Potassium Homeostasis in the Fetus and Neonate

Regulation of Internal Potassium Balance

The task of maintaining potassium homeostasis is complex, in large part because the daily dietary intake of potassium (approximately 100 mEq in the adult) typically approaches or exceeds the total potassium normally present within the extracellular fluid space (approximately 70 mEq in 17 L of extracellular fluid, with a potassium concentration averaging approximately 4 mEq/L) (see Fig. 98.1 ). To maintain zero balance in the adult, all the dietary intake of potassium must ultimately be eliminated, a task performed primarily by the kidney. However, renal excretion of potassium is rather sluggish, requiring several hours to be accomplished. Approximately 50% of an oral load of potassium is excreted during the first 4 to 6 hours after it is ingested, yet life-threatening hyperkalemia is not generally observed during this period because of the rapid (within minutes) hormonally mediated translocation of extracellular potassium into cells, particularly those of muscle and liver. The buffering capacity of the combined cellular storage reservoirs in the adult, capable of sequestering up to approximately 3500 mEq of potassium, is vast compared with that of the extracellular pool (see Fig. 98.1 ).

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 Na ⁺ , K ⁺ -ATPase pump, which catalyzes the hydrolysis of cytosolic adenosine triphosphate, thereby providing energy for the active extrusion of sodium from cells in exchange for the uptake of potassium in a ratio of 3:2, respectively. A cell interior negative potential is created by the unequal cation exchange ratio and the subsequent leak of potassium out of the cells through potassium-selective channels in the plasma membrane. The Na ⁺ , K ⁺ -ATPase pump consists of a catalytic (α) and a regulatory (β) subunit.

Thirty percent to 50% of very-low-birth-weight and premature infants of less than 28 weeks’ GA exhibit nonoliguric hyperkalemia (defined as a serum potassium concentration of >6.5 mEq/L) during the first 48 hours after birth despite the intake of negligible amounts of potassium. This phenomenon is not observed in mature infants or very low-birth-weight infants after 72 hours. ^, This biochemical observation has been proposed to reflect a shift of potassium from the intracellular to the extracellular fluid space because of low Na ⁺ -K ⁺ pump activity as well as a limited renal potassium secretory capacity. ^{, ,} Prenatal steroid treatment may prevent this nonoliguric hyperkalemia via induction of Na ⁺ ,K ⁺ -ATPase pump activity in the fetus. ^,

Na ⁺ ,K ⁺ -ATPase pump activity is regulated by numerous circulating hormones that exert short- and long-term control. Whereas long-term stimulation of pump activity is generally mediated by changes in gene and protein expression, short-term regulation generally results from alterations in the phosphorylation status of the pump, changes in the subcellular or cell surface distribution of pumps (i.e., membrane trafficking), and/or interaction with regulatory proteins. Regulation of internal potassium balance in the neonate may be influenced by developmental stage-specific expression of potassium transporters (such as the cation pump) and channels, receptors, and signal transduction pathways.

The chemical, physical, and hormonal factors that acutely influence the internal balance of potassium are listed in Table 98.1 . Potassium uptake into cells is acutely stimulated by insulin, β ₂ -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 cellular potassium uptake in large part determines the intracellular pool of potassium. An increase in plasma potassium, either because of a dietary or parenteral potassium load or a chronic progressive loss of functional renal mass, decreases the concentration gradient (dependent on the ratio of intracellular to extracellular potassium concentration) against which the Na ⁺ , K ⁺ -ATPase pump must function. Thus an increase in cellular potassium uptake is favored. In those 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 potassium uptake and sodium efflux in the kidney, skeletal muscle, adipocytes, and brain, a response that is independent of the hormonal effects on glucose metabolism. The mechanism of insulin’s action in these tissues differs, in part because of differences in the isoform complement 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 (as in skeletal muscle), and/or increasing cytoplasmic sodium content (as in adipocytes), or by increasing the apparent affinity of the enzyme for sodium (as in kidney). Basal insulin secretion is necessary to maintain the fasting plasma potassium concentration within the normal range. 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.

The effect of epinephrine on potassium balance in the adult is biphasic and characterized by an initial increase, followed by a prolonged fall in plasma potassium concentration to a final value lower than baseline. The initial transient rise in plasma potassium results from stimulation of the α-adrenergic receptor, causing release of potassium from hepatocytes. ^, Stimulation of the β ₂ -receptor, via stimulation of adenylate cyclase leading to generation of the second messenger cyclic adenosine monophosphate, activates the Na ⁺ , K ⁺ -ATPase pump and thus promotes enhanced uptake of potassium by skeletal and cardiac muscle. These effects are inhibited by β ₂ blockers. Interestingly, similar effects are also seen with β ₁ -selective antagonist metoprolol and the nonselective β antagonist carvedilol, which has α-adrenergic effects. ^, β ₂ blockers also contribute to hyperkalemia by a reduction of circulating angiotensin and possibly renin, thereby reducing the potassium secretory activity of the renin-angiotensin-aldosterone (RAAS) axis. ^, 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 intra- and extracellular compartments have been exploited to effectively treat disorders of homeostasis. For example, the β ₂ -adrenoreceptor agonist albuterol has been used to treat life-threatening hyperkalemia in premature and term neonates, children, and adults. Administration of albuterol to treat hyperkalemia is associated with few side effects (mild, reversible tachycardia and tremors). Administration of glucose, insulin, and furosemide may be associated with significant fluid, electrolyte, and glucose derangements in premature infants. Administration of sodium bicarbonate has been associated with an increased incidence of intraventricular hemorrhage. Oral or rectal administration of ion exchange resins can increase total body sodium and cause cecal perforation. Furthermore, it may be ineffective in small infants. ^,

The side-effect profile of the newly approved calcium-based cation exchanger patiromer is not well studied in neonates, but it can be used to decant formula and reduce the potassium content. ^,

Aldosterone is best known for its effect on “transporting tissue”—that is, increasing potassium secretion in distal segments of the nephron and colon (discussed later). Thyroid hormone may also promote the cellular uptake of potassium as a result of its long-term stimulation of Na ⁺ -K ⁺ pump activity.

Acid-Base Balance

It is well known that the transcellular distribution of potassium and acid-base balance are interrelated. Whereas acidemia (increased extracellular hydrogen ion concentration) is associated with an increase in plasma potassium resulting from 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.

Acute metabolic acidosis after administration of a mineral acid including 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 nonpermanent anions, enter the cell where neutralization by intracellular buffers occurs, potassium (or sodium) is displaced from the cells, thus maintaining electroneutrality. 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. 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.

Changes in plasma bicarbonate concentration, independent of the effect on extracellular pH, can reciprocally affect plasma potassium concentration. Movement of bicarbonate (outward at a low extracellular bicarbonate concentration and inward at a high extracellular bicarbonate concentration) between the intra- and extracellular compartments may be causally related to a concomitant transfer of potassium. This 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 (hence inward net bicarbonate and potassium movement) as compared with acute metabolic acidosis with a low serum bicarbonate concentration (hence outward net bicarbonate and potassium movement).

Other Factors

Many other pathologic perturbations alter the internal potassium balance. An increase in plasma osmolality resulting from severe dehydration 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 troublesome in patients with hyperglycemia, as observed in those with diabetes, in whom the absence of insulin exacerbates the hyperkalemia.

Renal Contribution

The kidney is the major excretory organ for potassium. In adults, urinary potassium excretion parallels dietary intake (see Fig. 98.1 ), and the speed of renal adaptation depends on the baseline potassium intake and the magnitude of the change in dietary potassium intake. Extreme adjustments in the rate of renal potassium conservation cannot be achieved as rapidly as for sodium, and the adjustments are not as complete. In contrast, urinary sodium can be virtually eliminated within 3 to 4 days of sodium restriction, and a minimum urinary potassium loss of approximately 5 mEq/day occurs in the adult, even after several weeks of severe potassium restriction. 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. ^, Interestingly, in pinealocytes, calcium-activated potassium channels (BKCa, which are also localized in the kidney) are involved in melatonin secretion in a negative-feedback mechanism and thereby contribute to the regulation of the circadian rhythm. It is unknown whether a circadian cycle of urinary potassium excretion exists in infancy.

The processes involved in renal potassium handling in the fully differentiated kidney include filtration, reabsorption, and secretion ( Fig. 98.3 ). Filtered potassium is reabsorbed almost entirely in proximal segments of the nephron, and urinary potassium is derived predominantly from distal secretion. Therefore renal secretion, rather than a balance of filtration and tubular reabsorption, maintains potassium homeostasis at least in the adult.

Renal potassium clearance is low in newborns, even when it is corrected for their low glomerular filtration rate. ^, Infants, like adults, when given a potassium load, can excrete potassium at a rate that exceeds its glomerular filtration—a finding indicating the capacity for net tubular secretion. However, the rate of potassium excretion per unit of body weight or kidney weight in response to exogenous loading is less in newborns than in older animals. ^, Clearance studies in saline-expanded dogs also provide indirect evidence of a diminished secretory and enhanced reabsorptive capacity of the immature distal nephron to potassium. A similar conclusion can be drawn from a longitudinal prospective study in premature neonates demonstrating 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. 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. In general, the limited potassium secretory capacity of the immature kidney becomes clinically relevant only under conditions of potassium excess. As stated earlier, under normal circumstances, potassium retention by the newborn kidney is appropriate and is required for somatic growth.

Sites of Potassium Transport Along the Nephron

Potassium is freely filtered at the glomerulus. Approximately 65% of the filtered load of potassium is reabsorbed along the proximal tubule of the suckling rat, a fraction similar to that measured in the adult (see Fig. 98.3 ). Reabsorption is passive in this segment, closely following water reabsorption, and is driven in part by the positive transepithelial voltage that prevails along part of the proximal tubule.

Approximately 10% of the filtered load of potassium reaches the early distal tubule of the adult, a finding reflecting significant further net reabsorption of this cation in the thick ascending limb of the loop of Henle (TALH) (see Fig. 98.3 ). In contrast, up to 35% of the filtered load of potassium reaches the distal tubule of the very young (2-week-old) rat. Observations in the maturing rodent—that the fractional reabsorption of potassium along the TALH, expressed as a percentage of delivered load, increases by 20% between the second and sixth weeks of postnatal life and that both the diluting capacity and TALH Na ⁺ , K ⁺ -ATPase pump activity increase after birth—are consistent with a developmental maturation of potassium absorptive pathways in this segment. ^{, ,} However, direct functional analysis of the potassium transport capacity of the TALH in the developing nephron has not been performed.

The avid potassium reabsorption characteristic of the fully differentiated TALH is mediated by a Na ⁺ , K ⁺ -2Cl ⁻ co-transporter, which translocates a single potassium ion into the cell accompanied by a sodium and two chloride (Cl ⁻ ) ions ( Fig. 98.4A ). This secondary active transport is ultimately driven by the basolateral Na ⁺ , K ⁺ -ATPase pump, which generates an electrochemical gradient favoring sodium entry at the apical membrane. Diuretics such as furosemide and bumetanide, which inhibit the Na ⁺ , K ⁺ -2Cl ⁻ co-transporter, block potassium reabsorption at this site and promote potassium secretion, leading to profound urinary potassium losses.

Activity of the Na ⁺ , K ⁺ -2Cl ⁻ transporter requires the presence of a parallel potassium conductance in the urinary membrane. This luminal secretory potassium (SK) channel is encoded by the renal outer medullary K ⁺ channel (ROMK) gene. ^, Loss-of-function mutations in ROMK lead to antenatal Bartter syndrome, also known as the hyperprostaglandin E syndrome, which is characterized by severe renal salt and water losses, consistent with a pattern of impaired TALH function and similar to the clinical picture observed with the chronic administration of loop diuretics. The typical presentation of antenatal Bartter syndrome includes polyhydramnios, premature delivery, and life-threatening episodes of dehydration during the first week of life. This group of patients also has severe growth failure, hypercalciuria with early-onset nephrocalcinosis, hyperreninism, and hyperaldosteronism but normal blood pressure.

In the healthy adult, regulated potassium secretion by the distal tubule and the collecting duct contributes prominently to urinary potassium excretion, which can approach 20% of the filtered load (see Fig. 98.3 ). Two major populations of cells compose the distal nephron. Principal cells reabsorb sodium and secrete potassium, whereas intercalated cells primarily function in acid-base homeostasis but can reabsorb potassium in response to dietary potassium restriction or metabolic acidosis. Potassium secretion by the collecting duct requires potassium to be actively transported into principal cells in exchange for sodium at the basolateral membrane by the action of the Na ⁺ , K ⁺ -ATPase pump (see Fig. 98.4B ). Potassium accumulates within the cell and then passively diffuses across the apical membrane through SK channels. The magnitude of potassium secretion is determined by its electrochemical gradient and the apical permeability to this cation. The electrochemical gradient is established by the potassium concentration gradient between the cell and lumen and lumen-negative voltage, generated by apical sodium entry through epithelial sodium channels (ENaCs), and its basolateral electrogenic extrusion.

Two apical potassium-selective channels have been functionally identified in the distal nephron. The small-conductance SK channel, encoded by the ROMK gene, is considered to mediate baseline potassium secretion, whereas the high-conductance, stretch- and calcium-activated BK (maxi-K) channel mediates flow-stimulated potassium secretion. Whereas BK channels in intercalated cells are now considered to mediate flow-stimulated potassium secretion, BK channels are also localized in the primary cilia of principal cells in the collecting duct, where they mediate flow signaling. Surprisingly, in the primary cilia, the BK channels do not contribute to urinary potassium secretion but mediate cellular signaling together with calcium channels such as polycystin-2 and TRPV4. Higher intracellular calcium concentration stimulates stretch- and calcium-activated BK channels. Any factor that enhances the electrochemical driving force or increases the apical membrane’s permeability to potassium will favor potassium secretion.

The direction and magnitude of net potassium transport in the distal nephron vary according to physiologic need. Thus, in response to dietary potassium restriction or potassium depletion, the distal nephron may reabsorb potassium. Potassium reabsorption is mediated by an H ⁺ , K ⁺ -ATPase, an enzyme that exchanges a single potassium ion for a proton (see Fig. 98.4C ), localized to the apical membrane of acid-base–transporting intercalated cells.

Potassium secretion in the distal nephron and specifically in the cortical collecting duct (CCD) is low early in life and cannot be stimulated by high urinary flow rates. The limited capacity of the neonatal CCD for baseline potassium secretion appears not to be due to an unfavorable electrochemical gradient. Although Na ⁺ , K ⁺ -ATPase activity in neonatal collecting duct segments is only 50% of that measured in the mature nephron, cell potassium content of this segment is similar at both ages, presumably reflecting a relative paucity of membrane potassium channels early in life. ^{, ,} The rate of sodium absorption in the CCD at 2 weeks of age is approximately 60% of that measured in the adult and is not considered to be limiting for potassium secretion. Electrophysiologic analysis has confirmed the absence of functional potassium secretory channels in the luminal membrane of the neonatal CCD. Cumulative evidence now suggests that the postnatal increase in the potassium secretory capacity of the distal nephron is due to a developmental increase in number of SK/ROMK and BK channels, reflecting an increase in transcription and translation of functional channel proteins. Molecular analyses demonstrate that ROMK messenger RNA and protein are first detectable in the second week of postnatal life in the rodent, immediately preceding the appearance of functional channels and potassium secretion in this segment. ^, Messenger RNA encoding the BK channel first becomes detectable after weaning in the rodent, as does functional BK channel activity.

Indirect evidence suggests that the neonatal distal nephron absorbs potassium. As indicated earlier, saline-expanded newborn dogs absorb 25% more of the distal potassium load than adult animals. Functional analysis of the collecting duct in the rabbit has shown that the activity of apical H ⁺ , K ⁺ -ATPase in neonatal intercalated cells is equivalent to that in mature cells. The latter data alone do not predict transepithelial potassium absorption under physiologic conditions. However, 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 pump.

The major factors that influence the external balance of potassium are listed in Box 98.1 and are discussed in the following sections.

Box 98.1

Factors Regulating the External Balance of Potassium

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