Potassium Homeostasis in the Fetus and Neonate

Potassium Homeostasis in the Fetus and Neonate

105 

Matthias T. Wolf  |  Corinne Benchimol  |  Lisa M. Satlin  |  Raymond Quigley

Potassium is the most abundant intracellular cation. Maintenance of a high intracellular potassium concentration (100 to 140 mEq/L) is essential for many basic cellular processes, including cell growth and division, DNA and protein synthesis, conservation of cell volume and pH, and optimal enzyme function. The steep gradient between potassium concentration in the cell and that in the extracellular fluid, maintained by the ubiquitous sodium-potassium adenosine triphosphatase (Na+,K+-ATPase), is the major determinant of the resting membrane potential across the cell membrane, and thus it affects neuromuscular excitability and contractility. Approximately 98% of the total body potassium content in the adult resides within cells (primarily muscle) (Figure 105-1), whereas the remaining 2% is located within the extracellular fluid. The extracellular potassium concentration (generally ranging from 3.5 to 5.0 mEq/L) is tightly regulated by mechanisms that govern the internal distribution between the intracellular and extracellular compartments and the external balance between intake and output.

POTASSIUM HOMEOSTASIS The homeostatic goal of the adult is to remain in zero potassium balance. Thus, of the typical daily potassium intake of 1  mEq/kg body weight, approximately 90% to 95% is ultimately eliminated from the body in the urine; the residual 5% to 10% of the daily potassium load is lost through the stool (see Figure 105-1). Normally, the amount of potassium lost through sweat is negligible. In contrast to the situation in the adult, infants older than approximately 30 weeks’ gestational age (GA) must conserve potassium for growth.1,2 Postnatal growth is associated with an increase in total body potassium from approximately 8 mEq/cm body height at birth to more than 14 mEq/cm body height by 18 years of age.3,4 The rate of accretion of body potassium per kilogram body weight in the neonate is greater than in later childhood (Figure 105-2), a finding reflecting an increase in both cell number and potassium concentration (at least in skeletal muscle) with advancing age.4-6 Given the requirement of the growing organism for potassium conservation, infants must maintain a state of positive potassium balance.2,7 This 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.2,7 In fetal life, potassium is transported across the placenta from mother to fetus. Indeed, the fetal serum potassium concentration is maintained at levels exceeding 5 mEq/L even in the presence of maternal potassium deficiency.8,9 Urinary potassium excretion varies considerably, depending in large part on dietary intake. 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 1.2,10 Although breast milk and commercially available infant formulas generally provide a sodium-to-potassium ratio of approximately 0.5 to 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.2 Because of the many vital processes dependent on potassium homeostasis, multiple complex and efficient mechanisms have developed to regulate total potassium balance and distribution.

REGULATION OF INTERNAL POTASSIUM BALANCE The task of maintaining potassium homeostasis is complex, in large part because the daily dietary intake of potassium (~100 mEq in the adult) typically 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) (see Figure 105-1). 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, 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 the extracellular pool (see Figure 105-1). 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 cation 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 potassiumselective channels in the plasma membrane. Na+,K+-ATPase consists of a catalytic (α) and a regulatory (β) subunit. Thirty percent to 50% 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 48 hours after birth, despite the intake of negligible amounts of potassium.11-15 This phenomenon is not observed in mature infants or very-low-birth-weight infants after 72 hours.13,14 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.13,14,16 Prenatal steroid treatment may prevent this nonoliguric hyperkalemia via induction of Na+,K+-ATPase activity in the fetus.17,18 Na+,K+-ATPase activity is regulated by numerous circulating hormones that exert short- and long-term control.19 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.19 Regulation of internal potassium

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SECTION XVI — The Kidney Gl intake (100 mEq/d)

Intracellular compartment

Muscle (2650 mEq)

Exracellular fluid (ECF) (70 mEq)

Liver (250 mEq)

RBC (250 mEq)

Urine (90-95 mEq/d)

Stool (5-10 mEq/d)

Bone (300 mEq)

Figure 105-1  Potassium homeostasis in the adult: internal and external balance. External potassium balance is maintained by the urinary (90% to 95%) and fecal (5% to 10%) excretion of the daily potassium intake of approximately 1 mEq/kg/day in the typical adult. Internal potassium balance depends on the distribution of potassium between the extracellular fluid (ECF) compartment and the vast intracellular storage reservoirs provided by muscle, liver, erythrocytes (RBC), and bone. GI, Gastrointestinal.

Males Females

Total body K (g)

100

10

1 10

20

30

40

50

60

70

80

90 100 110 120 130 140 150 160 170 180 190 Height (cm)

Figure 105-2  Relationship between total body potassium (K) and height for infants and children. The rate of accretion of body potassium in the neonate is faster than in later childhood, likely reflecting an increase in both cell number and potassium concentration, at least in skeletal muscle, with advancing age. (From Flynn MA, Woodruff C, Clark J, et al: Total body potassium in normal children. Pediatr Res 6:239, 1972.)



Chapter 105 — Potassium Homeostasis in the Fetus and Neonate

Table 105-1  Factors Relevant to the Infant That Acutely Regulate the Internal Balance of Potassium Factor

Effect on Cell Uptake of Potassium

Physiologic Factors Plasma K Concentration Increase Decrease Insulin

Increase Decrease Increase

Catecholamines α-Agonists β-Agonists

Decrease Increase

Pathologic Factors Acid-Base Balance Acidosis Alkalosis Hyperosmolality Cell breakdown

Decrease Increase Enhances cell efflux Enhances cell efflux

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 105-1. 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 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.20 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)21-24 and/or increasing cytoplasmic sodium content (as in adipocytes)25-27 or

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by increasing the apparent affinity of the enzyme for sodium (as in kidney).28 Basal insulin secretion is necessary to maintain 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.29 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 α-adrenergic receptor stimulation causing release of potassium from hepatocytes.30,31 β2-Receptor stimulation, via stimulation of adenylate cyclase leading to generation of the second messenger cyclic adenosine monophosphate, activates Na+,K+-ATPase and thus promotes enhanced uptake of potassium by skeletal and cardiac muscle. These effects are inhibited by the β2-blocker propranolol.30-35 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. For example, the β2-adrenoreceptor agonist albuterol has been used to treat life-threatening hyperkalemia in premature and term neonates, children, and adults.36-38 Administration of albuterol to treat hyperkalemia is associated with few side effects (mild, reversible tachycardia and tremors).39 Administration of glucose, insulin, and furosemide may be associated with significant fluid, electrolyte, and glucose derangements in premature infants.40-42 Administration of sodium bicarbonate has been associated with an increased incidence of intraventricular hemorrhage.43 Oral or rectal administration of ion exchange resins can increase total body sodium and cause cecal perforation.44 Furthermore, it may be ineffective in small infants40,45 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.19

ACID-BASE BALANCE It is well known that the transcellular distribution of potassium and acid-base balance are interrelated.46 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.46 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 (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

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SECTION XVI — The Kidney

not elicit a detectable change in plasma potassium.46-48 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.46 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 intracellular 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).

REGULATION OF EXTERNAL   POTASSIUM BALANCE RENAL CONTRIBUTION The kidney is the major excretory organ for potassium. In adults, urinary potassium excretion parallels dietary intake (see Figure 105-1), 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.49 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 (Figure 105-3).50 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.2,7 Infants,

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 hyperos­ molality on potassium balance becomes especially troublesome in patients with hyperglycemia, as observed in patients with diabetes in whom the absence of insulin exacerbates the hyperkalemia.

Distal convoluted tubule

Proximal convoluted tubule

Glomerulus

A: 65% NB: 65% K

Filtered load (Pk × GFR)

K

K Thick ascending limb of Henle

K

K

Cortical collecting tubule

A: 25%

Medullary collecting tubule K K Figure 105-3  Tubular sites of potassium (K) transport along the nephron. The percentages of filtered potassium reabsorbed along the proximal tubule and the thick ascending limb of the loop of Henle are indicated for the adult (A) and, when known, the newborn (NB). Arrows identify the direction of net potassium transport as either out of (reabsorption) or into (secretion) the urinary fluid. GFR, Glomerular filtration rate.



Chapter 105 — Potassium Homeostasis in the Fetus and Neonate

like adults, can excrete potassium at a rate that exceeds its glomerular filtration when given a potassium load, a finding indicating the capacity for net tubular secretion.51 However, the rate of potassium excretion per unit body weight or kidney weight in response to exogenous loading is less in newborn than older animals.52,53 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.54 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.1 To the extent that the filtered load of potassium increased almost three-fold 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.1 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 Figure 105-3).55-58 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 Figure 105-3).57 In contrast, up to 35% of the filtered load of potassium reaches the distal tubule of the very young (2-week-old) rat.55 The 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 activity increase after birth are consistent with a developmental maturation of potassium absorptive pathways in this segment.55,59,60 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− cotransporter, which translocates a single potassium ion into the cell accompanied by a sodium and two chloride (Cl−) ions (Figure 105-4, A). This secondary active transport is ultimately driven by the basolateral Na+,K+-ATPase that generates an electrochemical gradient favoring sodium entry at the apical membrane. Diuretics such as furosemide and bumetanide that inhibit the Na+,K+-2Cl− cotransporter block potassium reabsorption at this site and uncover 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 channel is encoded by the renal outer medullary K+ channel (ROMK) gene.61,62 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.63 The typical presentation of antenatal Bartter syn-

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drome includes polyhydramnios, premature delivery, and lifethreatening 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.64 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 Figure 105-3).50 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 Na+,K+-ATPase (see Figure 105-4, B). Potassium accumulates within the cell and then passively diffuses across the apical membrane through secretory potassium 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 secretory potassium (SK) channel, encoded by the ROMK gene, is considered to mediate baseline potassium secretion, whereas the high-conductance, stretch- and calcium-activated maxi-K channel mediates flow-stimulated potassium secretion.65 Any factor that enhances the electrochemical driving force or increases the apical membrane 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 a H+,K+-ATPase, an enzyme that exchanges a single potassium ion for a proton (see Figure 105-4, C), 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.66 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.59,67,68 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.66 Electrophysiologic analysis has confirmed the absence of functional potassium secretory channels in the luminal membrane of the neonatal CCD.69 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 maxi-K channels, reflecting an increase in transcription and translation of functional channel proteins.69-71 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.66,69-71 Messenger RNA encoding the maxi-K channel first becomes detectable after weaning in the rodent, as does functional maxi-K channel activity.72

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SECTION XVI — The Kidney Principal cell

Thick ascending limb Lumen

Lumen

Blood

Na

Blood (NKCC1)

(ENaC)

2Cl K

(NKCC2)

Na

(Na/K ATPase)

Na

Na

(ROMK)



2Cl K

(Na/K ATPase) Na

(maxi-K)

K K

K K

K

(ROMK)

A

B Intercalated cell (A type)

Intercalated cell (B type)

Lumen

Blood (V-ATPase)

(NKCC1)

(maxi-K) K K

(H/K ATPase)

Na (Na/K ATPase) Na K (AE1)

H

Cl

(NDCBE)

(NKCC1)

Cl

K

Na (Pendrin)

Na

HCO3 K K

Cl

(AE4) HCO3

(maxi-K) (H/K ATPase) ADP + Pi H

C

2Cl K

2HCO3

HCO3

(CIC-Kb) Cl

Blood

Na

2Cl K

H

Lumen

ATP

ATP ADP + Pi (V-ATPase)

H

D

Figure 105-4  Potassium (K +) transport pathways in specific renal tubular cells. A, In the thick ascending limb of the loop of Henle, potassium is avidly absorbed by specialized luminal Na+-K+-2Cl− (NKCC2) cotransport. A luminal secretory potassium channel, the renal outer medullary potassium channel (ROMK) in this cell, allows potassium to recycle back into the tubular fluid, thereby ensuring a continuous and abundant supply of potassium for the cotransporter. B, In the cortical collecting duct, potassium is pumped into the cell in exchange for sodium by the basolateral Na+,K+-ATPase. Basolateral NKCC1 also contributes to uptake of intracellular potassium. After entry into and accumulation in the cell, potassium is secreted preferentially across the apical membrane through the ROMK or maxi-K channel, a process driven by a favorable electrochemical gradient. The electrochemical gradient is composed of two components: the cell-to-lumen concentration, or chemical gradient, and the cell-to-lumen electrical gradient. The latter is generated by apical sodium entry through amiloride-sensitive epithelial sodium channels (ENaCs) and its electrogenic basolateral extrusion. C, Type A intercalated cells of the collecting duct mediate potassium absorption via apical H+,K+-ATPase, a pump that catalyzes the exchange of a single proton for potassium. Maxi-K channels secrete potassium in a flow-dependent manner. At the basolateral membrane, potassium absorption occurs by NKCC1 and Na+,K+-ATPase. While the chloride channel ClC-Kb facilitates chloride movement outside the cell, the anion exchanger (AE1) exchanges intracellular bicarbonate (HCO3−) with extracellular chloride (Cl). D, Type B intercalated cells of the collecting duct mediate potassium absorption via apical H+,K+-ATPase, while maxi-K channels secrete potassium. NDCBE and pendrin channels contribute to cellular uptake and secretion of HCO3−. At the basolateral membrane anion exchanger, AE4 moves bicarbonate out of the cell.

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.51 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.73 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.55

The major factors that influence the external balance of potassium are listed in Box 105-1 and are discussed in the following sections.

DISTAL SODIUM DELIVERY AND TRANSEPITHELIAL VOLTAGE As predicted from the principal cell model (see Figure 105-4, B), an increase in sodium absorption enhances the electrochemical driving force for potassium diffusion into the lumen. The magnitude of passive apical sodium entry and its electrogenic basolateral extrusion determine the apical membrane electrical



Chapter 105 — Potassium Homeostasis in the Fetus and Neonate

Box 105-1  Factors Regulating the

External Balance of Potassium Renal Factors • • • • •

Distal sodium delivery and transepithelial voltage Tubular (urinary) flow rate Potassium intake–plasma potassium concentration Hormones (mineralocorticoids, vasopressin) Acid-base balance

Gastrointestinal Tract Factors • Stool volume • Hormones

potential and rate of basolateral Na+-K+ exchange. The dependence of potassium secretion on distal sodium delivery becomes evident at tubular fluid sodium concentrations less than 30 mEq/L, a value below which potassium secretion falls sharply.74,75 In vivo measurements of the sodium concentration in distal tubular fluid generally exceed 35 mEq/L in both adult and suckling rats and thus should not restrict distal potassium secretion.55,60,74,76 Extracellular volume expansion or administration of many diuretics (osmotic diuretics, carbonic anhydrase inhibitors, loop and thiazide diuretics) is accompanied by an increase in excretion of both sodium and potassium. The kaliuresis is mediated not only by the increased delivery of sodium to the distal nephron but also by the increased tubular fluid flow rate, which activates the BK channel and maximizes the chemical driving forces, as described later, favoring potassium secretion. Other potassiumsparing diuretics, such as amiloride and triamterene, block distal sodium reabsorption, which reduces the electrical potential gradient favoring potassium secretion. Sodium delivered to the distal nephron is generally accompanied by chloride. Chloride reabsorption, which occurs predominantly via the paracellular pathway, tends to reduce the lumen-negative potential that would otherwise drive potassium secretion. When sodium 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.

TUBULAR FLOW RATE High rates of urinary flow in the mature, but not the neonatal or weanling, distal nephron stimulate potassium secretion.66 Thus volume expansion and diuretics, both of which increase distal tubular fluid flow rate, enhance potassium secretion in the fully differentiated kidney. A number of factors are responsible for the flow stimulation of potassium secretion. First, flow stimulates sodium reabsorption, which enhances the electrochemical gradient favoring potassium secretion.77,78 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. 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 tubular fluid flow rate increase the intracellular calcium concentration, which activates the maxi-K channel in the collecting duct to secrete potassium, thereby enhancing urinary potassium excretion.65,72 The capacity for flow-stimulated potassium secretion is developmentally regulated. Flow-stimulated potassium secretion,

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studied in single rabbit CCDs, does not appear until week 5 of postnatal life, approximately 2 weeks after baseline potassium secretion is first detected.66,72 Maxi-K channel messenger RNA and protein are not consistently detected in the CCD until weeks 4 and 5 of life, respectively, suggesting that the postnatal appearance of flow-dependent potassium secretion is determined by the transcriptional and/or translational regulation of expression of maxi-K channels in the distal nephron.72

POTASSIUM INTAKE AND CELLULAR POTASSIUM CONTENT Ingestion of a potassium-rich meal is rapidly followed by enhanced urinary excretion of potassium. The increase in potassium entry into principal cells from the basolateral (blood) side 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. It has also been suggested that a reflex increase in potassium excretion via vagal afferents follows activation of potassium-specific sensors in the gut or hepatic portal circulation, a control system that may be regulated in the absence of change in the plasma potassium concentration.49 Chronic potassium loading leads to potassium adaptation, an acquired tolerance to an otherwise lethal acute potassium load.50 This adaptation occurs in the distal nephron and colon; the rate of potassium secretion in these segments varies directly with body stores of potassium. 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. The mechanisms underlying this adaptation in the principal cell include not only an increase in the density of apical membrane potassium channels, but also an increase in the number of conducting sodium 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. When potassium intake is chronically reduced, potassium secretion by principal cells falls as reabsorption by intercalated cells increases. Stimulation of luminal H+,K+-ATPase activity in intercalated cells results not only in potassium retention but also in urinary acidification and metabolic alkalosis.

HORMONES Mineralocorticoids stimulate sodium reabsorption and potassium secretion in principal cells of the distal nephron.79,80 In the adult, the mineralocorticoid-induced stimulation of renal potassium secretion is considered to be due primarily to an increase in the electrochemical driving force favoring potassium exit across the apical membrane, generated by stimulation of apical sodium entry and reabsorption. Aldosterone action requires its initial binding to the mineralocorticoid receptor, followed by translocation of the hormone-receptor complex to the nucleus in which specific genes are stimulated to code for physiologically active proteins (e.g., Na+,K+-ATPase). Cellular effects within the fully differentiated CCD include increases in the density of active ENaC channels, caused by recruitment of intracellular channels to the apical membrane, de novo synthesis of ENaC subunits, and activation of preexisting channels.81,82 Aldosterone also stimulates Na+,K+-ATPase activity through both recruitment of preexisting pumps to the plasma membrane and increased total amounts of sodium pump subunits.83 The sum effect of these actions is the stimulation of net sodium absorption, leading to an increase in lumen negative transepithelial voltage, thereby facilitating net potassium secretion. The effects of aldosterone on ENaC and, to some extent, the Na+-K+ pump appear to be

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SECTION XVI — The Kidney

indirect, mediated by aldosterone-induced proteins, including serum- and glucocorticoid-inducible kinase (sgk).84 Plasma aldosterone concentrations in the newborn are high compared with those in the adult.2,85 Yet clearance studies in fetal and newborn animals demonstrate a relative insensitivity of the immature kidney to this hormone.2,86-88 The density of aldosterone-binding sites, receptor affinity, and degree of nuclear binding of hormone receptor are thought to be similar in mature and immature rats.88 Thus the early hyposensitivity to aldosterone is considered to represent a postreceptor phenomenon.2,88 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 by using the equation: TTKG = [K + ]urine ( U P ) osmolality [K + ]plasma



[105-1]

+

where [K ] equals the potassium concentration in either urine (U) or plasma (P), as indicated.89-91 Measurements of TTKG have been reported to be lower in 27- than in 30-week GA preterm infants followed over the first 5 weeks of postnatal life.92 The low TTKG has been attributed to a state of relative hypoaldosteronism but may also reflect the absence of potassium secretory transport pathways (i.e., channel proteins).92

ACID-BASE BALANCE Disorders of acid-base homeostasis can induce changes in tubular potassium secretion. Acute metabolic acidosis decreases the urine pH and reduces potassium excretion, whereas both acute respiratory alkalosis and metabolic alkalosis result in increases in urine pH and potassium excretion. Chronic metabolic acidosis has variable effects on urinary potassium excretion. The alkalosis-induced stimulation of potassium secretion reflects two direct effects on principal cells: (1) the stimulation of Na+,K+-ATPase activity and basolateral potassium uptake, and (2) 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.50 Alkalosis also decreases acid secretion in intercalated cells, thereby reducing H+,K+-ATPase–mediated countertransport. Acute metabolic acidosis reduces cell potassium concentration and leads to a reduction in urine pH, which in turns inhibits apical potassium channel (SK/ROMK) activity.50 The net effect is a fall in urinary potassium secretion. 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.50 The latter two factors may lead to an increase rather than a decrease in potassium secretion and excretion.

CONTRIBUTION OF THE GASTROINTESTINAL TRACT Under normal conditions in the adult, 5% to 10% of daily potassium intake is excreted in the stool (see Figure 105-1). The colon is considered to be the main target for regulation of intestinal potassium excretion.93 Potassium transport in the colon represents the balance of secretion and absorption.94 Under baseline conditions, net potassium secretion predominates over absorption in the adult, whereas the neonatal gut is poised for net potassium absorption.93 Potassium secretion requires potassium uptake by the Na+,K+ATPase and 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.95-98 Stool potassium content can be enhanced by any factor that increases colonic secretion, including aldosterone, epinephrine, and prostaglandins.99-101 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 because of the presence of nonreabsorbed anions (which obligate K+ secretion), an enhanced electrochemical gradient established by active chloride secretion, and secondary hyperaldosteronism resulting from volume contraction. Potassium adaptation in the colon is demonstrated by increased fecal potassium secretion after potassium loading and increased excretion with renal insufficiency. Fecal potassium excretion may triple in patients with severe chronic renal insufficiency.99,102-104 The enhanced colonic potassium secretion characteristic of chronic renal insufficiency requires induction and/ or activation of apical maxi-K channels in surface colonic epithelial cells.105 Net colonic potassium absorption is significantly higher in young versus adult rats.93 The higher rate of potassium absorption during infancy is due to robust activity of potassium absorptive pumps located in apical membrane and limited activity of the basolateral transporters that mediate secretion.106,107

CONDITIONS OF ABNORMAL   POTASSIUM LEVELS HYPERKALEMIA In preterm infants and neonates, reference ranges for serum potassium are usually higher compared with adults; this is consistent with the increased physiologic requirement for potassium due to accelerated growth and cell division in infancy. In addition, higher baseline serum potassium levels in preterm and neonates are partially due to a lower response of the distal nephron to aldosterone due to immaturity. Frequently, hyperkalemia, defined as serum potassium levels above 6.5 mmol/L, is due to extrarenal etiologies (Table 105-2).108 For example, hyperkalemia is observed with severe bruising, cephalohematoma, hemolysis, acidosis, thrombocytosis, hypoglycemia, and ischemia.109 Renal causes for hyperkalemia may include poor renal perfusion due to a traumatic delivery and subsequent renal injury or medications such as indomethacin or angiotensin-converting enzyme (ACE) inhibitors (Table 105-2). Hyperkalemia can be diagnosed by analysis of blood chemistry and confirmed by peaked T waves on an electrocardiogram. Hyperkalemia may cause fatal cardiac arrhythmia, brain hemorrhage, periventricular leukomalacia, and sudden death.110

NONOLIGURIC HYPERKALEMIA As discussed, up to 50% of all premature infants with very low birth weight and extreme low birth weight develop hyperkalemia within the first 72 hours of life with no obvious organ injury, Table 105-2  Etiology of Hyperkalemia in Preterm Infants and Neonates Extrarenal

Renal

Hemolysis

Renal failure (e.g., prerenal, intrinsic, or postrenal) Pseudohypoaldosteronism (PHA) type I PHA type II Transient PHA due to urinary tract infection, obstructive uropathy Renal tubular dysplasia Renal outer medullary K+ channel mutations in Bartter syndrome (transient hyperkalemia)

Bruising Cephalohematoma Thrombocytosis Acidosis Medication (angiotensinconverting enzyme inhibitors, indomethacin) Nonoliguric hyperkalemia Congenital adrenal hyperplasia



Chapter 105 — Potassium Homeostasis in the Fetus and Neonate

due to a condition termed nonoliguric hyperkalemia.111-113 Most infants with this condition are asymptomatic. Nonoliguric hyperkalemia is thought to be due to loss of intracellular potassium into the extracellular space caused by immature Na+/K+-ATPase activity.114 Lower erythrocyte Na+/K+-ATPase activity has been described in hyperkalemic premature infants compared with infants with normal potassium levels.16 No relationship between nonoliguric hyperkalemia and hemolysis, bruising, or intracranial hemorrhage has been found.14 Prenatal steroid treatment could potentially prevent hyperkalemia by up-regulation of Na+/K+-ATPase.18 Early initiation of parenteral and enteral nutrition is believed to have reduced the incidence of this disorder.

PSEUDOHYPOALDOSTERONISM TYPE I Pseudohypoaldosteronism type I (PHAI) is caused by mineralocorticoid resistance due to rare mutations in the genes encoding either the mineralocorticoid receptor (NR3C2 for the renal form of PHAI) or one of the three subunits that form the apical epithelial Na+ channel, called ENaC (SCNN1A, SCNN1B, SCNN1G for the general form of PHAI).115 Classic features of PHAI include neonatal renal salt wasting, failure to thrive, and dehydration (Table 105-3). PHAI is characterized by inadequate potassium and hydrogen secretion resulting in hyperkalemia and metabolic acidosis; it is associated with hyponatremia and highly elevated renin and aldosterone levels. Patients have inappropriately high urine Na+ excretion, reduced urinary K+ secretion, and occasional hypercalciuria.116 Two different forms of PHAI are differentiated; they vary significantly regarding disease severity (Table 105-3).

RENAL PSEUDOHYPOALDOSTERONISM TYPE I Renal PHAI is caused by heterozygous mutations of the mineralocorticoid receptor (encoded by the gene NR3C2), and it is inherited in an autosomal-dominant fashion.117,118 Due to the tissue distribution of NR3C2, mineralocorticoid resistance is restricted to the kidney. Mutations, including de novo mutations, have been identified throughout the entire NR3C2 gene. Renal PHAI is typically milder and more common than the general form of PHAI.117 Infants with renal PHAI exhibit renal salt wasting, hyponatremia, hyperkalemia, failure to thrive, vomiting, dehydration, metabolic acidosis, and elevated renin and aldosterone levels in early infancy. Symptoms usually improve in early childhood between 18 and 24 months of age. It remains unclear

Table 105-3  Clinical and Laboratory Characteristics of Pseudohypoaldosteronism (PHA) Type I Renal and Generalized Forms Renal PHAI

Generalized PHAI

Gene

NR3C2

Inheritance Disease severity Failure to thrive Dehydration Hyponatremia Hyperkalemia Renin Aldosterone Cardiac involvement Respiratory involvement Skin eczema Sweat Na+

Autosomal-dominant Mild + Mild + + Elevated Elevated −

SCNN1A, SCNN1B, SCNN1G Autosomal-recessive Severe + Severe + + Elevated Elevated +

−

+

− Normal

+ Elevated

1019

which mechanism results in improvement of symptoms with increasing age, but it is suspected that maturation of tubular function, compensatory increase of proximal Na+ reabsorption, and easier access to salt play a role.

GENERALIZED PSEUDOHYPOALDOSTERONISM TYPE I The generalized form of PHAI is due to homozygous- or compound heterozygous-inactivating mutations of one of the three ENaC subunits SCNN1A, SCNN1B, and SCNN1G, resulting in nonfunctional ENaC protein in kidney, colon, sweat, and salivary glands.119 In contrast to the clinically more benign form of renal PHAI, generalized PHAI is characterized by severe renal salt wasting, hyponatremia, and dehydration due to systemic salt loss in early infancy.115 Because of end-organ resistance, renin and aldosterone levels are elevated. In contrast to renal PHAI, patients with generalized PHAI can also develop cardiac, respiratory, or skin involvement.120-122 The clinical course can be complicated by arrhythmias, collapse, shock, and cardiac arrest. The Na+ concentration in sweat and saliva is typically elevated, and this finding can be utilized as an additional diagnostic tool. Pulmonary involvement is characterized by cough, tachypnea, and wheezing and is due to impaired Na+-dependent fluid absorption in the lung. Absence of the amiloride-sensitive Na+ channel ENaC was found in a neonate with generalized PHAI.121,123 Pulmonary involvement can be confused with cystic fibrosis. Generalized PHAI is a lifelong condition; it does not improve with age and remains lifethreatening due to the risk of dehydration and hyperkalemia.

TRANSIENT PSEUDOHYPOALDOSTERONISM Considered to be a secondary form of PHAI, transient PHA is frequently caused by medications or tubulo-interstitial nephropathies. Transient PHA is thought to be caused by tubular resistance to aldosterone.124 The clinical presentation is very similar to PHAI with dehydration, hyperkalemia, hyponatremia, metabolic acidosis, hyperaldosteronism, and elevated renin levels. Medications causing transient PHA include amiloride, triamterene, trimethoprim, and pentamidine as ENaC blockers. In addition, spironolactone (a mineralocorticoid receptor antagonist) and cyclosporine can contribute to transient PHA.125 Other medications contributing to transient PHA either interfere with the renin-angiotensin system (e.g., ACE inhibitors) or are nonsteroidal antiinflammatory substances or β-blockers. The most common causes for transient PHA in neonates are urinary tract infections and obstructive uropathy.126 Neonatal medullary necrosis and renal vein thrombosis also can result in transient PHA.125

PSEUDOHYPOALDOSTERONISM TYPE II CLINICAL PRESENTATION

Both PHAI and PHAII share metabolic acidosis and hyperkalemia. In contrast, PHAI patients are characterized by volume depletion, whereas PHAII patients present with salt-sensitive hypertension. They also have low plasma renin activity and inadequately normal aldosterone levels (given the level of hyperkalemia), suggesting renal Na+ retention and volume expansion.127,128 PHAII patients respond well to thiazides, suggesting a role for thiazidesensitive Na-Cl cotransporter (NCC) in the enhanced Na+ retention. Individuals with PHAII, which is also called Gordon syndrome, can present in preterm or in early infancy with hyperkalemia and metabolic acidosis in the presence of normal adrenal and renal function. Frequently, hyperkalemia presents first and hypertension may occur later.

GENETICS Heterozygous mutations causing PHAII were found in two genes called WNK1 and WNK4, which encode With-no-lysine (K)

1020

SECTION XVI — The Kidney

kinases 1 and 4.129 The name derives from the replacement of a highly conserved lysine residue by cysteine in the catalytic unit of these two proteins. Persons with PHAII were found to carry either intronic WNK1 deletions, resulting in a higher WNK1 abundance, or WNK4 missense mutations.129 In 2012, Boyden and colleagues identified mutations in two additional genes called cullin 3 (CUL3) and kelch-like 3 (KLHL3) causing PHAII in 52 families.130,131 The encoded proteins are components of an E3 ubiquitination ligase complex. Interestingly, KLHL3 mutations can be inherited in a dominant or recessive fashion, whereas CUL3 mutations are solely inherited in a dominant fashion. Disease severity is dependent on the affected gene with CUL3 mutations causing the most severe phenotype, presenting in early infancy with more severe hyperkalemia and acidosis. This has been confirmed by other reports of hyperkalemia and acidosis in young infants.132,133 Carriers of recessive KLHL3 mutations are more severely affected than patients with dominant KLHL3, WNK4, or WNK1 mutations.

blood pressure regulation has much improved. WNK 1 or WNK4 is expressed in the aldosterone-sensitive distal nephron. WNKs are thought to switch the aldosterone response in the kidney to be kaliuretic or antinatriuretic—dependent on the physiologic requirement.134 Due to the impressive response of PHAII patients to thiazides, a link between WNK1 and WNK4 was hypothesized, but it has been controversial. Initially, WNK4 overexpression studies in oocytes demonstrated inhibition of NCC by wild-type WNK4. However, Wnk4 knockout mice displayed a phenotype similar to NCC loss-of-function mutations with decreased NCC phosphorylation and NCC abundance, suggesting that WNK4 is actually a positive regulator of NCC in vivo135 (Figure 105-5). Animal studies of transgenic and knock-in mice carrying a Wnk4 mutation (Q562E or D561A) exhibit a phenotype similar to that in PHAII patients.136,137 The hyperkalemia in PHAII patients may be due to increased NCC activity in the DCT, which results in decreased distal Na+ delivery, subsequently less lumen-negative potential difference, and thus less K+ secretion in the connecting tubule.138 Wild-type WNK4 also decreases ROMK activity. An additional component in the hyperkalemia of PHAII patients is that WNK1 and WNK4 mutations result in even further decreased cell surface

PHYSIOLOGY By identifying the link between PHAII and WNK 1 or WNK4 mutations, our understanding of Na+ and K+ homeostasis and

NORMAL

PHAII Mutant WNK4

Mutant KLHL3/CUL3

Mutant WNK4

Ub Ub Ub

Ub

WNK4

Ub

CUL

Ub Ub

Ub

3

KLHL3

3

3

KLHL3

Ub

CUL

CUL

WNK4

WNK4

WNK4

Mutant WNK4

WNK4 degradation

Mutant KLHL3

WNK4

Ub KLHL3

Mutant CUL3

Decreased degradation

WNK4

WNK4

Accumulation Mutant WNK4

WNK4

Mutant WNK4 + OSR1/SPAK

Mutant WNK4

Mutant WNK4

WNK4

Mutant WNK4 Mutant WNK4

WNK4 +++ OSR1/SPAK

WNK4

WNK4

WNK4

+++

+ NCC

WNK4

NCC Activation of OSR1/SPAK-NCC signaling

Figure 105-5  Under physiologic conditions WNK4 levels are maintained at a lower level due to ubiquitination. The KLHL3-CUL3 E3 ligase complex binds and transfers WNK4 to ubiquitination. Pseudohypoaldosteronism type II (PHAII)-causing mutations in WNK4 or KLHL3 affect the binding of WNK4, which results in decreased WNK4 ubiquitination. CUL3 mutations result in decreased E3 ligase activity, which also increases WNK4 levels. Increased WNK4 levels were confirmed in a PHAII mouse model together with elevated OSR1/SPAK levels. Finally, along the WNK-OSR1/SPAK axis, NCC activity is enhanced. (With permission from Uchida S, Sohara E, Rai T, Sasaki S: Regulation of withno-lysine kinase signaling by Kelch-like proteins. Biol Cell 106:45–56, 2014).



Chapter 105 — Potassium Homeostasis in the Fetus and Neonate

abundance of ROMK by increasing ROMK endocytosis.139,140 Finally, increased distal chloride reabsorption was hypothesized to contribute to a less electronegative lumen, which subsequently decreases the electrochemical gradient for K+ secretion.141 In vitro experiments confirmed increased paracellular chloride reabsorption with WNK4.142,143 Interestingly, patients with WNK4 mutations were also found to exhibit hypercalciuria. In vitro experiments demonstrated less activity of renal calcium channel TRPV5 due to increased endocystosis of TRPV5 by WNK4144 (see Figure 105-5). WNK regulation of NCC, NKCC, and ROMK channels also involves two other kinases called SPAK (Ste20p family protein kinases) and OSR-1 (oxidative stress responsive kinase-1) that are downstream of WNK1 and WNK4145 (Figure 105-5). WNK1 and WNK4 associate with OSR1/SPAK and activate OSR1/SPAK by phosphorylation that in turn results in increased NKCC activity. WNK1 is phosphorylated by hyperosmotic stress and releases OSR1 to interact with NKCC1. OSR/SPAK is also involved in the regulation of NCC, and the phenotype of PHAII does not develop in a Wnk4 D561A-mutant mouse if OSR and SPAK are mutated.146 The physiologic significance of WNKs comes into play when the body has to regulate Na+ and K+ homeostasis in individuals with hypovolemia or hyperkalemia. In individuals with hypovolemia, Na+ reabsorption is increased without any effect on K+ secretion, and in those with hyperkalemia Na+ reabsorption is decreased and K+ secretion is increased (Figure 105-6). High versus low salt intake decreased or increased the phosphorylation of OSR1/SPAK and NCC in the kidney, thus adjusting urinary salt excretion dependent on dietary intake. Interestingly, OSR1/ SPAK signaling was increased in PHAII knock-in mouse model.137 A high salt diet did not decrease the WNK-OSR1/SPAK-NCC signaling in a PHA2 mouse model. The WNK-OSR1/SPAK-NCC axis is also regulated by potassium with high K diet decreasing the signaling and low K diet increased the signaling.147 WNK1 also activates SPAK/OSR1 and increases NKCC activity. In conclusion, the hypertension observed in PHAII patients may be caused by elevated Na+ reabsorption via NCC, NKCC2, ENaC, and paracellular Cl− pathways. A combination of events contributes to the laboratory constellation seen in PHAII: (1) increased NCC activity, contributing to hypervolemia and decreased distal sodium delivery, thus impairing distal K+ secretion via ROMK, (2) directly depressed ROMK activity, and (3) increased paracellular Cl− reabsorption causing a less electronegative lumen in the collecting duct and less ENaC activity, thus decreasing K+ secretion via ROMK. The discovery of novel proteins, including WNKs, CUL3, and KHLH3, contributing to Na+ and K+ homeostasis has expanded our understanding of electrolytes and volume regulation significantly.

CONGENITAL ADRENAL HYPERPLASIA Severe aldosterone deficiency is seen in neonates with salt-losing congenital adrenal hyperplasia (CAH) due to 21-hydroxylase activity or aldosterone synthase defects. Whereas the first group of children is glucocorticoid- and mineralcorticoid-deficient because of compromised hydrocortisone and aldosterone synthesis, the latter group has no genital or glucocorticoid abnormalities. Characteristic symptoms include hyponatremia, hyperkalemia, failure to thrive, hypotension, and dehydration. For more details regarding CAH, we refer to Chapter 147. Alternatively, primary hypoaldosteronism may be caused by trauma, infections, hemorrhage, or thrombosis of the adrenal cortex.

RENAL TUBULAR DYSGENESIS Homozygous- or compound heterozygous-inactivating mutations of different components of the renin-angiotensin system, including renin, angiotensinogen, ACE, and the angiotensin II receptor were found to cause inherited forms of renal tubular dysgenesis (RTD).148 RTD is characterized by oligohydramnios, fetal anuria,

1021

WNK1 and WNK4 ↑ mutation

SPAK/ OSR1 ↑

TRPV5 ↓

NCC ↑

Decreased Ca2+ release in DCT/CNT

Decreased K+ release in DCT/CNT

Increased Na+ reabsorption

Decreased Na+ Ca2+ reabsorption in PCT

Hyperkalemia Metabolic acidosis

High blood pressure

Urinary Ca2+ loss

ROMK ↓

Osteoporosis Figure 105-6  Physiologic consequences of WNK1 and WNK4 mutations regarding Na+, K+, and Ca2+ channel regulation. Increased NCC activity due to WNK1 and WNK4 mutations increase tubular Na+ and Cl− absorption and contribute to hypertension. Hyperkalemia in pseudohypoaldosteronism type II is caused by stronger inhibition of renal outer medullary K+ channel (ROMK) activity due to enhanced ROMK endocytosis. In addition, increased Na+ reabsorption in distal convoluted tubule (DCT) results in decreased Na+ delivery to the collecting duct, thus further aggravating hyperkalemia. Finally, increased paracellular Cl− shunting may decrease the lumen negative charge and so also decrease a stimulus for K+ secretion. TRPV5 activity is further inhibited by WNK4 mutations, which result in hypercalciuria and subsequently osteoporosis. (With permission from Pathare G, Hoenderop JG, Bindels RJ, San-Cristobal P: A molecular update on pseudohypoaldosteronism type II. Am J Physiol Renal Physiol 305:F1513–1520, 2013).

perinatal death, and frequently wide fontanels. The clinical presentation can also be mimicked by the maternal intake of ACE inhibitors or angiotensin receptor blockers149 (Figure 105-7).

HYPOKALEMIA Hypokalemia can be transient as a result of shifting of potassium from the extracellular fluid compartment into the intracellular fluid compartment, or it can be chronic as a result of excess potassium excretion or insufficient potassium intake. Conditions that cause a shifting of potassium from the extracellular fluid into the cells include acute metabolic alkalosis or administration of insulin or β-agonists (see Table 105-1). As discussed, TTKG can be helpful in determining if there is excess loss of potassium from the kidneys.92 In conditions of hypokalemia with a normal renal response, one should see a low value of TTKG. Thus an inappropriately high value would indicate renal wasting of potassium in the face of hypokalemia. Chronic hypokalemia is usually the result of a genetic disease that results in the wasting of potassium from the kidney. The most common cause of renal potassium wasting is Bartter syndrome.64,150,151 This can be caused by a mutation of one of the transport proteins involved in ion transport in the TALH (listed

1022

SECTION XVI — The Kidney REN mutations

AGT mutations

FI

R375Q Hom

R49X Hom

IVS3–12 TC → AG Hom

R230K Hom

A A GG A A T G A GG T G

C C T C T G A G C C C C T

A C A A C A A G T GGGG

A AG G A A C G A G G T G

F II

C C T C T G T C C C C C T

F III

G T C T T T G A C A C T G

C T C C C C A G T A G G A

Control C T C C C C G G T A G G A

Control

Control

FV

Control Angiotensinogen (AGT–1q42) Renin (REN–1q32)

ACE mutations Y266X Het

D104N Het

C C G A T A C G G A G A C

C C G A T A C G G A G A C

G T C T T T C A C A C T G

Angiotensin I

F VII

Angiotensinconverting enzyme (ACE–17q23)

F IV

G T C T T T G A C A C T G

Angiotensin II

Control

Control

IVS3 + 1G → A Het C C T G T G G T G A G A C

F IV

nt 1319–1322del TGGA Hom AT2 (AGTR2–Xq22)

AT1 (AGTR1–3q24)

C C T G C C C G T G T C A

C C T G T G G T G A G A C

Control C C T G C T G G A C C G T

F IX T282M Het

nt 110–111 insT Het C C C C C C T C A T C T

T GG A C A C GG C C A T

Control AGTR1 mutations A C A G T A T C A T C T

Control

F VI

T G G A C A C G G C C A T

F VI

Control

Figure 105-7  Mutations in different components of the renin-angiotensin system (RAS) (e.g., AGT, REN, ACE, and AGTR1) result in the same phenotype of renal tubular dysplasia. Diagrams outline the intron-exon structure. Chromatograms of the different mutations are shown for each family. F, Family; het, heterozygous; hom, homozygous. (With permission from Gribouval O, Gonzales M, Neuhaus T, et al: Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet 37[9]:964–968, 2005.)



Chapter 105 — Potassium Homeostasis in the Fetus and Neonate

Box 105-2  Genetic Causes of

Bartter Syndrome

1. Na-K-Cl-cotransporter 2 (NKCC2) 2. Chloride channel (CLCNKB) 3. Renal outer medullary K+ channel (ROMK) 4. Barttin (with sensorineural deafness) (BSND) 5. Calcium-sensing receptor (CaSR)

in Box 105-2). Many of these patients will have polyhydramnios because of the polyuria in utero. It should be noted that patients with the ROMK defect will often present with hyperkalemia in the neonatal period because they have a limited ability to excrete potassium (previously discussed). As the infant matures, the maxi-K channel expression will increase and they will then become hypokalemic. Gitelman syndrome also causes renal wasting of potassium.150,151 This is due to a defect in the thiazide-sensitive cotransporter in the distal convoluted tubule. These patients usually present as older children and in general have milder symptoms compared with patients with Bartter syndrome. Hypomagnesemia is more consistent with Gitelman syndrome than with Bartter syndrome. Another cause of renal potassium wasting is the EAST syndrome.152,153 This is a rare syndrome that causes epilepsy, ataxia, sensorineural deafness and renal tubulopathy. It is caused by a defect in a potassium channel, KCNJ10. Children with renal tubular acidosis types 1 and 2 can present with hypokalemia due to renal wasting of potassium. Potassium can also be lost through the stool in a condition known as congenital chloride diarrhea.154 This condition is due to a mutation in the chloride hydroxyl exchanger in the gastrointestinal tract. Thus the TTKG would be low, indicating a nonrenal source of potassium loss.92 Complete reference list is available at www.ExpertConsult.com.

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Pediatrics 106(3):561–567, 2000. 19. Therien AG, Blostein R: Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol 279(3):C541–C566, 2000. 20. Zierler KL, Rabinowitz D: Effect of very small concentrations of insulin on forearm metabolism. persistence of its action on potassium and free fatty acids without its effect on glucose. J Clin Invest 43:950–962, 1964. 21. Hundal HS, Marette A, Mitsumoto Y, et al: Insulin induces translocation of the alpha 2 and beta 1 subunits of the Na+/K(+)-ATPase from intracellular compartments to the plasma membrane in mammalian skeletal muscle. J Biol Chem 267(8):5040–5043, 1992. 22. Omatsu-Kanbe M, Kitasato H: Insulin stimulates the translocation of Na+/K(+)dependent ATPase molecules from intracellular stores to the plasma membrane in frog skeletal muscle. Biochem J 272(3):727–733, 1990. 23. Marette A, Krischer J, Lavoie L, et al: Insulin increases the Na(+)-K(+)-ATPase alpha 2-subunit in the surface of rat skeletal muscle: morphological evidence. Am J Physiol 265(6 Pt 1):C1716–C1722, 1993. 24. Kanbe M, Kitasato H: Stimulation of Na,K-ATPase activity of frog skeletal muscle by insulin. Biochem Biophys Res Commun 134(2):609–616, 1986. 25. Lytton J: Insulin affects the sodium affinity of the rat adipocyte (Na+,K+)ATPase. J Biol Chem 260(18):10075–10080, 1985. 26. Sargeant RJ, Liu Z, Klip A: Action of insulin on Na(+)-K(+)-ATPase and the Na(+)-K(+)-2Cl- cotransporter in 3T3-L1 adipocytes. Am J Physiol 269(1 Pt 1):C217–C225, 1995. 27. Sweeney G, Klip A: Regulation of the Na+/K+-ATPase by insulin: why and how? Mol Cell Biochem 182(1–2):121–133, 1998. 28. Feraille E, Carranza ML, Rousselot M, Favre H: Insulin enhances sodium sensitivity of Na-K-ATPase in isolated rat proximal convoluted tubule. Am J Physiol 267(1 Pt 2):F55–F62, 1994. 29. Dluhy RG, Axelrod L, Williams GH: Serum immunoreactive insulin and growth hormone response to potassium infusion in normal man. J Appl Physiol 33(1):22–26, 1972. 30. DeFronzo RA, Bia M, Birkhead G: Epinephrine and potassium homeostasis. Kidney Int 20(1):83–91, 1981. 31. Williams ME, Gervino EV, Rosa RM, et al: Catecholamine modulation of rapid potassium shifts during exercise. N Engl J Med 312(13):823–827, 1985. 32. Rosa RM, Silva P, Young JB, et al: Adrenergic modulation of extrarenal potassium disposal. N Engl J Med 302(8):431–434, 1980. 33. Angelopoulous M, Leitz H, Lambert G, MacGilvray S: In vitro analysis of the Na(+)-K+ ATPase activity in neonatal and adult red blood cells. Biol Neonate 69(3):140–145, 1996. 34. Gillzan KM, Stewart AG: The role of potassium channels in the inhibitory effects of beta 2-adrenoceptor agonists on DNA synthesis in human cultured airway smooth muscle. Pulm Pharmacol Ther 110(2):71–79, 1997. 35. Clausen T, Flatman JA: The effect of catecholamines on Na-K transport and membrane potential in rat soleus muscle. J Physiol 270(2):383–414, 1977. 36. Mandelberg A, Krupnik Z, Houri S, et al: Salbutamol metered-dose inhaler with spacer for hyperkalemia: how fast? How safe? Chest 115(3):617–622, 1999. 37. Singh BS, Sadiq HF, Noguchi A, Keenan WJ: Efficacy of albuterol inhalation in treatment of hyperkalemia in premature neonates. J Pediatr 141(1):16–20, 2002. 38. Helfrich E, de Vries TW, van Roon EN: Salbutamol for hyperkalaemia in children. Acta Paediatr 90(11):1213–1216, 2001. 39. Semmekrot BA, Monnens LA: A warning for the treatment of hyperkalaemia with salbutamol. Eur J Pediatr 156(5):420, 1997. 40. Shortland D, Trounce JQ, Levene MI: Hyperkalaemia, cardiac arrhythmias, and cerebral lesions in high risk neonates. Arch Dis Child 62(11):1139–1143, 1987. 41. Yeh TF, Raval D, John E, Pildes RS: Renal response to frusemide in preterm infants with respiratory distress syndrome during the first three postnatal days. Arch Dis Child 60(7):621–626, 1985. 42. Lui K, Thungappa U, Nair A, John E: Treatment with hypertonic dextrose and insulin in severe hyperkalaemia of immature infants. Acta Paediatr 81(3):213– 216, 1992. 43. Papile LA, Burstein J, Burstein R, et al: Relationship of intravenous sodium bicarbonate infusions and cerebral intraventricular hemorrhage. J Pediatr 93(5):834–836, 1978.

44. Bennett LN, Myers TF, Lambert GH: Cecal perforation associated with sodium polystyrene sulfonate-sorbitol enemas in a 650 gram infant with hyperkalemia. Am J Peninatol 13(3):167–170, 1996. 45. Malone TA: Glucose and insulin versus cation-exchange resin for the treatment of hyperkalemia in very low birth weight infants. J Pediatr 118(1):121–123, 1991. 46. Adrogue HJ, Madias NE: Changes in plasma potassium concentration during acute acid-base disturbances. Am J Med 71(3):456–467, 1981. 47. Fulop M: Serum potassium in lactic acidosis and ketoacidosis. N Engl J Med 300(19):1087–1089, 1979.

48. Graber M: A model of the hyperkalemia produced by metabolic acidosis. Am J Kidney Dis 22(3):436–444, 1993. 49. Rabinowitz L: Aldosterone and potassium homeostasis. Kidney Int 49(6):1738– 1742, 1996. 50. Giebisch G: Renal potassium transport: mechanisms and regulation. Am J Physiol 274(5 Pt 2):F817–F833, 1998.

Chapter 105 — Potassium Homeostasis in the Fetus and Neonate 1024.e1



REFERENCES 1. Delgado MM, Rohatgi R, Khan S, et al: Sodium and potassium clearances by the maturing kidney: clinical-molecular correlates. Pediatr Nephrol 18(8):759–767, 2003. 2. Sulyok E, Nemeth M, Tenyi I, et al: Relationship between maturity, electrolyte balance and the function of the renin-angiotensin-aldosterone system in newborn infants. Biol Neonate 35(1–2):60–65, 1979. 3. Butte NF, Hopkinson JM, Wong WW, et al: Body composition during the first 2 years of life: an updated reference. Pediatr Res 47(5):578–585, 2000. 4. Flynn MA, Woodruff C, Clark J, Chase G: Total body potassium in normal children. Pediatr Res 6(4):239–245, 1972. 5. Dickerson JW, Widdowson EM: Chemical changes in skeletal muscle during development. Biochem J 74:247–257, 1960. 6. Rutledge MM, Clark J, Woodruff C, et al: A longitudinal study of total body potassium in normal breastfed and bottle-fed infants. Pediatr Res 10(2):114– 117, 1976. 7. Satlin LM: Regulation of potassium transport in the maturing kidney. 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Sato K, Kondo T, Iwao H, et al: Internal potassium shift in premature infants: cause of nonoliguric hyperkalemia. J Pediatr 126(1):109–113, 1995. 15. Shaffer SG, Kilbride HW, Hayen LK, et al: Hyperkalemia in very low birth weight infants. J Pediatr 121(2):275–279, 1992. 16. Stefano JL, Norman ME, Morales MC, et al: Decreased erythrocyte Na+,K(+)ATPase activity associated with cellular potassium loss in extremely low birth weight infants with nonoliguric hyperkalemia. J Pediatr 122(2):276–284, 1993. 17. Uga N, Nemoto Y, Ishii T, et al: Antenatal steroid treatment prevents severe hyperkalemia in very low-birthweight infants. Pediatr Int 45(6):656–660, 2003. 18. Omar SA, DeCristofaro JD, Agarwal BI, LaGamma EF: Effect of prenatal steroids on potassium balance in extremely low birth weight neonates. Pediatrics 106(3):561–567, 2000. 19. Therien AG, Blostein R: Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol 279(3):C541–C566, 2000. 20. Zierler KL, Rabinowitz D: Effect of very small concentrations of insulin on forearm metabolism. persistence of its action on potassium and free fatty acids without its effect on glucose. J Clin Invest 43:950–962, 1964. 21. Hundal HS, Marette A, Mitsumoto Y, et al: Insulin induces translocation of the alpha 2 and beta 1 subunits of the Na+/K(+)-ATPase from intracellular compartments to the plasma membrane in mammalian skeletal muscle. J Biol Chem 267(8):5040–5043, 1992. 22. Omatsu-Kanbe M, Kitasato H: Insulin stimulates the translocation of Na+/ K(+)-dependent ATPase molecules from intracellular stores to the plasma membrane in frog skeletal muscle. Biochem J 272(3):727–733, 1990. 23. Marette A, Krischer J, Lavoie L, et al: Insulin increases the Na(+)-K(+)-ATPase alpha 2-subunit in the surface of rat skeletal muscle: morphological evidence. Am J Physiol 265(6 Pt 1):C1716–C1722, 1993. 24. Kanbe M, Kitasato H: Stimulation of Na,K-ATPase activity of frog skeletal muscle by insulin. Biochem Biophys Res Commun 134(2):609–616, 1986. 25. Lytton J: Insulin affects the sodium affinity of the rat adipocyte (Na+,K+)ATPase. J Biol Chem 260(18):10075–10080, 1985. 26. Sargeant RJ, Liu Z, Klip A: Action of insulin on Na(+)-K(+)-ATPase and the Na(+)-K(+)-2Cl- cotransporter in 3T3-L1 adipocytes. Am J Physiol 269(1 Pt 1):C217–C225, 1995. 27. Sweeney G, Klip A: Regulation of the Na+/K+-ATPase by insulin: why and how? Mol Cell Biochem 182(1–2):121–133, 1998. 28. Feraille E, Carranza ML, Rousselot M, Favre H: Insulin enhances sodium sensitivity of Na-K-ATPase in isolated rat proximal convoluted tubule. Am J Physiol 267(1 Pt 2):F55–F62, 1994. 29. Dluhy RG, Axelrod L, Williams GH: Serum immunoreactive insulin and growth hormone response to potassium infusion in normal man. J Appl Physiol 33(1):22–26, 1972. 30. DeFronzo RA, Bia M, Birkhead G: Epinephrine and potassium homeostasis. Kidney Int 20(1):83–91, 1981. 31. Williams ME, Gervino EV, Rosa RM, et al: Catecholamine modulation of rapid potassium shifts during exercise. N Engl J Med 312(13):823–827, 1985. 32. Rosa RM, Silva P, Young JB, et al: Adrenergic modulation of extrarenal potassium disposal. N Engl J Med 302(8):431–434, 1980.

33. Angelopoulous M, Leitz H, Lambert G, MacGilvray S: In vitro analysis of the Na(+)-K+ ATPase activity in neonatal and adult red blood cells. Biol Neonate 69(3):140–145, 1996. 34. Gillzan KM, Stewart AG: The role of potassium channels in the inhibitory effects of beta 2-adrenoceptor agonists on DNA synthesis in human cultured airway smooth muscle. Pulm Pharmacol Ther 110(2):71–79, 1997. 35. Clausen T, Flatman JA: The effect of catecholamines on Na-K transport and membrane potential in rat soleus muscle. J Physiol 270(2):383–414, 1977. 36. Mandelberg A, Krupnik Z, Houri S, et al: Salbutamol metered-dose inhaler with spacer for hyperkalemia: how fast? How safe? Chest 115(3):617–622, 1999. 37. Singh BS, Sadiq HF, Noguchi A, Keenan WJ: Efficacy of albuterol inhalation in treatment of hyperkalemia in premature neonates. J Pediatr 141(1):16–20, 2002. 38. Helfrich E, de Vries TW, van Roon EN: Salbutamol for hyperkalaemia in children. Acta Paediatr 90(11):1213–1216, 2001. 39. Semmekrot BA, Monnens LA: A warning for the treatment of hyperkalaemia with salbutamol. Eur J Pediatr 156(5):420, 1997. 40. Shortland D, Trounce JQ, Levene MI: Hyperkalaemia, cardiac arrhythmias, and cerebral lesions in high risk neonates. Arch Dis Child 62(11):1139–1143, 1987. 41. Yeh TF, Raval D, John E, Pildes RS: Renal response to frusemide in preterm infants with respiratory distress syndrome during the first three postnatal days. Arch Dis Child 60(7):621–626, 1985. 42. Lui K, Thungappa U, Nair A, John E: Treatment with hypertonic dextrose and insulin in severe hyperkalaemia of immature infants. Acta Paediatr 81(3):213–216, 1992. 43. Papile LA, Burstein J, Burstein R, et al: Relationship of intravenous sodium bicarbonate infusions and cerebral intraventricular hemorrhage. J Pediatr 93(5):834–836, 1978. 44. Bennett LN, Myers TF, Lambert GH: Cecal perforation associated with sodium polystyrene sulfonate-sorbitol enemas in a 650 gram infant with hyperkalemia. Am J Peninatol 13(3):167–170, 1996. 45. Malone TA: Glucose and insulin versus cation-exchange resin for the treatment of hyperkalemia in very low birth weight infants. J Pediatr 118(1):121– 123, 1991. 46. Adrogue HJ, Madias NE: Changes in plasma potassium concentration during acute acid-base disturbances. Am J Med 71(3):456–467, 1981. 47. Fulop M: Serum potassium in lactic acidosis and ketoacidosis. N Engl J Med 300(19):1087–1089, 1979. 48. Graber M: A model of the hyperkalemia produced by metabolic acidosis. Am J Kidney Dis 22(3):436–444, 1993. 49. Rabinowitz L: Aldosterone and potassium homeostasis. Kidney Int 49(6): 1738–1742, 1996. 50. Giebisch G: Renal potassium transport: mechanisms and regulation. Am J Physiol 274(5 Pt 2):F817–F833, 1998. 51. Tudvad F, McNamara H, Barnett HL: Renal response of premature infants to administration of bicarbonate and potassium. Pediatrics 13(1):4–16, 1954. 52. Lorenz JM, Kleinman LI, Disney TA: Renal response of newborn dog to potassium loading. Am J Physiol 251(3 Pt 2):F513–F519, 1986. 53. McCance RA, Widdowson EM: The response of the new-born piglet to an excess of potassium. J Physiol 141(1):88–96, 1958. 54. Kleinman LI, Banks RO: Segmental nephron sodium and potassium reabsorption in newborn and adult dogs during saline expansion. Proc Soc Exp Biol Med 173(2):231–237, 1983. 55. Lelievre-Pegorier M, Merlet-Benichou C, Roinel N, de Rouffignac C: Developmental pattern of water and electrolyte transport in rat superficial nephrons. Am J Physiol 245(1):F15–F21, 1983. 56. Malnic G, Klose RM, Giebisch G: Microperfusion study of distal tubular potassium and sodium transfer in rat kidney. Am J Physiol 211(3):548–559, 1966. 57. Malnic G, Klose RM, Giebisch G: Micropuncture study of distal tubular potassium and sodium transport in rat nephron. Am J Physiol 211(3):529–547, 1966. 58. Solomon S: Absolute rates of sodium and potassium reabsorption by proximal tubule of immature rats. Biol Neonate 25(5–6):340–351, 1974. 59. Schmidt U, Horster M: Na-K-activated ATPase: activity maturation in rabbit nephron segments dissected in vitro. Am J Physiol 233(1):F55–F60, 1977. 60. Zink H, Horster M: Maturation of diluting capacity in loop of Henle of rat superficial nephrons. Am J Physiol 233(6):F519–F524, 1977. 61. Hebert SC: An ATP-regulated, inwardly rectifying potassium channel from rat kidney (ROMK). Kidney Int 48(4):1010–1016, 1995. 62. Zhou H, Tate SS, Palmer LG: Primary structure and functional properties of an epithelial K channel. Am J Physiol 266(3 Pt 1):C809–C824, 1994. 63. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. International Collaborative Study Group for Bartter-like Syndromes. Hum Mol Genet 6(1):17–26, 1997. 64. Simon DB, Lifton RP: The molecular basis of inherited hypokalemic alkalosis: Bartter’s and Gitelman’s syndromes. Am J Physiol 271(5 Pt 2):F961–F966, 1996. 65. Woda CB, Bragin A, Kleyman TR, Satlin LM: Flow-dependent K+ secretion in the cortical collecting duct is mediated by a maxi-K channel. Am J Physiol Renal Physiol 280(5):F786–F793, 2001. 66. Satlin LM: Postnatal maturation of potassium transport in rabbit cortical collecting duct. Am J Physiol 266(1 Pt 2):F57–F65, 1994.

1024.e2 SECTION XVI — The Kidney 67. Constantinescu AR, Lane JC, Mak J, et al: Na(+)-K(+)-ATPase-mediated basolateral rubidium uptake in the maturing rabbit cortical collecting duct. Am J Physiol 279(6):F1161–F1168, 2000. 68. Satlin LM, Evan AP, Gattone VH, III, Schwartz GJ: Postnatal maturation of the rabbit cortical collecting duct. Pediatr Nephrol 2(1):135–145, 1988. 69. Satlin LM, Palmer LG: Apical K+ conductance in maturing rabbit principal cell. Am J Physiol 272(3 Pt 2):F397–F404, 1997. 70. Benchimol C, Zavilowitz B, Satlin LM: Developmental expression of ROMK mRNA in rabbit cortical collecting duct. Pediatr Res 47(1):46–52, 2000. 71. Zolotnitskaya A, Satlin LM: Developmental expression of ROMK in rat kidney. Am J Physiol 276(6 Pt 2):F825–F836, 1999. 72. Woda CB, Miyawaki N, Ramalakshmi S, et al: Ontogeny of flow-stimulated potassium secretion in rabbit cortical collecting duct: functional and molecular aspects. Am J Physiol Renal Physiol 285(4):F629–F639, 2003. 73. 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Chapter 105 — Potassium Homeostasis in the Fetus and Neonate 1024.e3

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