Hypokalemia is characterized by a decrease in potassium secretion, which is caused by a low-potassium diet or loss of potassium in diarrhea fluid. This condition inhibits the Na+,K+-ATPase, reduces the driving force for potassium efflux across the apical membrane, decreases permeability of the apical membrane to potassium, and lowers plasma aldosterone levels.

Chronic hypokalemia, defined as a plasma potassium concentration of less than 3.5 mEq/L, is commonly observed in patients receiving diuretics for hypertension. It can also occur in individuals who vomit, undergo nasogastric suction, experience diarrhea, abuse laxatives, or have hyperaldosteronism. Hypokalemia arises due to increased kidney excretion of potassium compared to dietary intake. Vomiting, nasogastric suction, diuretics, and diarrhea can lead to a decrease in extracellular fluid volume (ECFV), which in turn stimulates aldosterone secretion. Since aldosterone promotes potassium excretion by the kidneys, it contributes to the development of hypokalemia.

Chronic hyperkalemia, defined as a plasma potassium concentration of greater than 5.0 mEq/L, is most commonly seen in individuals with reduced urine flow, low plasma aldosterone levels, and renal disease with a glomerular filtration rate (GFR) below 20% of normal. Hyperkalemia occurs in these individuals because kidney excretion of potassium is insufficient to balance dietary intake. Less common causes of hyperkalemia include deficiencies in insulin, epinephrine, and aldosterone secretion, as well as metabolic acidosis caused by inorganic acids.

Elevated plasma aldosterone levels for at least 24 hours enhance potassium secretion across principal cells in the late segment of the distal tubule and collecting duct, known as the aldosterone-sensitive distal nephron (ASDN). This is achieved through various mechanisms: increasing the amount of Na+,K+-ATPase in the basolateral membrane, upregulating expression of the epithelial sodium channel (ENaC) in the apical cell membrane, elevating levels of SGK1 (serum glucocorticoid-stimulated kinase) to increase ENaC expression and activate potassium channels, stimulating CAP1 (channel-activating protease) to directly activate ENaC, and enhancing permeability of the apical membrane to potassium. Aldosterone accomplishes the latter by increasing the number of potassium channels in the membrane, although the precise cellular mechanisms involved are not fully understood. Increased Na+,K+-ATPase expression facilitates potassium uptake into cells across the basolateral membrane, raising intracellular potassium levels. The increased number and activity of sodium channels enhance sodium entry into the cell from tubular fluid, leading to apical membrane depolarization. This depolarization, combined with increased intracellular potassium levels, strengthens the electrochemical driving force for potassium secretion from the cell into the tubule fluid. Overall, these actions promote potassium uptake into the cell via the basolateral membrane and enhance potassium exit from the cell via the apical membrane. Hyperkalemia and angiotensin II (produced after activation of the renin-angiotensin system) stimulate aldosterone secretion, while hypokalemia and natriuretic peptides released from the heart decrease aldosterone secretion.
Hypokalemia (e.g., caused by a low-K+ diet or loss of K+ in diarrhea fluid) decreases K+ secretion via actions opposite those described for hyperkalemia. Hence hypokalemia inhibits Na+,K+-ATPase, decreases the electrochemical driving force for efflux of K+ across the apical membrane, reduces permeability of the apical membrane to K+ , and decreases plasma aldosterone levels.
Chronic hypokalemia (plasma [K+] < 3.5 mEq/L) occurs most often in patients who receive diuretics for hypertension. Hypokalemia also occurs in patients who vomit, undergo nasogastric suction, have diarrhea, abuse laxatives, or have hyperaldosteronism. Hypokalemia occurs because excretion of K+ by the kidneys exceeds dietary intake of K+ . Vomiting, nasogastric suction, diuretics, and diarrhea can all decrease ECF volume (ECFV), which in turn stimulates secretion of aldosterone (see ). Because aldosterone stimulates excretion of K+ by the kidneys, its action contributes to development of hypokalemia.
Chronic hyperkalemia (plasma [K+] > 5.0 mEq/L) occurs most frequently in individuals with reduced urine flow, low plasma aldosterone levels, and renal disease in which the glomerular filtration rate (GFR) falls below 20% of normal. In these individuals, hyperkalemia occurs because excretion of K+ by the kidneys is less than dietary intake of K+ . Less common causes of hyperkalemia occur in people with deficiencies in insulin, epinephrine, and aldosterone secretion or in people with metabolic acidosis caused by inorganic acids.
Chronically elevated (i.e., ≥24 hours) plasma aldosterone levels enhance secretion of K+ across principal cells in the late segment of the distal tubule and collecting duct (i.e., aldosterone-sensitive distal nephron [ASDN]) via five mechanisms (Fig. 36.7 ): (1) by increasing the amount of Na+,K+-ATPase in the basolateral membrane; (2) by increasing expression of the epithelial sodium channel (ENaC) in the apical cell membrane; (3) by elevating SGK1 (serum glucocorticoid-stimulated kinase) levels, which also increases expression of ENaC in the apical membrane and activates K+ channels; (4) by stimulating CAP1 (channelactivating protease, also called prostatin), which directly activates ENaC; and (5) by stimulating the permeability of the apical membrane to K+ . Aldosterone increases the permeability of the apical membrane to K+ by increasing the number of K+ channels in the membrane. However, the cellular mechanisms involved in this response are not completely known. Increased expression of Na+,K+-ATPase facilitates uptake of K+ across the basolateral membrane into cells and thereby elevates intracellular [K+]. The increase in the number and activity of Na+ channels enhances entry of Na+ into the cell from tubular fluid, an effect that depolarizes the apical membrane voltage. Depolarization of the apical membrane and increased intracellular [K+] enhance the electrochemical driving force for secretion of K+ from the cell into the tubule fluid. Taken together, these actions increase uptake of K+ into the cell across the basolateral membrane and enhance exit of K+ from the cell across the apical membrane. Secretion of aldosterone is increased by hyperkalemia and by angiotensin II (after activation of the renin-angiotensin system). Secretion of aldosterone is decreased by hypokalemia and natriuretic peptides released from the heart.
CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis