Abstract
Potassium is the most abundant intracellular cation. Approximately 98% of the total body potassium content is located within cells, primarily muscle, where its concentration ranges from 100–150 mEq/L; the remaining 2% resides in the extracellular fluid, where the potassium concentration is tightly regulated within a narrow range (3.5–5.0 mEq/L in the adult). The ratio of the intra- to extracellular potassium concentration determines, in large part, the resting membrane potential, and is thus critical for normal function of electrically excitable cells, including nerve and muscle. Maintenance of a high intracellular potassium concentration is essential for many cellular processes, including DNA and protein synthesis, cell growth and apoptosis, mitochondrial enzyme function, and conservation of cell volume and pH (1–7). Because of the many vital processes dependent on potassium homeostasis, multiple complex and efficient mechanisms have developed to regulate total potassium balance and distribution.
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Potassium is the most abundant intracellular cation. Approximately 98% of the total body potassium content is located within cells, primarily muscle, where its concentration ranges from 100–150 mEq/L; the remaining 2% resides in the extracellular fluid, where the potassium concentration is tightly regulated within a narrow range (3.5–5.0 mEq/L in the adult). The ratio of the intra- to extracellular potassium concentration determines, in large part, the resting membrane potential, and is thus critical for normal function of electrically excitable cells, including nerve and muscle. Maintenance of a high intracellular potassium concentration is essential for many cellular processes, including DNA and protein synthesis, cell growth and apoptosis, mitochondrial enzyme function, and conservation of cell volume and pH (1–7). Because of the many vital processes dependent on potassium homeostasis, multiple complex and efficient mechanisms have developed to regulate total potassium balance and distribution.
Potassium Homeostasis
Total body potassium content reflects the balance between intake and output, the latter regulated primarily by renal and, to a lesser extent, fecal excretion; the amount of potassium lost through sweat is negligible. The homeostatic goal of the healthy adult is to remain in zero potassium balance. Thus, ∼90% of the daily potassium intake, which typically averages 1 mEq/kg body weight, is eliminated by the kidneys and the residual ∼10% lost through the stool (8).
Total body potassium content increases from approximately 8 mEq/cm body height at birth to >14 mEq/cm body height by 18 years of age (9, 10) (Fig. 8-1 ), with the rate of accumulation of body potassium per kilogram body weight in the infant exceeding that in the older child and adolescent. The increase in total body potassium content correlates with an increase in cell number and potassium concentration (at least in skeletal muscle) with advancing age (10–12). This robust somatic growth early in life requires the maintenance of a state of positive potassium balance (13, 14), as has been demonstrated in growing infants greater than approximately 30 weeks gestational age (GA) (15, 16). The tendency to retain potassium early in postnatal life is reflected, in part, in the higher plasma potassium values in infants, and particularly in preterm neonates (16, 17).
Relationship between total body potassium (gm) and height (cm) for infants and children. The rate of accretion of body potassium in the neonate is faster than in later childhood, likely reflecting both an increase in cell number and potassium concentration, at least in skeletal muscle, with advancing age (10).
Thirty to fifty percent of very low birth weight and premature infants < 28 weeks GA exhibit nonoliguric hyperkalemia, defined as a serum potassium concentration of >6.5 mEq/L, during the first few days of life, despite the intake of negligible amounts of potassium (18–22). This phenomenon, not observed in mature infants or VLBW infants after 72 h (20, 21), has been proposed to reflect principally an intra- to extracellular shift of potassium (20, 21, 23). Prenatal steroid treatment may prevent this nonoliguric hyperkalemia via induction of sodium-potassium-adenosine triphosphatase (Na-K-ATPase) activity (see below) in the fetus (24, 25).
Studies in rats suggest that the accumulation of potassium in the growing fetus is facilitated by the active transport of potassium across the placenta from mother to fetus (26). This notion is further supported by studies in dog (27) and rat (28) that show that fetal plasma potassium concentrations are maintained during maternal hypokalemia, an adaptation proposed to be due to an increase in the ratio of maternofetal-to-fetomaternal unidirectional potassium transport.
Regulation of Internal Potassium Balance
The task of maintaining potassium homeostasis is challenging because the daily dietary intake of potassium in the adult (∼50–100 mEq) approaches or exceeds the total potassium normally present within the extracellular fluid space (∼70 mEq in 17 L of extracellular fluid with a potassium concentration averaging ∼4 mEq/L). To maintain zero balance in the adult, all the dietary intake of potassium must be ultimately eliminated, a task performed primarily by the kidney. However, excretion of potassium by the kidney is sluggish. Only 50% of an oral or intravenous load of potassium is excreted during the first 4–6 h after it is administered (29, 30). Life-threatening hyperkalemia is not generally observed during this period because of the rapid (within minutes) hormonally mediated translocation of ∼80% of the retained potassium load from the extracellular space into cells (31). The buffering capacity of the combined cellular storage reservoirs, which includes muscle, bone, liver, and red blood cells (RBCs), is capable of sequestering up to approximately 3,500 mEq of potassium and is vast compared with the extracellular pool (8).
Cells must expend a significant amount of energy to maintain the steep potassium (and sodium) concentration gradients across their cell membranes. This is accomplished by the ubiquitous Na-K-ATPase which transports 3 sodium ions out of and 2 potassium ions into the cell at the expense of the hydrolysis of cytosolic ATP. The unequal cation exchange ratio produces a charge imbalance across the cell membrane, and thus the Na-K-ATPase is defined as an electrogenic pump. Positively charged potassium ions, present in high concentration within the cell, passively leak out of cells down a concentration gradient through ubiquitously expressed potassium-selective channels. A steady state is reached at which the outward movement of positively charged potassium is opposed by the negative cell potential. At this cell equilibrium potential, the net transmembrane flux of potassium is zero.
The basic functional unit of the Na-K-ATPase is comprised of a catalytic α and a β subunit; the β subunit acts a molecular chaperone that directs the correct membrane insertion of the α subunit (32). The α/β-heterodimer complexes with phospholemman (PLM, FXYD1) in heart and skeletal muscle (33); the latter interaction modulates pump activity (33). The cardiac glycoside digoxin binds to the catalytic α subunit of the enzyme, inhibiting its activity. Thus, digoxin overdose may thus be associated with hyperkalemia, especially in the presence of a concomitant perturbation of potassium homeostasis.
Na-K-ATPase is regulated by changes in its intrinsic activity, subcellular distribution, and cellular abundance. Long-term stimulation of pump activity is generally mediated by changes in gene and protein expression, whereas short-term regulation typically results from changes in the intracellular sodium concentration, alterations in the phosphorylation status of the pump and/or interaction with regulatory proteins, or changes in membrane trafficking of preexisting pumps (33–35). Regulation of internal potassium balance in the neonate may be influenced by developmental stage-specific expression of potassium transporters, such as Na-K-ATPase, as well as channels, receptors, and signal transduction pathways (36, 37).
The chemical, physical, and hormonal factors that acutely influence the internal balance of potassium are listed in Table 8-1 , and are discussed below. Potassium uptake into cells is acutely stimulated by insulin, β2-adrenergic agonists, and alkalosis and is impaired by α-adrenergic agonists, acidosis, and hyperosmolality. Generally, deviations in extracellular potassium concentration arising from fluctuations in internal distribution are self-limited as long as the endocrine regulation of internal balance and mechanisms responsible for regulation of external balance are intact.
Plasma Potassium Concentration
Active basolateral cellular potassium uptake by the ubiquitous Na-K-ATPase in large part determines the intracellular pool of potassium. An increase in potassium input into the extracellular fluid space, which may arise from exogenous or endogenous sources or result from a chronic progressive loss of functional renal mass, decreases the concentration gradient against which the Na-K-ATPase must function and thus favors an increase in cellular potassium uptake. Sources of exogenous potassium input may not be readily apparent and include not only diet, but also potassium-containing drugs (potassium penicillin G), salt substitutes, protein-calorie supplements, herbal medications and packed RBCs (38). The extracellular fluid potassium concentration can also increase in response to endogenous release of potassium as accompanies tissue breakdown (rhabdomyolosis, tumor lysis syndrome) and exercise, the latter mediated by adenosine triphosphate (ATP) depletion and opening of ATP-dependent potassium channels. In those epithelial cells of the kidney and colon specifically responsible for potassium secretion, the resulting increase in intracellular potassium maximizes the concentration gradient between cell and lumen, thereby promoting potassium diffusion into the tubular lumen and thus potassium excretion.
Hormones
Insulin, the most important hormonal regulator of internal potassium balance, stimulates Na-K-ATPase-mediated cellular potassium uptake and thus the rapid transfer of potassium from the extracellular to the intracellular fluid space of insulin-responsive cells in liver, skeletal muscle, adipocytes, and brain, a response that is independent of the hormonal effects on glucose metabolism (39). The mechanism of insulin action in these tissues differs, in part, because of differences in the isoform composition of the catalytic α-subunit of the pump. Insulin stimulates Na-K-ATPase activity by promoting the translocation of preformed pumps from intracellular stores to the cell surface (40–44), and/or increasing cytoplasmic sodium content (45–47) or the apparent affinity of the enzyme for sodium (48).
Basal insulin secretion is necessary to maintain fasting plasma potassium concentration within the normal range (29). An increase in plasma potassium in excess of 1.0 mEq/L in the adult induces a significant increase in peripheral insulin levels to aid in the rapid disposal of the potassium load, yet a more modest elevation of approximately 0.5 mEq/L is without effect (29, 49, 50). In the setting of insulin deficiency, i.e., diabetes, there is a reduction in uptake of potassium by muscle and liver (31, 51).
Catecholamines enhance the cell uptake of potassium via stimulation of Na-K-ATPase activity in skeletal muscle and hepatocytes through 2-adrenergic receptors (52, 53). The effect of epinephrine on potassium balance in the adult is biphasic and is characterized by an initial increase, followed by a prolonged fall in plasma potassium concentration to a final value below baseline. The initial transient rise in plasma potassium results from α-adrenergic receptor stimulation which causes release of potassium from hepatocytes and impairs cell uptake of potassium (51, 54–56). β2-Receptor stimulation, via stimulation of adenylate cyclase leading to generation of the second messenger cyclic adenosine monophosphate (cAMP) and activation of downstream protein kinases, stimulates the sodium pump and thus promotes enhanced uptake of potassium by skeletal and cardiac muscle, effects that are inhibited by nonselective β-blockers including propranolol and labetalol (51, 55, 57–60). The observation that the potassium-lowering effects of insulin and epinephrine are additive suggests that their responses are mediated by different signaling pathways.
The effects of these hormones on the distribution of potassium between the intracellular and extracellular compartments have been exploited to effectively treat disorders of homeostasis (Fig. 8-2 ). Administration of β2-adrenoreceptor agonists (albuterol or salbutamol via nebulizer), which promote potassium uptake by cells, has been to treat hyperkalemia in neonates, children and adults (62–64). A single dose of nebulized albuterol can lower serum potassium by as much as 0.5 mEq/L (65, 66). Transient side effects associated with this class of drugs include mild tachycardia, tremor and mild vasomotor flushing (67). Administration of glucose alone (to induce endogenous insulin release) or glucose plus insulin is efficacious, although patients must be monitored for complications of hyperglycemia (without insulin) or hypoglycemia (with insulin), especially in neonates (68–70). It should be kept in mind that the treatment options discussed thus far are only temporizing. To remove potassium from the body, renal potassium excretion must be enhanced, either by stimulating potassium secretion in the distal nephron (see below) or, in the presence of renal insufficiency, by dialysis.
Changes in plasma potassium concentration (mmol/L) during intravenous infusion of bicarbonate (8.4%), epinephrine, or insulin and glucose, and during hemodialysis in adult patients on maintenance hemodialysis (61).
Aldosterone is best known for its effect on transporting tissue, increasing potassium secretion in distal segments of the nephron and colon (see below). Triiodothyronine (T3) also promotes Na-K-ATPase-mediated potassium cellular uptake in skeletal muscle (34). Whereas T3 had been thought to act as a direct transcriptional activator of target genes, recent studies emphasize the importance of nongenomic effects, including the stimulation of translocation of Na-K-ATPase to the plasma membrane by a pathway that requires activation of MAPK and phosphatidylinositol 3-kinase (PI3K) (71, 72). The postnatal increases in Na-K-ATPase expression in kidney, brain, and lung depend on normal thyroid hormone status (73).
Acid–Base Balance
It is well known that the transcellular distribution of potassium and acid-base balance are interrelated (74–77). Whereas acidemia (increase in extracellular hydrogen ion concentration) is associated with a variable increase in plasma potassium secondary to potassium release from the intracellular compartment, alkalemia (decrease in extracellular hydrogen ion concentration) results in a shift of potassium into cells and a consequent decrease in plasma potassium. However, the reciprocal changes in plasma potassium that accompany acute changes in blood pH differ widely among the four major acid-base disorders; metabolic disorders cause greater disturbances in plasma potassium than do those of respiratory origin, and acute changes in pH result in larger changes in plasma potassium than do chronic conditions (74).
Acute metabolic acidosis after administration of a mineral acid that includes an anion that does not readily penetrate the cell membrane, such as the chloride of hydrochloric acid or ammonium chloride, consistently results in an increase in plasma potassium. As excess extracellular protons, unaccompanied by their nonpermeant anions, enter the cell where neutralization by intracellular buffers occurs, potassium is displaced from the cells, thus maintaining electroneutrality and leading to hyperkalemia. However, comparable acidemia induced by acute organic anion acidosis (lactic acid in lactic acidosis, acetoacetic and β-hydroxybutyric acids in uncontrolled diabetes mellitus) may not elicit a detectable change in plasma potassium (74, 78, 79). In organic acidemia, the associated anion diffuses more freely into the cell and thus does not require a shift of potassium from the intracellular to the extracellular fluid.
In respiratory acid-base disturbances, in which carbon dioxide and carbonic acid readily permeate cell membranes, little transcellular shift of potassium occurs because protons are not transported in or out in association with potassium moving in the opposite direction (74).
Changes in plasma bicarbonate concentration, independent of the effect on extracellular pH, can reciprocally affect plasma potassium concentration (80). Movement of bicarbonate (outward at a low extracellular bicarbonate concentration and inward at a high extracellular bicarbonate concentration) between the intracellular and extracellular compartments may be causally related to a concomitant transfer of potassium. This relationship may account for the less marked increase in plasma potassium observed during acute respiratory acidosis, a condition characterized by an acid plasma pH with an elevated serum bicarbonate (leading to inward net bicarbonate and potassium movement), as compared with acute metabolic acidosis with a low serum bicarbonate concentration (leading to outward net bicarbonate and potassium movement). Though recommended as a mainstay of therapy, alkalinization of the extracellular fluid with sodium bicarbonate to promote the rapid cellular uptake of potassium may not be useful in patients on maintenance hemodialysis for end stage renal disease (61) (Fig. 8-2 ). However, this maneuver remains valuable if metabolic acidosis is at all responsible for the hyperkalemia. The major toxicities of bicarbonate therapy include sodium overload and precipitation of tetany in the face of preexisting hypocalcemia.
Other Factors
A number of other pathologic perturbations alter the internal potassium balance. An increase in plasma osmolality secondary to severe dehydration or administration of osmotically active agents causes water to shift out of cells. The consequent increase in intracellular potassium concentration exaggerates the transcellular concentration gradient and favors movement of this cation out of cells. The effect of hyperosmolality on potassium balance becomes especially problematic in diabetic patients with hyperglycemia, in whom the absence of insulin exacerbates the hyperkalemia.
Succinylcholine, a depolarizing paralytic agent and an agonist of nicotinic acetylcholine receptors, which are found predominantly in skeletal myocyte membranes, may lead to efflux of potassium from myocytes into the extracellular fluid under certain pathologic states associated with upregulation and redistribution of the receptors, including states characterized by physical or chemical upper or lower motor neuron denervation, immobilization, infection, muscle trauma or inflammation and burn injury (81, 82).
Finally, parenteral administration of cationic amino acids such as lysine, arginine or epsilon-amino caproic acid (used to improve hemostasis in patients undergoing cardiac surgery) may lead to electroneutral exchange of cell potassium for the cationic amino acid in skeletal myocytes (83–85).
Regulation of External Potassium Balance
Renal Contribution
The kidney is the major excretory organ for potassium. In the adult, urinary potassium excretion generally parallels dietary intake. However, the renal adaptation to variations in dietary intake is rather sluggish. Extreme adjustments in the rate of renal potassium conservation cannot be achieved as rapidly as for sodium, nor are the adjustments as complete; whereas urinary sodium can be virtually eliminated within 3–4 days of sodium restriction, there is a minimum urinary potassium loss of about 10 mEq/day in the adult, even after several weeks of severe potassium restriction (86). An increase in dietary potassium intake is matched by a parallel increase in renal potassium excretion within hours, yet maximal rates of potassium excretion are not attained for several days after increasing potassium intake. In adults, renal potassium excretion follows a circadian rhythm, presumably determined by hypothalamic oscillators, and it is characterized by maximum output during times of peak activity (87). It is unknown whether a circadian cycle of urinary potassium excretion prevails in infancy.
Children and adults ingesting an average American diet that contains sodium in excess of potassium excrete urine with a sodium-to-potassium ratio greater than one (16, 88). Although breast milk and commercially available infant formulas generally provide a sodium-to-potassium ratio of approximately 0.5–0.6, the urinary sodium-to-potassium ratio in the newborn up to 4 months of age generally exceeds 1. This high ratio may reflect the greater requirement of potassium over sodium for growth. In fact, some premature (<34 weeks GA) newborns may excrete urine with a sodium-to-potassium ratio greater than 2, a finding suggesting significant salt wasting and a relative hyporesponsiveness of the neonatal kidney to mineralocorticoid activity (16).
Net urinary potassium excretion in the fully differentiated kidney reflects the sum of three processes: glomerular filtration, reabsorption along the proximal tubule and the loop of Henle, and bidirectional transport (secretion and reabsorption) in the distal nephron (8, 89). Most of the factors known to modulate potassium excretion do so by altering the rate of potassium secretion.
Renal potassium clearance is low in newborns, even when it is corrected for their low glomerular filtration rate (16, 17). Infants, like adults, can excrete potassium at a rate that exceeds its glomerular filtration, reflecting the capacity for net tubular secretion. However, they are unable to excrete an exogenously administered potassium load as efficiently as the adult (90); specifically, the rate of potassium excretion normalized to body weight or kidney weight is less in newborn than older animals (91, 92). Comparison of the fractional delivery of potassium to the early distal tubule with that present in the final urine reveals that the distal nephron of the young (2-week-old) rat secretes approximately fivefold less potassium than the older (5-week-old) rat (93). Similarly, clearance studies in saline-expanded dogs also provide indirect evidence of a diminished secretory and enhanced reabsorptive capacity of the distal nephron to potassium early in life (94). Furthermore, premature neonates studied weekly after birth exhibited a 50% reduction in the fractional excretion of potassium between 26 and 30 weeks GA, in the absence of significant change in absolute urinary potassium excretion (15). To the extent that the filtered load of potassium increased almost threefold during this same time interval, the constancy of renal potassium excretion could be best explained by a developmental increase in the capacity of the kidney for potassium reabsorption (15). Please note that, in general, the limited potassium secretory capacity of the immature kidney becomes clinically relevant only under conditions of potassium excess.
Sites of Potassium Transport along the Nephron
Proximal Tubule
Potassium is freely filtered at the glomerulus. Thus, the concentration of potassium entering the proximal convoluted tubule (PCT) is similar to that of plasma. Approximately 65% of the filtered load of potassium is reabsorbed along the initial two-thirds of the proximal tubule, a fractional rate of reabsorption similar to that of sodium and water (95–97) (Fig. 8-3 ). A similar fraction (50–60%) of the filtered load of potassium is reabsorbed along the proximal tubules of suckling (13–15 days old) rats (93, 99).
Potassium transport along the nephron. (left panel) The percentages of filtered potassium reabsorbed along the proximal tubule and thick ascending limb of the loop of Henle (TALH) are indicated for the adult (A). Arrows show direction of net potassium transport (reabsorption or secretion). GFR = glomerular filtration rate. (right panel) Simplified cell models of potassium transport along the nephron, showing apical transporters unique to discrete nephron segments and cells therein, and basolateral transporters which are similar in all nephron segments (adapted from 98).
Reabsorption of potassium along the early proximal tubule is passive, closely following that of sodium and water (100), and has been proposed to occur via solvent drag via the paracellular pathway and diffusion (101–103). Solvent drag depends on active sodium reabsorption, which generates local hypertonicity in the paracellular compartment, providing an osmotic force driving water reabsorption that entrains potassium in the reabsorbate. Potassium diffusion is driven by the lumen-positive transepithelial voltage in the second half of the proximal tubule, and the slightly elevated concentrations of potassium in the lumen (104).
In the proximal tubule, as in all other nephron segments discussed below, transepithelial sodium reabsorption requires the coordinated function of apical sodium transport proteins and the basolateral Na-K-ATPase which actively extrudes intracellular sodium into the interstitium, and thereby maintains the low intracellular sodium concentration and steep sodium concentration gradient critical to the driving force for apical sodium entry (Fig. 8-3 ). There is no evidence for specific regulation of potassium reabsorption along the proximal tubule, and most observed modulation of proximal reabsorption of this cation can be accounted for by alterations in sodium transport.
Electrogenic sodium-coupled entry of substrates such as amino acids and glucose across the luminal cell membrane of the proximal tubule as well as bicarbonate exit across the basolateral cell membrane are driven by the potential differences across the respective cell membranes, which are maintained by potassium flux through potassium channels (105). Electrophysiological studies in isolated perfused proximal tubules suggest that potassium movement from the cell to lumen maintains the electrical driving force for sodium-coupled cotransport in the proximal tubule. Immunohistochemical studies reveal that KCNE1 and KCNQ1, which together constitute the slowly activated component of the delayed rectifying potassium current in heart, also colocalize in the luminal membrane of the proximal tubule in mouse kidney, as does the cyclic nucleotide-gated, voltage-activated potassium channel KCNA10 (106, 107). The observation that KCNE1 knock-out mice exhibit an increased fractional excretion of fluid (with accompanying volume depletion), sodium, chloride, and glucose compared to their wild type littermates supports the critical role of KCNE1 in repolarizing the membrane potential in proximal tubule in response to sodium-coupled transport (107). Notably, mutations in KCNQ1 give rise to the long QT syndrome (108).
Thick Ascending Limb of the Loop of Henle (TALH)
Approximately 10% of the filtered load of potassium reaches the early distal tubule of the adult rat (96), an observation that implies that significant reabsorption of this cation occurs beyond the proximal tubules. The site responsible for this additional avid potassium reabsorption is the TALH where potassium reabsorption is mediated, at least in part, by the apical Na-K-2Cl cotransporter (NKCC2) that translocates a single potassium ion into the cell accompanied by one sodium and two chloride ions (Fig. 8-3 ). This secondary active transport is ultimately driven by the low intracellular sodium concentration, established by the basolateral Na-K-ATPase, which drives sodium entry from the lumen into the cell. The diuretics furosemide and bumetanide specifically inhibit NKCC2 and thus block sodium, potassium and chloride reabsorption at this site.
Critical to the function of NKCC2 is the presence of a secretory potassium channel in the urinary membrane which provides a pathway for potassium, taken up into the cell via the cotransporter, to recycle back into the lumen. This “recycling” of potassium ensures that a continuous supply of substrate is available for the apical cotransporter. Potassium secretion into the urinary space creates a lumen positive transepithelial potential difference, which in turn provides a favorable electrical driving force that facilitates paracellular reabsorption of sodium, potassium, calcium and magnesium.
The luminal potassium secretory channel in the TALH has been identified as ROMK, a channel originally cloned from the TALH in the rat outer medulla (109–111); this low-conductance ATP-sensitive potassium channel is encoded by the KCNJ1 gene. Loss-of-function mutations in ROMK lead to antenatal Bartter syndrome (type 2), also known as the hyperprostaglandin E syndrome, which is characterized by severe renal salt and fluid wasting, electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypercalciuria), and elevated renin and aldosterone levels (112). The clinical picture observed is similar to that of chronic administration of loop diuretics. The typical presentation of antenatal Bartter syndrome includes polyhydramnios, premature delivery, life threatening episodes of dehydration during the first week of life, and profound growth failure (113). It should be noted that mutations in NKCC2 (SLC12A1) or the basolateral chloride channel CLC-Kb (CLCNKB) can also give rise to Bartter syndromes type 1 and 3, respectively (114, 115).
In contrast to the situation in the adult, up to 35% of the filtered load of potassium reaches the early distal tubule of the young (2-week-old) rat (93), suggesting that the TALH undergoes a significant postnatal increase in its capacity for reabsorption. Consistent with this premise are the observations from studies in rats of significant increases in the (i) fractional reabsorption of potassium along the TALH, expressed as a percentage of delivered load, between the second and sixth weeks of postnatal life (93), and (ii) osmolarity of early distal fluid between the second and fourth weeks of life (116). While these findings provide compelling evidence for a developmental maturation of potassium absorptive pathways and diluting capacity of the TALH, respectively, direct functional analysis of the transport capacity of this segment in the developing nephron has not been performed.
Molecular studies in rat kidney indicate that mRNA encoding NKCC2, absent at birth, is first expressed on postnatal day 8 in rat, coincident with completion of nephronogenesis (37), and increases, at least in medulla, between postnatal days 10 and 40 (117). Na-K-ATPase activity in the TALH of the neonatal rabbit is only 20% of that measured in the adult when expressed per unit of dry weight (118). The postnatal increase in pump activity is associated with a parallel increase in expression of medullary Na-K-ATPase mRNA (117). Although the balance of the studies summarized above identifies a functional immaturity of the TALH early in life and would thus predict limited effects of inhibitors of NKCC2 on transepithelial transport, administration of furosemide (2 mg/kg) to newborn lambs leads to a natriuretic response equivalent to that observed in adult animals (119).
Distal Nephron
Within the distal nephron of the fully differentiated kidney, the late DCT, CNT and the CCD are considered to be the primary sites of potassium secretion, and thus urinary potassium excretion, which can approach 20% of the filtered load (96, 97, 120, 121) (Fig. 8-3 ). The DCT secretes a constant small amount of potassium into the urinary fluid (122). Regulated bidirectional potassium transport occurs in the CNT and CCD, comprised of two major populations of cells, each with distinct functional and morphologic characteristics. CNT/principal cells reabsorb sodium and secrete potassium, whereas intercalated cells regulate acid-base balance but can reabsorb potassium in response to dietary potassium restriction or metabolic acidosis (123, 124) (Fig. 8-3 ). Thus, the direction and magnitude of net potassium transport in these segments depend on the metabolic needs of the organism and reflect balance of potassium secretion and absorption, processes mediated by CNT/principal and intercalated cells, respectively.
Potassium Secretion
Potassium secretion in the CNT and CCD is critically dependent on the reabsorption of filtered sodium delivered to these segments. Sodium passively diffuses into the CNT/principal cell from the urinary fluid down a favorable concentration gradient through the luminal amiloride-sensitive epithelial Na channel (ENaC) and is then transported out of the cell at the basolateral membrane in exchange for the uptake of potassium via the basolateral Na-K-ATPase (Fig. 8-3 ). The accumulation of potassium within the cell and the lumen-negative voltage, created by movement of sodium from the tubular lumen into the cell and its electrogenic extrusion, creates a favorable electrochemical gradient for intracellular potassium to diffuse into the urinary space through apical potassium-selective channels. The magnitude of potassium secretion is determined by its electrochemical gradient and the apical permeability to this cation. Basolateral potassium channels in these same cells provide a route for intracellular potassium ions to recycle back into the interstitium, thereby maintaining the efficiency of the Na-K pump. Any factor that increases the electrochemical gradient across the apical membrane or increases the apical potassium permeability will promote potassium secretion. An apical electroneutral potassium-chloride cotransporter has also been functionally identified in the CCD (125, 126).
Two apical potassium-selective channels have been functionally identified in the distal nephron: the small-conductance secretory potassium (SK) channel and the high-conductance maxi-K channel. The density of these channels appears to be greater in the CNT than in the CCD (127).
The SK channel, restricted to the CNT/principal cell, mediates baseline potassium secretion (128, 129). ROMK, originally cloned from the TALH (described in the section above on the TALH), is considered to be a major functional subunit of the SK channel. A complex interplay of hormones, second messengers and kinases/phosphatases regulate the SK/ROMK channel in the distal nephron, thereby allowing the kidney to respond appropriately to the metabolic needs of the organism (130, 131). Protein kinase A (PKA)-induced phosphorylation of the channel is essential for its activity (129, 132), and may account for the well-documented stimulatory effect of vasopressin on renal potassium secretion (133). Protein tyrosine kinase (PTK) mediates the endocytosis of ROMK channels in the rat CCD in the face of dietary potassium restriction (134, 135). Tyrosine phosphorylation of ROMK enhances channel internalization and thus the removal of channels from the plasma membrane (136), leading to a reduction in number of apical channels and net potassium secretion. Tyrosine phosphorylation of ROMK channels decreases in response to dietary potassium loading (137).
The “with-no-lysine-kinases,” or WNKs, comprise a recently discovered family of serine/threonine kinases that act as molecular switches that direct differential effects on downstream ion channels, transporters, and the paracellular pathway to allow either maximal sodium chloride reabsorption or maximal potassium secretion in response to hypovolemia or hyperkalemia, respectively (138). WNK4 inhibits sodium and chloride absorption in the DCT by reducing the surface expression of the apical thiazide-sensitive NaCl cotransporter NCCT (139), an effect that would be expected to increase sodium delivery to and reabsorption by the CCD, in turn augmenting the driving force for potassium secretion. However, WNK4 decreases surface expression of ROMK by enhancing endocytosis of this channel (140), thereby negating the effect of the augmented electrochemical gradient on stimulation of net potassium secretion. Mutations in WNK1 or 4 lead to pseudohypoaldosteronism type II (PHA II; Gordon’s Syndrome), an autosomal dominant disorder characterized by hypertension sensitive to thiazide diuretics, hyperkalemia, and metabolic acidosis (141). Loss-of-function mutations in WNK4 lead to increased apical expression of the NaCl cotransporter and stimulation of sodium absorption in the DCT (139, 142). The consequent reduction in sodium delivery to the CNT and CCD would be expected to reduce potassium secretion. However, the same mutations in WNK4 that relieve the inhibition of NCCT further decrease surface expression of ROMK, reduce potassium secretion in the CCD, and likely are the cause of hyperkalemia in patients with Gordon’s Syndrome. WNK1 suppresses the activity of WNK4. Therefore, a gain-in-function mutation in WNK1 will also produce the clinical signs and symptoms of PHA II (141).
The maxi-K channel, present in CNT/principal and intercalated cells, is considered to mediate flow-stimulated potassium secretion (143, 144). In the CNT and CCD, the density of conducting maxi-K channels is greater in intercalated than CNT/principal cells (145, 146). The maxi-K channel is comprised of two subunits: a channel pore-forming α subunit and a regulatory β subunit. This channel is rarely open at the physiologic resting membrane potential, but can be activated by cell depolarization, membrane stretch, and increases in intracellular Ca2+ concentration, as accompany increases in urinary flow rate (146–149). The proposed role of the maxi-K channel in flow-stimulated urinary potassium secretion has been confirmed in a mouse model with targeted deletion of the β1 subunit; the fractional excretion of potassium in maxi-K β1−/− mice subjected to acute volume expansion was significantly lower than that in wild type mice (150).
The maxi-K channel appears to assume great importance in regulating potassium homeostasis under conditions where SK/ROMK channel-mediated potassium secretion is limited. Thus, adult animals with targeted deletion of ROMK (i.e., Bartter phenotype) are not hyperkalemic, as would be expected in the absence of a primary potassium secretory channel, but instead lose urinary potassium (151). The sensitivity of distal potassium secretion in this rodent model of Bartter syndrome to iberiotoxin, a specific inhibitor of maxi-K channels, presumably reflects recruitment of the latter channels to secrete potassium in response to high distal flow rates as accompany loss-of-function of the TALH NKCC2 cotransporter (151). Similarly, although infants with antenatal Bartter syndrome due to loss-of-function mutations in ROMK may exhibit severe hyperkalemia during the first few days of life (152), the hyperkalemia is not sustained. In fact, these patients typically exhibit modest hypokalemia beyond the neonatal period (153, 154).
Potassium Absorption
In response to dietary potassium restriction or metabolic acidosis, the distal nephron may reverse the direction of net potassium transport from secretion to absorption. Potassium reabsorption is mediated by a H-K-ATPase, localized to the apical membrane of acid-base transporting intercalated cells, that couples potassium reabsorption to proton secretion (Fig. 8-3 ) (123, 155–157). Two isoforms of the H-K-ATPase are found in the kidney: the gastric isoform, HKAg, is normally found in gastric parietal cells and is responsible for acid secretion into the lumen whereas the colonic HKAc isoform is a structurally related H-K-ATPase found in distal colon that mediates active potassium reabsorption (156). Expression of the apical gastric-like H-K-ATPase in the rat and rabbit intercalated cell is increased in response to dietary potassium restriction and metabolic acidosis (123, 155, 158, 159).
A reduction in potassium intake leads to a fall in potassium secretion by the distal nephron within 5–7 days in rat (160). This adaptation is associated with a decrease in the number of apical SK/ROMK (161) and maxi-K (162) channels and stimulation of H-K-ATPase-mediated potassium reabsorption in intercalated cells in the distal nephron (163). The reduction in number of SK/ROMK channels in potassium-restricted animals is mediated by the effect of dietary potassium on circulating levels of aldosterone and other effectors, such as PTK, as described above. Stimulation of luminal H-K-ATPase activity in intercalated cells results not only in potassium retention, but also in urinary acidification and metabolic alkalosis.
Developmental Regulation of Distal Potassium Transport
Potassium secretion in the distal nephron, and specifically in the cortical collecting duct (CCD) studied in vitro, is low early in life and cannot be stimulated by high urinary flow rates (121). Indeed, basal potassium secretion can not be detected in the rabbit CCD until after the third week of postnatal life, with potassium secretory rates increasing thereafter to reach adult levels by 6 weeks of age (121). Consistent with the relatively undifferentiated state of the newborn CCD are the ultrastructural and morphometric findings in neonatal principal cells of few organelles, mitochondria and basolateral infoldings, the site of Na-K-ATPase (164, 165).
The limited capacity of the CCD for potassium secretion early in life could be explained by either an unfavorable electrochemical gradient across the apical membrane and/or a limited apical permeability to this ion. Cumulative evidence suggests that the electrochemical gradient is not limiting for potassium secretion in the neonate. Activity of the Na-K-ATPase, present along the basolateral membrane of corticomedullary collecting ducts in the neonatal rabbit (166), is 50% of that measured in the mature nephron; the observation that the intracellular potassium concentration in this segment is similar in the neonate and adult presumably reflects a relative paucity of membrane potassium channels in the distal nephron early in life (118, 165, 167). Concordant with the measurements of sodium pump activity, the rate of sodium absorption in the CCD at 2 weeks of age is approximately 60% of that measured in the adult (121). However, electrophysiologic analysis has confirmed the absence of functional SK/ROMK channels in the luminal membrane of the neonatal rabbit CCD with the number of open channels per patch increasing progressively after the second week of life (168). Thus, the postnatal increase in the basal potassium secretory capacity of the distal nephron appears to be due primarily to a developmental increase in number of SK/ROMK channels, reflecting an increase in transcription and translation of functional channel proteins (168–170).
The appearance of flow-stimulated net potassium secretion is a relatively late developmental event. Flow-stimulated potassium secretion can not be elicited in rabbit CCDs until the fifth week of postnatal life, which is approximately 2 weeks after basal net potassium secretion is first detected (121, 171). The absence of flow-stimulated potassium secretion early in life is not due to a limited flow-induced rise in net sodium absorption and/or intracellular calcium concentration, each of which is required for flow stimulation of potassium secretion and is equivalent to that detected in the adult by the second week of postnatal life (171). The observation that mRNA encoding the maxi-K channel α-subunit and immunodetectable channel protein can not be demonstrated until the fourth and fifth weeks of postnatal life, respectively (171) suggests that flow-dependent potassium secretion is determined by the transcriptional/translational regulation of expression of maxi-K channels.
While the neonatal distal nephron is limited in its capacity for potassium secretion, indirect evidences suggests that this nephron segment absorbs potassium. As indicated above, saline-expanded newborn dogs absorb 25% more of the distal potassium load than do their adult counterparts (91). Functional analysis of the rabbit collecting duct has shown that the activity of apical H-K-ATPase in neonatal intercalated cells is equivalent to that in mature cells (123). The latter data alone do not predict transepithelial potassium absorption under physiologic conditions, as the balance of transport will depend on the presence and activity of apical and basolateral potassium conductances and the potassium concentration of the tubular fluid delivered to this site. The high distal tubular fluid potassium concentrations, as measured In vivo in the young rat, may facilitate lumen-to-cell potassium absorption mediated by the H-K-ATPase (93).
Luminal and Peritubular Factors Affecting Potassium Transport
The major factors that influence the external balance of potassium are listed in Table 8-2 and are discussed in the following sections.
Sodium Delivery and Absorption
The magnitude of sodium reabsorption in the distal nephron determines the electrochemical driving force favoring potassium secretion into the luminal fluid, as described above. Processes that enhance distal sodium delivery and increase tubular fluid flow rate, such as extracellular volume expansion or administration of a variety of diuretics (osmotic diuretics, carbonic anhydrase inhibitors, loop and thiazide diuretics), lead to an increase in urinary excretion of both sodium and potassium. The kaliuresis is due not only to the increased delivery of sodium to the distal nephron, but also to the increase in tubular fluid flow rate, which maximizes the chemical driving forces, as described below, favoring potassium secretion.
Processes that decrease sodium delivery to less than 30 mM in the distal tubular fluid (172, 173) and/or sodium reabsorption sharply reduce potassium secretion in the CCD and can lead to hyperkalemia. In vivo measurements of the sodium concentration in distal tubular fluid generally exceed 35 mEq/L both in healthy adult and suckling rats and thus should not restrict distal sodium secretion (93, 116, 172, 174). However, in edema-forming states, including congestive heart failure, cirrhosis and nephrotic syndrome, the urinary sodium concentration typically falls to less than 10 mEq/L; a reduction in potassium excretion in these patients may be ascribed to the low rates of distal sodium delivery as well as urinary flow. The potassium-sparing diuretics, amiloride and triamterene, inhibit ENaC and thus block sodium absorption, thereby diminishing the electrochemical gradient favoring potassium secretion (175). Trimethoprim and pentamidine can also limit urinary potassium secretion via the same mechanism (177, 178).
Sodium delivered to the distal nephron is generally accompanied by chloride. Chloride reabsorption occurs predominantly via the paracellular pathway. The movement of the negative charged chloride out of the lumen dissipates the lumen negative potential, creating a less favorable driving force for luminal potassium secretion (179). When sodium delivered to the distal nephron is accompanied by an anion less reabsorbable than chloride, such as bicarbonate (in proximal renal tubular acidosis), β-hydroxybutyrate (in diabetic ketoacidosis), or carbenicillin (during antibiotic therapy), luminal electronegativity is maintained, thereby eliciting more potassium secretion than occurs with a comparable sodium load delivered with chloride (180).
Tubular Flow Rate
High rates of urinary flow in the mature, but not the neonatal or weanling, distal nephron, as elicited by extracellular fluid volume expansion or administration of diuretics or osmotic agents, stimulate potassium secretion (121). There are a number of factors responsible for the flow-stimulation of potassium secretion. First, increases in tubular fluid flow rate in the distal nephron enhance sodium reabsorption due to an increase in the open probability of ENaC (time the channel spends in the open state), which augments the electrochemical gradient favoring potassium secretion (176, 181). Second, the higher the urinary flow rate in the distal nephron, the slower the rate of rise of tubular fluid potassium concentration because secreted potassium is rapidly diluted in urine of low potassium concentration (182). Maintenance of a low tubular fluid potassium concentration maximizes the potassium concentration gradient (and thus the chemical driving force) favoring net potassium secretion. Finally, increases in luminal flow rate transduce mechanical signals (circumferential stretch, shear stress, hydrodynamic bending moments on the cilium decorating the apical surface of virtually all renal epithelial cells) into increases in intracellular calcium concentration, which in turn activate apical maxi-K channels to secrete potassium, thereby enhancing urinary potassium excretion (143, 144, 171).
Potassium Intake and Cellular Potassium Content
The kidney adjusts potassium excretion to match input, in large part by regulating the magnitude of potassium secretion and reabsorption in the distal nephron. Thus, for example, an increase in dietary potassium intake stimulates whereas a decrease in intake reduces net potassium secretion (97). An increase in potassium concentration in the extracellular fluid space increases potassium entry into principal cells via the basolateral Na-K-ATPase, which in turn maximizes the concentration gradient favoring apical potassium secretion into the urinary fluid. Simultaneously, the increase in circulating levels of plasma aldosterone that accompanies potassium loading enhances the electrochemical driving force favoring potassium secretion in the distal nephron by stimulation of ENaC-mediated sodium absorption and its electrogenic absorption via the Na-K-ATPase. Within 6 h of an increase in dietary potassium intake, the density of apical ROMK channels increases in principal cells in rats due to activation of a previously “silent” pool of channels or closely associated proteins (183). Chronic potassium loading also increases maxi-K channel message, apical protein, and function in the distal nephron (162). Finally, the inhibition of proximal tubule and loop of Henle salt and water reabsorption in response to a potassium load (184, 185) increases tubule fluid flow rate which in turn stimulates potassium secretion via activation of maxi-K channels and increased distal of delivery of sodium to the distal nephron.
The trigger for the renal adaptation to dietary potassium loading remains uncertain. It is now believed that after a potassium-rich meal, a reflex increase in potassium excretion is initiated by sensors in the splanchnic bed (gut, portal circulation, and/or liver) that respond to local increases in potassium concentration that occur in the absence of or before changes in plasma potassium concentration are detected (87, 186). In support of the notion of potassium sensing, intraportal delivery of potassium chloride to rats leads to an increase in hepatic afferent nerve activity and urinary potassium excretion, responses that are unaccompanied by increases in plasma potassium concentration (187). Increases in the intraportal concentration of glucagon, as follows ingestion of a protein- and potassium-rich meal, also increases renal excretion of potassium (188, 189), a response proposed to be due to the release of cAMP, the second messenger of glucagon in the liver, into the circulation and its uptake by kidney (186).
Chronic potassium loading leads to potassium adaptation, an acquired tolerance to an otherwise lethal acute potassium load (8). Potassium adaptation, which begins after a single potassium-rich meal, includes increases in the rate of skeletal muscle uptake of potassium from the extracellular fluid (53) due to stimulation of Na-K-ATPase activity (190) and secretion of potassium by the distal nephron and colon. The process is facilitated by the increase in circulating levels of aldosterone elicited by the increase in serum potassium concentration (191). A similar adaptive response is seen in renal insufficiency such that potassium balance is maintained during the course of many forms of progressive renal disease, as long as potassium intake is not excessive (192). The molecular mechanisms underlying this adaptation in the distal nephron (and colon) include not only an increase in the density of apical membrane potassium channels, but also an increase in the number of conducting ENaC channels and activity of the basolateral Na-K pump. The latter two processes result in increases in transepithelial voltage and the intracellular potassium concentration, events that enhance the driving force favoring potassium diffusion from the cell into the urinary fluid.
Hormones
Mineralocorticoids are key regulators of renal sodium absorption and potassium excretion, and thus of circulating volume, blood pressure and sodium and potassium homeostasis. The major stimuli for aldosterone release from the zona glomerulosa in the adrenal gland are angiotensin II and elevations in serum potassium concentrations (193). ACE inhibitors, by reducing the conversion of angiotensin I to angiotensin II and thus aldosterone secretion by the adrenal gland, may lead to hyperkalemia as the ability of the distal nephron to secrete potassium is impaired. Angiotensin receptor blockers (ARBs), by competitively binding to angiotensin II type 1 (AT1) receptors and thus antagonizing the action of angiotensin II on aldosterone release, may have similar effects.
Aldosterone stimulates sodium reabsorption and potassium secretion in principal cells of the fully differentiated aldosterone-sensitive distal nephron (ASDN) (194, 195). Circulating mineralocorticoids bind to their cytosolic receptors in the ASDN; the aldosterone antagonist spironolactone competitively inhibits this binding. The hormone-receptor complex translocates to the nucleus where it promotes the transcription of aldosterone-induced physiologically active proteins (e.g., Na-K-ATPase). Among the cellular and molecular effects of an increase in circulating levels of aldosterone are increases in density of ENaC channels, achieved by the recruitment to and retention of intracellular channels at the apical membrane, de novo synthesis of new ENaC subunits, and activation of preexistent channels, as well as and stimulation of Na-K-ATPase activity by translocation of preformed transporters to the membrane and translation of new sodium pump subunits (196–201). The sum effect of the stimulation of apical sodium entry and Na-pump-mediated reabsorption is an increase in lumen negative transepithelial voltage and thus electrochemical driving force favoring potassium exit across the apical membrane (199, 200, 202).
The effects of aldosterone on ENaC and, to some extent, the Na-K pump appear to be indirect, mediated by aldosterone-induced proteins, including serum and glucocorticoid-inducible kinase (sgk). Aldosterone rapidly induces Sgk1 in the distal nephron (203). Phosphorylated Sgk stimulates sodium reabsorption, in large part by inhibiting ubiquitin-ligase Nedd4-2-mediated endocytic retrieval of ENaCs from the luminal membrane (204). Renal water and electrolyte excretion is indistinguishable in sgk1-knockout (sgk1−/−) and wild-type (sgk1+/+) mice fed a normal diet (205), indicating that the kinase is not necessary for basal sodium absorption. However, dietary sodium restriction reveals an impaired ability of sgk1−/− mice to reduce sodium excretion despite increases in plasma aldosterone levels and proximal tubular sodium and fluid reabsorption (206). Sgk1−/−mice exhibit an impaired upregulation of renal potassium excretion in response to potassium loading, presumably due to the impact of the mutation on ENaC and/or Na-K-ATPase activity and thus the electrochemical gradient favoring potassium secretion (207). Corticosteroid hormone induced factor (CHIF) is another aldosterone-induced protein that is expressed in the basolateral membrane of the collecting duct where it increases the affinity of Na-K-ATPase for sodium (208–211).
Plasma aldosterone concentrations in premature infants and newborns are higher than those measured in the adult (16, 212). Yet, clearance studies in fetal and newborn animals demonstrate a relative insensitivity of the immature kidney to the hormone (16, 213–215). The density of aldosterone binding sites, receptor affinity, and degree of nuclear binding of hormone-receptor are believed to be similar in mature and immature rats (215).
The transtubular potassium gradient (TTKG) provides an indirect, semiquantitative measure of the renal response to mineralocorticoid activity in the aldosterone-sensitive cortical distal nephron and is calculated using the equation:
where [K+] equals the potassium concentration in either urine (U) or plasma (P), as indicated (216–218). Measurements of TTKG have been reported to be lower in 27 than 30-week GA preterm infants followed over the first 5 weeks of postnatal life (219). The low TTKG has been attributed to a state of relative hypoaldosteronism (219), but may also reflect the absence of potassium secretory transport pathways (i.e., channel proteins).
Acid-Base Balance
Disorders of acid-base homeostasis induce changes in tubular potassium secretion in the distal nephron (179). In general, acute metabolic acidosis causes the urine pH and potassium excretion to decrease, whereas both acute respiratory alkalosis and metabolic alkalosis increase urine pH and potassium excretion (179, 220). Chronic metabolic acidosis has variable effects on urinary potassium excretion.
Acute metabolic acidosis reduces cell potassium concentration and leads to a reduction in urine pH, which in turns inhibits activity of the SK/ROMK channel and thereby limits potassium secretion in the distal nephron (220–223). The effect of chronic metabolic acidosis on potassium secretion is more complex and may be influenced by modifications of the glomerular filtrate (e.g., chloride and bicarbonate concentrations), tubular fluid flow rate, and circulating aldosterone levels (8, 179). The latter two factors may lead to an increase rather than a decrease in potassium secretion and excretion.
The alkalosis-induced stimulation of potassium secretion reflects two direct effects on principal cells: an increase in net sodium absorption (224), which enhances the electrochemical gradient for net potassium secretion, and (74) an increase in the permeability of the apical membrane to potassium resulting from an increase in duration of time the potassium-selective channels remain open (8). Alkalosis also decreases acid secretion in intercalated cells, thereby reducing H-K-ATPase-mediated countertransport of potassium.
Potassium deficiency stimulates proton secretion in the distal nephron, increases the production of the urinary buffer ammonia (225), and may stimulate bicarbonate generation by increasing expression H-K-ATPase in the distal nephron (226).
Contribution of the Gastrointestinal Tract
Under normal conditions in the adult, 5–10% of daily potassium intake is excreted in the stool. The colon is considered to be the main target for regulation of intestinal potassium excretion (227). Potassium transport in the colon represents the balance of secretion and absorption (228). Under baseline conditions, net potassium secretion predominates over absorption in the adult, whereas the neonatal gut is poised for net potassium absorption (227).
Potassium secretion requires potassium uptake by the Na-K-ATPase and furosemide-sensitive Na-K-2Cl cotransporter located in the basolateral membrane of colonocytes; potassium is then secreted across the apical membrane through potassium channels, including a calcium-activated maxi-K channel similar to that found in the distal nephron (229–233). Potassium absorption is mediated by two H-K-ATPases localized to the apical membrane of the distal colon (234).
Stool potassium content can be enhanced by any factor that increases colonic secretion, including aldosterone, epinephrine, and prostaglandins (31, 235, 236). Indomethacin and dietary potassium restriction reduce potassium secretion by inhibiting the basolateral transporters and apical potassium channels. Diarrheal illnesses are typically associated with hypokalemia, presumably due to the presence of nonreabsorbed anions (which obligate potassium), an enhanced electrochemical gradient established by active chloride secretion, and secondary hyperaldosteronism due to volume contraction (237).
Potassium adaptation in the colon is demonstrated by increased fecal potassium secretion after potassium loading and in the face of renal insufficiency. Fecal potassium excretion may increase substantially to account for 30–50% of potassium excretion in patients with severe chronic renal insufficiency (31, 238–240). The enhanced colonic potassium secretion characteristic of renal insufficiency requires induction and/or activation of apical maxi-K channels in surface colonic epithelial cells (241).
Net colonic potassium absorption is significantly higher in young compared to adult rats (227). The higher rate of potassium absorption during infancy is due to robust activity of apical K-ATPases and limited activity of the basolateral transporters that mediate secretion (227, 231, 242).
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Satlin, L.M. (2009). Potassium. In: Avner, E., Harmon, W., Niaudet, P., Yoshikawa, N. (eds) Pediatric Nephrology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-76341-3_8
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DOI: https://doi.org/10.1007/978-3-540-76341-3_8
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