Potassium Distribution

After absorption from the GI tract, potassium distributes into the extracellular fluid (ECF) and intracellular fluid (ICF) compartments. Potassium is the major intracellular cation, with K⁺ concentrations from about 100 to 120 mmol/l in the cytosol. Total intracellular K⁺ content is 3000 to 3500 mmol in healthy adults, found primarily in muscle (70%), with a lesser amount in bone, red blood cells, liver, and skin (Table 9-2). Only 1% to 2% total body potassium is present in the ECF. The electrogenic sodium pump, Na⁺-K⁺-ATPase, which is present in virtually all cells, affects this asymmetric potassium distribution by active cellular K⁺ uptake. Na⁺-K⁺-ATPase transports two potassium ions into cells in exchange for extrusion of three sodium ions, which results in high intracellular potassium concentration (high [K⁺]) and low intracellular sodium concentration (low [Na⁺]). Potassium-selective ion channels are the predominant determinant of the resting membrane potential. Therefore, the intracellular/extracellular [K⁺] ratio largely determines the resting cell membrane potential and the intracellular electronegativity. Normal maintenance of this ratio and membrane potential is critical for normal nerve conduction and muscular contraction.

Serum potassium is tightly regulated through multiple mechanisms. Recent studies support a “feed forward” regulatory system involving gut or portal potassium sensors. This system adjusts renal potassium excretion through mechanisms independent of serum potassium and aldosterone.^2,3 This reflex system, which is still not understood fully, allows the kidney to “sense” dietary intake and alter renal potassium excretion despite no discernible changes in serum potassium or aldosterone concentration.

In addition, several hormones and factors can induce potassium shifts between the extracellular and intracellular potassium pools (Fig. 9-1). The most common causes include acid-base disorders, specific hormones, plasma osmolality, and exercise.

Aldosterone lowers serum potassium by two major mechanisms. First, aldosterone stimulates potassium movement into cells through stimulation of Na⁺-K⁺-ATPase (i.e., redistribution). Second, it can increase potassium excretion by the kidney and, to a lesser extent, by the GI tract. In the kidney, aldosterone stimulates sodium reabsorption in both the distal convoluted tubule and the collecting duct, and if there is sufficient sodium delivery to the collecting duct, this increased sodium reabsorption promotes potassium secretion. Mineralocorticoids can also stimulate potassium absorptive pumps, which may explain the equivocal effects of mineralocorticoids on potassium excretion despite their consistent effect on sodium absorption.^4,5

Another important factor that alters cellular potassium uptake is plasma osmolality. Increased plasma osmolality, or hyperosmolality, when resulting from “effective osmoles,” can cause hyperkalemia. The likely mechanism is that increased plasma osmolality induces water movement out of the cells, which decreases cell volume and increases intracellular [K⁺]. This in turn results in feedback inhibition of Na⁺-K⁺-ATPase, decreasing cellular potassium uptake and normalizing intracellular [K⁺]. The clinician should remember that this occurs only with effective osmoles, such as with mannitol, or with hyperglycemia in diabetic patients. Both glucose in patients with intact insulin secretion and urea are “ineffective osmoles” because they rapidly cross plasma membranes and therefore do not alter cell volume. Importantly, administration of a glucose load to a nondiabetic patient, through stimulation of endogenous insulin secretion, can cause insulin-induced cellular potassium uptake and result in hypokalemia.

Exercise may result in hyperkalemia due to α-adrenergic receptor activation that shifts potassium out of the skeletal muscle cells. The increased serum potassium induces arterial dilation, which increases skeletal muscle blood flow and acts as an adaptive mechanism during exercise. Simultaneous β₂-adrenoceptor activation stimulates skeletal muscle cellular potassium uptake and minimizes the severity of exercise-induced hyperkalemia, but this can lead to hypokalemia after cessation of exercise. In patients with preexisting potassium depletion, postexercise hypokalemia may be severe and can cause rhabdomyolysis.⁶

Renal Potassium Handling with Normal Renal Function

Long-term potassium homeostasis is accomplished primarily through changes in renal potassium excretion, almost entirely through regulated collecting duct potassium transport. Serum potassium is almost completely ionized, is not bound to plasma proteins, and is filtered efficiently by the glomerulus (Fig. 9-2). The proximal tubule reabsorbs the majority (~65% to 70%) of filtered potassium, but there is relatively little variation in proximal tubule potassium reabsorption in response to hypokalemia or hyperkalemia. In the loop of Henle, potassium is secreted in the descending loop, at least in deep nephrons, and is reabsorbed in the ascending loop through the action of the Na⁺-K⁺-2Cl⁻ cotransporter (Fig. 9-3, A). However, the majority of K⁺ transported by this protein is recycled back into the tubular lumen through an apical K⁺ channel. As a result, there is only modest net potassium reabsorption in the Henle loop. This absorption can be reversed to secretion, however, by administration of a loop diuretic or by substantial potassium loading. However, the magnitude of the change in Henle loop potassium transport in various physiologic conditions is rather small. Consequently, potassium excretion is regulated under most conditions through variations in distal convoluted tubule and collecting duct potassium transport.

The collecting duct consists of two fundamentally different cell types with distinctly different roles in potassium transport. The principal cell in the cortical collecting duct secretes potassium, whereas intercalated (IC) cells appear to reabsorb potassium. In the principal cell, sodium is reabsorbed through the apical epithelial sodium channel (ENaC), which stimulates basolateral Na⁺-K⁺-ATPase (Fig. 9-3, B); active potassium uptake by this protein maintains a high intracellular [K⁺]. Subsequent to basolateral potassium uptake, K⁺ is secreted across the apical plasma membrane of principal cells into the luminal fluid by apical potassium channels and KCl cotransporters. IC cells, in contrast, reabsorb potassium through an apical H⁺-K⁺-ATPase⁷ (Fig. 9-3, C); this protein actively secretes H⁺ into the luminal fluid in exchange for reabsorption of luminal potassium. The presence of two separate potassium transport processes, secretion by principal cells and reabsorption by IC cells, enables rapid and effective regulation of renal potassium excretion.

Several factors regulate principal cell potassium secretion and, in relative order of importance, include luminal flow rate, distal sodium delivery, aldosterone, extracellular potassium, and extracellular pH. An increase in luminal flow rate reduces luminal [K⁺], thereby increasing the concentration gradient across the apical membrane, which stimulates potassium secretion. In addition, flow rate directly influences cellular potassium secretion, possibly by modulating the activity of potassium channels. Conversely, reduced luminal flow, such as occurs in pre-renal azotemia and obstruction, may result in hyperkalemia. Decreased sodium reabsorption, whether from reduced luminal sodium delivery or sodium channel inhibitors, decreases K⁺ secretion by altering electrochemical forces for K⁺ secretion. “Potassium-sparing diuretics” function by blocking principal cell ENaC-mediated sodium reabsorption, which inhibits principal cell potassium secretion. Conversely, increased sodium delivery to the collecting duct, as may occur with loop or thiazide diuretics, increases principal cell sodium reabsorption and causes a secondary increase in potassium secretion. Aldosterone has many effects that increase principal cell potassium secretion, including increases in Na⁺-K⁺-ATPase expression and increased apical expression of eNaC. The net effect is increased K⁺ secretion. Increasing extracellular potassium directly stimulates Na⁺-K⁺-ATPase activity, leading to increased K⁺ secretion. Metabolic acidosis decreases K⁺ secretion, both through direct effects on potassium channels and through changes in interstitial ammonia concentration, which decreases K⁺ secretion.⁸ Respiratory acidosis has minimal effect on K⁺ secretion, whereas chronic respiratory alkalosis causes marked increases in K⁺ excretion because of increases in urinary bicarbonate excretion.

Potassium reabsorption, which occurs in parallel with potassium secretion, decreases net renal K⁺ excretion, and occurs through the action of the potassium-reabsorbing protein, H⁺-K⁺-ATPase. The major factors regulating H⁺-K⁺-ATPase expression and activity include potassium balance, aldosterone, and acid-base status. Potassium depletion increases H⁺-K⁺-ATPase expression, resulting in increased active potassium reabsorption and decreased potassium excretion. Aldosterone also increases H⁺-K⁺-ATPase expression and activity and, by decreasing net potassium excretion, may function to minimize the hypokalemia that otherwise results from aldosterone’s effect on both potassium redistribution and principal cell–mediated K⁺ secretion. Metabolic acidosis has both direct and indirect effects, mediated through alterations in ammonia metabolism, that increase H⁺-K⁺-ATPase potassium transport. In some patients, this may contribute to the hyperkalemia that can occur with metabolic acidosis.

An important class of intracellular signaling proteins have been identified that are fundamental in the regulation of renal K⁺ transport in the distal nephron. The “with no lysine” or “WNK” kinases are a family of proteins expressed in many cells of the body including the kidney. Under basal conditions, WNK kinases inhibit Na⁺ reabsorption as well as decreasing potassium secretion, in part by inhibiting the rectifying renal outer medulla potassium (ROMK) channel. Genetic defects that inactivate WNK kinases result in enhanced Na⁺ reabsorption and reduced K⁺ secretion.

Renal Potassium Handling in Chronic Kidney Disease

Potassium homeostasis is relatively well preserved and serum potassium usually remains in the normal range until glomerular filtration rate is reduced substantially. This adaptation is due largely to increased rates of per nephron potassium excretion in the connecting segment and the collecting duct. Both aldosterone and an increase in serum potassium may contribute to this adaptation. Intestinal potassium secretion increases, also, although quantitatively this is less important.

Patients with chronic kidney disease (CKD) have more difficulty handling an acute potassium load, even when they have a normal serum [K⁺]. Because these patients have decreased nephron number, their maximal capacity for K⁺ secretion is limited. Patients with CKD are also routinely treated with medications that alter renal potassium handling, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers. These can decrease renal potassium sensitivity and result in higher serum potassium concentrations.

Patients with CKD generally tolerate hyperkalemia with fewer cardiac and electrocardiographic (ECG) abnormalities than do patients with normal renal function. The mechanism of this adaptation is incompletely understood. In particular, patients with CKD appear to tolerate serum [K⁺] of 5.0 to 5.5 mmol/l with no significant adverse effect, and levels of 5.5 to 6.0 mmol/l are associated with lower mortality than [K⁺] of 3.5 to 3.9 mmol/l.⁹ Nevertheless, severe hyperkalemia (>6.0 mmol/l or presence of ECG changes) can have lethal effects and should be treated aggressively.

Clinical Manifestations

Potassium deficiency, because it alters the ratio of extracellular to intracellular potassium, alters the resting membrane potential, which can impair normal functioning of almost every cell in the body. This particularly is true for cells in the heart and blood vessels, nerves, muscles, gut, and kidneys. Overall, children and young adults tolerate hypokalemia better than elderly persons. Prompt correction is warranted in patients with coronary heart disease or in patients receiving digitalis glycosides, because of an increased risk of lethal cardiac arrhythmias.

Etiology

Hypokalemia results typically from one of four etiologies: pseudohypokalemia, redistribution, extrarenal potassium loss, or renal potassium loss. However, multiple etiologies may coexist in the specific patient.

Pseudohypokalemia

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

Normal Acid-Base Balance Retarding Progression of Kidney Disease Herbal and Over-the-Counter Medicines and the Kidney Complications of Peritoneal Dialysis Immunologic Principles in Kidney Transplantation Gastroenterology and Nutrition in Chronic Kidney Disease

Stay updated, free articles. Join our Telegram channel

Join