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.
Activity of ROMK and BK potassium channels in principal cells under different conditions. When the body is conserving potassium and little is being excreted, ROMK channels are mostly sequestered in intracellular vesicles and BK channels are closed; thus there is virtually no secretion. Under modest potassium loads (normal conditions), ROMK channels secrete potassium, whereas BK channels remain closed. When potassium excretion is very high, as on a high-potassium diet, ROMK channel activity is maximized and BK channels are open, allowing substantial secretion.
The main determinant of potassium secretion is sodium delivery to principal cells beyond the distal tubule.
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.
Factors that influence secretion of potassium by principal cells as described in the text.
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).
Pathways by which diuretic drugs affecting either the loop of Henle (loop diuretics) or distal convoluted tubule (thiazide diuretics) cause potassium depletion. Loop diuretics block potassium reabsorption in the thick ascending limb, but for both classes of diuretic the major factor leading to increased potassium excretion is the increased delivery of sodium to principal cells in the distal nephron, which stimulates potassium secretion.
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.