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Transport of Potassium
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).
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 + .
N37-8
Causes of Hypoaldosteronism
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. 37-7 C ).
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)
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Congenital adrenal hypoplasia
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Deficiency in the enzyme aldosterone synthase (see Fig. 50-2 )
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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.
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. 
N37-1 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 + ].](https://storage.googleapis.com/dl.dentistrykey.com/clinical/TransportofPotassium/2_3s20B9781455743773000379.jpg "Figure 37-3, K + uptake into cells in response to high plasma [K + ].")
N37-1
Hormonal Response to Acute K + Loading
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 H-K exchange is most likely the indirect result of two effects of low pH o ( Fig. 37-4 ). Extracellular acidosis inhibits Na-H exchange and Na/HCO 3 cotransport, both raising [H + ] i (i.e., lowering pH i ) 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 pH i 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. N37-2
N37-2
Ability of Inorganic Versus Organic Acids to Cause Hyperkalemia
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/HCO 3 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 [ 
] enhance Na + entry into the cell via Na-H exchange and Na/HCO 3 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 + ]. N37-3
N37-3
Hyperkalemia During Hyperosmolality
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 ( V m − E K ) = (−80 − [−95]) = +15 mV (see Fig. 6-10 ), where V m is membrane potential and E K 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 E K to shift by ~1.3 mV in the negative direction and increasing the net electrochemical driving force for K + (i.e., V m − E K ) from +15 mV to +16.3 mV. Assuming V m and K + conductance are unaffected by shrinkage, *
* In fact, V m probably would shift slightly in the negative direction, inasmuch as V m depends on the K + gradient. Thus, the increase in outward K + driving force would be less than in this example.
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 E Cl 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 E Cl 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 E Cl 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.
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.
Potassium Transport by Different Segments of the Nephron
The proximal tubule reabsorbs most of the filtered K + , whereas the distal nephron reabsorbs or secretes K + , depending on K + intake
Figure 37-5 summarizes the pattern of K + transport along the nephron under conditions of low or normal/high K + intake. In either case, the kidney filters K + in the glomerulus and then extensively reabsorbs it along the proximal tubule (~80%) and the loop of Henle (~10%), so that only ~10% of the filtered K + enters the distal convoluted tubule (DCT). Moreover, in either case, the medullary collecting duct (MCD) reabsorbs K + . The K + handling depends critically on dietary K + in five nephron segments: the DCT, the connecting tubule (CNT), the initial collecting tubule (ICT), the cortical collecting tubule (CCT), and the MCD.
Low Dietary K +
When the body is trying to conserve K + , the “classic distal tubule” (i.e., DCT, CNT, and ICT) and CCT all reabsorb K + , so that only a small fraction of the filtered load (1% to 3%) appears in the urine (see Fig. 37-5 A ). In states of K + depletion, this additional K + reabsorption can be lifesaving by retrieving from the tubule lumen precious K + that escaped reabsorption along the proximal tubule and loop of Henle. Despite the degree to which the kidneys can enhance K + reabsorption, they cannot restrict K + loss in the urine as effectively as they can restrict Na + loss. Therefore, a negative K + balance and hypokalemia may develop when K + intake has been abnormally low for prolonged periods of time.
Normal or High Dietary K +
When external K + balance demands that the kidneys excrete K + , the ICT, CCT, and the more proximal portion of the MCD secrete K + into the tubule lumen (see Fig. 37-5 B ). Together, these segments, known as the distal K + secretory system, account for most of the urinary excretion of K + . It is also this distal K + secretory system that responds to many stimuli that modulate K + excretion. Even at normal rates of K + excretion (10% to 15% of the filtered load), the proximal tubules and loop of Henle first absorb very large amounts of K + (~90% of the filtered load), so that the K + appearing in the urine may largely represent K + secreted by more distal segments of the nephron.
Medullary trapping of K + helps to maximize K + excretion when K + intake is high
The kidney traps K + in the medullary interstitium, with the interstitial [K + ] being highest at the tip of the papilla and falling toward the cortex. This medullary K + trapping is the result of three steps along the nephron. First, because interstitial [K + ] rises toward the tip of the papilla, juxtamedullary nephrons, whose long loops of Henle dip into the inner medulla ( p. 724 ), secrete K + passively into the thin descending limb of the loop of Henle (tDLH). Indeed, analysis of fluid collected from the hairpin bend of the long loops of Henle of juxtamedullary nephrons shows that the amount of K + delivered to the collection site at the hairpin bend can exceed not only the amount of K + present at the end of the proximal tubule, but also the amount of K + filtered. This K + secretion by the tDLH is the first step of a process known as medullary K + recycling ( Fig. 37-6 ).
The second step of medullary K + recycling is K + reabsorption by the thin (tALH) and thick (TAL) ascending limbs, which deposit K + in the medullary interstitium. This newly deposited interstitial K + contributes to the high interstitial [K + ]. Together, the tALH and TAL of a juxtamedullary loop reabsorb more K + than the descending limb secretes, so that net K + reabsorption occurs along the loop and thereby contributes to medullary K + trapping.
The third step of medullary K + recycling is the reabsorption of K + by the MCDs. Regardless of whether the distal K + -secretory system (ICT, CCT, early MCD) reabsorbs K + (see Fig. 37-5 A ) or secretes K + (see Fig. 37-5 B ), the medullary collecting ducts reabsorb some K + and thereby contribute to medullary K + trapping.
One would think that—with respect to K + excretion—medullary K + recycling is inefficient because K + exits the ascending limb and MCD only to re-enter the nephron upstream, in the tDLH. However, medullary recycling and concomitant K + trapping may be important in maximizing the excretion of K + when K + intake is high. Under these conditions, K + secretion by the distal K + -secretory system is intense, so that luminal [K + ] in the MCD may rise to ≥200 mM. Thus, enhanced K + trapping in the medullary interstitium minimizes the [K + ] difference between the MCD lumen and its peritubular environment, thus reducing the passive loss of K + from the MCD.
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