Acid-Base, Electrolyte and Fluid Alterations: Review

Kidney Dis 2016;2:72–79 Received: March 2, 2016

Accepted: April 19, 2016
DOI: 10.1159/000446268
Published online: May 26, 2016

Potassium: From Physiology to Clinical

Implications
Miriam Zacchia a Maria Luisa Abategiovanni a Spiros Stratigis b
Giovambattista Capasso a
a
Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences, Second University of Naples,
Naples, Italy; b Department of Nephrology, University Hospital of Heraklion, Heraklion, Greece

Key Words mediating K+ reabsorption and secretion along the nephron;

Hypokalemia · Hyperkalemia · K+ channels · Aldosterone (2) the pathophysiology of the principal K+ derangements
due to renal dysfunction, and (3) the effect of ingested K+ on
blood pressure and renal electrolyte handling. Key Messag-
Abstract es: Maintaining plasma K+ levels in a tight range is crucial for
Background: Potassium (K+) is the major intracellular cation, life; thus, multiple factors are implicated in K+ homeostasis,
with 98% of the total pool being located in the cells at a con- including kidney function. Recent studies have suggested
centration of 140–150 mmol/l, and only 2% in the extracel- that K+ plasma levels, in turn, affect renal salt absorption in
lular fluid, where it ranges between 3.5 and 5 mmol/l. A fine animal models; this effect may underlie the reduction of
regulation of the intracellular-extracellular gradient is crucial blood pressure observed in hypertensive subjects under K+
for life, as it is the main determinant of membrane voltage; supplementation. © 2016 S. Karger AG, Basel
in fact, acute changes of K+ plasma levels may have fatal con-
sequences. Summary: An integrated system including an
‘internal’ and ‘external’ control prevents significant fluctua-
tions of plasma levels in conditions of K+ loading and deple- Potassium Homeostasis
tion. The internal control regulates the intra-extracellular
shift, a temporary mechanism able to maintain a constant K+ Potassium (K+) is the most abundant intracellular cat-
plasma concentration without changing the total amount of ion. Of the 3,500 mEq that constitute the total pool of the
body K+. The external control is responsible for the excretion body, about 98% is confined to the intracellular fluid
of the ingested K+, and it has the kidney as the major player. (ICF), at concentrations of 140–150 mEq/l, and only 2%
The kidney excretes nearly 90% of the daily intake. Along the
proximal tubule and the thick ascending limb on Henle’s
loop, the amount of K+ reabsorption is quite fixed (about 80– This study was presented at the 1st Conference of the Internation-
al Network of Diagnosis and Management of Acid-Base, Electrolyte,
90%); conversely, the distal nephron has the ability to adjust and Fluid Alterations ‘Diagnosis and Management of Acid-Base, Elec-
K+ excretion in accordance with homeostatic needs. The trolyte and Fluid Alterations in Critically Ill Patients’ held in Shanghai
present review analyzes: (1) the main molecular mechanisms and Hangzhou on January 14–16, 2016.

© 2016 S. Karger AG, Basel Miriam Zacchia

2296–9381/16/0022–0072$39.50/0 Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences
Second University of Naples
E-Mail [email protected]
Via Pansini 5, IT–80131 Naples (Italy)
www.karger.com/kdd
E-Mail miriamzacchia @ virgilio.it
 The internal K+ homeostasis is mainly dependent on
K+£LQWDNH hormones such as insulin and catecholamines; in addi-
²£P(TGD\
tion, acid base balance and plasma osmolality regulate
cellular K+ uptake. This process is extremely efficient and
guarantees constant plasma [K+] through the regulation
of the Na+-K+ ATPase activity. The kidney is the main
([WUDFHOOXODU £ £ +]
,QWUDFHOOXODU>.
>.+] determinant of external K+ homeostasis, being responsi-
ble for the excretion of 90% of the K+ ingested, versus 10%
²£P(TO ²£P(TO eliminated via stools.
*£OLWHUV *£OLWHUV

Renal Homeostasis of K+
49–77 mEq ²£P(T A small fraction of plasmatic K+ ions may bind nonfil-
terable proteins, with a consequent restriction to glomer-
ular filtration. Unbound K+ is freely filtered across the
glomerulus, and the concentration of K in the glomerular
K+ £excretion
filtrate is equal to the plasmatic concentration.
Clearance studies during the 1940s and the 1950s dem-
²£P(TGD\ onstrated that the bulk of tubular K+ reabsorption occurs
along the proximal tubule (PT) and the thick ascending
8ULQH £ 6WRRO limb on Henle’s loop (TAL) [1] (fig. 2). In vivo micro-
(~90%) (~10%) £ puncture experiments in the 1960s showed that ∼50% of
the filtered load reaches the late PCT in the collections
from tubular fluids [2], indicating that the PT reabsorbs
Fig. 1. Schematic representation of K+ homeostasis.
the majority of the filtered load. The evidence of a strong
association between the rate of fluid and K+ reabsorption
suggests that, at least in part, K+ absorption occurs with a
solvent drag mechanism. In addition, a paracellular dif-
(nearly 70 mEq) is located in the extracellular fluids (ECF), fusion from the lumen to the interstitium is driven by the
where it ranges from 3.5 to 5 mEq/l. The K+ gradient be- difference of concentration (that is higher in the lumen
tween the ICF and the ECF is based on the activity of the upon fluid absorption) and by the favorable electrochem-
Na-K ATPase, located on the plasma membrane of all an- ical gradient, especially along the latest part of the PT. The
imal cells. As the intracellular K+ pool is much higher than role of transcellular transport is partially known. The ba-
the extracellular pool, clearly changes of total K+ content solateral Na-K ATPase mediates the electrogenic trans-
and/or distribution cause more dramatic fluctuations of port of K+ from the interstitium to the cell, generating a
extracellular rather than intracellular K+ concentration high intracellular [K+] and a cell-positive electric poten-
[K+]. However, several factors modulate K+ redistribution tial. Along the final part of the PT (segment S3), which
between the ICF and the ECF and its excretion in order to includes the fraction of the PT that enters the outer me-
maintain the extracellular concentration in a tight range. dulla, K+ is secreted into the luminal fluid. The presence
It is well known that an ingested K+ load does not re- of K+ channels has been demonstrated at both the baso-
sult in a significant increase in plasma [K+]. Theoretically, lateral and luminal sites. The K+ efflux to the lumen and
an intake of 35 mEq of K+ would raise its plasma level by to the interstitium generates a cell-negative gradient that
2.5 mEq/l in humans if the distribution was totally extra- provides the driving force for cation reabsorption. Im-
cellular. In contrast, only about a quarter of the ingested munofluorescence studies have demonstrated the pres-
K+ remains in the ECF, as a large cellular storage reservoir ence of KCNE1 and KCNQ1 proteins on the brush-bor-
(including muscle, liver and red blood cells) buffers plas- der membrane of PT, which colocalize to form an apical
ma K+ upon its intake. K+ channel. KCNE1–/– mice show hypokalemia and vol-
Both internal and external homeostasis contributes to ume depletion [3]. Micropuncture studies showed a
maintaining a normal K+ balance, by controlling its dis- strong reduction of K+ secretion along the PT. These
tribution (the first) and its excretion (the second) in ei- channels are supposed to mediate membrane repolariza-
ther conditions of K+ loading and K+ depletion (fig. 1). tion, as Na+ substrate absorption leads to membrane de-

Potassium: From Physiology to Clinical Kidney Dis 2016;2:72–79 73

Implications DOI: 10.1159/000446268
 K+ handling along the nephron

70% 10–20%

20% 5–30%

15–80%
Fig. 2. K+ reabsorption and secretion along
the nephron.

polarization. Accordingly, a defective function of the (DCT) has a minor role in K+ secretion compared with
KCNE-KCNQ1 channels, as in KCNE1–/– mice, affects the connecting tubule (CNT) and the cortical collecting
solute absorption leading to osmotic polyuria. Luminal duct (CCD). Microperfusion studies in rats showed that
[K+] concentration at the tip of the Henle’s loop is 10-fold the DCTs are able to secrete K+ through the K-Cl cotrans-
the plasma concentration. porter [5].
Along the descending limb, K+ is delivered to the tu- At the basolateral level, the presence of the K+ channel
bular fluid. It has been postulated that K+ ions are trapped KCNJ 10 kir4.1 has been shown to mediate K+ recycling
in the medulla by the countercurrent mechanism after to the interstitium, safeguarding the activity of the Na-K
being actively absorbed along the TAL and passively enter ATPase pump; genetic defects of this channel lead to salt
the lumen along the descending limb. K+ reabsorption wasting because of a reduced activity of the Na-K ATPase.
along the TAL is primary mediated by the Na-K-2Cl co- The CNT and collecting duct (CD) are the main seg-
transporter (NKCC2), following the Na+-favorable gradi- ments mediating K+ secretion. Along these segments, the
ent generated by the Na-K ATPase. The high intracellular epithelium is constituted mainly of principal cells, which
[K+] favors its recycling back to the lumen through the represent 70–75% of the total population; these cells
apical K+ channels ROMK. Several lines of evidence dem- mainly mediate Na reabsorption and K+ secretion. The
onstrate that K+ recycling through ROMK is crucial to latter requires several transmembrane proteins: first, the
guarantee Na-K-2Cl reabsorption; the uptake of these basolateral Na-K ATPase increasing the intracellular [K+]
ions is dramatically reduced by either reducing luminal provides the gradient for K+ efflux; in addition, apical Na+
[K+] and by blocking ROMK activity [4]. At the basolat- entry through the ENaC channels provides a favorable
eral level, the K+ efflux is mediated by the K-Cl and K- electrochemical gradient for K+ secretion; eventually, K+
HCO3– cotransporters besides the K channels. exit to the lumen is mediated by the ROMK channels, BK
Only 10% of the filtered load reaches the distal neph- (big potassium) channels and K-Cl cotransporter. Sev-
ron. The evidence that the amount of K+ excreted could eral lines of evidence demonstrate that BK channels me-
exceed the amount of K+ filtered suggested the presence diate the bulk of K+ secretion along the CNT and CCD in
of K+ secretion along the nephron. The final K+ excretion response to a high urinary flux [6]. Those channels are
(which is generally 10–20% of the filtered load) is mainly relatively inactive under normal conditions but are acti-
a function of distal secretion. The distal convolute tubule vated by a high urinary flow.

74 Kidney Dis 2016;2:72–79 Zacchia/Abategiovanni/Stratigis/Capasso

DOI: 10.1159/000446268
 A small fraction of epithelial cells along the distal Table 1. Main features of BS and GS patients
nephron is represented by intercalated cells that are scat-
tered among the principal cells. These cells are able to BS GS
reabsorb K+ under certain conditions, such as K+ deple- Polyhydramnios (due to fetus excessive Hypokalemia
tion. The α-intercalated cells show several isoforms of urine output) Metabolic alkalosis
K-H ATPase. The latter is also expressed along the gastric Polyuria and subsequent polydipsia Hypomagnesemia
and colonic mucosa, and it is inhibited by omeprazole. Dehydration due to volume depletion Hypocalciuria
These transporters are activated by hypokalemia and may Hypokalemic metabolic alkalosis
Hypercalciuria/nephrocalcinosis
serve as a compensatory machinery mediating increased
K+ reabsorption when needed.
As the rate of K+ reabsorption along the PT and the
TAL is mainly fixed, the final excretion depends mainly
on K secretion along the distal nephron. This process is gest that K+ homeostasis is under a feedforward control
under a fine regulation by several factors. that is inducted when minimal changes in plasma [K+]
occur. It has been established that the regulation of plas-
Feedback Control of K+ Homeostasis ma aldosterone by K+ is activated when the plasma [K+]
The feedback control in physiology is, by definition, a is higher or lower than normal, with little effect when it is
regulatory mechanism of a biological function that main- within the physiological range. In animal models, it has
tains specific parameters (temperature, pH, electrolyte been shown that after an oral K+ load, significant urinary
levels, etc.) in the optimal range through an internal con- K+ excretion occurs without changes in plasma aldoste-
trol. The negative feedback implicates the sensation of a rone concentration. However, the existence of a kaliuret-
stimulus (high plasma [K+]), which in turn activates some ic reflex has been suggested arising from an unknown
effectors that finally return the parameter back to normal. sensor in the splanchnic bed.
Several hormones constitute the effectors of the feedback The K+ adaptation refers to the increased K+ secretion
control of K+ homeostasis. A K+-rich meal induces the along the distal nephron after an ingested K+ load, without
pancreatic secretion of insulin, which stimulates the Na-K any significant change in aldosterone plasma levels. In an-
pump, minimizing the increase in plasma [K+] by pro- imal models, this adaptation is mediated by an increased
moting K+ uptake into the muscle cells [7]. When K+ plas- ROMK channel, Na-K ATPase and ENaC activity.
ma levels increase enough, hyperkalemia induces aldoste- Glucagon has been proposed as a potential effector of
rone secretion. Aldosterone, in turn, promotes renal K+ the feedforward control. This hormone is secreted upon
secretion through the upregulation of both the basolat- a protein-rich meal, and intraportal glucagon infusion
eral Na-K ATPase and the luminal K+ channels along the produces significant increases in renal blood flow and the
principal cells. In addition, aldosterone enhances K+ se- glomerular filtration rate. The feedforward regulation of
cretion along the colon, an essential function especially in K+ homeostasis may include several mechanisms: (1) in-
the presence of kidney disease. Conversely, when the ex- sulin release that rapidly induces cellular K+ uptake into
tracellular K+ content is reduced because of a deficient insulin-responsive tissues; (2) glucagon secretion that
intake or an increased urine excretion, K+ is released from promotes renal K+ excretion after a protein-rich meal; (3)
the intracellular space to the plasma. In this condition, a yet-unidentified gut sensor that enhances renal K+ ex-
skeletal muscle becomes insulin resistant to K+ (but not cretion after ingestion. When plasma [K+] increases be-
glucose) uptake, even before plasma [K+] decreases. In yond these layers of control, feedback regulation is acti-
addition, hypokalemia leads to the downregulation of the vated.
skeletal muscle Na-K ATPase isoform 2, with the conse-
quent leak of K+ to the plasma, and to the inhibition of
aldosterone release, with the reduction of urinary K+ se- Hypokalemia: Lessons from the Salt-Losing
cretion. Tubulopathies

Feedforward Control of K+ Homeostasis Genetic studies of inborn errors resulting in renal salt
A feedforward loop refers to a control system that re- wasting have provided novel insights into the pathophys-
sponds to a specific stimulus in a predefined manner. Be- iology of renal electrolyte handling. Additional studies on
sides the feedback control, several lines of evidence sug- engineered mice and cell culture have further highlighted

Potassium: From Physiology to Clinical Kidney Dis 2016;2:72–79 75

Implications DOI: 10.1159/000446268
the function of specific transport proteins and the mo- CLCKNA mutations in BS. ClCk1 (the ortholog of CLC-
lecular pathways regulating their activity. Ka)-deficient mice show a phenotype of nephrogenic dia-
Bartter (BS) and Gitelman (GS) syndromes are genet- betes insipidus.
ic disorders leading to hypokalemic metabolic alkalosis The fact that CLCKb is very abundant along the DT
due to renal loss, with a compensatory activation of the explains why this variant of BS is less commonly associ-
RAAS axis. Genetic studies have shed light onto the mo- ated with a defect of urinary concentration and with hy-
lecular basis underlying these disorders that have long percalciuria. Often, those patients show an overlapping
been considered two forms of the same disease (table 1). phenotype between BS and GS.
BS type IV refers to the BS forms correlated with BSND
Bartter Syndrome mutations, encoding for the Barttin subunit of the baso-
BS is a rare tubular dysfunction caused by a genetic lateral chloride channel. The CLC-K/Barttin Cl channels
mutation leading to a defective NaCl absorption along the also localize to the cochlea. In fact, patients carrying a
TAL. To date, mutations of five genes have been de- BSND mutation show a phenotype of BS associated with
scribed. The defect determines fluid and electrolyte loss hearing defects.
resulting in hypovolemia, with a compensatory activation BS type V is caused by gain-of-function mutations of
of the RAS axis, leading to hypokalemia and metabolic the calcium-sensing receptor (CaSR). The protein is ex-
alkalosis. pressed in the parathyroid and in the kidney, and it is
mainly involved in calcium homeostasis. Along the TAL,
Genetics the CaSR is expressed on the basolateral membrane. In
BS type I is caused by mutations of the SLC12A1 gene, the presence of hypercalcemia, the protein inhibits salt
encoding the kidney-specific Na-K-2Cl cotransporter absorption, with consequent calcium and magnesium
NKCC2. BS type II depends on KCNJ1 mutations, leading loss. Some case reports show that activating mutations of
to a defective function of the K+ channel ROMK. Immu- the CaSR show a BS phenotype.
nostaining studies have shown an apical distribution of
ROMK channels along the TAL, DCT and CD in rats, con- Clinical Presentation
sistent with a role in K+ secretion along the renal epithelia. BS may have different clinical presentations:
Along the TAL, ROMK channels mediate K+ efflux back to – Antenatal BS, or hyper-prostaglandin E2 syndrome, re-
the lumen, favoring NaCl reabsorption by supplying K+ to fers to the most severe form, characterized by polyhy-
the NKCC2, as described above. Thus, it is not surprising dramnios due to excessive urinary output and prema-
that the loss of function of ROMK results in a defective flu- ture birth. BS types I and II and sometimes type III are
id and salt reabsorption. As a consequence of NaCl and flu- associated with this clinical subtype. After birth, pa-
id loss, a stimulation of K+ secretion along the distal neph- tients commonly show fever, vomiting and lethargy.
ron leads to hypokalemia, a hallmark of all forms of BS. Biochemical analysis shows metabolic alkalosis, hypo-
Interestingly, patients carrying KCNJ1 mutations may show kalemia, iso-hypostenuria and hypercalciuria. Nephro-
hyperkalemia as an initial sign of the disease, soon after calcinosis is frequent. A high urinary excretion of pros-
birth; then, this defect is even reversed [8]. Micropuncture taglandin E2 or its metabolites is typical. High renin and
[9] and clearance [10] studies in young rats have demon- aldosterone plasma levels are due to volume depletion.
strated limited ability in K+ secretion compared with adults. The cause of the high urinary and plasmatic prostaglan-
Accordingly, in microperfused CCD from mammalians, din levels is still unknown; it is possible that this is due
K+ secretion is low in newborns and cannot be stimulated to the defective NaCl reabsorption along the TAL.
by tubular flow [11]. This defective adaptation has been – Classic BS is sustained by BS type III. The onset of the
linked to the low expression of the apical BK channels that disease occurs generally during childhood. The clini-
are known to mediate the flux-dependent K secretion. cal course is milder than in the antenatal subtype; pa-
BS type III depends on the mutation of the CLCKNB tients show polyuria and polydipsia; nephrocalcinosis
gene, encoding the basolateral Cl– channel, CLC-Kb. Two is uncommon.
proteins, CLC-Kb and CLC-Ka, encoded by the CLCNKb – BS with sensorineural deafness. BS type IV may have a
and CLCNKa genes, respectively, mediate the basolateral high variable of the severity of hydroelectrolyte imbal-
Cl– efflux along this segment. Both proteins are associated ance. The clinical form may range from the antenatal
with the Barttin subunit, essential for protein insertion form to mild hydroelectrolyte defects. Hearing loss is
into the plasma membrane. There is no evidence of typical for BS type IV.

76 Kidney Dis 2016;2:72–79 Zacchia/Abategiovanni/Stratigis/Capasso

DOI: 10.1159/000446268
 Gitelman Syndrome Hyperkalemia in the Setting of Renal Failure
Genetics
GS is a genetic tubular disorder sharing several analo- Hyperkalemia is a potential life-threatening electro-
gies with BS. It is caused by mutations of the SLC12A3 lyte imbalance. This condition may result from the dis-
gene, encoding the thiazide-sensitive sodium chloride co- ruption of the equilibrium between the ICF and ECF con-
transporter (NCC). Patients with heterozygous muta- centrations or from an increased total body content,
tions do not show the disease; some studies have shown caused by excessive food intake or defective excretion.
that they may have a tendency to exhibit hypotension, The resulting increased plasma [K+] leads to a partial
while complete GS phenotype occurs solely when the mu- membrane depolarization that may eventually cause car-
tation is in homozygosis. A minority of patients show dioplegia and skeletal muscle paralysis.
mutations of the CLCNKB gene, which is also responsible In the clinical setting, chronic renal failure is the most
for BS type III. The presence of the basolateral Cl– chan- common risk factor for chronic hyperkalemia [14]. As the
nel along the TAL and DT explains why patients carrying GFR declines, plasma [K+] is maintained in the normal
CLCKNB mutations often show a phenotype overlapping range until the latest stages of renal failure. A previous
between BS and GS. study demonstrated that stage IV CKD patients showed
the same increase in K+ secretion after K+ ingestion com-
Pathophysiology and Clinical Presentation pared with people with normal renal function, indicating
The defective NaCl absorption along the DCT leads to a conserved ability to excrete K+. This is possible because
an increased Na+ load to the distal nephron. The latter, the remaining nephrons enhance their ability to secrete
together with the activation of the RAAS induced by vol- K+ through the upregulation of the entire machinery me-
ume depletion, stimulates Na+ reabsorption along the diating its secretion along the distal nephron, including
CD, which in turn favors H+ and K+ secretion. the Na-K ATPase, the ENaC and ROMK channels [15].
Besides hypokalemia and metabolic alkalosis, hypo- However, those patients showed a higher increase in plas-
magnesemia and hypocalciuria are other hallmarks of the ma [K+] after K+ ingestion. This evidence suggested that
disease. The renal handling of Ca2+ and Mg2+ is only par- CKD patients may have an impaired internal K+ homeo-
tially understood in GS. stasis. However, this issue has been extensively investi-
Normally, Mg2+ is freely filtered by the glomerulus; it gated in animal models and humans, with conflicting re-
is then reabsorbed along the PT by 10% and along the sults. Thus, whether the tissue K+ distribution is impaired
TAL by 50–70% via a paracellular pathway [12]. Along in CKD is still debated [15]. When the GFR falls below 15
the DT, Mg2+ reabsorption occurs through a transcellular ml/min, the adaptive mechanisms that enable the re-
pathway, via the TRPM6 channels. Mice lacking the NCC maining nephrons to excrete the ingested K+ are over-
cotransporter show a downregulation of TRPM6 in either whelmed, and hyperkalemia may occur.
the DCT or in the intestine, leading to stool and urinary Several pathophysiological factors favor the develop-
Mg2+ loss. ment of hyperkalemia in CKD patients: (1) the reduced
Similar to Mg2+, Ca2+ ions are filtered by the glomeru- urine output in the latest stage of CKD impairs the flux-
lus and reabsorbed along the PT and TAL in a paracellu- dependent K+ secretion; (2) the presence of metabolic ac-
lar manner, following the favorable electrochemical gra- idosis, another common complication of the late CKD,
dient. Transcellular Ca2+ absorption occurs along the affects K+ distribution between the ICF and ECF by favor-
DCT, mediated by the voltage-sensitive Ca2+ channel ing K+ release to the extracellular space; (3) the presence
TRPV5 expressed on the apical membrane. of comorbidities, such as diabetes, with the reduction in
Low urine calcium excretion in GS is attributed to two insulin plasma levels and plasma hyperosmolality, in-
mechanisms: (1) the volume contraction induced by the creases the risk of hyperkalemia, and (4) the use of medi-
defective salt absorption along the CDT leads to a com- cations such as ACE inhibitors or ARBs.
pensatory increased NaCl absorption along the PT, which Deregulation of the RAS axis has a proven critical role
also drives paracellular Ca2+ absorption; (2) NCC inacti- in determining hyperkalemia in CKD patients. Several
vation determines cell hyperpolarization, which activates studies have demonstrated that the use of ACE inhibitors
TRPV5 channels leading to the increased Ca2+ absorption and/or ARBs reduces the intraglomerular pressure, re-
[13]. duces tubulointerstitial damage and slows the progres-
sion of kidney disease in animal models of CKD. Accord-
ingly, several trials have demonstrated the beneficial ef-

Potassium: From Physiology to Clinical Kidney Dis 2016;2:72–79 77

Implications DOI: 10.1159/000446268
 er effect in hypertensive patients [20]. Altogether, a num-
ber of epidemiological studies strongly suggest that in-
Urinary sodium excretion (mmol/day)

180
creasing dietary K+ intake has a protective effect on the
160 ** development of hypertension [21]. Whether K+ may have
140
a regulatory effect on the control of blood pressure is an
120
object of intensive investigations.
100
A number of potential mechanisms have been impli-
80
cated, including sodium retention, hormonal activation
60
and direct effect on the vascular smooth muscle function.
40
KCl supplementation has been shown to inhibit, while
20
low KCl diet enhances, NaCl reabsorption along the
0
Low K+ diet Normal K+ diet DCT, via the upregulation of NCC [22].
Dietary K+ loading, as well as increased plasma [K+] by
KCl infusion, resulted in increased urinary Na+ excretion
Fig. 3. Effect of K+ intake on urine Na+ excretion. ** p < 0.001 com-
pared with low K+ diet. Adapted from Krishna et al. [25].
in association with reduced NCC phosphorylation in rats
[23] (fig. 3). These findings suggest that K+ dietary intake,
through changes in plasma [K+], modulate NCC activity,
and therefore NaCl balance. Genetic diseases leading to
the activation (Gordon syndrome) and inactivation (GS)
fects of ACE and/or ARBs in CKD patients. The RAS of NCC cause opposite effects on plasma [K+], namely
inhibitor therapy has been shown to reduce the risk of hyperkalemia and hypokalemia, respectively. However, it
renal failure and cardiovascular events in CKD patients, is not surprising that extracellular [K+] may modulate
rendering RAS inhibitors the first-choice antihyperten- NCC function.
sive drugs [16]. However, the intensive treatment with Terker et al. [24] have recently demonstrated that ex-
RAS inhibitors in CKD patients increases the risk of ad- tracellular [K+] regulates NCC function directly, without
verse effects. The risk to develop hyperkalemia in stage 3 hormonal mediation. They showed that plasma [K+] af-
or higher CKD patients is low in those taking monother- fects urinary K+ excretion by altering Na+ delivery to the
apy with RAS blockers, unless volume depletion occurs CNT. Low K+ intake, leading to low plasma [K+], hyper-
[17]. Conversely, dual RAS blockade, even though it has polarizes plasma membrane and causes a reduction of in-
been proven to reduce proteinuria, does not show sig- tracellular [Cl–] in the DCT. The latter has been shown to
nificant benefits in slowing the progression of kidney dis- activate NCC via the WNK pathway, inducing a tempo-
ease or in reducing cardiovascular events, but increases rary increase in blood pressure in mice. This study indi-
the risk of hyperkalemia. The most recent KDIGO rec- cates that plasma [K+] modulates NCC function in a hor-
ommendations declare that there are insufficient data to mone-independent manner, through changes in intracel-
prove a real benefit of dual RAS blockade in slowing CKD lular [Cl–] that in turn modulate the function of WNK
progression, so it should not be routinely prescribed. kinases, known regulatory proteins of several transport-
ers, including NCC.
The opposite effect is supposed to be determined by
Effect of Plasma [K+] on Blood Pressure high K+ intake, which may lead to NCC inhibition with
consequent increased Na delivery to the distal nephron,
Epidemiological studies have demonstrated an inverse resulting in increased Na+ absorption and K+ secretion.
relationship between hypertension and dietary K+ intake.
In the 1980s, Lever et al. [18] demonstrated that ex-
changeable total Na+ and K+ showed a positive and nega- Conflict of Interest Statement
tive correlation, respectively, with hypertension. Further
All authors declared no competing interests.
independent survey studies have shown that low K+ in-
take correlates with high blood pressure [19]. A recent
meta-analysis has demonstrated that K+ supplementation
resulted in a reduction of systolic and diastolic blood
pressure by 4.7 and 3.5 mm Hg, respectively, with a great-

78 Kidney Dis 2016;2:72–79 Zacchia/Abategiovanni/Stratigis/Capasso

DOI: 10.1159/000446268
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Potassium: From Physiology to Clinical Kidney Dis 2016;2:72–79 79

Implications DOI: 10.1159/000446268