Pediatr Nephrol (2017) 32:2037–2049
DOI 10.1007/s00467-017-3635-2
EDUCATIONAL REVIEW
Potassium regulation in the neonate
Melvin Bonilla-Félix 1
Received: 11 September 2016 / Revised: 13 February 2017 / Accepted: 21 February 2017 / Published online: 4 April 2017
# IPNA 2017
Abstract Potassium, the major cation in intracelluar fluids, is
essential for vital biological functions. Neonates maintain a
net positive potassium balance, which is fundamental to en-
sure somatic growth but places these infants, especially those
born prematurely, at risk for life-threatening disturbances in
potassium concentration [K+] in the extracellular fluid com-
partment. Potassium conservation is achieved by maximizing
gastrointestinal absorption and minimizing renal losses. A
markedly low glomerular filtration rate, plus adaptations in
tubular transport along the nephron, result in low potassium
excretion in the urine of neonates. Careful evaluation of clin-
ical data using reference values that are normal for the neo-
nate’s postmenstrual age is critical to avoid over-treating in-
fants with laboratory results that represent physiologic values
for their developmental stage. The treatment should be aimed
at correcting the primary cause when possible. Alterations in
the levels or sensitivity to aldosterone are common in neo-
nates. In symptomatic patients, the disturbances in [K+]
should be corrected promptly, with close electrocardiographic
monitoring. Plasma [K+] should be monitored during the first
72 h of life in all premature infants born before 30 weeks of
postmenstrual age as these infants are prone to develop non-
oliguric hyperkalemia with potential serious complications.
Keywords Potassium . Neonate . Potassium channels . Renal
development . Hyperkalemia . Hypokalemia
* Melvin Bonilla-Félix
melvin.bonilla1@upr.edu
1
Department of Pediatrics, University of Puerto Rico, Medical
Sciences Campus, PO Box 365067, San Juan, Puerto Rico
00936-5067
Introduction
Potassium is the major cation in intracellular (IC) fluids and is
essential for vital biological functions. Almost all total body
potassium (98%) is located intracellularly, where it plays a key
role in protein synthesis, cell growth and cell volume regula-
tion. In the growing infant, a positive potassium balance is
fundamental for somatic growth. The marked difference be-
tween IC and extracellular (EC) potassium ion concentration
([K+]), which is tightly maintained by the sodium-potassium
ATPase pump (Na+/K+-ATPase), determines the resting mem-
brane potential, which in turn is critical for the normal func-
tion of excitable cells.
The plasma [K+] in neonates is elevated compared to that in
older infants, children and adults. In a study involving a group
of preterm infants with a birthweight of <1 kg and
postmenstrual age of <30 weeks, the mean plasma [K+] in
the first day of life was >6 meq/L [1]. The highest [K+] was
observed between 9 and 72 h of life, with a peak value at
around 24 h. After the third day of life it started to decrease,
stabilizing at between days 4 and 5. In about one-third of these
infants the peak plasma [K+] was >6.7 meq/L [1]. Although
hyperkalemia in neonates can cause serious complications, it
is important to use reference values that are normal for
postmenstrual age to avoid making therapeutic decisions
based on values that could be physiologic for the developmen-
tal stage of the patient.
Potassium balance in adults
Total body potassium content depends on both dietary intake
and excretion, primarily through the kidneys [2]. The EC [K+]
is a function of the total body potassium content and the rel-
ative distribution of potassium between the EC and IC fluid
2038
compartments. To maintain homeostasis, potassium intake
should be equal to potassium excretion. The kidneys are re-
sponsible for excreting 90% of potassium intake, while only
10% is excreted through the gastrointestinal tract. Changes in
potassium intake result in changes in renal excretion.
However, the renal response to changes in potassium intake
is a slow process that may take several hours before proper
adjustments occur. Consequently, to prevent life-threatening
fluctuations in EC [K+], the human body shifts potassium
from the EC to the IC compartment, thereby maintaining a
normal serum level.
Intestinal handling of potassium
Up to 90% of the dietary potassium is absorbed in the gastro-
intestinal tract, primarily in the small intestine, with only a
small amount lost in the feces. Although the colon has the
capacity to absorb and secrete potassium, under normal con-
ditions it plays a minimal role in the overall intestinal handling
of potassium [3]. When the renal excretion of potassium is
limited, as in individuals with chronic kidney disease
(CKD), intestinal excretion acquires a more prominent role
regulating the EC [K+]. Under chronic dietary potassium re-
striction, a condition which favors potassium absorption in the
distal colon, the mRNA encoding the colonic alpha-isoform of
proton-potassium ATPase (H+/K+-ATPase) pump (HKα2), is
upregulated [4].
The kidney is the major regulator of EC [K+]. An acute oral
potassium load produces only a transient rise in plasma [K+]
[5]. To induce a significant increase in the [K+] in the EC
space a chronic oral potassium load is required, which en-
hances potassium secretion in the distal nephron mediated
by aldosterone [6]. On the other hand, low potassium intake
and hypokalemia inhibit aldosterone secretion, thereby limit-
ing renal potassium excretion. These principles constitute the
basis for the feedback control of potassium balance.
Feedforward mechanism
Even minor changes in dietary potassium can induce
kaliuresis, i.e. the excretion of potassium in the urine.
Kaliuresis can occur before an increase in the plasma potassi-
um level or changes in aldosterone concentration are detect-
able, suggesting a gut sensing mechanism that directly stimu-
lates renal potassium excretion, not mediated by aldosterone
[7]. After ingestion of a potassium-containing meal, an in-
crease in the [K+] in the splanchnic circulation stimulates local
sensors that can directly induce a kaliuretic response. This
process, known as the feedforward mechanism, does not re-
quire an increase in plasma [K+] and is not regulated by aldo-
sterone [8]. Evidence for a potassium sensor in the
hepatoportal system arises from experiments showing that
an infusion of KCl directly into the hepatoportal circulation
Pediatr Nephrol (2017) 32:2037–2049
increases urinary potassium excretion in the absence of any
elevation in plasma [K+]. This effect is abolished by bumeta-
nide, suggesting that the presence of an isoform of the Na+-
K+-2Cl− cotransporter, NKCC1, in the hepatoportal system
that mediates a signal transmission to the kidneys with conse-
quent kaliuresis [9, 10]. The inverse is observed during con-
ditions of chronic dietary potassium restriction. Before hypo-
kalemia develops, the renal excretion of potassium is reduced,
probably mediated by sensors in the gastric or hepatoportal
circulation that in some way inactivates renal outer medullary
potassium channels (ROMK) [11].
Developmental adaptations in the intestinal handling
of potassium
In neonates, a positive potassium balance is necessary
to ensure somatic growth. The initial step to achieve
this positive balance involves maximizing intestinal po-
tassium absorption. Experimental data have demonstrat-
ed that the immature intestine absorbs potassium more
avidly than the adult one. Intestinal potassium absorp-
tion measured after intragastric administration of KCl
was higher in infant rats than in adult ones. In addition,
rates of total cumulative Rb+ uptake, a marker of potas-
sium transport, are higher in isolated distal colons from
infant rats, suggesting increased potassium absorption in
the distal colon of immature animals [12]. It has been
proposed that the higher rates of intestinal potassium
absorption in infant animals are the consequence of
lower activity of the basolateral Na+/K+-ATPase and in-
creased activity of apical potassium absorptive pumps,
such as H+/K+-ATPase and ouabain-sensitive Na+-inde-
pendent K+-ATPase. This results in lower IC [K+], pro-
moting net intestinal absorption in the neonate, in con-
trast to net secretion in the adult colon and will con-
tribute to a state of total body potassium retention and
higher EC concentration in the neonatal period [13].
There is no information on the role of the feedforward
mechanism of potassium regulation in the maturing
kidney.
Extrarenal regulation of potassium—internal
distribution
Consumption of an acute load of potassium does not lead to
death from hyperkalemia because some of the potassium that
is absorbed is rapidly shifted into the IC compartment,
preventing a dangerous rise in plasma [K+]. This is the result
of a coordinated action between active uptake by the cells
(primarily muscle cells) via the Na+/K+-ATPase pump and
passive backleak of potassium from the cells through potassi-
um channels.
Pediatr Nephrol (2017) 32:2037–2049
Developmental adaptations in the mechanisms regulating
internal potassium distribution
The mechanisms which regulate internal potassium distribu-
tion are not fully developed in the neonate. Adult rats admin-
istered an intragastric potassium load demonstrate a signifi-
cant rise in tissue (skeletal muscle) [K+] 2 h later, but not a
significant change in plasma [K+]. To the contrary, the same
intervention in infant rats results in a significant increase in
plasma [K+] without a significant impact in the content of
potassium in the skeletal muscle [12]. Studies in humans show
that premature infants with hyperkalemia exhibit lower Na+/
K+-ATPase activity associated with lower IC [K+]/serum [K+]
ratios when compared with normokalemic premature infants
[14]. Moreover, prenatal treatment with steroids, which pre-
sumably stimulates maturation of Na+/K+-ATPase, prevents
non-oliguric hyperkalemia (NOH) without affecting potassi-
um excretion [15]. Together, these studies suggest immaturity
of the mechanisms that regulates the internal distribution of
potassium as the most likely cause of NOH in premature in-
fants [16].
Adrenergic receptors, insulin and acid–base balance are the
major regulators of internal potassium distribution. β2-
agonists and insulin increase cellular potassium uptake by
stimulating the activity of the Na+/K+-ATPase pump, primar-
ily in skeletal muscle, although through different signaling
pathways [17]. To the contrary, metabolic acidosis, mainly if
caused by inorganic anions (normal anion gap acidosis), re-
duces the activity of Na+/K+-ATPase and the entry of potassi-
um into the cell.
Renal potassium excretion—developmental
adaptations
The immature kidney is programmed to preserve potassium.
Young (20 days old) rats have a blunted ability to excrete an
acute potassium load compared with adults (50 days old), with
nephrogenesis in rats completed by 1 week, weaning by 4
weeks and maturity by 6 weeks. Clearance studies in humans
show similar results. In fact, it has been shown that the ability
of children to excrete an acute load of potassium is lower than
that of adults until 10–11 years of age [12].
The renal handling of potassium is a complex process that
involves filtration, reabsorption and secretion. Plasma potas-
sium is freely filtered at the glomerulus. In the mature kidney,
the proximal tubule (PT) reabsorbs 60–70% of filtered potas-
sium along with sodium, chloride and fluid. An additional
25% of filtered potassium is reabsorbed in the thick ascending
limb of the loop of Henle. There are several developmental
adaptations in the process of renal handling of potassium in
the immature kidney.
2039
Glomerular filtration
The first step in renal potassium excretion involves filtration
through the glomerulus. It is known that glomerular filtration
rate (GFR) is lower in premature newborn infants than in full-
term newborns, such that the lower the postmenstrual age, the
lower the GFR. In adults and older children with CKD, once
the GFR is <25 ml/min/1.73m2, hyperkalemia may develop
due to limited potassium filtration. Almost all premature in-
fants have a GFR of <25 ml/min/1.73m2 during the first week
of life, and this low GFR continues during the first month of
life in very low birthweight infants. Therefore, a low GFR in
neonates, especially in premature infants, is definitely a limit-
ing factor for renal potassium excretion (Fig. 1). However,
potassium clearances in neonates are low, even after correc-
tion for the low GFR, suggesting that the tubular handling of
potassium in the neonatal kidney differs from that in the adult
[18].
Before the tubular handling of potassium in the neonate is
reviewed, I will focus on the Na+/K+-ATPase which plays a
key role in the regulation of potassium secretion and absorp-
tion along the nephron. Although the distribution is similar,
the activity of Na+/K+-ATPase measured in isolated dissected
rabbit tubules is significantly lower in neonates than in adults.
Of all the nephron segments studied, the ascending loop of
Henle shows the highest Na+/K+-ATPase activity and the most
striking increase in Na+/K+-ATPase activity with maturation
[19]. The mean activity of Na+/K+-ATPase in the PT during
the first week of life is one-third that of the adult level, with
adult levels reached by 7 weeks of age [20]. Moreover, while
the Km [substrate concentration at half the maximum velocity
(Vmax)] of Na+/K+-ATPase, an indirect measurement of en-
zyme affinity, is identical in the neonatal and mature tubule,
the Vmax is fivefold lower in neonatal tubules, indicating
lower enzyme content in the immature nephron segments.
This state is observed along the entire nephron, representing
an extremely important developmental adaptation in the im-
mature kidney [19].
Proximal tubule
In mature kidneys 60–70% of filtered potassium is reabsorbed
in the PT through paracellular pathways. This process is pri-
marily the result of solvent drag driven by sodium absorption
and a favorable electrochemical gradient, especially in the late
segment of the PT [21, 22]. A lower Na+/K+-ATPase activity
in the immature tubule limits proximal absorption of sodium,
diminishing the solvent drag effect (Fig. 1). On the other hand,
developmental changes in paracellular transport, characterized
by low chloride permeability, have been reported in isolated
microperfused PT of rats and rabbits [23, 24]. The low chlo-
ride permeability is probably the result of developmental ad-
aptations in the expression of tight junction proteins, including
2040
Fig. 1 Developmental adaptations in renal potassium transport along the
nephron. 1 Low glomerular filtration rate (GFR) limits the filtration of
potassium ions (K+) through the glomerulus. 2 Low Na+-K+-ATPase
activity decreases proximal sodium ion (Na+) and fluid absorption,
limiting the solvent drag effect. Immaturity of tight junctions alters K+
absorption through paracellular pathways. Similar to adult nephrons, the
immature proximal tubule delivers 30–40% of filtered K+ to the thick
ascending limb. 3 Low Na+-K+-ATPase maintains a higher intracellular
(IC) sodium ion concentration [Na+] and lower IC [K+]. Renal outer
medullary potassium channel (ROMK) activity and NKCC2 (a Na+-K+-
2Cl− cotransporter isoform) expression are low, limiting K+ absorption in
increased expression of claudin 2 and decreased expression of
occludin in comparison with adult tubules [25]. The exact
effect of these changes on K+ transport are not known, but
they are likely to affect K+ absorption in this segment.
Micropuncture studies in rats show that the fraction of the
K+-filtered load absorbed by the PT is similar in immature
and adult kidneys [26].
Loop of Henle
The mature loop of Henle absorbs 25% of filtered po-
tassium through both, transcellular and paracellular path-
ways [27]. The ubiquitous Na+/K+-ATPase present in
the basolateral membrane maintains low IC
[Na+], which provides the driving force for the luminal
Na-K+-2Cl− transporter NKCC2 [28]. A high IC [K+]
promotes recycling of some of the absorbed potassium
into the lumen via an apical low-conductance secretory
potassium channel, known as the renal outer medullary
potassium (ROMK) channel since it was originally iden-
tified in the thick ascending limb of the rat outer
Pediatr Nephrol (2017) 32:2037–2049
this segment. The immature aldosterone-sensitive distal nephron receives
35% of filtered K+ load, compared to 20% in mature nephrons. 4 The
immature collecting duct is resistant to aldosterone. Low Na+-K+-ATPase
activity maintains higher IC [Na+] concentration and in conjunction with
low epithelial sodium channel (ENaC) activity Na+ absorption is limited
in this segment. Low ROMK activity decreases K+ secretion at physio-
logic flow. Low big-conductance potassium (BK) channel activity limits
flow-stimulated K+ secretion. High H+-K+-ATPase expression in α-
intercalated cells favors K+ absorption over secretion in the immature
collecting duct (CD)
medulla [29]. This channel provides a continuous sup-
ply of potassium ions required for the NKCC2 pump
and keeps a positive luminal voltage that drives potas-
sium absorption through paracellular pathways, as well
as calcium and magnesium. The IC potassium leaves the
cell through the basolateral membrane, primarily
cotransported with chloride, or via a potassium channel.
Igarashi and colleagues demonstrated that mRNA ex-
pression of NKCC2 in mice is developmentally regulated
[30]. During the early embryonic stage the signal is un-
detectable, with expression first observed in the meta-
nephros by day 14.5 post conception, following which
time it continues to increase progressively through late
gestation. By the end of the first week of postnatal life
the mRNA expression is stronger, which coincides with
completion of nephrogenesis in rats [30]. This delay in
NKCC2 expression limits potassium absorption in this
segment during early development. As a result, the imma-
ture distal nephron receives up to 35% of the potassium
filtered load, in contrast to 15–20% in the adult kidney
[26, 31].
Pediatr Nephrol (2017) 32:2037–2049
Aldosterone-sensitive distal nephron
The immature distal nephron is resistant to mineralocorticoids.
Healthy newborn infants exhibit high plasma levels of aldo-
sterone and renin, which contrast with biologic signs of func-
tional hypoaldosteronism, including hyperkalemia and uri-
nary sodium loss [32]. Aperia and colleagues demonstrated
that the correlation between aldosterone excretion and the uri-
nary potassium/sodium quotient is higher in full-term infants
than in pre-term ones, suggesting unresponsiveness to aldo-
sterone at this developmental stage [33]. Moreover, in rabbits
Vehaskari demonstrated that glucocorticoid pretreatment did
not affect Na+ transport measured in isolated microperfused
cortical collecting ducts (CCD) in the first 2 weeks of life.
However, a marked increase in the response to aldosterone
pretreatment is observed after 22 days of age [34]. More re-
cently, low renal expression of mineralocorticoid receptor, de-
spite high aldosterone levels, was shown in human and mouse
kidney at birth, which could partly explain aldosterone resis-
tance in the immature kidney [35].
The three major players in potassium secretion in this seg-
ment are: (1) Na+/K+-ATPase, (2) apical potassium secretory
channels and (3) epithelial sodium channel (ENaC) [17]. A
negative luminal charge favoring potassium efflux from cells
through apical potassium channels is generated by sodium
absorption via ENaC. Potassium secretion in this segment is
enhanced by high-flow rates, probably the result of activation
of BK channels by increased intracellular Ca++ mediated by
hydrodynamic forces on the apical cilia of principal and inter-
calated cells of the CD [36–38].
Earlier in this review I mentioned that the activity of Na+/
+
K -ATPase is very low in all nephron segments during early
development [19]. The resulting high IC [Na+] diminishes
apical sodium absorption and potassium secretion. There are
at least two different potassium channels: the ROMK
[low-conductance secretory K (SK)] channel, which is respon-
sible for basal potassium secretion under physiologic flow
rates and is expressed in apical membranes along the entire
distal nephron from the thick ascending limb through the CD,
and the big-conductance (BK or maxi-K channel), which re-
sponds to stretch and mediates flow-dependent potassium se-
cretion and is expressed along the distal nephron, but more
prominently in the apical membranes of intercalated cells
[39–43].
The thiazide-sensitive NaCl co-transporter (NCC), al-
though not directly involved in potassium secretion, is very
sensitive to EC [K+] and plays a key role in renal potassium
excretion [44]. Its importance in K+ regulation is evident in
Gitelman syndrome in which a mutation in the NCC gene is
associated with renal potassium wasting [45]. NCC is regulat-
ed by dietary potassium and aldosterone. A high K+ diet turns
off NCC and turns on ENAC. Inhibition of NCC decreases
sodium absorption in the distal convoluted tubule, resulting in
2041
increases in sodium delivery to the connecting tubule and CD;
this turns on ENAC, which in turn enhances K+ secretion in
the CD [46]. Moreover, mutations in the serine–threonine ki-
nases WNK1 and WNK4, which regulate NCC, result in
hyperkalemia and hypertension (pseudohypoaldosteronism
Type II) by inhibiting ROMK and stimulating NCC [47, 48].
Except for an in situ hybridization study in neonatal rats show-
ing that NCC expression follows expression of NKCC2, little
information is currently available on the ontogeny of NCC
[49]. Similarly, the maturation of WNK in the kidney has
not been characterized, except for a study in mouse tissues
using in situ hybridization that showed more prominent renal
expression of WNK1 in the postnatal period, compared with
embryos [50].
Potassium secretion, measured as transtubular potassium
gradient (TTKG), is decreased in premature infants during
the first 2 weeks of life, especially in those born at <30 weeks
of postmenstrual age [51]. Satlin et al. demonstrated in isolat-
ed microperfused CCD from neonatal rabbits that at physio-
logic flow rates net potassium secretion was absent at birth,
first becoming evident at 4 weeks of age and increasing
abruptly thereafter, reaching maturity by 6 weeks of age
[52]. Patch clamp analysis in maturing rabbit CCDs showed
a clear developmental increase in ROMK channel activity
between 2 and 5 weeks of age, consistent with data from
isolated perfused CCDs at low flow rates. This observation
suggests that the appearance of baseline potassium secretion
in the CCD is the result of the development of SK/ROMK
channels [53]. Flow-stimulated potassium secretion in the rab-
bit appears by 5 weeks of postnatal life, parallel with the
appearance of BK expression [54]. In human fetuses, the ex-
pression of ENAC is low during early development. After 32
weeks of postmenstrual age the expression increases, correlat-
ing with better abilities to absorb sodium. This increase pre-
cedes the maturation of potassium secretion [55].
Role of H+/K+-ATPase
In the CCD, the alpha intercalated cells absorb potassium
actively in exchange for protons through H+/K+-ATPase
(HKα2). In adults, this mechanism is important in conditions
of potassium depletion. Scanning electron micrographs of rat
CDs demonstrate that potassium deprivation induces hyper-
trophy of the luminal surface of the intercalated cells, where
H+/K+-ATPase is expressed [56]. Chronic hypokalemia is the
most potent stimulus for upregulation of HKα2, suggesting a
key role for this exchanger in preserving body potassium [57].
In rats the mRNA and protein expression of HKα2C, one of
the splice variants of HKα2, is specifically upregulated in
neonates, eventually becoming undetectable in adults. These
data suggest a mechanism for increased potassium absorption
in the neonate via HKα2C [57].
2042 Pediatr Nephrol (2017) 32:2037–2049

Hypokalemia complex is associated with a lower incidence of hypokalemia

[59]. Hereditary disorders associated with alkalosis (Bartter and
Hypokalemia in the neonate is defined as a plasma [K+] of Gitelman syndromes) or acidosis (renal tubular acidosis) cause
<3.5 meq/L. Since potassium is primarily an IC cation, the hypokalemia during the neonatal period. Bartter syndrome, char-
serum [K+] is not an accurate estimate of total body potassium. acterized by large sodium losses, is associated with hypokalemic
Under normal conditions, changes in IC [K+] parallel those in alkalosis and polyhydramnios. Type 1 (antenatal) Bartter syn-
serum [K+]. Factors that regulate internal potassium distribu- drome, caused by a mutation in the apical NKCC2 transporter,
tion may affect this relationship [58]. presents as hypokalemia early in life as a result of impaired
The most common causes of hypokalemia in the neonate are potassium absorption in the loop of Henle [60]. A transient
shown in Table 1. Gastrointestinal disturbances, such as X-linked form of antenatal Bartter characterized by severe
vomiting, diarrhea or unreplaced electrolyte losses from nasogas- polyhydramnios and prematurity has recently been described
tric or intestinal drainage, may lead to hypokalemia. Infants with and attributed to a mutation in melanoma associated antigen
necrotizing enterocolitis or congenital intestinal anomalies requir- D2 (MAGE-D2), which positively regulates the expression of
ing surgery of the intestinal tract are at particular risk. NKCC2 and NCC [61]. Although Gitelman syndrome, caused
Hypertrophic pyloric stenosis rarely presents before the third by a mutation in NCC, usually presents later in life, hypokalemia
week of life; thus, it is seldom a cause of gastrointestinal potas- has been reported in the newborn period [62]. Renal tubular
sium losses during the neonate period, especially in premature acidosis, especially Type 2 (proximal), often features early hypo-
infants. Renal potassium losses often result from the use of med- kalemia along with metabolic acidosis. In Fanconi syndrome,
ications, including diuretics, such as furosemide (inhibits hypokalemia is associated with acidosis, hypophosphatemia
NKCC2) and thiazides (inhibit NCC), or the antifungal and hypouricemia; the urine is usually dilute with glycosuria,
amphotericin B (forms pores in the cell membrane that allows aminoaciduria and tubular proteinuria. Nephropathic cystinosis,
K+ to leak out of the cell). The use of the aldosterone inhibitor the most common hereditary form of Fanconi syndrome, needs
spironolactone as a potassium sparing agent may prevent hypo- to be ruled out since early treatment with cysteamine can prevent
kalemia in patients receiving diuretics. The amphotericin B lipid systemic complications and delay progression to renal failure
[63]. Although uncommon in newborns, the presence of hyper-
tension in a child with mild hypokalemic alkalosis should prompt
Table 1 Causes of hypokalemia in neonates the diagnosis of glucocorticoid-remediable aldosteronism, espe-
Causes Specific examples cially if there is familial history of premature cerebrovascular
events [64, 65].
Poor intake Prolonged starvation
Insufficient support in TPN
Evaluation and management of neonatal hypokalemia
Increased renal losses Mineralocorticoid excess
Bartter and Gitelman syndromes
Severe hypokalemia can cause cardiac arrhythmias, ileus,
Renal tubular acidosis
muscle weakness and lethargy. Changes in the electrocardio-
Magnesium deficiency
gram (ECG) include flattened T waves, prolongation of the
Gastrointestinal losses Vomiting
QT interval and the appearance of U waves. The primary
Diarrhea
cause of hypokalemia should be identified and treated accord-
GI fistulas
ingly. To this end, a random assessment of the urinary [K+] in
Ostomies
patients with disturbances of potassium balance is inadequate
Drugs Anti-infectives
to assess if the etiology resides in the kidney.
Amphotericin B
Alternatively, the kidney’s handling (excretion rate) of po-
Aminoglycosides
tassium and, indirectly, aldosterone activity in the CD, can be
Diuretics
assessed by calculating the TTKG using the equation:
Thiazides
Loop diuretics ðUrine ½KþÞðPlasma OsmolalityÞ
TTKG ¼
Steroids ðPlasma ½KþÞðUrine OsmolalityÞ
Redistribution (internal shifts) Alkalosis
Insulin [66]. A low value of TTKG in a hyperkalemic patient may
Theophylline/caffeine help to determine whether the elevated serum [K+] is due to low
Thyrotoxicosis
aldosterone levels/aldosterone resistance, although during recent
β agonists, epinephrine
years several pitfalls have been identified in this calculation of
TTKG. In states where the rate of excretion of urea deviates
GI, Gastrointestinal; TPN, total parenteral nutrition appreciably from normal, TTKG may overestimate the true renal
Pediatr Nephrol (2017) 32:2037–2049
K+ excretion [67]. In addition, an adequate urine [Na+] (>25
meq/L) and a urine that is hypertonic compared to plasma are
two parameters required to be able to use TTKG for the evalua-
tion of patients with potassium disturbances [67].
TTKG in preterm neonates is low during the early neonatal
period and does not correlate with plasma aldosterone levels,
consistent with the low tubular K+ excretion and mineralocor-
ticoid resistance. This finding probably has a physiologic ba-
sis or is related to the presence of associated medical condi-
tions, such as the use of mechanical ventilation [51].
Therefore, TTKG should not be used in premature infants as
the interpretation of this test is troublesome since immaturity
of the nephron and normal developmental changes in renal
potassium handling and urine concentration may confound
the results.
In patients with hypokalemia the serum concentration of
magnesium should be measured as hypokalemia might
Fig. 2 Management of
hypokalemia in newborn infants.
GI Gastrointestinal, ECG
electrocardiogram, NS normal
saline, iv intravenous, IVF’s
intravenous fluids
2043
worsen and become refractory to treatment in the presence
of hypomagnesemia [68]. If hypokalemia is associated with
polyuria, which is common, intravascular volume should be
promptly restored. The rate and route for replacement of po-
tassium depends on the presence of symptoms or changes in
the ECG.
The safest treatment of mild asymptomatic hypokalemia is
via the oral/enteral route using potassium salts in a dose of 1–2
meq/kg/day (Fig. 2). In the presence of alkalosis, potassium
should be given as KCl to replenish chloride [69].
Moderate-to-severe symptomatic hypokalemia ([K+] <2.5
meq/L) or patients with gastrointestinal complications who
cannot tolerate oral salts should be treated using intravenous
preparations of potassium. The addition of KCl to intravenous
fluid (not to exceed 40 meq/L) can be sufficient in cases of
moderate hypokalemia. Higher concentrations (60–80 meq/L)
are required if the patient fails to respond, but these should be
2044 Pediatr Nephrol (2017) 32:2037–2049

given through a central vein under continuous ECG monitor-
ing. Rapid administration of KCl can lead to life-threatening
arrhythmias. In cases of profound (serum [K+] <1.5 meq/L) or
symptomatic hypokalemia, KCl diluted in normal saline can
be carefully given intravenously in doses up to 0.5–1 meq/kg
over 1–2 h [70]. Continuous ECG monitoring is required.
Potassium salts should not be diluted in dextrose-containing
solutions as it provokes insulin secretion and cellular potassi-
um uptake, lowering the plasma [K+] even further [71].
Hyperkalemia
Hyperkalemia in the neonatal period can be defined as a plas-
ma [K+] of >6 meq/L in full-term neonates and of >6.5 meq/L
in premature infants. In very premature infants (postmenstrual
age <32 weeks), normal plasma [K+] could be up to 6.7 meq/L
during the first week of life [1, 72]. Hyperkalemia is life-
threatening as it causes cardiac arrhythmias.
The most common causes of hyperkalemia in the neonate
are shown in Table 2. Pseudohyperkalemia or in vitro hemo-
lysis due to technical difficulties in obtaining an adequate
blood sample in small infants are the most common sources
of an elevated [K+], as K+ is released from the IC compartment
into the serum. In most instances, assessment of the degree of
hemolysis in a blood sample is subjective, based on visual
inspection of the color of the plasma. Therefore, as a general
rule, therapeutic decisions should not be based on samples
obtained by a heelstick, from fingertip or after prolonged use
Table 2 Causes of hyperkalemia in neonates
Causes Specific examples
Pseudohyperkalemia Heelstick
Finger tip
Prolonged tourniquet
Increased potassium load Diet
Blood transfusions
Hemorrhages (GI, IVH)
Hemolysis
Tissue necrosis
Decreased renal excretion AKI and CKD
Aldosterone deficiency/resistance
RTA Type 4
Urinary obstruction
Drugs Spironolactone
Amiloride
Trimethoprim
Redistribution (internal shifts) Acidosis
Non-oliguric hyperkalemia
AKI, Acute kidney injury; CKD, chronic kidney disease; IVH, intraven-
tricular hemorrhage; RTA, renal tubular acidosis
of tourniquet as these should be considered to be hemolyzed
samples. Other sources of hyperkalemia include elevated
platelet, leukocyte or red blood cell counts [73].
The presence of metabolic acidosis promotes a shift of
potassium from the cell to the EC space. Several medications
can promote cellular shifts of potassium. Succinylcholine, by
depolarizing the muscle membrane, induces the efflux of K+
from the cell, which can lead to life-threatening hyperkalemia.
Digoxin overdose and β 2 adrenergic blockers cause
hyperkalemia by inhibiting Na+/K+-ATPase [74]. Other med-
ications can induce hyperkalemia by acting on the angioten-
sin–aldosterone axis. Spironolactone is an antagonist of min-
eralocorticoids. Indomethacin produces hyporeninemic
hypoaldosteronism and decreased GFR. Angiotensin
converting enzyme inhibitors can also cause hyperkalemia
by blocking angiotensin II synthesis and the subsequent gen-
eration of aldosterone. Amiloride and trimethoprim inhibit
ENaC, thereby reducing sodium reabsorption and potassium
excretion [75]. Endogenous potassium load results from tissue
breakdown, as in hemolysis, gastrointestinal bleeding and tis-
sue necrosis. Because of the developmental adaptations
discussed earlier in this review (see Fig. 1), neonates are more
susceptible to the effects of these medications, which can limit
the already compromised Na+/K+-ATPase activity, the ability
to shift K + into the cell and the tubular response to
mineralocorticoids.
Careful attention should be given to excess oral or in-
travenous potassium supplementation/nutrition, medica-
tions with potassium salts, such as penicillin, or blood
transfusions. Acute kidney injury and CKD also result in
impairment of urinary potassium excretion. Decreased al-
dosterone activity results from a deficiency in mineralo-
corticoids or resistance to its effects. Both will result in
variable degrees of metabolic acidosis, renal salt wasting
and hyperkalemia. Aldosterone synthase deficiency is a
rare autosomal recessive disease characterized by defec-
tive biosynthesis of aldosterone that results in isolated
hypoaldosteronism. Patients exhibit salt wasting, recurrent
dehydration, hyperkalemia and failure to thrive. Neonatal
screening using 17-hydroxyprogesterone measurement
identifies a defect in 21-hydroxylase but fails to detect
aldosterone synthase deficiency, a diagnosis which may
be missed until the patient presents with a salt-wasting
crisis [76, 77]. Pseudohypoaldosteronism is a rare hered-
itary disorder that results from end-organ resistance to
aldosterone, characterized by high plasma aldosterone
and renin concentrations. Type 1 is caused by a defect
in the mineralocorticoid receptor and presents in the neo-
natal period as hypovolemia, hyponatremia,
hyperkalemia, vomiting, failure to thrive, metabolic aci-
d o s i s a n d d e h y d r a t i o n o r s h o c k [ 7 8 ] . Ty p e 2
pseudohypoaldosteronism, also known as Gordon syn-
drome, is a rare form of familial hypertension caused by
Pediatr Nephrol (2017) 32:2037–2049
mutations in WNK kinases [48]. Previously known as the
adolescent chloride shunt, because it typically presents
during adolescence as hypertension and hyperkalemic ac-
idosis, the disorder responds to treatment with salt restric-
tion and thiazide diuretics. Although hypertension does
not develop until late childhood, the electrolyte distur-
bances (hyperkalemic acidosis) can already be present in
the neonatal period [79]. A renal ultrasound looking for
hydronephrosis should be carried out as renal tubular ac-
idosis type 4 is a common finding in infants with urinary
tract obstruction.
NOH in the neonate
This entity is defined as a plasma [K+] of >6.5 meq/L within
the first 72 h of life in very low birthweight (birthweight lower
than 1500 g) or very pre-term (less than 32 weeks
postmenstrual age) infants in the presence of normal renal
Fig. 3 Management of
hyperkalemia in newborn infants.
po Orally
2045
function for age. Although the pathophysiology is not
completely understood, it seems to be the result of immaturity
of the mechanisms that regulate internal distribution of potas-
sium (see section Extrarenal regulation of potassium—inter-
nal distribution) [14]. Because hyperkalemia could cause se-
rious arrhythmias and mortality, it is important to monitor
plasma [K+] during the first 72 h of life in all premature infants
born at <32 weeks of postmenstrual age [80, 81].
Evaluation and management of neonatal hyperkalemia
The evaluation of hyperkalemia starts by identifying
life-threatening signs. Initial ECG changes are a prolonged
PR interval and peaked T waves, followed by the absence of
P wave, widened QRS with S–T depression and persistent
peaked T waves. The QRS continues to widen with higher
serum [K+] until ventricular fibrillation develops. Muscle
weakness and hypotension occur only rarely. The blood
2046
pressure, as well as volume status and the genitalia, should
also be assessed since infants with congenital adrenal hyper-
plasia can present with salt wasting, severe dehydration, hy-
potension and virilization.
Pseudohyperkalemia should always be considered and the
blood collection technique identified. In the case of true
hyperkalemia, the plasma concentrations of sodium, chloride,
bicarbonate, creatinine should be evaluated, as well a com-
plete blood count ordered. If the GFR is normal and no
offending agent can be identified, hypoaldosteronism should
be ruled out. In these patients, hyperkalemia will be accom-
panied by hyponatremia and metabolic acidosis. TTKG could
assist to discriminate between renal and extrarenal causes in
term infants—keeping in mind the previously discussed lim-
itations. In children with hyperkalemia due to a non-renal
cause, the urinary potassium excretion is very high and there-
fore the TTKG is high (>11). In newborns with
hypoaldosteronism and pseudohypoaldosteronism, the
TTKG is very low (1.4–4.1) [66]. If adrenal etiology is
suspected, one should measure serum levels of aldosterone,
renin and cortisol.
Therapeutic targets for hyperkalemia are to prevent ar-
rhythmias and to decrease the plasma [K+] by stimulating its
shift into the cell or by depleting body potassium. If the ECG
shows changes consistent with hyperkalemia, calcium gluco-
nate 10% should be administered at a dose of 0.5 ml/kg over
5–15 minutes (Fig. 3). The effect of stabilizing the cardiac
membrane is evident within 1–3 min and lasts for 30–60
min. The dose may be repeated after 5 min if the ECG changes
persist [82]. Insulin/glucose administration and albuterol neb-
ulization enhance transcellular potassium shifts into the cell.
Insulin can be administered at a dose of 0.1–0.6 U/kg/h with a
glucose infusion of 0.5–1 g/kg/h (5–10 ml/kg/h of glucose
10%) [83]. The onset of action is approximately 15 min and
lasts a few hours. β-agonists, such as albuterol, have a rapid
onset of action. Albuterol can be administered by nebulizer at
a dose of 400 μg to 2.5 mg diluted in 2 ml of normal saline
[84]. This decreases the plasma concentration of potassium by
0.5–1 meq/L. Intravenous albuterol at a dose of 4 μg/kg, given
as an intravenous slow bolus over 5 min, decreases plasma
[K+] by 0.9–1.5 meql/L [85, 86]. In the presence of metabolic
acidosis, sodium bicarbonate infusion can also promote potas-
sium shifting into the cell. Because sodium bicarbonate is
hyperosmolar and due to its potential association with intra-
ventricular hemorrhages in premature infants, it should be
used very judiciously [87–89]. In our department, we recom-
mend a dose of 1 meq/kg diluted 1:4 in sterile water, admin-
istered over 30–60 minutes to decrease the adverse hemody-
namic effects. The efficacy is questionable in the absence of
acidosis. To remove body potassium stores, loop or thiazide
diuretics can be used if the patient is making urine; for severe,
unremitting hyperkalemia, dialysis is required. The use of
resins, such as sodium polystyrene given at a dose of 1 g/kg
Pediatr Nephrol (2017) 32:2037–2049
orally or as enemas, is of questionable efficacy in neonates
[90]. Moreover, because this treatment carries a risk of intes-
tinal perforation and obstruction, it is contraindicated in in-
fants with necrotizing enterocolitis or very premature infants
[91, 92].
Key summary points
1. Neonates are in a net positive potassium balance.
Although this balance is appropriate for somatic growth,
it places the infant at high risk for life-threatening
hyperkalemia.
2. The positive potassium balance is the result of increased
intestinal absorption of potassium and decreased renal
excretion.
3. Infants born at <32 weeks of postmenstrual age should be
monitored for NOH during the first 72 h of life.
4. When treating hyperkalemia in the neonate, resins should
be used very cautiously due to the risk of serious compli-
cations, such as intestinal obstruction and perforation.
Multiple choice questions (answers are provided
following the reference list)
1. Potassium regulation by the feedforward mechanism:
a. Is mediated by aldosterone
b. Is activated 6 h after a glucose-containing meal
c. Is activated 6 h after ingesting a potassium-containing
meal
d. Is triggered by elevated [K+] in gastrointestinal tract
e. Is triggered by elevated [K+] in plasma.
2. The neonatal kidney is programmed to preserve potassi-
um. A potential mechanism involves the following:
a. Increased activity of Na+/K+-ATPase
b. Increased activity of apical ROMK
c. Increased expression of H+/K+-ATPase
d. Increased expression of Maxi-K channels
e. Increased expression of NKCC2.
3. Which following statement is TRUE, regarding NOH of
the newborn:
a. Is a benign condition
b. Is more frequent in late pre-term infants
c. Is the result of impaired feedforward mechanism
d. Is the result of impaired transcellular potassium shift
e. Should be treated if plasma [K+] exceeds 6 meq/L.
Pediatr Nephrol (2017) 32:2037–2049
4. A 4-day-old premature infant developed a plasma [K+] =
2.3 meq/L, [HCO3−] = 26 meq/L. The ECG is normal. Of
the following, the BEST therapeutic approach is:
a. Add 40 meq/L of KCl to 0.45 saline solution with 5%
dextrose water
b. Add 40 meq/L of KCl to 0.45 saline solution without
dextrose
c. Add 60 meq/L of KCl to 0.45 saline solution without
dextrose
d. Administer KCl at a dose of 1 mEq/kg in 0.9 normal
salts intravenously in 1 h
e. Administer potassium citrate at a dose of 1–2 meq/kg/
day by oral route
5. You get a laboratory report of [K+] = 7 meq/L in a 2-day-
old infant, born at 29 weeks of postmenstrual age. The
ECG is normal. You should:
a. Administer sodium polysterene resin 1 g/kg as enema
b. Administer NaHCO3 1 meq/kg intravenously over 1 h
c. Administer calcium gluconate 10% 1 ml/kg intrave-
nously over 15 min
d. Administer albuterol by nebulizer continuously until
[K+] <6 meq/L
e. Repeat blood sample.
Compliance with ethical standards
Conflict of interest statement None to declare
References
1. Lorenz JM, Kleinman LI, Markarian K (1997) Potassium metabo-
lism in extremely low birth weight infants in the first week of life. J
Pediatr 131:8–86
2. Youn JH, McDonough AA (2009) Recent advances in understand-
ing integrative control of potassium homeostasis. Annu Rev
Physiol 71:381–401
3. Agarwal R, Afzalpurkar R, Fordtran JS (1994) Pathophysiology of
potassium absorption and secretion by the human intestine.
Gastroenterology 107:548–571
4. Codina J, Pressley TA, DuBose TD Jr (1997) Effect of chronic
hypokalemia on H-K-ATPase expression in rat colon. Am J
Physiol 272:F22–F30
5. Rabelink TJ, Koomans HA, Hené RJ, Dorhout Mees EJ (1990)
Early and late adjustment to potassium loading in humans.
Kidney Int 38:942–947
6. Giebisch G, Krapf R, Wagner C (2007) Renal and extrarenal regu-
lation of potassium. Kidney Int 72:397–410
7. Youn JH (2013) Gut sensing of potassium intake and its role in
potassium homeostasis. Semin Nephrol 33:248–256
8. Rabinowitz L (1996) Aldosterone and potassium homeostasis.
Kidney Int 49:1738–1742
2047
9. Morita H, Fujiki N, Miyahara T, Lee K, Tanaka K (2000)
Hepatoportal bumetanide-sensitive K-sensor mechanism controls
urinary K excretion. Am J Physiol 278:R1134–R1139
10. Tsuchiya Y, Nakashima S, Banno Y, Suzuki Y, Morita H (2004)
Effect of high-NaCl or high-KCl diet on hepatic Na+- and K+-re-
ceptor sensitivity and NKCC1 expression in rats. Am J Physiol 286:
R591–R596
11. Chen P, Guzman JP, Leong PK, Yang LE, Perianayagam A,
Babilonia E, Ho JS, Youn JH, Wang WH, McDonough AA
(2006) Modest dietary K restriction provokes insulin resistance of
cellular K uptake and phosphorylation of renal outer medulla K
channel without fall in plasma K+ concentration. Am J Physiol
290:C1355–C1363
12. Aizman R, Grahnquist L, Celsi G (1998) Potassium homeostasis:
ontogenic aspects. Acta Paediatr 87:609–617
13. Aizman R, Celsi G, Grahnquist L, Wang Z, Finkel Y, Aperia A
(1996) Ontogeny of K+ transport in rat distal colon. Am J Physiol
271:G268–G274
14. Stefano JL, Norman ME, Morales MC, Goplerud JM, Mishra OP,
Delivoria-Papadopoulos M (1993) Decreased erythrocyte Na+, K(+
)-ATPase activity associated with cellular potassium loss in ex-
tremely low birth weight infants with nonoliguric hyperkalemia. J
Pediatr 122:276–284
15. Omar SE, DeCristofaro JD, Agarwal BI, LaGamma EF (2000)
Effect of prenatal steroids on potassium balance in extremely low
birth weight neonates. Pediatrics 106:561–567
16. Sato K, Kondo T, Iwao H, Honda S, Ueda K (1995) Internal potas-
sium shift in premature infants: cause of nonoliguric hyperkalemia.
J Pediatr 126:109–113
17. Palmer BF (2015) Regulation of potassium homeostasis. Clin J Am
Soc Nephrol 10:1050–1060
18. Vieux R, Hascoet JM, Merdariu D, Fresson J, Guillemin F (2010)
Glomerular filtration rate reference values in very preterm infants.
Pediatrics 125:e1186–e1192
19. Schmidt U, Horster M (1977) Na-K-activated ATPase: activity mat-
uration in rabbit nephron segments dissected in vitro. Am J Physiol
233:F55–F60
20. Schwartz GJ, Evan AP (1984) Development of solute transport in
rabbit proximal tubule. III. Na-K-ATPase activity. Am J Physiol
246:F845–F852
21. Wareing M, Wilson RW, Kibble JD, Green R (1995) Estimated
potassium reflection coefficient in perfused proximal convoluted
tubules of the anaesthetized rat in vivo. J Physiol 488:153–161
22. Kibble JD, Wareing M, Wilson RW, Green R (1995) Effect of
barium on potassium diffusion across the proximal convoluted tu-
bule of the anaesthetized rat. Am J Physiol 268:F778–F783
23. Quigley R, Baum M (2005) Developmental changes in rabbit prox-
imal straight tubule paracellular permeability. Am J Physiol 283:
F525–F531
24. Baum M, Quigley R (2005) Maturation of rat proximal tubule chlo-
ride permeability. Am J Physiol 289:R1659–R1664
25. Haddad M, Lin F, Dwarakanath V, Cordes K, Baum M (2005)
Developmental changes in proximal tubule tight junction mem-
brane proteins. Pediatr Res 57:453–457
26. Lelievre-Pegorier M, Merlet-Benichou C, Roinel N, de Rouffignac
C (1983) Developmental pattern of water and electrolyte transport
in rat superficial nephrons. Am J Physiol 245:F15–F21
27. Palmer LG, Schnermann J (2015) Integrated control of Na transport
along the nephron. Clin J Am Soc Nephrol 10:676–687
28. Mount DB (2014) Thick ascending limb of the loop of Henle. Clin J
Am Soc Nephrol 9:1974–1986
29. Welling PA, Ho K (2009) A comprehensive guide to the ROMK
potassium channel: form and function in health and disease. Am J
Physiol 29:F849–F863
30. Igarashi P, Vanden-Heuvel GB, Payne JA, Forbush B III (1995)
Cloning, embryonic expression, and alternative splicing of a murine
2048
kidney-specific Na-K-Cl cotransporter. Am J Physiol 269:F405–
F418
31. Gurkan S, Estilo GK, Wei Y, Satlin LM (2007) Potassium transport
in the maturing kidney. Pediatr Nephrol 22:915–925
32. Martinerie L, Pussard E, Foix-L’hélias L, Petit F, Cosson C, Boileau
P, Lombès M (2009) Physiological partial aldosterone resistance in
human newborns. Pediatr Res 66:323–328
33. Aperia A, Broberger O, Herin P, Zetterström R (1979) Sodium
excretion in relation to sodium intake and aldosterone excretion in
newborn pre-term and full-term infants. Acta Paediatr Scand 68:
813–817
34. Vehaskari VM (1994) Ontogeny of cortical collecting duct sodium
transport. Am J Physiol 267:F49–F54
35. Martinerie L, Viengchareun S, Delezoide AL, Jaubert F, Sinico M,
Prevot S, Boileau P, Meduri G, Lombe M (2009) Low renal min-
eralocorticoid receptor expression at birth contributes to partial al-
dosterone resistance in neonates. Endocrinology 150:4414–4424
36. Kunau RT Jr, Webb HL, Borman SC (1974) Characteristics of the
relationship between the flow rate of tubular fluid and potassium
transport in the distal tubule of the rat. J Clin Invest 54:1488–1495
37. Engbretson BG, Stoner LC (1987) Flow-dependent potassium se-
cretion by rabbit cortical collecting tubule in vitro. Am J Physiol
253:F896–F903
38. Carrisoza-Gaytan R, Carattino MD, Kleyman TR, Satlin LM
(2016) An unexpected journey: conceptual evolution of
mechanoregulated potassium transport in the distal nephron. Am
J Physiol 310:C243–C259
39. Wang WH, Giebisch G (2009) Regulation of potassium (K) han-
dling in the renal collecting duct. Pflugers Arch 458:157–168
40. Woda CB, Bragin A, Kleyman TR, Satlin LM (2001) Flow-
dependent K+ secretion in the cortical collecting duct is mediated
by a maxi-K channel. Am J Physiol 280:F786–F793
41. Satlin LM (2004) Developmental regulation of expression of renal
potassium secretory channels. Curr Opin Nephrol Hypertens 13:
445–450
42. Pácha J, Frindt G, Sackin H, Palmer LG (1991) Apical maxi K
channels in intercalated cells of CCT. Am J Physiol 261:F696–
F705
43. Nüsing RM, Pantalone F, Gröne HJ, Seyberth HW, Wegmann M
(2005) Expression of the potassium channel ROMK in adult and
fetal human kidney. Histochem Cell Biol 123:553–559
44. Velázquez H, Ellison DH, Wright FS (1987) Chloride dependent
potassium secretion in early and late renal distal tubules. Am J
Physiol 253:F555–F562
45. Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE,
Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza
FJ, Gitleman HJ, Lifton RP (1996) Gitelman’s variant of Bartter’s
syndrome, inherited hypokalaemic alkalosis, is caused by muta-
tions in the thiazide sensitive Na-Cl cotransporter. Nat Genet 12:
24–30
46. Ellison DH, Terker AS, Gamba G (2016) Potassium and its discon-
tents: new insight, new treatments. J Am Soc Nephrol 27:981–989
47. Kahle KT, Wilson FH, Leng Q, Lalioti MD, O’Connell AD, Dong
K, Rapson AK, MacGregor GG, Giebisch G, Hebert SC, Lifton RP
(2003) WNK4 regulates the balance between renal NaCl reabsorp-
tion and K+ secretion. Nat Genet 35:372–376
48. O’Shaughnessy KM (2015) Gordon Syndrome: a continuing story.
Pediatr Nephrol 30:1903–1908
49. Schmitt R, Ellison DH, Farman N, Rossier BC, Reilly RF, Reeves
WB, Oberbäumer I, Tapp R, Bachmann S (1999) Developmental
expression of sodium entry pathways in rat nephron. Am J Physiol
276:F367–F381
50. Shekarabi M, Lafrenière RG, Gaudet R, Laganière J,
Marcinkiewicz MM, Dion PA, Rouleau GA (2013) Comparative
analysis of the expression profile of Wnk1 and Wnk1/Hsn2 splice
Pediatr Nephrol (2017) 32:2037–2049
variants in developing and adult mouse tissues. PLoS One 8:
e57807
51. Nako Y, Ohki Y, Harigaya A, Tomomasa T, Morikawa A (1999)
Transtubular potassium concentration gradient in preterm neonates.
Pediatr Nephrol 13:880–885
52. Satlin LM (1994) Postnatal maturation of potassium transport in
rabbit cortical collecting duct. Am J Physiol 266:F57–F65
53. Satlin LM, Palmer LG (1997) Apical K+ conductance in maturing
rabbit principal cell. Am J Physiol 272:F397–F404
54. Woda CB, Miyawaki N, Ramalakshmi S, Ramkumar M, Rojas R,
Zavilowitz B, Kleyman TR, Satlin LM (2003) Ontogeny of flow-
stimulated potassium secretion in rabbit cortical collecting duct:
functional and molecular aspects. Am J Physiol 285:F629–F639
55. Delgado MM, Rohatgi R, Khan S, Holzman IR, Satlin LM (2003)
Sodium and potassium clearances by the maturing kidney: Clinical-
molecular correlates. Pediatr Nephrol 18:759–767
56. Hansen GP, Tisher CC, Robinson RR (1980) Response of the
collecting duct to disturbances of acid-base and potassium balance.
Kidney Int 17:326–337
57. Codina J, DuBose TD Jr (2006) Molecular regulation and physiol-
ogy of the H+, K+-ATPases in kidney. Semin Nephrol 26:345–351
58. Suarez-Rivera M, Bonilla-Felix M (2014) Fluid and electrolyte dis-
orders in the newborn: sodium and potassium. Curr Pediatr Rev 10:
115–122
59. Auron A, Auron-Gomez M, Raina R, Viswanathan S, Mhanna MJ
(2009) Effect of amphotericin B lipid complex (ABLC) in very low
birth weight infants. Pediatr Nephrol 24:295–299
60. Seyberth HW, Schlingmann KP (2011) Bartter- and Gitelman-like
syndromes: salt-losing tubulopathies with loop or DCT defects.
Pediatr Nephrol 26:1789–1802
61. Laghmani K, Beck BB, Yang SS, Seaayfan E, Wenzel A, Reusch B,
Vitzthum H, Priem D, Demaretz S, Bergmann K, Duin LK, Göbel
H, Mache C, Thiele H, Bartram MP, Dombret C, Altmüller J,
Nürnberg P, Benzing T, Levtchenko E, Seyberth HW, Klaus G,
Yigit G, Lin SH, Timmer A, de Koning TJ, Scherjon SA,
Schlingmann KP, Bertrand MJ, Rinschen MM, de Backer O,
Konrad M, Kömhoff M (2016) Polyhydramnios, transient antenatal
Bartter’s syndrome, and MAGED2 mutations. N Engl J Med 374:
1853–1863
62. Tammaro F, Bettinelli A, Cattarelli D, Cavazza A, Colombo C,
Syrén ML, Tedeschi S, Bianchetti MG (2010) Early appearance
of hypokalemia in Gitelman syndrome. Pediatr Nephrol 25:2179–
2182
63. Greco M, Brugnara M, Zaffanello M, Taranta A, Pastore A, Emma
F (2010) Long-term outcome of nephropathic cystinosis: a 20-year
single-center experience. Pediatr Nephrol 25:2459–2467
64. Vehaskari VM (2009) Heritable forms of hypertension. Pediatr
Nephrol 24:1929–1937
65. Dluhy RGMD, Anderson B, Harlin B, Ingelfinger J, Lifton R
(2001) Glucocorticoid-remediable aldosteronism is associated with
severe hypertension in early childhood. J Pediatr 138:715–720
66. Rodriguez-Soriano J, Ubetagoyena M, Vallo A (1990) Transtubular
potassium concentration gradient: a useful test to estimate renal
aldosterone bio-activity in infants and children. Pediatr Nephrol 4:
105–110
67. Kamel KS, Halperin ML (2011) Intrarenal urea recycling leads to a
higher rate of renal excretion of potassium: an hypothesis with
clinical implications. Curr Opin Nephrol Hypertens 20:547–554
68. Huang CL, Kuo E (2007) Mechanism of hypokalemia in magne-
sium deficiency. J Am Soc Nephrol 18:2649–2652
69. Luke RG, Galla JH (2012) It is chloride depletion alkalosis, not
contraction alkalosis. J Am Soc Nephrol 23:204–207
70. Welfare W, Sasi P, English M (2002) Challenges in managing pro-
found hypokalaemia. BMJ 324:269–270
71. Rodriguez-Soriano J (1995) Potassium homeostasis and its distur-
bances in children. Pediatr Nephrol 9:364–374
Pediatr Nephrol (2017) 32:2037–2049
72. Chevalier RL (1998) What are normal potassium concentrations in
the neonate? What is a reasonable approach to hyperkalemia in the
newborn with normal renal function? Sem Nephrol 18:360–361
73. Ong YL, Deore R, El-Agnaf M (2010) Pseudohyperkalaemia is a
common finding in myeloproliferative disorders that may lead to
inappropriate management of patients. Int J Lab Hematol 32:151–
157
74. Lehnhardt A, Marcus J, Kemper MJ (2011) Pathogenesis, diagnosis
and management of hyperkalemia. Pediatr Nephrol 26:377–384
75. Perazella MA (2000) Trimethoprim-induced hyperkalaemia: clini-
cal data, mechanism, prevention and management. Drug Saf 22:
227–236
76. White PC (1997) Abnormalities of aldosterone synthesis and action
in children. Curr Opin Pediatr 9:424–430
77. White PC (2004) Aldosterone synthase deficiency and related dis-
orders. Mol Cell Endocrinol 217:81–87
78. Sudeep K, Rajpoot SK, Maggi C, Bhangoo A (2014)
Pseudohypoaldosteronism in a neonate presenting as life-
threatening arrhythmia. Endocrinol Diabetes Metab Case Rep
2014:130077
79. Gereda JE, Bonilla-Felix M, Kalil B, Dewitt SJ (1996) Neonatal
presentation of Gordon syndrome. J Pediatr 129:615–617
80. Shortland D, Trounce JQ, Levene MI (1987) Hyperkalaemia, car-
diac arrhythmias, and cerebral lesions in high risk neonates. Arch
Dis Child 62:1139–1143
81. Yaseen H (2009) Nonoliguric hyperkalemia in neonates: a case-
controlled study. Am J Perinatol 26:185–189
82. Masilamani K, van der Voort J (2012) The management of acute
hyperkalaemia in neonates and children. Arch Dis Child 97:376–380
83. Ditzenberger GR, Collins SD, Binder N (1999) Continuous insulin
intravenous infusion therapy for VLBW infants. J Perinat Neonatal
Nurs 13:70–82
84. Singh BS, Sadiq HF, Noguchi A, Keenan WJ (2002) Efficacy of
albuterol inhalation in treatment of hyperkalemia in premature ne-
onates. J Pediatr 141:16–20
2049
85. Helfrich E, de Vries TW, van Roon EN (2001) Salbutamol for
hyperkalaemia in children. Acta Paediatr 90:1213–1216
86. Yaseen H, Khalaf M, Dana A, Yaseen N, Darwich M (2008)
Salbutamol versus cation-exchange resin (kayexalate) for the treat-
ment of nonoliguric hyperkalemia in preterm infants. Am J
Perinatol 25:193–197
87. Wigglesworth JS, Keith IH, Girling DJ, Slade SA (1976) Hyaline
membrane disease, alkali, and intraventricular haemorrhage. Arch
Dis Child 51:755–762
88. Papile LA, Burstein J, Burstein R, Koffier H, Koops B (1978)
Relationship of intravenous sodium bicarbonate in fusions and ce-
rebral intraventricular hemorrhage. J Pediatr 93:834–836
89. Szpecht D, Szymankiewicz M, Nowak I, Gadzinowski J (2016)
Intraventricular hemorrhage in neonates born before 32 weeks of
gestation-retrospective analysis of risk factors. Childs Nerv Syst 32:
1399–1404
90. Vemgal P, Ohlsson A (2012) Interventions for non-oliguric
hyperkalaemia in preterm neonates. Cochrane Database Syst Rev
5:CD005257
91. Ohlsson A, Hosking M (1987) Complications following oral ad-
ministration of exchange resins in extremely low-birth-weight in-
fants. Eur J Pediatr 146:571–574
92. Bennett LN, Myers TF, Lambert GH (1996) Cecal perforation as-
sociated with sodium polystyrene sulfonate-sorbitol enemas in a
650 grams infant with hyperkalemia. Am J Perinatol 13:167–170
Answers
1. d
2. c
3. d
4. b
5. e