8: Regulation of Potassium Balance

• ▸ State the normal balance and distribution of potassium between cells and extracellular fluid.

• ▸ Describe how potassium moves between cells and the extracellular fluid, and how, on a short-term basis, the movement protects the extracellular fluid from large changes in potassium concentration.

• ▸ State why plasma levels of potassium do not always reflect the status of total-body potassium.

• ▸ State how insulin and epinephrine influence the cellular uptake of potassium and identify the situations in which these hormonal influences are most important.

• ▸ State the relative amounts of potassium reabsorbed by the proximal tubule and thick ascending limb of Henle's loop regardless of the state of potassium intake.

• ▸ Describe how nephron segments beyond the thick ascending limb can manifest net secretion or reabsorption; describe the role of principal cells and intercalated cells in these processes.

• ▸ List inputs that control the rate of potassium secretion by the distal nephron.

• ▸ Describe the actions of ROMK and BK potassium channels in conditions of low, normal, and high potassium excretion.

• ▸ Describe how changes in plasma potassium influence aldosterone secretion.

• ▸ State the effects of most diuretic drugs on potassium excretion.

The vast majority of body potassium is freely dissolved in the cytosol of tissue cells and constitutes the major osmotic component of the intracellular fluid (ICF). Only about 2% of total-body potassium is in the extracellular fluid (ECF). This small fraction, however, is absolutely crucial for body function, and the concentration of potassium in the ECF is a closely regulated quantity. Major increases and decreases (called hyperkalemia and hypokalemia) in plasma values are cause for medical intervention. The importance of maintaining this concentration stems primarily from the role of potassium in the excitability of nerve and muscle, especially the heart. The ratio of the intracellular to extracellular concentration of potassium is the major determinant of the resting membrane potential in these cells. A significant rise in the extracellular potassium concentration causes a sustained depolarization. Low extracellular potassium may hyperpolarize or depolarize depending on how changes in extracellular potassium affect membrane permeability. Both conditions lead to muscle and cardiac disturbances.

Given that the vast majority of body potassium is contained within cells, the extracellular potassium concentration is crucially dependent on (1) the total amount of potassium in the body and (2) the distribution of this potassium between the extracellular and intracellular fluid compartments. Total-body potassium is determined by the balance between potassium intake and excretion. Healthy individuals remain in potassium balance, as they do in sodium balance, by excreting potassium in response to dietary loads and withholding excretion when body potassium is depleted. The urine is the major route of potassium excretion, although some is lost in the feces and sweat. Normally the losses via sweat and the gastrointestinal tract are small, but large quantities can be lost from the digestive tract during vomiting or diarrhea. The control of renal potassium transport is the major mechanism by which total-body potassium is maintained in balance.

The fact that most body potassium is in the ICF follows strictly from the size and properties of the intracellular and extracellular compartments. About two thirds of the body fluids are in the ICF, and typical cytosolic potassium concentrations are about 140 to 150 mEq/L. One third of the body fluids are in the ECF, with a potassium concentration of about 4 mEq/L. In a clinical setting, only the extracellular concentration can be measured (the intracellular potassium is, in a sense, hidden behind the wall of the cell membrane). Furthermore, the extracellular value does not necessarily reflect total-body potassium. A patient may, for example, be hyperkalemic (high plasma potassium concentration) and yet at the same time be depleted of total-body potassium.

The high level of potassium within cells is maintained by the collective operation of the Na-K-ATPase plasma membrane pumps, which actively transport potassium into cells. Because the total amount of potassium in the extracellular compartment is so small (40–60 mEq total), even very slight shifts of potassium into or out of cells produce large changes in extracellular potassium concentration. Similarly, a meal rich in potassium (eg, steak, potato, and spinach) could easily double the extracellular concentration of potassium if most of that potassium were not transferred from the blood to the intracellular compartment. It is crucial, therefore, that dietary loads be taken up into the intracellular compartment rapidly to prevent major changes in plasma potassium concentration.

The tissue contributing most to the sequestration of potassium is skeletal muscle, simply because muscle cells collectively contain the largest intracellular volume. Muscle effectively buffers extracellular potassium by taking up or releasing it to keep the plasma potassium concentration close to normal. On a moment-to-moment basis, this is what protects the ECF from large swings in potassium concentration. Major factors involved in these homeostatic processes include insulin and epinephrine, both of which cause increased potassium uptake by muscle and certain other cells through stimulation of plasma membrane Na-K-ATPases. Another influence is the gastrointestinal (GI) tract, which contains an elaborate neural network (the “gut brain”) that sends signals to the central nervous system. It also contains a complement of enteroendocrine cells that release an array of peptide hormones. Together these neural and hormonal signals affect many target organs, including the kidneys (see later discussion) in response to dietary input.

The increase in plasma insulin concentration after a meal is a crucial factor in moving potassium absorbed from the GI tract into cells rather than allowing it to accumulate in the ECF. This newly ingested potassium then slowly comes out of cells between meals to be excreted in the urine. Moreover, a large increase in plasma potassium concentration facilitates insulin secretion at any time, and the additional insulin induces greater potassium uptake by the cells, a negative feedback system for opposing acute elevations in plasma potassium concentration. In the natural order of things, insulin also stimulates glucose uptake and metabolism by cells: a necessary source of energy to drive the insulin-activated Na-K-ATPase responsible for moving potassium into cells.

The effect of epinephrine on cellular potassium uptake is probably of greatest physiological importance during exercise when potassium moves out of muscle cells that are rapidly firing action potentials. In fact, very intense intermittent exercises such as wind sprints can actually double plasma potassium for a brief period. However, at the same time, exercise increases adrenal secretion of epinephrine, which stimulates potassium uptake by the Na-K-ATPase in muscle and other cells and the transiently high potassium levels are restored to normal with a few minutes of rest.¹ Similarly, trauma causes loss of potassium from damaged cells and epinephrine released due to stress stimulates other cells to take up plasma potassium.

Still another influence on the distribution of potassium between the ICF and ECF is the ECF hydrogen ion concentration: An increase in ECF hydrogen ion concentration (acidemia; see Chapter 9) is often associated with net potassium movement out of cells, whereas a decrease in ECF hydrogen ion concentration (alkalemia) causes net potassium movement into them. It is as though potassium and hydrogen ions were exchanging across plasma membranes (ie, hydrogen ions moving into the cell during acidemia and out during alkalemia and potassium doing just the opposite), but the precise mechanism underlying these “exchanges” has not yet been clarified. However, like the effect of insulin, it probably involves an inhibition (acidemia) or activation (alkalemia) of the Na-K-ATPase.

Overview

Although skeletal muscle and other tissues play an important role in the moment-to-moment control of plasma potassium concentration, in the final analysis, the kidney determines total-body potassium content. Therefore, understanding potassium handling by the kidneys is the key to understanding whole body potassium balance. It is helpful to keep in mind several major differences between the renal handling of sodium and potassium. First, the filtered load of sodium is 30 to 40 times greater than the filtered load of potassium and the tubules always have to recover the majority of filtered sodium. This is not the case for potassium. Second, sodium is only reabsorbed, never secreted. In contrast, potassium is both reabsorbed and secreted, and its regulation is primarily focused on secretion. Third, the renal handling of sodium has a much greater effect on potassium than vice versa, which, as explained later, is a major feature of control.

Potassium is freely filtered into Bowman's space. Under all conditions, almost all the filtered load (~90%) is reabsorbed by the proximal tubule and thick ascending limb of the loop of Henle. Then, if the body is conserving potassium, most of the rest is reabsorbed in the distal nephron and medullary collecting ducts, leaving almost none in the urine. In contrast, if the body is ridding itself of potassium, a large amount is secreted in the distal nephron, resulting in a substantial excretion. When secretion occurs at high rates, the amount excreted may exceed the filtered load. The chief means of regulation lies in control of secretion in parts of the nephron beyond the loop of Henle. Let us look at potassium handling by various nephron segments and then address the issue of control.

At a normal plasma level of 4 mEq/L and GFR of 150 L/day or more, and given that potassium is freely filtered, this results in a daily filtered load of about 600 mEq/day. The subsequent events in various tubule segments are summarized in Table 8–1. In the proximal tubule about 65% of the filtered load is reabsorbed, mostly via the paracellular route. The flux is driven by the concentration gradient set up when water is reabsorbed, which concentrates potassium and other solutes remaining in the tubular lumen. This flux is essentially unregulated and varies mostly with how much sodium, and therefore water, is reabsorbed.

The active transport of potassium is always coupled to the active transport of another solute, either sodium or hydrogen. In the proximal tubule the efflux of sodium by the Na-K-ATPase is very vigorous, requiring a high rate of potassium uptake from the interstitium. Since we know that there is net potassium transport into the interstitium, this pumped potassium must therefore recycle right back by passive flux through channels in the basolateral membrane. In some regions (described later) influx of potassium across apical membranes occurs via H-K antiporters that are simultaneously secreting protons. In describing the renal handling of potassium in various segments, particularly in the context of regulation, we always have to keep in mind the fate of these other solutes.

The loop of Henle continues the reabsorption of potassium. The major events take place in the thick ascending limb, where the Na-K-2Cl multiporter in the apical membrane of the tubular cells takes up potassium (see Figure 6–4). The interaction with sodium in these cells is even more complicated than in the proximal tubule because potassium is transported into the tubular cells both from the lumen with sodium via Na-K-2Cl symporters and from the interstitium via the Na-K-ATPase. The tubule contains far less potassium than sodium, but the Na-K-2Cl transporter moves equal amounts of each one. Therefore to supply enough potassium to accompany the large amount of sodium being reabsorbed by the symporter, potassium must recycle back to the lumen by passive channel flux. If this did not happen then sodium reabsorption would be limited only to the amount of potassium present in the tubular fluid. A genetic defect in this channel leads to type 3 Bartter's syndrome.

Some potassium entering from the lumen does move through the cells and exit across the basolateral membrane along with the potassium entering via the Na-K-ATPase. It exits by a combination of passive flux through channels and through K-Cl symporters with chloride, thus yielding net transcellular reabsorption. Some potassium is also reabsorbed by the paracellular route in this segment, driven by a lumen-positive voltage. The sum of these transcellular and paracellular processes is net potassium reabsorption of about 25% of the filtered load. Combined with the 65% previously reabsorbed in the proximal tubule, only about 10% is passed on to the distal nephron.

As described in Chapter 6, the distal nephron is composed of a number of segments. The distal convoluted tubule and connecting tubule stand out as being particularly important in potassium handling because of their rich complement of transport elements and their location prior to segments where most of the water is absorbed (ie, the cortical collecting duct). These regions play a major role in potassium secretion when total body potassium is high (high potassium diet). The distal nephron expresses both reabsorptive and secretory mechanisms, and it is the quantitative amount of each that determines net potassium excretion. There are several cell types in the epithelium of the connecting tubule and cortical collecting duct. Principal cells (approximately 70% of the cells) and intercalated cells. The intercalated cells are further subdivided into type A (more numerous), type B (sparse) and a third type called non-A non-B cells. Potassium secretion occurs in principal cells, whereas the type A intercalated cells reabsorb potassium. The mechanisms of both secretion and reabsorption are straightforward. Secretion of potassium by principal cells involves the uptake of potassium from the interstitium via the Na-K-ATPase and secretion into the tubular lumen through channels (Figure 8–1). Type A intercalated cells reabsorb potassium via the H-K-ATPase in the apical membrane, which actively takes up potassium from the lumen (Figure 9–3A). They then allow potassium to enter the interstitium across the basolateral membrane via potassium channels.

Finally, the medullary collecting ducts reabsorb small amounts of potassium under all conditions. When the sum of upstream processes has already reabsorbed almost all the potassium, the medullary collecting ducts bring the final urine excretion down to a few percent of the filtered load, for an excretion of about 10 to 15 mEq/day (compared to a filtration rate of approximately 600 mEq/day). On the other hand, if upstream segments are secreting avidly, the modest reabsorption in the medullary collecting ducts does little to prevent an excretion that can reach 1000 mEq/day. Figure 8–2 depicts the overall renal handling of potassium in different tubule regions in conditions of high and low potassium excretion.

The mechanisms regulating potassium excretion are as complex, and perhaps more so, than those regulating sodium excretion. And as pointed out earlier, active potassium transport is intertwined with sodium and hydrogen transport. But within the complexity one thing is abundantly clear–the healthy kidneys do a remarkable job of integrating signals to increase potassium excretion in response to high dietary loads and reduce excretion in the face of restricted diets.

The key regulated variable is potassium secretion by principal cells in the distal nephron. There are 3 transport processes in these cells that determine the amount of secretion: potassium influx by the Na-K-ATPase, potassium efflux into the lumen, and potassium efflux back into the interstitium (recycling). Much of the control is exerted on the activity of potassium channels. The kidneys and other body organs express numerous potassium channel species; for simplicity we do not usually differentiate between types. However in the apical membrane of principal cells in the distal nephron, 2 types of channels stand out as being those that secrete potassium in a regulated manner: ROMK (standing for renal outer medulla, because that is where they were first identified) and BK (since each channel has a “big” capacity to secrete potassium, also called maxi-K). Although ROMK and BK channels are both permeable to potassium, they play different roles and are regulated by quite different mechanisms.² At very low dietary loads of potassium, there is virtually no secretion by either kind of channel. ROMK channels are sequestered in intracellular vesicles and BK channels are closed. At normal potassium loads, ROMK channels are moved to the apical membrane and secrete potassium at a modest rate. BK channels are still closed, held in reserve and ready to respond to appropriate signals when needed. At high excretion rates, both types of channel are present in the luminal membrane and avidly secreting potassium (Figure 8–3) being pumped in by the Na-K-ATPase.

Figure 8–4 shows key factors known to influence the secretion, and thus the ultimate excretion of potassium. The following text provides a brief description of how specific factors affect potassium excretion. (1) Plasma potassium. The role of plasma potassium is the most understandable influence. First, the filtered load is directly proportional to plasma concentration. Second, the environment of the principal cells that secrete potassium, that is, the cortical interstitium, has a potassium concentration that is nearly the same as in plasma. The Na-K-ATPase that takes up potassium is highly sensitive to the potassium concentration in this space, and varies its pump rate up and down when potassium levels in the plasma vary up and down. Thus plasma potassium concentration exerts an influence on potassium excretion, but is not the dominant factor under normal conditions. (2) Dietary potassium. Dietary potassium must be matched by renal excretion. The healthy kidneys do this very well by increasing and decreasing potassium excretion in parallel with dietary load. Just how the kidneys “know” about dietary input is still somewhat mysterious. Although very large potassium loads can increase plasma potassium somewhat, the changes in excretion associated with ordinary fluctuations in dietary input do not seem to be accounted for on the basis of either changes in plasma potassium or the other identified factors. One factor known to exert an influence, but not the major one, is the previously mentioned gastrointestinal peptide hormones released in response to ingested potassium. They influence not only the cellular uptake of potassium absorbed from the GI tract, but also the renal handling of potassium, and seem to be one of the links between dietary load and excretion.

A manifestation of changing dietary loads over time is to regulate the distribution of ROMK channels between the apical membrane and intracellular storage, that is, high-potassium diets lead to insertion of apical channels and therefore higher potassium secretion. In contrast, during periods of prolonged low potassium ingestion, there are few ROMK channels in the apical membrane. Yet another adaptation to prolonged periods of low potassium ingestion is an increase in H-K-ATPase activity in intercalated cells, resulting in even more efficient reabsorption of filtered potassium. (3) Aldosterone. We discussed the role of aldosterone in regulating sodium excretion in Chapter 7. Here we describe its role in potassium excretion. A stimulator of aldosterone secretion by the adrenal cortex, in addition to AII, is an increase in plasma potassium concentration. This is a direct action of potassium and does not involve the renin-angiotensin system. If anything, high levels of potassium decrease the formation of AII. Aldosterone, as well as increasing expression of the Na-K-ATPase and ENaC sodium channels, also stimulates the activity of ROMK channels in principal cells of the distal nephron. Both actions have the effect of increasing potassium secretion. Greater pumping by the Na-K-ATPase supplies more potassium from the interstitium to the cytosol of the principal cells, and more functioning ROMK channels provide more pathways for secretion. Conversely, low levels of aldosterone deter potassium secretion. A common symptom of hypoaldosteronism is hyperkalemia (see later discussion). (4) Angiotensin II. AII is an inhibitor of potassium secretion. Its mechanism of action is to decrease the activity of ROMK channels in principal cells and distal convoluted cells, thereby limiting the potassium flux from cell to lumen. Thus AII and aldosterone exert influences on potassium excretion in opposite directions. (5) Delivery of sodium to principal cells. Sodium delivery to principal cells in the connecting tubule and cortical collecting duct is a major regulator. High sodium delivery stimulates potassium secretion. It does so in 2 ways. First, sodium entry via sodium channels in principal cells depolarizes the apical membrane and thereby increases the electrochemical gradient driving the outward flow of potassium through channels (similar in principle to what happens during action potentials in excitable cells). Second, more sodium delivered means more sodium taken up, and therefore more sodium pumped out by the Na-K-ATPase, in turn causing more potassium to be pumped in. Sodium delivery to principal cells, and hence potassium secretion, is strongly affected by the amount of sodium reabsorption in prior segments (see later discussion).

Simultaneous Regulation of Sodium and Potassium

Sodium and potassium loads vary over time, sometimes in parallel and sometimes in opposite directions. The healthy body is able to excrete or withhold excretion of each one independently. We have just seen that a major signal that controls the excretion of both sodium and potassium is aldosterone, which raises the question: how can one signal result in independent regulation? This question is often called the “aldosterone paradox.” It is resolved by recognizing the roles of AII, sodium delivery to principal cells, and the influence of potassium on aldosterone secretion. If almost all the filtered sodium is reabsorbed in tubular elements prior to the connecting tubule (ie, proximal tubule, loop of Henle, and distal tubule), little remains to reach principal cells in the connecting tubule and collecting duct, and thus potassium secretion is not stimulated. In contrast, if modest or large amounts of sodium reach the principal cells, this results in considerable potassium secretion. Let us consider several examples of differing requirements for sodium and potassium excretion.

Case 1: volume/sodium depletion with normal body potassium. The goal is to reabsorb as much sodium as possible while excreting potassium modestly. The volume/sodium depletion strongly activates the RAAS, generating high levels of both AII and aldosterone. The AII stimulates sodium reabsorption in the proximal tubule and distal tubule. Consequently, relatively little sodium remains in the tubular fluid by the time it reaches the principal cells in the connecting tubule. Although those cells are being stimulated by the aldosterone, and thus potentially secreting large amounts of potassium, the relatively low amount of sodium available to be reabsorbed limits how much sodium, and therefore potassium, can be transported by the Na-K-ATPase. Furthermore, AII specifically inhibits ROMK activity in principal cells. The end result is that sodium is saved without excessive loss of potassium.

Case 2: potassium overload with normal ECF volume. The goal now is to increase potassium secretion without excessive reabsorption of sodium. AII levels are low (there is nothing to stimulate it), but aldosterone levels are high due to the high potassium. Significant amounts of sodium escape reabsorption in the distal tubule (because there is no stimulation by AII) and reach the principal cells. Enough sodium is reabsorbed via ENaCs, stimulated by aldosterone, to prevent excessive sodium loss. Simultaneously the secretion of potassium occurs at a high rate, stimulated by aldosterone without the inhibiting influence of AII. The combined result is high potassium excretion and normal sodium excretion.

Case 3: depletion of both sodium and potassium. The goal is to maximize reabsorption of both sodium and potassium and excrete little of either one. The sodium depletion stimulates renin secretion and the production of AII, but the low potassium inhibits the ability of the adrenal glands to secrete aldosterone. Sodium is strongly reabsorbed upstream from the principal cells stimulated by AII, and principal cells are not stimulated by aldosterone. Since little potassium can be excreted without significant secretion, both sodium and potassium are reabsorbed.

There is yet another mechanism to allow control of potassium excretion independent of sodium that comes into play in cases of prolonged high dietary potassium and low dietary sodium. An adaptation to this condition is an increase in the activity of basolateral Na-H antiporters in principal cells. This supports the influx of sodium when the availability of sodium from the luminal side is very limited. Sodium entering via the Na-H antiporters is then removed by the Na-K-ATPase, that is, it is recycled. The continued operation of the Na-K-ATPase imports potassium, which is then secreted across the apical membrane. This adaptation allows the kidneys to excrete potassium while conserving sodium and underscores the remarkable ability of the kidneys to modify transporter abundance in order to preserve balance on a longer time scale.

Perturbations in Potassium Excretion: Diuretics

Up to this point, we have emphasized the ability of the kidneys to regulate the excretion of sodium, potassium, and other substances independently and to handle any combination of loads. However, there are situations in which pathology, medical intervention, or excessive loss of one of these substances affects the excretion of another. We address this issue here and again in Chapter 9 in association with acid-base balance.

A common medical intervention is the use of diuretics. These are agents that increase urine flow, often called “water pills” by patients. The goal of diuretic use is to reduce ECF volume, thereby correcting or preventing edema. Diuretics work by increasing sodium excretion, which increases the osmotic load in the urine, taking water with it. Many diuretics, although effective at increasing water and sodium excretion, have the unwanted and serious side effect of increasing the renal excretion of potassium, leading to hypokalemia. The most powerful diuretics act by blocking sodium reabsorption by the Na-K-2Cl symporter in the thick ascending limb. These are called “loop diuretics” because they act in the loop of Henle. Another group, called thiazide diuretics, blocks the Na-Cl symporter in the distal tubule. Both classes of diuretic reduce sodium reabsorption upstream from the connecting tubule, and therefore result in a large amount of sodium delivered to downstream principal cells. This greatly stimulates sodium uptake (but the load is so great that most of it passes by and is excreted) and, at the same time, stimulates potassium secretion. The potassium loss may cause severe potassium depletion (Figure 8–5).

Because potassium loss is so troubling, other classes of diuretics have been developed that are called “potassium-sparing.” Some block the ENaC sodium channels in principal cells, thereby obviating the stimulation of potassium secretion. Another class of diuretics blocks the renal actions of aldosterone. Such drugs are weak diuretics, but are also potassium-sparing because they block the stimulation of potassium channels by aldosterone that promotes potassium secretion. As with many drugs, they may have beneficial effects not directly associated with their diuretic actions.

Perturbations in Potassium Excretion: Hyperkalemia

Hyperkalemia is a condition of elevated plasma potassium concentration (usually defined as potassium levels above 5.5 mEq/L). In principle, hyperkalemia can develop in 2 ways: (1) as a result of shifts of potassium from the ICF to the ECF or (2) from an increase in total-body potassium. Shifts can be induced by an increase in plasma hydrogen ion concentration, as occurs during a metabolic acidosis (see Chapter 9), and occurs transiently during intense exercise as described earlier. Most cases of chronic hyperkalemia are a result of whole body potassium overload and involve inability of the kidneys to excrete potassium adequately.

An obvious renal cause of hyperkalemia is chronic renal failure. In terms of excretion, the kidneys can compensate for reduced GFR to a considerable extent (eg, we can get by perfectly well with just one kidney), but when GFR falls to only 10% of normal, hyperkalemia is a likely consequence. The reason is simply that the kidneys have lost potassium transport capacity. Because chronic hyperkalemia is life threatening, renal dialysis or transplant becomes necessary.

Another pathology leading to hyperkalemia is hypoaldosteronism. This condition can itself be the result of several causes, including primary adrenal insufficiency (the adrenal gland cannot synthesize aldosterone) and hyporeninemic hypoaldosteronism, which is failure to secrete enough renin. The result either way is that plasma levels of aldosterone are abnormally low, and the actions of aldosterone to stimulate potassium secretion are severely decreased. A variant of this condition is pseudohypoaldosteronism, in which the principal cells do not respond to aldosterone. Again the result is decreased capacity to secrete, and therefore to excrete potassium.

Another common cause of hyperkalemia is medical intervention. Just as powerful diuretics often lead to hypokalemia, some treatments for cardiac failure often lead to hyperkalemia. Common treatments for cardiac failure involve concomitant use of ACE inhibitors (block production of AII) and potassium-sparing diuretics. The combination prevents sufficient action of aldosterone in renal principal cells, again leading to decreased potassium secretion.

• Only a small fraction of body potassium is in the ECF, and the extracellular concentration may not be a good indicator of total-body potassium status.

• On a short-term basis, uptake and release of potassium by tissue cells prevents large swings in extracellular potassium concentration.

• Overall renal handling is accomplished by reabsorbing nearly all filtered potassium and then secreting an amount of potassium that maintains balance between ingestion and excretion.

• It is mainly the principal cells of the connecting tubule and cortical collecting duct that alter rates of potassium secretion.

• Potassium secretion (and thus excretion) is increased by high sodium delivery to the distal nephron, particularly when this is caused by diuretics acting upstream.