Pediatr Nephrol (2007) 22:915–925 DOI 10.1007/s00467-007-0432-3

REVIEW

Potassium transport in the maturing kidney Sevgi Gurkan & Genevieve K. Estilo & Yuan Wei & Lisa M. Satlin

Received: 16 November 2006 / Revised: 12 December 2006 / Accepted: 15 December 2006 / Published online: 2 March 2007 # IPNA 2007

Abstract The distal nephron and colon are the primary sites of regulation of potassium (K+) homeostasis, responsible for maintaining a zero balance in adults and net positive balance in growing infants and children. Distal nephron segments can either secrete or reabsorb K+ depending on the metabolic needs of the organism. In the healthy adult kidney, K+ secretion predominates over K+ absorption. Baseline K+ secretion occurs via the apical low-conductance secretory K+ (SK) channel, whereas the maxi-K channel mediates flow-stimulated net urinary K+ secretion. The K+ retention characteristic of the neonatal kidney appears to be due not only to the absence of apical secretory K+ channels in the distal nephron but also to a predominance of apical H-K-adenosine triphosphatase (ATPase), which presumably mediates K+ absorption. Both luminal and peritubular factors regulate the balance between K+ secretion and absorption. Perturbation in any of these factors can lead to K+ imbalance. In turn, these factors may serve as effective targets for the treatment of both hyper-and hypokalemia. The purpose of this review is to present an overview of recent advances in our understanding of mechanisms of K+ transport in the maturing kidney. Sevgi Gurkan and Genevieve K. Estilo contributed equally to this paper. S. Gurkan : Y. Wei : L. M. Satlin (*) Department of Pediatrics, Division of Nephrology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1664, New York, NY 10029, USA e-mail: [email protected] G. K. Estilo : L. M. Satlin Department of Internal Medicine, Division of Renal Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1664, New York, NY 10029, USA

Keywords Collecting duct . Maxi-K channel . ROMK channel . H-K-ATPase . Protein kinases

Potassium (K+) homeostasis Potassium (K+) is the most abundant intracellular cation. Approximately 98% of the total body K+ content in the adult is located within cells, where its concentration ranges from 100–150 mEq/l; the remaining 2% resides in the extracellular fluid. Maintenance of an intracellular K+ concentration within the normal range is essential for a variety of cellular functions, including cell growth and division, DNA and protein synthesis, and enzymatic functions [1, 2]. Extracellular K+ concentration, generally ranging from 3.5–5.0 mEq/l, is tightly regulated by mechanisms that control the distribution between the intra-and extra-cellular compartments. Total-body K+ content depends on the balance between intake and output, the latter regulated primarily by renal and, to a lesser extent, fecal excretion. The homeostatic goal of the adult is to remain in zero K+ balance. Thus, in the healthy adult, K+ excretion matches dietary intake, with ∼90% of the daily K+ intake (usually 1 mEq/kg) eliminated by the kidneys and the residual 10% lost through the stool [3]. In contrast to adults, growing infants and children typically maintain a state of positive K+ balance [4, 5]. Total-body K+ increases from approximately 8 mEq/cm body height at birth to >14 mEq/cm body height by 18 years of age [6, 7]. The rate of accumulation of body K+ per kilogram body weight in the infant is more rapid than in the older child and adolescent, correlating with the increase in cell number with advancing age [6, 8, 9]. The notion that the growing subject is a “sink” for K+ was clearly

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demonstrated in a study in which plasma K+ concentrations were compared in newborn piglets that were given equivalent K+ loads (25 mEq/kg per day) in either water or milk for the first 40 h of life. K+-loaded animals provided water alone lost weight and experienced lifethreatening hyperkalemia and paralysis, whereas animals fed an equivalent amount of K+ in milk grew well and remained normokalemic [10].

Sites of K+ transport along the nephron Most of our basic understanding about renal K+ handling derives from in vivo micropuncture and in vitro microperfusion studies performed in mature animals. The few parallel studies that have been performed during early life reveal that the developing kidney is uniquely adapted to meet the demands of the growing organism. K+ handling by the adult kidney involves three processes: filtration, reabsorption, and secretion [3, 11] (Fig. 1). Reabsorption of filtered K+ occurs predominantly in the proximal segments of the nephron, whereas secretion occurs in the distal segments, specifically in the late part of the distal convoluted tubule (DCT), connecting tubule [(CNT); the segment of the nephron located between the DCT and the cortical collecting duct (CCD)] and the CCD.

Fig. 1 Model of the mammalian nephron identifying the segments and cells that mediate significant transport of potassium (K+) out of (absorption) or into (secretion) the tubular lumen. Only the major K+ transport pathways are shown. See text for details. L lumen, B basolateral side of the cell membrane

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Proximal tubule K+ is freely filtered at the glomerulus. Thus, the concentration of K+ entering the proximal convoluted tubule (PCT) is similar to that of plasma. Micropuncture studies in suckling (13–15 days old) and adult rats indicate that approximately 50–60% of the filtered load of K+ is reabsorbed along the initial two thirds of the proximal tubule [12–14]. Reabsorption of K+ along this segment closely follows that of sodium (Na+) and water [15] (Fig. 1). Most K+ reabsorption in the PCT is passive and occurs by solvent drag via the paracellular pathway [16, 17]. The positive transepithelial voltage of the late proximal tubule provides a favorable driving force for diffusion of K+ out of the lumen [18]. A number of apical K channels have been identified in the proximal tubule, including KCNE1 and KCNQ1, which are believed to form a K-channel complex [19], and the cyclic, nucleotide-gated, voltage-activated, K channel KCNA10 [20]. K+ movement from the cell to the lumen through these channels is thought to contribute to the maintenance of the electrical driving force for Na+-coupled transport (glucose and amino acids) in the proximal tubule. KCNE1 knockout mice exhibit increased renal excretion of Na+ and glucose and signs of volume depletion [19].

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Thick ascending limb of the loop of Henle (TALH) In the adult, 5–15% of the filtered load of K+ reaches the early distal tubule, indicating that significant K+ reabsorption occurs beyond the end of the proximal tubule [3, 12, 13]. The thick ascending limb of the loop of Henle (TALH) is an avid site of K+ reabsorption. Within this segment, K+ reabsorption is mediated, at least in part, by the apical bumetanide-sensitive Na-K-2-chloride (Cl) cotransporter (NKCC2) (Fig. 1). Activity of this transporter is ultimately driven by the low intracellular Na+ concentration, established by the basolateral Na-K-adenosine triphosphatase (ATPase), which drives Na+ entry from the lumen into the cell. An apical low-conductance secretory K+ (SK) channel is considered to play a critical role in K+ secretion in the TALH, where it provides a pathway for K+, taken up into the cell via the Na-K-2Cl cotransporter, to recycle back into the lumen and thus sustain activity of the apical cotransporter (Fig. 1). K+ secretion creates a lumen-positive transepithelial potential difference, which in turn provides an electrical driving force for paracellular K+ as well as Ca2+ and magnesium (Mg2+) reabsorption. The observation that heterologous expression of renal outer medulla potassium (ROMK) channel, originally cloned from the TALH in the rat outer medulla, generates a channel with biophysical and regulatory properties similar to those of the SK channel [21–23] has led to the notion that ROMK represents a major functional subunit of the SK channel. Loss-of-function mutations in ROMK lead to antenatal Bartter syndrome, which is characterized by severe renal salt and fluid wasting and electrolyte abnormalities, including hypokalemia, hypomagnesemia, and hypercalciuria [24]. Typically, such patients are born prematurely, with complications that may include polyhydramnios and severe dehydration early in life. Other clinical manifestations include profound growth failure, hypercalciuria, and early onset of nephrocalcinosis. In vitro microperfusion and morphologic studies of TALH in hamsters have confirmed the existence of two cell populations: a smooth-surface cell characterized by a high basolateral and low apical membrane K+ conductance (HBC) and a rough-surface cell exhibiting a low basolateral and high apical K+ conductance (LBC). HBC are more prevalent in the medulla, whereas LBC predominate in the cortex [25]. Based on the results of measurements of net transepithelial K+ fluxes in these two segments, it is believed that the HBC reabsorbs K+, whereas the LBC secretes K+ [25]. The physiological significance of these findings remains to be elucidated. In contrast to the situation in the adult, up to 35% of the filtered load of K+ in the newborn rat reaches the early distal tubule [14], reflecting the postnatal maturation of

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segments beyond the proximal tubule. Indeed, cumulative evidence suggests that the TALH undergoes a significant postnatal increase in its capacity for K+ and Na+ reabsorption. Expression of NKCC2 messenger ribonucleic acid (mRNA) is absent in whole kidney until postnatal day 8 in the rat, coincident with completion of nephrogenesis [26]. Expression of NKCC2 mRNA in medulla increases between postnatal days 10 and 40 in this same species [27]. Na-K-ATPase activity in the neonatal rabbit TALH is only 20% of that measured in the mature nephron when expressed per unit of dry weight [28]. The increase in pump activity is associated with a postnatal increase in expression of medullary Na-K-ATPase mRNA [27]. Monoclonal antibodies directed against Na-K-ATPase applied to cryosections of the neonatal rabbit kidney revealed basolateral expression along the corticomedullary collecting ducts, apical and basolateral localization in the CCDs adjacent to the ampullae, and absence of labeling in the ampulla [29]. The observation that the osmolarity of early distal fluid is significantly lower in 12- to 15-day-old rats compared with 27- to 35-day-old rats provides additional evidence for functional immaturity of the diluting capacity of the TALH [30]. Although the preponderance of evidence, summarized above, is consistent with functional immaturity of the TALH, it should be noted that newborn and adult lambs show similar natriuretic responses to furosemide [31].

Distal nephron The late DCT, CNT, and CCD are considered to be the primary sites of K+ secretion in the fully differentiated kidney, contributing largely to urinary K+ excretion, which in the adult can approach 20% of the filtered load [12, 13, 32–35]. Micropuncture studies reveal that the true DCT secretes a constant small amount of K+ into the urinary fluid [36]. The capacity of the CNT and CCD, segments not accessible to micropuncture, for net K secretion has been assessed by in vitro microperfusion of isolated segments. Although neonates—as with adults—can excrete K+ at a rate that exceeds its filtration, reflecting the capacity for net tubular secretion, they are unable to excrete a K+ load as efficiently as are adults [11, 37]. Comparison of the fractional delivery of K+ to the early distal tubule with that present in the final urine reveals that the distal nephron of the young (13–15 days old) rat secretes approximately five-fold less K+ than the older rat (30–39 days old) [14]. Within the CNT and CCD are two distinct cell types, CNT/principal cells and intercalated cells, which differ in morphology and function. In general, CNT/principal cells [3, 38] function to reabsorb Na+ and

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secrete K+, whereas intercalated cells regulate acid-base balance and reabsorb K+ in response to dietary K+ restriction or metabolic acidosis [39, 40] (Fig. 1). Thus, the direction and magnitude of net K+ transport in these segments depend on the balance of K+ secretion and absorption, processes mediated by CNT/principal and intercalated cells, respectively.

K+ secretion The traditional model by which K+ secretion occurs in the CNT and CCD is summarized in Fig. 1. Na+ passively diffuses into the CNT/principal cell from the urinary fluid through the luminal amiloride-sensitive epithelial Na channel (ENaC) and is then transported out of the cell at the basolateral membrane in exchange for K+ via the basolateral Na-K-ATPase. The resulting high intracellular K+ concentration and lumen-negative voltage creates a favorable electrochemical gradient for intracellular K+ to diffuse into the urinary space through apical K+-selective channels [3]. Basolateral K+ channels in these same cells provide a route for intracellular K+ ions to recycle back into the interstitium, thereby maintaining the efficiency of the Na-K pump [3, 41]. Any factor that increases the electrochemical gradient across the apical membrane or increases the apical K+ permeability will promote K+ secretion. It should be noted that an apical electroneutral K+-Cl- cotransporter has also been functionally identified in the CCD [42, 43]. Patch-clamp analysis of the rat and rabbit CNT and CCD has identified two functional apical K+ channels [3, 44–50]. The density of these channels appears to be greater in the CNT than in the CCD [47]. The low-conductance SK channel, restricted to the CNT/principal cell, has a high open probability (Po ) at the resting membrane potential and is thought to mediate baseline K+ secretion [3, 44–48]. As indicated above, ROMK is considered to be a major functional subunit of the SK channel [21–23]. Conversely, the high-conductance maxi-K channel, present in CNT/ principal and intercalated cells of the distal nephron as well as the proximal tubule and TALH, is rarely open at the physiologic resting membrane potential [49–57]. This channel is activated by cell depolarization, membrane stretch, and increases in intracellular Ca2+ concentration ([Ca2+]i), and is inhibited by the scorpion venom toxin, iberiotoxin [56–61]. In the CNT and CCD, conducting maxi-K channels are more readily identified in intercalated than CNT/principal cells [47, 57]. Recent studies suggest that the maxi-K channel mediates flow-stimulated K+ secretion and is activated by flow-induced increases in [Ca2+]i [62, 63].

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SK/ROMK channel Regulation of the SK/ROMK channel has been extensively studied in mammalian renal epithelial cells. Channel activity is regulated by a variety of hormones and other factors, acting individually or in concert with each other, which primarily determine the density of active SK/ROMK channels resident on the apical membrane. While a number of excellent reviews focus on the regulation of the SK/ ROMK channel by factors such as adenosine triphosphate (ATP), intracellular pH (pHi), and arachidonic acid [3, 64], emerging evidence underscores the important role of protein kinases including cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA), protein kinase C (PKC), serum-glucocorticoid-regulated kinase (Sgk-1), and with-no-lysine-kinases (WNKs) in the regulation of this channel. PKA-induced phosphorylation is essential for SK/ ROMK-channel activity [65–67] and may account for the well-documented stimulatory effect of vasopressin on renal K+ secretion [68]. The channel is also maintained in open state via direct interaction with the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) [69]. In the face of PIP2 depletion from the membrane, as follows PKC activation, channel activity falls [70]. PKC also inhibits the channel by a phosphorylation mechanism that differs from that of PKA [71]. Protein tyrosine kinase (PTK) mediates the endocytosis of ROMK channels in the rat CCD under conditions of dietary K+ restriction [72, 73]. Tyrosine phosphorylation of ROMK enhances channel internalization via a dynamic process involving clathrin-coated pits [74]. The reduction in number of apical channels leads to a fall in K+ secretion. Tyrosine phosphorylation of ROMK channels decreases with high dietary K+ [75]. WNKs comprise a recently discovered family of serine/ threonine kinases that regulate ROMK-channel activity [76, 77]. WNK4 inhibits Na+ absorption in the DCT by reducing the surface expression of the apical thiazidesensitive NaCl cotransporter [78], an effect that would be expected to increase Na delivery to the CCD, enhance Na absorption, and augment the driving force for K+ secretion. However, oocyte expression studies indicate that WNK4 decreases surface expression of ROMK by enhancing clathrin-dependent endocytosis [79]. Thus, the effect of an enhanced electrochemical gradient on stimulation of net K+ secretion would not be obvious. Mutations in WNK1 or WNK4 lead to pseudohypoaldosteronism type II (PHA II; Gordon’s syndrome), an autosomal dominant disorder characterized by hypertension sensitive to thiazide diuretics, hyperkalemia, and metabolic acidosis [80]. As predicted, loss-of-function mutations in WNK4 lead to increased apical expression of the NaCl

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cotransporter and stimulation of Na+ absorption in the DCT [77, 78]. The consequent reduction in Na+ delivery to the CNT and CCD would be expected to reduce K+ secretion. However, the same mutations in WNK4 that relieve the inhibition of the NaCl cotransporter further decrease surface expression of ROMK, reduce K+ secretion in the CCD, and likely are the cause of hyperkalemia in patients with Gordon’s syndrome [79]. WNK1 suppresses the activity of WNK4. Therefore, a gain-in-function mutation in WNK1 will also produce the clinical signs and symptoms of PHA II [80].

Maxi-K channel The maxi-K channel exists as a multimeric complex comprised of two subunits: a pore-forming α subunit, a member of the slo family of K+ channels that was originally cloned from Drosophila melanogaster, and a regulatory β subunit [81–84]. Alternative splicing generates variants distinguishable by their responses to changes in Ca2+, voltage, and hormones as well as differences in localization and interactions with proteins [85]. In Xenopus oocytes, the β subunit does not carry current when studied by patch clamp alone. However, coexpression of the β with the α subunit enhances the channel sensitivity to Ca2+, voltage, and inhibitors [81–84]. Two isoforms of the α subunit, Rbslo, exist in rabbit [51, 52]. Rbslo1 is expressed in the apical membrane, whereas Rbslo2 is expressed intracellularly [51, 52]. Four maxi-K channel subunits, β1–β4, have been identified in the mammalian kidney [86–89]. Whereas immunodetectable β1 subunit is present in the CNT [88], this subunit appears to be absent in the CCD, which expresses messageencoding β2, β3, and β4 subunits [89]. Of note is that the fractional excretion of K+ in maxi-K β1-/- mice subjected to acute volume expansion was significantly lower than that in wild-type mice [90]. This observation suggests a role for the maxi-K β1 subunit in flowstimulated K+ secretion. The role of the maxi-K channel appears to assume great importance in regulating K+ homeostasis under conditions where SK channel-mediated K+ secretion is limited. Although infants with antenatal Bartter syndrome due to loss-of-function mutations in ROMK may exhibit severe hyperkalemia during the first few days of life [91], as would be expected in the absence of a primary K+ secretory channel, the hyperkalemia is not sustained [92, 93]. In fact, these patients typically exhibit modest hypokalemia beyond the neonatal period [92, 93]. On a similar note, adult ROMK knockout mice are not hyperkalemic but lose urinary K+ [94]. This rodent model of Bartter syndrome exhibits significant iberiotoxin-sensitive K+ secretion [94],

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presumably reflecting the effect of high distal flow rates on activating maxi-K channels.

K+ absorption As mentioned above, the direction and magnitude of net K+ transport in the distal nephron depend on the balance of K+ secretion and absorption mediated by principal and intercalated cells, respectively. Intercalated cells account for approximately 30% of the cells in the fully differentiated CCD and are primarily responsible for transepithelial hydrogen (H+) and HCO3 transport [11, 39, 40]. Two major subtypes of intercalated cells have been identified (Fig. 1): α cells possess apical vacuolar H+ pumps and secrete H+, whereas β cells possess apical Cl-/HCO3 exchangers and secrete HCO3 . Intercalated cells can also reabsorb K+ under conditions of K+ depletion and metabolic acidosis via an apical H-K-ATPase that couples K+ reabsorption to H+ secretion [39, 95–101]. Functional and molecular studies identify two isoforms of the H-K-ATPase in the kidney that share similar features with gastric (HKAg) and colonic (HKAc) H-K-ATPases [95]. HKAg is found in gastric parietal cells and is responsible for acid secretion into the lumen, whereas HKAc is a structurally related H-K-ATPase found in the distal colon that mediates active K+ reabsorption [95]. A gastric-like H-K-ATPase is located at the apical membrane of the rat and rabbit intercalated cell [95, 96, 99, 100]. Expression of this protein is increased in response to dietary K+ restriction and metabolic acidosis [39, 95–99].

Developmental aspects CCDs isolated from newborn rabbits and studied by in vitro microperfusion show no net K+ secretion until after the third week of postnatal life; net K+ secretory rates increase to adult levels by 6 weeks of age [33] (Fig. 2). Consistent with the relatively undifferentiated state of the newborn CCD are the ultrastructural and morphometric findings in neonatal principal cells of few organelles, mitochondria and basolateral infoldings, the site of Na-K-ATPase [102, 103]. The limited capacity of the CCD for K+ secretion early in life could be explained by either an unfavorable electrochemical gradient across the apical membrane and/ or limited apical permeability to this ion. The electrochemical gradient is not considered to be limiting for K+ secretion, as at 2 weeks of age, the rate of net Na+ absorption in the CCD is approximately 60% of that measured in the adult [33] (Fig. 2). Additionally, intracellular K+ concentration in this secretory epithelium at birth is comparable to that measured in the adult despite Na-KATPase activity that is only 50% of that measured in adult

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Fig. 2 Effect of luminal flow rate on a net sodium (Na+) absorption and b net potassium (K+) secretion in isolated microperfused cortical collecting ducts (CCDs) isolated from 2-, 4-, 5- and ≥ 6-week-old New Zealand White rabbits. Weaning occurs at 4 weeks in this species. An increase in luminal flow rate leads to an increase in net Na+ absorption in

all age groups. CCDs from 2-week-old animals fail to secrete K+ at any flow rate. By 4 weeks of age, baseline K+ secretion was apparent but was not augmented by an increase in flow rate. Flow-stimulated net K+ secretion first appeared at 5 weeks and increased significantly by 6 weeks of age. Adapted from [33, 58, 110, 111]

[28, 104]. The capacity for the neonatal cell to maintain a mature intracellular K+ concentration in the face of limited basolateral-pump activity is consistent with a scarcity of apical membrane K+ channels early in life [46]. Patchclamp studies of the apical membrane of CCDs isolated from maturing rabbits showed that the mean number of open channels per patch (NPo) increased progressively after birth [46]. Cumulative evidence suggests that the maturational increase in the basal CCD K+ secretory capacity is due to an increase in rates of transcription and/or translation of SK/ROMK-channel proteins [105, 106]. The appearance of flow-stimulated net K+ secretion is a relatively late developmental event (Fig. 2). Flow-stimulated K+ secretion cannot be elicited in isolated microperfused rabbit CCDs until the fifth week of postnatal life, which is approximately 2 weeks after baseline K+ secretion is first detected [33, 58]. The absence of flow-stimulated K+ secretion early in life is not due to a limited flow-induced rise in net Na+ absorption and/or [Ca2+]i, each of which is equivalent to that detected in the adult by the second week of postnatal life [58]. The observation that message encoding of the maxi-K channel α-subunit and immunodetectable channel protein cannot be demonstrated until the fourth and fifth weeks of postnatal life, respectively [58], suggests that flow-dependent K+ secretion is determined by the transcriptional/translational regulation of expression of maxi-K channels. H-K-ATPase activity, assessed as apical K+-dependent extrusion of an intracellular acid load, is similar in CCDs isolated from newborn and adult rabbits [39]. These findings alone do not predict that the reabsorptive K+ flux in the newborn CCD is greater than that in the adult. Although indirect evidence suggests that neonatal distal nephron absorbs K+ [107], the presence and activity of apical and basolateral K+ conductances and the K+ concentration of the tubular fluid delivered to this site are critical in predicting the

magnitude of the H-K-ATPase-mediated K+ absorption [101]. Of note is that the infant rat colon has a significantly higher net colonic K+ uptake than the adult, mainly through a higher activity of the apical K-ATPase [108].

Luminal and peritubular factors affecting K+ transport Na+ delivery and absorption Within the distal nephron, the magnitude of Na+ absorption determines the electrochemical driving force for K+ secretion into the luminal fluid. Processes that promote distal Na+ delivery and increase tubular fluid flow rate, such as extracellular volume expansion or administration of diuretics, cause a simultaneous increase in urinary excretion of Na+ and K+. The K+-sparing diuretics amiloride and triamterene block Na+ absorption via inhibition of ENaC, thereby diminishing the electrochemical gradient favoring K+ secretion. The frequently prescribed drugs trimethoprim-sulfamethoxazole and pentamidine can also limit urinary K+ secretion via the same mechanism. A reduction in luminal Na+ concentrations to less than 30 mM substantially reduces K+ secretion in the isolated perfused rabbit CCD [109]. Na+ delivery to the distal nephron is generally accompanied by Cl-, which traverses the epithelial cell predominantly via the paracellular route. Movement of the negative charge out of the lumen dissipates the lumen negative potential, creating a less favorable driving force for luminal K+ secretion. Under conditions where Na+ is delivered to the distal nephron with a less reabsorbable anion than Cl-, such as HCO3 in proximal renal tubular acidosis and ketoacids in diabetic ketoacidosis, luminal electronegativity is maintained, stimulating K+ secretion into the luminal fluid.

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Tubular fluid flow rate An increase in tubular fluid flow, as elicited by extracellular fluid volume expansion or administration of diuretics, is a potent stimulus for K+ secretion in the distal nephron (Fig. 2). An increase in tubular flow rate in the microperfused rabbit CCD is associated with an increase in net Na+ absorption [110] (Fig. 2) mediated by an increase in ENaC Po [111]; these events are expected to enhance the electrochemical gradient favoring K+ secretion. Increases in luminal flow rate transduce mechanical signals (circumferential stretch, shear stress, hydrodynamic bending moments on the cilium decorating the apical surface of virtually all renal epithelial cells) into biochemical responses, including an increase in [Ca2+]i, which in turn activate apical maxi-K channels [63, 112].

K+ intake Renal K+ secretion responds promptly to changes in dietary K+ intake; an increase in K+ intake stimulates whereas a decrease in K+ intake reduces K+ secretion [75, 89]. Within 6 h of an increase in dietary K+ intake, the density of apical SK/ROMK channels increases in rats [113]. This response is believed to be mediated by activation of a previously “silent” pool of channels or closely associated proteins, because ROMK mRNA abundance is not altered by the change in dietary intake of K+ [113]. Chronic K+ loading also leads to an increase in maxi-K channel message, apical immunodetectable protein, and function in the distal nephron [89]. A reduction in K+ intake leads to a fall in urinary K+ excretion and K+ secretion by the distal nephron within 5– 7 days in the rat [114]. This adaptation is associated with a decrease in the number of apical SK/ROMK [115] and maxi-K channels [89] and stimulation of H-K-ATPasemediated K+ reabsorption in intercalated cells in the distal nephron [116]. The reduction in number of SK/ROMK channels in K+- restricted animals is presumably mediated by the effect of dietary K+ on circulating levels of aldosterone and other effectors, such as PTK [72, 73, 75, 117].

Acid-base balance Secretion of K+ into the tubular lumen is affected by changes in acid-base homeostasis. In acute metabolic acidosis, the movement of H+ ions into the cells from the extracellular space is concomitantly associated with the movement of K+ out of the cells, causing hyperkalemia. Acidemia results in a reduction in urine pH, which inhibits activity of the SK/ROMK channel [3, 48, 118] and leads to an overall reduction in K+ excretion [119]. The effect of

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chronic metabolic acidosis on K+ excretion is dependent on various factors, including the concentrations of Cl- and HCO3 in the filtrate, tubular fluid flow rate, and aldosterone. Conversely, in acute metabolic and respiratory alkalosis, there is an increase in urine pH and K+ excretion for reasons opposite to those described above.

Mineralocorticoids It is well established that aldosterone stimulates K+ secretion in the distal nephron [3, 34, 120]. This response is due, in part, to the mineralocorticoid-induced stimulation of ENaC and Na-K-ATPase activity, which enhances the electrochemical gradient favoring K+ secretion [44, 121, 122]. Circulating mineralocorticoids bind to their cytosolic receptors in the distal nephron. The hormone-receptor complex translocates to the nucleus where it promotes the transcription of genes specific for physiologically active proteins. Among the cellular and molecular effects of an increase in circulating levels of aldosterone are increases in density of epithelial Na+ channels, achieved by the recruitment of intracellular channels to the apical membrane, de novo synthesis of new ENaC subunits, and activation of preexisting channels, as well as stimulation of Na-K-ATPase activity by translocation of preformed transporters to the membrane and translation of new Na+ pump subunits [121, 122]. Aldosterone rapidly induces serum and glucocorticoidinducible kinase 1 (Sgk1) in the distal nephron [123]. Sgk stimulates Na+ reabsorption, in part by inhibiting retrieval of ENaCs from the luminal membrane [124]. Although Sgk may stimulate SK/ROMK-channel activity by enhancing the cell-surface expression of this channel when expressed in Xenopus oocytes [125], Sgk1-deficient mice exhibit greater apical ROMK abundance in the aldosteronesensitive distal nephron in response to K+ loading compared with that observed in control animals [126]. This observation suggests that the in vivo effect of Sgk1 on K+ excretion is indirect and may be mediated by the effect of the kinase on ENaC and/or Na-K-ATPase activity. Premature infants and newborns have higher plasma aldosterone concentrations compared with adults [5, 127]. Although the density of aldosterone binding sites, receptor affinity, and degree of nuclear binding of hormone receptors appear to be similar in mature and immature rats, clearance studies in fetal and newborn animals demonstrate a relative insensitivity of the immature kidney to aldosterone [5, 128, 129]. This relative hyporesponsiveness is also demonstrated by the observation that the urinary Na+ to K+ ratio in the newborn typically exceeds 1, despite the fact that both breast milk and commercially available formulas provide Na+ to K+ in a ratio of 0.5 to 0.6 [4].

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Conclusions The distal nephron is a primary regulator of K+ homeostasis, responsible for maintaining a zero balance in adults and net positive balance in growing infants and children. Distal nephron segments can either secrete or reabsorb K+ depending on the metabolic needs of the organism. In the healthy adult kidney, K+ secretion predominates over K+ absorption. Baseline K+ secretion in the distal nephron occurs via the SK/ROMK channel, whereas the maxi-K channel mediates flow-stimulated net urinary K+ secretion. The K+ retention characteristic of the neonatal kidney appears to be due not only to the absence of apical secretory K+ channels in the distal nephron but also to a relative predominance of apical H-K-ATPase, which presumably mediates K+ absorption. The limited K+ secretory capacity of the neonatal distal nephron has been proposed to contribute to the nonoliguric hyperkalemia observed in up to 50% of very-low-birthweight infants [130–132]. Both luminal and peritubular factors regulate the balance between K+ secretion and absorption. Perturbation in any of these factors can lead to K+ imbalance. In turn, these factors may serve as effective targets for the treatment of both hyper-and hypokalemia. Acknowledgements The authors thank Andrew J. Tschesnok for his contribution to Fig. 1. This work was supported by National Institutes of Health grants DK038470 and DK051391 (LMS) and an American Heart Association Scientist Development Grant (YW).

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