the low plasma [K+] suppresses K+ secretion by the principal cells in the ICT and CCT (see Fig. 37-8, lower curve) both by reducing basolateral K+ uptake by principal cells and by reducing aldosterone secretion.
Second, low plasma [K+] stimulates K+ reabsorption via H-K pumps of intercalated cells of the ICT and CCT (see Fig. 37-7D). Whereas states of high K+ secretion (i.e., aldosterone or high-K+ diet) amplify the basolateral membrane area of principal cells, K+ deprivation amplifies the apical membrane of α-intercalated cells. Moreover, K+ depletion causes an increased incorporation of rod-shaped particles (presumably representing H-K pumps) in the apical membrane of α-intercalated cells, and the density of these particles correlates well with enhanced K+ reabsorption.
Third, the MCD responds to K+ depletion by increasing its reabsorption of K+ by enhancing both the activity of its apical K-H pump and its paracellular K+ permeability. As a result, the [K+] of the final urine falls sharply, sometimes to levels below that of the plasma. Nevertheless, when the diet is extremely low in K+, it may be impossible to maintain K+ balance and a normal plasma [K+] because urinary K+ excretion cannot fall to less than ~15 meq/day.
Acidosis decreases K+ secretion
Acid-base disturbances have marked effects on renal K+ transport. In general, either metabolic alkalosis (p. 635) or respiratory alkalosis (p. 634) leads to increased K+ excretion. Conversely, acidosis reduces K+excretion, although this response is more variable than that to alkalosis. Changes in systemic acid-base parameters affect K+ transport mainly by acting on the distal K+-secretory system.
Alkalosis leads to hypokalemia (p. 794), owing to K+ uptake by cells throughout the body. Despite this fall in plasma [K+], alkalosis stimulates K+ secretion in the distal K+-secretory system, thereby worsening the hypokalemia. Conversely, K+ secretion falls acutely in acidosis despite the shift of K+ from cells to ECF and the concomitant rise in plasma [K+].
The cellular events underlying the renal response to acid-base disturbances most likely involve effects of pHi on both the basolateral Na-K pump and the apical K+ channels of the principal cells in the ICT and CCT. Tubule perfusion studies with 42K indicate that decreasing basolateral pH—which also decreases pHi—inhibits the Na-K pump and thus K+ secretion. A fall in pHi also inhibits ENaC activity. Even more important is that the decrease in pHi also markedly decreases the open probability of apical ROMK (p. 198) K+ channels (Fig. 37-10). The reverse changes occur in alkalosis.
FIGURE 37-10 Effect of intracellular acidosis on K+ channel activity in the apical membrane of a principal cell. In A, the recordings show single channel K+ currents from inside-out patches, with different pH values on the “cytoplasmic” side. As shown in B, channels are almost never open at pH values of 7.0 or below. (Data from Wang W, Geibel J, Giebisch G: Regulation of small conductance K channel in the apical membrane of rat cortical collecting tubule. Am J Physiol 259:F494–F502, 1990.)
Changes in tubule flow (i.e., fluid delivery to the distal K+-secretory system) that occur in acid-base disturbances may modulate the effects of pH changes per se. For example, metabolic alkalosis increases the flow by delivering an -rich solution to the ICT and CCT. By itself, this increased flow enhances K+ secretion and thus potentiates the effect of alkalosis per se. Acidosis also increases distal flow, but in this case by inhibiting proximal fluid reabsorption, with the consequence that the tendency of increased flow to increase K+ secretion opposes the effect of acidosis per se to decrease it. Indeed, chronic acidosis, as with inherited renal tubule defects in acid secretion, tends to cause renal K+ wasting and hypokalemia (see Box 37-2).
Epinephrine reduces and AVP enhances K+ excretion
By both extrarenal and renal mechanisms, epinephrine lowers K+ excretion. First, epinephrine enhances K+ uptake by extrarenal tissues (p. 794), thereby lowering plasma [K+] and reducing the filtered K+ load. Second, catecholamines directly inhibit K+ secretion in nephron segments downstream of the ICT.
Although it is not a major regulator of K+ excretion, AVP (also known as antidiuretic hormone, or ADH) can stimulate the distal K+-secretory system by two mechanisms (see Fig. 37-7C): (1) AVP increases the apical Na+ conductance, thus depolarizing the apical membrane and providing a larger driving force for K+ efflux from cell to lumen; and (2) AVP increases apical K+ permeability. However, AVP also reduces urine flow, and thus inhibits K+ secretion. Therefore, the two opposing effects—a direct stimulation of K+ secretion and a flow-related reduction of K+ secretion—may cancel each other.
Opposing factors stabilize K+ secretion
The net effect of a specific disturbance on K+ excretion in the final urine often represents a result of two or more interacting factors. Changes in flow often indirectly amplify or attenuate the direct response of the distal K+-secretory system to a given stimulus.
Figure 37-11 shows four examples of disturbances affecting K+ excretion, the first three of which (acidosis, volume expansion, and high water intake) are characterized by the competition between a direct inhibitory effect on K+ secretion and an indirect stimulatory effect of increased flow (see Fig. 37-11A–C). The fourth example, extracellular volume contraction (see Fig. 37-11D), also has two effects on K+ secretion. First, volume contraction increases ANG II levels, which in turn increases aldosterone release and hence K+ secretion. However, the combination of high angiotensin with high aldosterone (p. 801) may lower ROMK activity, resulting in less K+ secretion than when aldosterone alone is elevated. Second, hypovolemia decreases distal flow and distal Na+ delivery, which inhibits the distal K+-secretory system. Thus, during hypovolemia, K+ excretion tends to remain constant despite the high aldosterone level.
FIGURE 37-11 Effects of interaction of opposing factors on K+ secretion. GFR, glomerular filtration rate.
In the following three examples, the direct actions of an agent and flow-related effects are additive.
First, metabolic alkalosis—as discussed—directly stimulates the distal K+-secretory system. In addition, the delivery of the poorly reabsorbable in metabolic alkalosis increases distal flow, thereby potentiating K+ excretion.
Second, hyperkalemia directly stimulates the distal K+-secretory system. In addition, because increased plasma [K+] inhibits Na+ and fluid reabsorption in the proximal tubule, distal flow increases, again potentiating K+ excretion.
Third, administration of diuretics that act on a site upstream of the ICT and CCT increases Na+ delivery to the distal K+-secretory system and thereby stimulates K+ secretion. In addition, the volume contraction induced by the diuretic raises aldosterone levels, which again potentiates K+ excretion. Hypokalemia is thus a possible harmful side effect of diuretic treatment.