Medical Physiology, 3rd Edition

Potassium Balance and the Overall Renal Handling of Potassium

Changes in K+ concentrations can have major effects on cell and organ function

The distribution of K+ in the body differs strikingly from that of Na+. Whereas Na+ is largely extracellular, K+ is the most abundant intracellular cation. Some 98% of the total-body K+ content (~50 mmol/kg body weight) is inside cells; only 2% is in the extracellular fluid (ECF). The body tightly maintains the plasma [K+] at 3.5 to 5.0 mM.

Table 37-1 summarizes the most important physiological functions of K+ ions. A high [K+] inside cells and mitochondria is essential for maintenance of cell volume, for regulation of intracellular pH and control of cell-enzyme function, for DNA and protein synthesis, and for cell growth. The relatively low extracellular [K+] is necessary for maintaining the steep K+ gradient across cell membranes that is largely responsible for the membrane potential of excitable and nonexcitable cells. Therefore, changes in extracellular [K+] can cause severe disturbances in excitation and contraction. As a general rule, either doubling the normal plasma [K+] or reducing it by half results in severe disturbances in skeletal and cardiac muscle function. The potentially life-threatening disturbances of cardiac rhythmicity that result from a rise in plasma [K+] are particularly important (Box 37-1).

TABLE 37-1

Physiological Role of Potassium Ions

A. Roles of Intracellular K+

Cell volume maintenance

Net loss of K+ → cell shrinkage

Net gain of K+ → cell swelling

Intracellular pH regulation

Low plasma [K+] → cell acidosis

High plasma [K+] → cell alkalosis

Cell enzyme functions

K+ dependence of enzymes: e.g., some ATPases, succinic dehydrogenase

DNA/protein synthesis, growth

Lack of K+ → reduction of protein synthesis, stunted growth

B. Roles of Transmembrane [K+] Ratio

Resting cell membrane potential

Reduced [K+]i/[K+]o → membrane depolarization

Increased [K+]i/[K+]o → membrane hyperpolarization

Neuromuscular activity

Low plasma [K+]: muscle weakness, muscle paralysis, intestinal distention, respiratory failure

High plasma [K+]: increased muscle excitability; later, muscle weakness (paralysis)

Cardiac activity

Low plasma [K+]: prolonged repolarization; slowed conduction; abnormal pacemaker activity, leading to tachyarrhythmias

High plasma [K+]: enhanced repolarization; slowed conduction, leading to bradyarrhythmias and cardiac arrest

Vascular resistance

Low plasma [K+]: vasoconstriction

High plasma [K+]: vasodilation

Chronic K+ depletion leads to several metabolic disturbances. These include the following: (1) inability of the kidney to form a concentrated urine (Box 38-1); (2) a tendency to develop metabolic alkalosis (pp. 834–835); and, closely related to this acid-base disturbance, (3) a striking enhancement of renal ammonium excretion (pp. 834–835).

K+ homeostasis involves external K+ balance between environment and body, and internal K+ balance between intracellular and extracellular compartments

Figure 37-1 illustrates processes that govern K+ balance and the distribution of K+ in the body: (1) gastrointestinal (GI) intake, (2) renal and extrarenal excretion, and (3) the internal distribution of K+ between the intracellular and extracellular fluid compartments. The first two processes accomplish external K+ balance (i.e., body versus environment), whereas the last achieves internal K+ balance (i.e., intracellular versus extracellular fluids).


FIGURE 37-1 Distribution and balance of K+ throughout the body. Intracellular K+ concentrations are similar in all tissues in the four purple boxes. The values in the boxes are approximations. RBC, red blood cell.

External K+ Balance

The relationship between dietary K+ intake and K+ excretion determines external K+ balance. The dietary intake of K+ is approximately equal to that of Na+, 60 to 80 mmol/day. This K+ intake is approximately equal to the entire K+ content of the ECF, which is only about 65 to 75 mmol. For the plasma K+ content to remain constant, the body must excrete K+ via renal and extrarenal mechanisms at the same rate as K+ingestion. Moreover, because dietary K+ intake can vary over a wide range, it is important that these K+-excretory mechanisms be able to adjust appropriately to variable K+ intake. The kidney is largely responsible for K+ excretion, although the GI tract plays a minor role. The kidneys excrete 90% to 95% of the daily K+ intake; the colon excretes 5% to 10%. Although the colon can adjust its K+ excretion in response to some stimuli (e.g., adrenal hormones, changes in dietary K+, decreased capacity of the kidneys to excrete K+), the colon—by itself—is incapable of increasing K+ secretion sufficiently to maintain external K+ balance.

Internal K+ Balance

Maintaining normal intracellular and extracellular [K+] requires not only the external K+ balance just described, but also the appropriate distribution of K+ within the body. Most of the K+ is inside cells—particularly muscle cells, which represent a high fraction of body mass—with smaller quantities in liver, bone, and red blood cells. The markedly unequal distribution between the intracellular and extracellular K+ content has important quantitative implications. Of the total intracellular K+ content of ~3000 mmol, shuttling as little as 1% to or from the ECF would cause a 50% change in extracellular [K+], with severe consequences for neuromuscular function (see Table 37-1).

Ingested K+ moves transiently into cells for storage before excretion by the kidney

What happens when the body is presented with a K+ load? By far, the most common source of a K+ load is dietary K+. When one ingests K+ salts, both the small intestine (p. 908) and the colon (p. 910) absorb the K+. Not only can K+ come from external sources, but substantial amounts of K+ may enter the ECF from damaged tissues (Box 37-2). Such K+ release from intracellular to extracellular fluid can lead to a severe, even lethal, increase in plasma [K+] (i.e., hyperkalemia). However, even a large meal presents the body with a K+ load that could produce hyperkalemia if it were not for mechanisms that buffer and ultimately excrete this K+.


Causes of Hypoaldosteronism

Contributed by Emile Boulpaep, Walter Boron

The reason that hypoaldosteronism can cause hyperkalemia is that renal K+ excretion largely depends on K+ secretion by the CCT. There, aldosterone is responsible for maintaining high levels of the apical ENaC. Decreased expression of ENaC leads to decreased Na+ uptake across the apical membrane, less depolarization of the apical membrane, and thus less driving force for the passive diffusion of K+ out across the apical membrane (see Fig. 37-7C).

Bear in mind that aldosterone is synthesized by the glomerulosa cells in the adrenal cortex (see Figs. 50-1 and 50-2 and the discussion of mineralocorticoids beginning on p. 1026). Causes of hypoaldosteronism include the following:

• Addison disease (in which part of the adrenal gland is destroyed)

• Congenital adrenal hypoplasia

• Deficiency in the enzyme aldosterone synthase (see Fig. 50-2)

• Low-renin states (because the renin–ANG II axis is the major stimulant for aldosterone secretion—see pp. 1027–1029). Examples of patients with low-renin states include otherwise normal older patients (who may have a reduced renin response to orthostasis) and diabetic patients. Another class of low-renin state is drug induced (e.g., secondary to the inhibition of the sympathetic division of the autonomic nervous system, which is a major stimulant of renin release).

• Pseudohypoaldosteronism types 1 and 2. Both cases represent defects in the ability of aldosterone to exert its effects (e.g., defects in the mineralocorticoid receptor or ENaC). In these syndromes, plasma levels of aldosterone are actually higher than normal.

Some four fifths of an ingested K+ load temporarily moves into cells, so that plasma [K+] rises only modestly, as shown in the upper panel of Figure 37-2. Were it not for this translocation, plasma [K+] could reach dangerous levels. The transfer of excess K+ into cells is rapid and almost complete after an hour (lower panel of Fig. 37-2, gold curve). With a delay, the kidneys begin to excrete the surfeit of K+ (lower panel of Fig. 37-2, brown curve), removing from the cells the excess K+ that they had temporarily stored.


FIGURE 37-2 K+ handling following an acute K+ load. (Data from Cogan MG: Fluid and Electrolytes: Physiology and Pathophysiology. Norwalk, CT, Appleton & Lange, 1991.)

What processes mediate the temporary uptake of K+ into cells during K+ loading? As shown in Figure 37-3, the hormones insulin, epinephrine (a β-adrenergic agonist), and aldosterone all promote the transfer of K+ from extracellular to intracellular fluid via the ubiquitous Na-K pump. imageN37-1 Indeed, the lack of insulin or a deficient renin-angiotensin-aldosterone system can significantly compromise tolerance to K+loading and can predispose to hyperkalemia. Similarly, administering β-adrenergic blockers (in treatment of hypertension) impairs sequestration of an acute K+ load.


FIGURE 37-3 K+ uptake into cells in response to high plasma [K+].


Hormonal Response to Acute K+ Loading

Contributed by Emile Boulpaep, Walter Boron

As noted in the text, ingestion of a K+-rich meal leads to only small increases in extracellular [K+]o because of the actions of insulin, epinephrine, and aldosterone on target tissues (see Fig. 37-3).

As discussed on p. 1039 of the text, increases in [K+]o depolarize β cells in the pancreatic islets, leading to the release of insulin.

As discussed on page 1031, chromaffin cells in the adrenal medulla secrete epinephrine and to a lesser extent norepinephrine. Extremely large increases in [K+]o—so large that they would be fatal—do indeed promote the secretion of the aforementioned catecholamines. Physiological increases in [K+]o do not. Thus, physiological levels of epinephrine are permissive for K+ sequestration.

As discussed on page 1028, increases in [K+]o depolarize glomerulosa cells in the adrenal cortex, promoting the secretion of aldosterone.

Acid-base disturbances also affect internal K+ distribution. As a rule, acidemia leads to hyperkalemia as tissues release K+. One can think of this K+ release as an “exchange” of intracellular K+ for extracellular H+, although a single transport protein generally does not mediate this exchange (p. 645). Rather, apparent K-H exchange is most likely the indirect result of two effects of low pHo (Fig. 37-4). Extracellular acidosis inhibits Na-H exchange and Na/HCO3 cotransport, both raising [H+]i (i.e., lowering pHi) and lowering [Na+]i. The intracellular acidosis compromises both the Na-K pump and the Na/K/Cl cotransporter NKCC2, both of which move K+ into cells. In addition, low pHi lessens the binding of K+ to nondiffusible intracellular anions, promoting K+ efflux. In parallel, the low [Na+]i reduces the supply of intracellular Na+ to be extruded by the Na-K pump and thus inhibits K+ uptake by the Na-K pump. These mechanisms all promote hyperkalemia. imageN37-2


FIGURE 37-4 Effect of acidosis on K+ uptake into cells.


Ability of Inorganic Versus Organic Acids to Cause Hyperkalemia

Contributed by Gerhard Giebisch, Erich Windhager, Peter Aronson

Interestingly, for the same degree of acidemia, mineral acids produce a greater degree of hyperkalemia than do organic acids. This difference occurs because organic anions like lactate enter the cell by H+cotransport. The resulting intracellular acidosis and fall in intracellular bicarbonate will tend to stimulate Na/HCO3 cotransporters (NBCs; see p. 122) and Na-H exchangers (NHEs; see pp. 123–124) and thereby oppose the inhibitory effects of extracellular acidosis.

Conversely, alkalemia causes cells to take up K+ and thus leads to hypokalemia. High extracellular pH and [image] enhance Na+ entry into the cell via Na-H exchange and Na/HCO3 cotransport. The resulting stimulation of the Na-K pump then causes hypokalemia by stimulating K+ transfer into cells. The opposite side of the coin, also appearing as the exchange of K+ for H+, is the effect of changes in extracellular [K+] on acid-base homeostasis. For example, hyperkalemia causes intracellular alkalosis (p. 645) and extracellular acidosis (p. 835). Conversely, K+ depletion causes intracellular acidosis and extracellular alkalosis (pp. 834–835).

In some clinical conditions, an increase in extracellular osmolality induces a transfer into the extracellular space not only of water but also of K+. An example of this phenomenon occurs in diabetic patients in whom severe hyperglycemia leads to cell shrinkage and thus a regulatory volume increase (p. 131), resulting in a rise in plasma [K+]. imageN37-3


Hyperkalemia During Hyperosmolality

Contributed by Emile Boulpaep

In the text, we introduce the example of hyperglycemia-induced hyperkalemia in diabetics. The insulin deficiency, by itself (even without cell shrinkage), will reduce K+ uptake into cells by the Na-K pump and thus lead to hyperkalemia.

In addition, hypertonicity will contribute to hyperkalemia by two possible mechanisms, one likely to be minor and the other major. In the first mechanism (i.e., presumably the minor one), we assume no regulation of cell volume after cell shrinkage. In isosmolal solutions, the net driving force for K+ in mammalian skeletal muscle is (Vm − EK) = (−80 − [−95]) = +15 mV (see Fig. 6-10), where Vm is membrane potential and EK is the equilibrium potential for K+. An increase in extracellular osmolality from 300 to 315 mOsm (i.e., a 5% increase in osmolality)—for example, caused by raising plasma [glucose] from 100 to 400 mg/dL (or from 5 to 20 mM), which is a large increase—would cause the cell to shrink by 5% of its initial volume. As a result, intracellular [K] would rise by 5%, thereby causing EK to shift by ~1.3 mV in the negative direction and increasing the net electrochemical driving force for K+ (i.e., Vm − EK) from +15 mV to +16.3 mV. Assuming Vm and K+ conductance are unaffected by shrinkage,* K+ efflux would increase by an unimpressive 9%. Thus, this direct effect of cell shrinkage on [K+]o is likely to be relatively small.

In the second mechanism, we assume that the skeletal muscle cell undergoes a regulatory volume increase (RVI; see p. 131). If the cell responds to the initial 5% shrinkage in 315 mOsm by returning cell volume to its initial level, the cell will gain 15 mOsm of NaCl (i.e., adding 7. 5 mM of Na+ and 7.5 mM of Cl). Note that the normal [Cl]i in mammalian skeletal muscle is only ~4.2 mM (see Table 6-1) and ECl is −89 mV (see Fig. 6-10). Thus, [Cl]i will rise from 4.2 mM to (4.2 + 7.5) = 11.7 mM, which is sufficient to shift ECl from −89 mV to −61 mV. Because the Cl conductance of skeletal muscle is high (approximately one half of total membrane conductance), this shift in ECl will cause a major depolarization of skeletal muscle and thereby promote the efflux of K+ into the ECF, contributing in a major way to hyperkalemia.


Lindinger MI, Leung M, Trajcevski KE, Hawke TJ. Volume regulation in mammalian skeletal muscle: The role of sodium-potassium-chloride cotransporters during exposure to hypertonic solutions. J Physiol. 2011;589:2887–2899.

*In fact, Vm probably would shift slightly in the negative direction, inasmuch as Vm depends on the K+ gradient. Thus, the increase in outward K+ driving force would be less than in this example.

The kidney excretes K+ by a combination of filtration, reabsorption, and secretion

At a normal glomerular filtration rate and at physiological levels of plasma [K+], the kidney filters ~800 mmol/day of K+, far more than the usual dietary intake of 60 to 80 mmol/day. Therefore, to achieve K+balance, the kidneys normally need to excrete 10% to 15% of the filtered K+. Under conditions of low dietary K+ intake, the kidneys excrete 1% to 3% of filtered K+, so that—with a normal- or low-K+ diet—the kidneys could in principle achieve K+ balance by filtration and reabsorption alone. Considering only the filtered K+ load and external K+ balance, we would have no reason to suspect that the kidneys would be capable of K+ secretion. However, with a chronic high intake of dietary K+, when the kidneys must rid the body of excess K+, urinary K+ excretion may exceed 150% of the total amount of filtered K+. Therefore, even if the tubules reabsorb none of the filtered K+, they must be capable of secreting an amount equivalent to at least 50% of the filtered K+ load.

As discussed below, even in the absence of a large dietary K+ load, K+ secretion by the tubules is an important component of urinary K+ excretion. Therefore, K+ handling is a complex combination of K+ filtration at the glomerulus as well as both K+ reabsorption and secretion by the renal tubules.