Clinical Note

Hyperkalemia and Its Treatment

Disturbances in K+ balance are seen frequently. Changes in plasma K+ concentration have effects on neuromuscular excitability because of the importance of the K+ concentration gradient across cell membranes in determining the resting membrane potential. For example, an acute increase in the ECF K+ concentration leads to depolarization of the resting potential, which, by itself, should increase neuromuscular excitability; however, with chronic depolarization of the resting potential, the voltage-gated Na+ channels that are responsible for the rising phase of the action potential are inactivated, leading to diminished excitability. Chronic hypokalemia has the opposite effect—the hyperpolarization of the membrane potential activates the Na+ channels. Whereas hypokalemia can be treated easily by dietary K+ supplements or, if severe, by administering intravenous K+, the proper treatment of hyperkalemia requires a better understanding of its origin.

Hyperkalemia results either from a shift of K+ out of cells to the ECF or from reduced K+ excretion in the urine. Metabolic alkalosis, uncontrolled diabetes mellitus, ^-adrenergic blocking drugs, and strenuous exercise are all causes of hyper-kalemia. In addition, tissue damage, such as occurs with traumatic injury or cancer chemotherapy, can produce massive K+ loss from cells. Hyperkalemia due to inadequate excretion is found in advanced renal failure or when the blood supply to the kidney is inadequate, as in low output heart failure. It can also be due to low plasma aldosterone concentrations. Plasma aldosterone is low not only in Addison's disease, but also in the presence of drugs such as converting enzyme inhibitors or angiotensin II receptor blockers, which interfere with the stimulation of aldosterone secretion by angiotensin II. Plasma aldosterone levels can also decrease with nonsteroidal anti-inflammatory drugs (NSAIDs) because they inhibit prostaglandin production, which is one of the stimuli to renin release and angiotensin II production. Finally, potassium-sparing diuretics, by blocking Na+ reabsorption in the collecting duct, indirectly decrease K+ secretion and can produce hyperka-lemia.

In treating hyperkalemia, it is necessary first to establish that it is not due to acidosis because, as will be discussed in Chapter 31, total body K+ depletion often accompanies hyperkalemia in chronic acidosis. In this case, merely correcting the cause of the acidosis usually will restore K+ balance. It should also be established that the hyperkalemia is not due to one of the drugs mentioned here. Mild hyperkalemia from other causes can be treated by giving a loop diuretic, which augments K+ secretion in the connecting tubule and collecting duct, for the reasons discussed later and in Chapter 27. More severe hyperkalemia must be treated more rapidly. A cation exchange resin that binds K+ in the intestinal tract can be given orally or by enema, and it can reduce plasma K+ within hours. An even more rapid response to dangerously high plasma K+ concentration can be achieved by administering insulin plus glucose, a ^-adrenergic agonist, or NaHCO3 to create metabolic alkalosis. All of these procedures operate within 30-60 min by shifting K+ into cells, as illustrated in Fig. 1. In life-threatening cases of hyperkalemia, when signs of cardiac arrhythmias are already present, Ca2+ is administered intravenously in the form of calcium gluconate because, by mechanisms that are not yet understood, it rapidly but transiently reverses the inactivation of Na+ channels.

The proximal tubule reabsorbs ~60% of the filtered load of K+ (about 430 mmol/day). This reabsorption is primarily passive and occurs because of the rise in the tubular fluid K+ concentration as fluid is reabsorbed. Diuretics that act proximally (such as acetazolamide or osmotic diuretics) increase K+ excretion by decreasing the amount of fluid and, hence, K+ reabsorbed in the proximal tubule.

Somewhat in excess of 30% of the filtered K+ (~230 mmol/day) is reabsorbed in the loop of Henle. Most of this reabsorption occurs in the thick ascending limb of the loop of Henle. As discussed in Chapter 27, K+ is transported by the same luminal membrane transport system that carries Na+ and Cl", i.e., the Na+-K+-2Cl" cotransporter. Although much of the K+ that is transported into the thick ascending limb cell by this mechanism diffuses back into the lumen via the K+ channel in the luminal membrane, substantial amounts move from the cell toward the plasma, resulting in net K+ reabsorption.

FIGURE 2 Sites of K+ reabsorption and secretion along the nephron. K+ is passively reabsorbed in the proximal tubule. Although there is passive potassium secretion by diffusion into the descending limb, overall there is net reabsorption in the loop of Henle due to greater reabsorption in the ascending limb, so that less than 10% of the filtered load is delivered to the distal convolution. Active secretion of K+ by the CNT and principal cells in the connecting tubule and collecting duct adds to the amount delivered so that the daily excretion of K+ ranges from 7-20% of the filtered load.

FIGURE 2 Sites of K+ reabsorption and secretion along the nephron. K+ is passively reabsorbed in the proximal tubule. Although there is passive potassium secretion by diffusion into the descending limb, overall there is net reabsorption in the loop of Henle due to greater reabsorption in the ascending limb, so that less than 10% of the filtered load is delivered to the distal convolution. Active secretion of K+ by the CNT and principal cells in the connecting tubule and collecting duct adds to the amount delivered so that the daily excretion of K+ ranges from 7-20% of the filtered load.

Reabsorption in the proximal tubule and the loop of Henle reduces the K+ delivered to the distal convolution to less than 10% of the filtered load. Because the amount of K+ normally excreted exceeds this amount, K+ must be added to the distal tubular urine by secretion. Normally, the connecting tubule and collecting duct secrete 20-90 mmol/day, and this amount is adjusted appropriately to match the daily excretion to the daily intake.

Not only are there marked changes in the rate of K+ secretion in response to changes in dietary K+ intake, but these functional changes are also associated with morphologic changes. Increased dietary K+ intake is associated with increased K+ secretion by the connecting tubule and collecting duct, an increase in the basolateral membrane surface area, and the density of Na+,K+-ATPase. These changes are mediated by increase in aldosterone release by the adrenal cortex that accompanies hyperkalemia. In addition, aldos-terone as well as vasopressin increases the activity of K+ channels in the luminal membrane of the CNT and principal cells in the ARDN.

On the other hand, with a K+-deficient diet K+ secretion is drastically reduced, and the ARDN can even exhibit net K+ reabsorption and reduce the K+ excretion virtually to zero. This net reabsorption of K+ is produced primarily by the intercalated cells of the cortical collecting duct. In chronic, severe K+ deficiency, these cells express a second type of H+ pump, the H+,K+-ATPase (see Chapter 31). This pump actively secretes H+ in exchange for an uptake of K+ into the cells that mediate its active reabsorption.

The plasma K+ concentration is an important regulator of K+ secretion by the connecting tubule and collecting duct, i.e., the ARDN. As shown in Fig. 3A, a rise in plasma K+ concentration stimulates secretion even in the presence of a constant aldosterone concentration. The mechanism for this direct effect of K+ concentration is not well understood, but it may relate to a corresponding increase in cell K+ that is available for secretion as the extracellular K+ concentration rises.

As shown in Fig. 3B, the daily regulation of K+ secretion by the ARDN is regulated by aldosterone. As discussed in Chapter 27, aldosterone acts to increase K+ secretion by CNT and principal cells in association with increased Na+ reabsorption. Extracellular volume depletion, in which increased plasma aldosterone

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