Acid-Base and Potassium Homeostasis

L. Lee Hamm, MD,*,† Kathleen S. Hering-Smith, MS, PhD,* and Nazih L. Nakhoul, PhD*

Summary: Acid-base balance and potassium disorders are often clinically linked. Importantly, acid-base
disorders alter potassium transport. In general, acidosis causes decreased K+ secretion and increased
reabsorption in the collecting duct. Alkalosis has the opposite effects, often leading to hypokalemia. Potassium
disorders also influence acid-base homeostasis. Potassium depletion causes increased H+ secretion,
ammoniagenesis and H-K-ATPase activity. Hyperkalemia decreases ammoniagenesis and NH4+ transport in
the thick ascending limb. Some combined potassium and acid-base disorders involve indirect factors such as
aldosterone, impaired renal function, volume depletion, and diarrhea. In summary, disorders of potassium and
acid-base homeostasis are mechanistically linked and clinically important.
Semin Nephrol 33:257-264 C 2013 Elsevier Inc. All rights reserved.
Keywords: Renal K+ regulation, pH, hypokalemia, hyperkalemia, potassium disorders, ammonia, acidosis,
alkalosis, aldosterone

C
linically, acid-base and potassium disorders
frequently are intertwined. The physiology of
potassium homeostasis and the interactions
with acid-base homeostasis are reviewed to provide a
background for understanding these clinical abnormal-
ities. Pathophysiology, rather than diagnosis or treat-
ment, is emphasized.
OVERALL POTASSIUM HOMEOSTASIS
Acid-base balance is one of the important factors that
affect potassium regulation. As such, an overview of
potassium homeostasis is necessary to put the influence
of acid-base disorders on potassium in context.
Although the kidneys are responsible for day-to-day
potassium balance, the first level of control of plasma
potassium involves the relationship with total body and
intracellular potassium. Importantly, some of the most
common abnormalities in potassium occur in the
setting of acute metabolic acidosis when the distribu-
tion of potassium between intracellular and extracel-
lular compartments is altered.
Most of the approximately 4,000 to 4,500 mEq
of total body potassium is inside cells, with a cytosolic
potassium concentration of approximately 120 to
140 mEq/L. As discussed elsewhere, the movement
*Departments of Medicine and Physiology, Tulane Hypertension
and Renal Center of Excellence, Tulane University Health
Sciences Center, New Orleans, LA.
†Medicine Service, Southeast Louisiana Veterans Health Care
System, New Orleans, LA.
Financial disclosure and conflict of interest statements: none.
Address reprint requests to L. Lee Hamm, MD, Professor and
Greenberg Chair of Medicine, Executive Vice Dean, Department
of Medicine, SL-12, Tulane University School of Medicine, 1430
Tulane Ave, New Orleans, LA 70112. E-mail: Lhamm@tulane.edu
0270-9295/ - see front matter
& 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.semnephrol.2013.04.006
of potassium into and out of cells is controlled predom-
inantly by Na-K-adenosine triphosphatase (ATPase) and
potassium channels, which, in turn, can be influenced by
many factors including insulin levels, adrenergic activ-
ity, plasma aldosterone concentration, osmolality, and,
importantly for the purposes here, acid-base homeo-
stasis. In general, clinical acidosis is associated with
hyperkalemia; alkalosis is associated with hypokalemia.
The effect of acidosis is complex because organic
metabolic acidoses (such as ketoacidosis and lactic
acidosis) do not directly promote hyperkalemia.1–4 In
addition, acute acidosis may be accompanied by release
of insulin, which tends to drive potassium back into
cells.5 Nonetheless, clinical conditions of organic acido-
sis, specifically ketoacidosis, lactic acidosis, and renal
failure, all are accompanied frequently by hyperkalemia;
the mechanisms may not directly involve the acidosis
per se, but rather other factors such as insulin deficiency
and decreased urinary excretion in these conditions. In
contrast, so-called mineral acidosis (or hyperchloremic
metabolic acidosis), even during experimental admin-
istration of mineral acids, is associated directly with
hyperkalemia. The mechanisms of the direct effects of
acidosis on K+ movement into and out of cells recently
was reviewed.6 The mechanisms whereby acidosis
causes potassium release out of cells have been thought
to involve a number of factors, likely including dimin-
ished Na-K-ATPase activity (owing to changes in cell
Na from secondary effects of other cell transporters
such as the Na-H exchanger), binding of protons to
negatively charged cellular proteins and pH-sensitive
K+ channels.6
RENAL POTASSIUM HANDLING
Maintaining normal potassium balance is dependent on
three basic processes: (1) Kþ intake; (2) Kþ excretion;
and (3) internal distribution of Kþ between the
extracellular and intracellular fluid compartments.

Seminars in Nephrology, Vol 33, No 3, May 2013, pp 257–264 257

258
Dietary Kþ intake (usually 80-120 mmol/d) must be
excreted to remain in balance. With the limited
excretion of Kþ by the colon (  5% to 10% of ingested
Kþ), the kidneys are largely responsible for excreting
the majority of ingested Kþ (about 90%-95% of daily
Kþ intake).
Of note, dietary Kþ intake often exceeds the total
content of the extracellular fluid compartment (  70
mmol), but sudden increases in extracellular Kþ (as
with dietary intake) are buffered by transiently moving
Kþ from the extracellular to the much larger intra-
cellular compartment.
Nephron Segmental Transport
The kidneys filter approximately 800 mmol of Kþ per
day and normally excretes 10% to 15% of the filtered
Kþ to maintain balance. However, the amount of
filtered Kþ that is excreted varies significantly depend-
ing on dietary intake. For example, during low Kþ
intake, renal excretion of Kþ is 1% to 3% of filtered
Kþ, but can reach up to 150% of filtered Kþ during
chronic high Kþ intake. In all cases (low or high
intake), the proximal tubule and the loop of Henle
absorb very large amounts of filtered Kþ (  90% of
filtered load). Under normal or high dietary Kþ intake,
the distal Kþ-secretory system composed of the initial
connecting tubule (ICT) and the cortical collecting duct
(CCD) as well as the initial segment of the medullary
collecting duct (MCD), secrete Kþ. Under low dietary
Kþ intake, these segments reabsorb Kþ. Regardless of
intake or function of the distal Kþ-secretory system,
the MCD reabsorbs Kþ. A fraction of the Kþ reab-
sorbed by the MCD is secreted into the lumen of the
thin descending loop of Henle, contributing to medul-
lary Kþ recycling.7
A bigger fraction of the reabsorbed Kþ is deposited
in the medullary interstitium, which contributes to
trapping Kþ in the deep medulla. The overall effect
in the loop of Henle is a net re-absorption of Kþ
despite some secretion in the thin descending limb of
the loop. Thus, the pattern of Kþ handling by the
nephron can be summarized as follows: filtered Kþ is
reabsorbed in the proximal tubule (  80%) and the
loop of Henle (  10%). Under normal or high Kþ
intake, the distal Kþ-secretory system (ICT, CCD,
initial MCD) secretes 20% to 180% of Kþ and the
medullary CD reabsorbs 20% to 40%, resulting in a net
excretion of Kþ (20%-150%). During low Kþ intake,
ICT, CCD, and initial MCD reabsorbs Kþ (  2%) and
the medullary CD reabsorbs about 6%, resulting in net
excretion of Kþ (  2%). It should be noted that even
during low Kþ intake the kidneys cannot fully prevent
Kþ loss in the urine, which may lead to potassium
depletion over time.7
L.L Hamm, K.S Hering-Smith, and N.L Nakhoul
Cellular Mechanisms of Renal Potassium Transport
At the cellular level, filtered Kþ is re-absorbed in the
proximal tubule through the paracellular pathway by
solvent drag and by diffusion.8,9 Kþ re-absorption
by solvent drag, whereby fluid re-absorption drives
Kþ re-absorption, occurs along the whole length of the
tubule. In the late proximal tubule, the transepithelial
positive voltage provides the necessary gradient to
drive Kþ re-absorption by diffusion across the para-
cellular pathway. The transcellular transport of Kþ
does not favor Kþ re-absorption. At the basolateral
membrane, Kþ transport by Na-K-ATPase leads to Kþ
influx, which usually is countered by Kþ efflux
through basolateral Kþ channels10 and a K-Cl cotrans-
porter. Kþ channels are present at the apical membrane
but are largely inactive unless activated by cell
swelling (stretch activated Kþ channels).11,12 Thus, in
the proximal tubule, there is net re-absorption of
Kþ exclusively through the paracellular pathway.
In the thick ascending limb of Henle’s loop (TAL)
Kþ is reabsorbed both by paracellular and trans-
cellular routes. Paracellular reabsorption of Kþ is
driven by the significant transepithelial positive volt-
age. Transcellular re-absorption of Kþ is predomi-
nately via the apical Na/K/2Cl cotransporter13,14
coupled to basolateral exit via Kþ channels. The apical
membrane of the TAL also has important Kþ con-
ductance via Kþ channels, called renal outer medullary
K+ channel (ROMK2).15 Kþ transport through this
channel (from cell to lumen) is important for recycling
cell Kþ to ensure that luminal Kþ concentration
remains high enough for Na/K/2Cl to function. The
presence of ROMK2 at the apical membrane explains
why TAL converts to Kþ secretion when Na/K/2Cl is
inhibited by loop diuretics.16 In the TAL almost half of
the Kþ re-absorption is via the paracellular route and
the other half is via the transcellular pathway. Part of
the reabsorbed Kþ in the TAL is secreted into the thin
descending loop (Kþ recycling). This process is
entirely passive, driven by high Kþ gradient and Kþ
permeability of this segment of the nephron.
As discussed earlier, in the distal tubule and
collecting duct, Kþ can be either reabsorbed or
secreted depending on the status of Kþ balance. Kþ
re-absorption occurs in the ICT, CCD, and MCD
during Kþ restriction.17,18 Kþ re-absorption in these
segments is transcellular and is performed by α
intercalated cells.19,20 In these cells, Kþ is reabsorbed
at the apical membrane via H-K-ATPase (a primary
active pump) and exits the cell at the basolateral
membrane via Kþ channels (Kþ leak). H-K-ATPase
is at least partly responsible for the development of
alkalosis during conditions of severe Kþ depletion.
Kþ secretion, during normal or high Kþ intake, is
mediated predominantly by the principal cells of the
Acid-base and potassium homeostasis 259

Table 1. Major Factors That Regulate Kþ Secretion

+
Net Effect on K
Factor Secretion Target of Action
Aldosterone ↑ Na-K pump; epithelial Na channel (ENaC); K+ conductance of
apical membrane
High Kþ intake ↑ Stimulates Na-K pump; Stimulates aldosterone release by
adrenal glands
High luminal flow ↑ Enhanced K+ conductance in principal cells; decreased
luminal [K+], enhancing gradient
Depolarization of luminal membrane, more ↑ ENaC in principal cells
negative luminal voltage
Glucocorticoids ↑ Increased glomerular filtration rate and luminal flow rate
Acidosis ↓ Decrease in intracellular pH inhibits Na-K pump and apical Kþ
conductance

ICT and CCD. The main pathways for Kþ secretion by
these cells are the basolateral Na-K-ATPase (causing
Kþ influx at the basolateral membrane) coupled to a
relatively high Kþ conductance at the apical membrane
(causing Kþ efflux into the lumen).21,22 Apical Kþ
conductance is mediated by two types of channels: an
inwardly rectifying, ATP-sensitive, low-conductance,
secretory K+ channel encoded by ROMK, and a high-
conductance, Ca2þ and/or stretch-activated BK channel
(or maxi-K channel). Maxi-K channels also are present
in intercalated cells.23 Maxi-K channels also are
present in intercalated cells. The electrochemical gra-
dient usually favors Kþ exit across the apical mem-
brane. The secretory K+ channel probably accounts for
baseline Kþ secretion and BK facilitates flow-
stimulated K+ secretion. Of note, the capacity for Kþ
secretion diminishes significantly from the cortical to
the medullary segments of the collecting ducts. In
addition to the K+ channels, there also may be coupled
KCl secretion via an electroneutral transporter in the
apical membrane.
REGULATION OF RENAL POTASSIUM TRANSPORT
The major variable component of renal Kþ transport is Kþ
secretion and is the target of most regulatory factors. These
factors are summarized in Table 1. As noted, aldosterone
and distal nephron sodium reabsorption are major regu-
lators of K+ secretion. One of the most potent factors that
stimulates Kþ secretion is the luminal flow rate.24,25 Under
all conditions, an increased luminal flow rate (including
increased urine flow during volume expansion, osmotic
diuresis, or use of diuretics) increases Kþ secretion. The
major effects are the high apical Kþ transport in principal
cells whereby washout of luminal Kþ (during high
luminal flow rate) increases the Kþ gradient and Kþ
efflux, and increased delivery and reabsorption of sodium.
Other factors that directly or indirectly influence luminal
flow rate also affect Kþ secretion.
EFFECTS OF ACID-BASE ABNORMALITIES
ON RENAL POTASSIUM TRANSPORT
Acid-base abnormalities alter potassium transport by
several well-known mechanisms that are discussed.
Potassium abnormalities also affect acid-base homeo-
stasis, which is discussed in a subsequent section
(Table 2 and Figure 1). Also, clearly a number of
conditions (such as disorders of aldosterone) affect
both potassium and acid-base homeostasis.
Acidosis, in addition to causing redistribution of
potassium between cells and extracellular fluid, causes
both decreased potassium secretion and increased
potassium reabsorption in the collecting duct.26
Decreased secretion and increased reabsorption obvi-
ously will cause increased extracellular potassium
levels. By causing intracellular acidosis, both meta-
bolic and respiratory acidosis decrease the activity of
the secretory apical potassium channels in the principal
cells of the collecting duct.27–29 In addition, acidosis,
by stimulating ammoniagenesis, will have further
effects on potassium secretion. Ammonium inhibits
sodium reabsorption in the collecting duct and hence
secondarily alters potassium secretion30,31 and may
directly impact apical K+ channels.29 In addition,
acidosis stimulates H-K-ATPase in the collecting duct
and thereby increases potassium reabsorption across
the apical membrane.32–34 The effects of acidosis may
be modulated chronically by changes in luminal flow
rate or aldosterone levels; notably, chronic metabolic
acidosis inhibits proximal tubule and thick ascending
limb reabsorption of salt and water and may contribute
to increased distal tubule flow rates, which would in
isolation increase potassium excretion.35,36 The effect
in the thick ascending limb may be from inhibition of
the ROMK channel present at the apical membrane,
which is inhibited by intracellular acidosis. Therefore,
acidosis immediately may cause increased plasma
potassium, but chronically acidosis can be associated
260 L.L Hamm, K.S Hering-Smith, and N.L Nakhoul

Table 2. Major Direct Interactions of Acid-Base Homeostasis and Potassium Balance

Acidosis directly leading to hyperkalemia
Redistribution of K+ out of cells (mineral acidosis)
Decreased K+ secretion in distal tubule
Direct effect on secretory K+ channels
Increased renal ammonium decreasing K+ secretion
Increased K+ reabsorption via increased H-K-ATPase
Alkalosis leading to hypokalemia
Increased distal tubule apical K+ channel activity
Increased KCl secretion with low luminal Cl
Direct effects of K+ on acid-base homeostasis
K+ depletion - intracellular acidosis - increased Hþ secretion in proximal and distal tubule, increased ammoniagenesis
K+ depletion increasing H-K-ATPase (and H-ATPase)
Hyperkalemia decreases ammoniagenesis and medullary thick ascending limb NH4þ transport

NOTE. A variety of conditions (such as disorders of aldosterone) cause simultaneous effects on K+ and acid-base homeostasis, which
initially are not directly secondary to their interactions.

with potassium deficits owing to increased urinary
excretion from secondary consequences of acidosis.37
Alkalosis increases apical K+ channel activity.28
Increasing luminal bicarbonate, as may occur in proximal
renal tubular acidosis or conversely in metabolic alkalosis,
will increase potassium secretion.38 Low luminal chloride,
which usually accompanies high luminal bicarbonate, will
stimulate neutral KCl secretion.39 The alkalosis also
increases basolateral potassium conductance.40
Influences of Potassium on Acid-Base Homeostasis
Not only can acidosis or alkalosis affect plasma
potassium through a variety of mechanisms, but

Gln pH Na+
PC
K+
NH4+
H+ K+
Na+ H+
K+
IC
H+

NH4+

K+

Figure 1. Simplified schematic of some of the renal interactions of acid-base homeostasis and K+. Upper left: a
proximal tubule cell; upper right: a principle cell (PC) and intercalated cell (IC). Acidosis (↓ pH) has a number of
effects to cause renal potassium retention: blocks secretory K+ channels, stimulates H-K-ATPase, which
reabsorbs K+, and increases ammoniagenesis, which will have downstream effects that may block K+ secretion.
Alkalosis can cause some of the reverse actions. Potassium depletion (↓ K+) stimulates proximal ammoniagenesis
and Hþ secretion/bicarbonate reabsorption, and also distal acid secretion, all of which can produce metabolic
alkalosis. Hyperkalemia can have many of the opposite effects; in addition, hyperkalemia blocks thick ascending
limb ammonium transport, further impairing urinary ammonium excretion, an effect that may cause acidosis.
Acid-base and potassium homeostasis
potassium disorders also can influence acid-base
homeostasis dramatically. Several notable mechanisms
are present. First, potassium depletion increases Hþ
secretion in both the proximal and distal nephron. The
mechanism is thought to be that potassium depletion
causes intracellular acidosis.41 The increased Hþ
secretion with potassium depletion is known to cause
increased bicarbonate reabsorption in the proximal
tubule42,43 and increased acid secretion in the collect-
ing duct. In the proximal tubule, potassium depletion
clearly stimulates basolateral bicarbonate extrusion via
the Na bicarbonate cotransport and apical Na-H
exchange also is induced and stimulated.44–47 Basolateral
Na bicarbonate cotransport in the thick ascending limb
also may be increased.46 In the distal tubule and
collecting duct, both H-K-ATPase and H-ATPase are
increased.48–53 Although some of this evidence supports
induction of the gastric form of H-K-ATPase, the colonic
form of H-K-ATPase is clearly stimulated.47,54,55
In contrast, hyperkalemia decreases ammonium
excretion, which is the major component of net acid
excretion by the kidneys. This results from hyper-
kalemia suppressing both ammoniagenesis in the
proximal tubule, and decreasing transport of ammo-
nium in the medullary thick ascending limb, which in
turn decreases medullary accumulation of ammo-
nium.56,57 Potassium depletion and/or hypokalemia
causes metabolic alkalosis,58 at least partly secondary
to stimulated ammoniagenesis,59 probably via effects
on multiple metabolic steps. Induction of H-K-ATPase
also may mediate increased secretion of ammonium.60
Interestingly, some of these effects of potassium
depletion on acid-base homeostasis are species-
dependent.47 The degree of alkalosis is accentuated
Table 3. Major Clinical Conditions of Simultaneous Acid-Base
and Potassium Abnormalities
Hyperkalemia and metabolic acidosis
Redistribution of intracellular K+ in acute acidosis
Hyperchloremic metabolic acidosis
Organic acidosis from indirect/other mechanisms: lactic
acidosis, ketoacidosis, and renal failure
Decreased urinary K+ excretion
Hypoaldosteronism or aldosterone antagonists
Hyperkalemic renal tubular acidosis
Chronic kidney disease
Hypokalemia and metabolic alkalosis
Volume or chloride depletion alkalosis (usually vomiting or
diuretics)
Primary hyperaldosteronism
Secondary hyperaldosteronism (eg, renal artery stenosis,
malignant hypertension)
Hypokalemia and acidosis
Diarrhea
Renal tubular acidosis: proximal RTA, classic distal RTA
261
when dietary sodium chloride is limited.61 Importantly,
potassium depletion per se should decrease aldosterone
secretion, thus eliminating this as a mechanism of the
effects of potassium on acid-base homeostasis.
CONDITIONS WITH COMBINED POTASSIUM
AND ACID-BASE DISORDERS
Hyperkalemia in Acidosis
In many conditions of acidosis, there is accompanying
hyperkalemia (Table 3). In cases of acute metabolic
acidosis, acute hyperkalemia frequently occurs from a
number of different mechanisms such as impaired
cellular potassium uptake from effects on Na,K-
ATPase, decreased urinary excretion of potassium or
tissue necrosis which directly leads to potassium
cellular efflux. As noted earlier, so-called mineral
acidosis or hyperchloremic acidosis directly can shift
K+ out of cells into the extracellular fluid. In cases of
diabetic ketoacidosis, the hyperkalemia undoubtedly is
caused in part by the insulin deficiency that prevents
normal potassium uptake into cells, particularly muscle
cells. In lactic acidosis, hyperkalemia may result from
damaged or hypoxic cells releasing potassium. In renal
failure, the hyperkalemia probably results predomi-
nantly from the decreased urinary excretion of potas-
sium. Fulop2 concluded that hyperkalemia in diabetic
ketoacidosis and lactic acidosis usually results from
hypercatabolism, impaired renal function, or both.
In chronic acidosis, a variety of other mechanisms
occur in addition to redistribution of potassium
between cells and extracellular fluid. These other
mechanisms lead to decreased urinary excretion of
potassium, chiefly owing to decreased distal tubule
secretion of potassium, as discussed earlier. The classic
example is that of aldosterone deficiency or inhibition.
Because plasma aldosterone concentration affects the
distribution of potassium between the intracellular and
extracellular compartments62 (hence plasma potassium
concentration) and also regulates acid excretion in the
distal nephron, aldosterone deficiency or inhibition will
result in both hyperkalemia and hyperchloremic meta-
bolic acidosis. (As discussed elsewhere, in most
circumstances, aldosterone stimulates K+ secretion in
the cortical portions of the distal nephron, but can
stimulate K+ absorption in the medullary collecting
duct, resulting in little net change in K+ excretion.)
Conditions such as primary hypoaldosteronism or use
of aldosterone antagonists (currently spironolactone
and eplerenone) can result in both hyperkalemia and
metabolic acidosis, although the latter may be rela-
tively mild. Adrenal insufficiency or Addison's disease
will similarly result in variable degrees of hyperkale-
mia and metabolic acidosis. Use of angiotensin-
converting enzyme inhibitors or angiotensin-receptor
262
blockers can similarly, in some cases, result in at least
a propensity for hyperkalemia and metabolic acidosis.
This will be manifested particularly in patients who
have some other condition favoring potassium and acid
retention, such as chronic kidney disease. Certain
conditions with impaired renal function (eg, post-
transplant particularly with certain calcineurin inhibitors)
also have this propensity and/or frank hyperkalemia and
acidosis. Also, genetic conditions mimicking aldosterone
deficiency such as pseudohypoaldosteronism type 1
(from loss-of-function mutations in the mineralocorticoid
receptor or the epithelial sodium channel) will cause
hyperkalemia and varying metabolic acidosis.
Related sets of conditions are sometimes classified
as type IV renal tubular acidosis or hyporeninemic
hypoaldosteronism or hyperkalemia renal tubular
acidosis. The most common occurrence of this happens
in some diabetic patients with mild to moderate renal
insufficiency. Presumably, mild volume expansion
leads to increased atrial natriuretic peptide levels,
which in turn suppress renin and aldosterone.63,64
Renin levels also may be low owing to diabetic
damage to the juxtaglomerular apparatus. In the patho-
genic sequence, presumably this results in a low
aldosterone level, which causes potassium retention
(and some metabolic acidosis); the hyperkalemia then
suppresses ammoniagenesis and ammonia secretion
into the urine, resulting in hyperchloremic metabolic
acidosis. The importance of hyperkalemia in suppress-
ing ammonia excretion and causing acidosis is illus-
trated by the fact that treatment of the hyperkalemia
alone (by loop diuretics or potassium binding resins)
frequently is sufficient to correct the acidosis. In addi-
tion to diabetes, other classic causes of hyperkalemic
renal tubular acidosis are sickle cell disease, chronic
partial urinary tract obstruction, and other causes of
interstitial renal disease. Some of these have been
classified as voltage-dependent renal tubular acidosis
because impaired transepithelial voltage generation in
the collecting duct impairs both potassium secretion
and acid secretion.
Hypokalemia with Alkalosis
The inverse of the earlier-described conditions is the
combination of alkalosis with hypokalemia; this also is
a relatively frequent occurrence and prompts consid-
eration of a set of disorders to be discussed. Although
there is some shift of potassium into cells with acute
alkalosis, this is not usually of a serious magnitude.
Most of the conditions whereby metabolic alkalosis
and hypokalemia occur together are chronic condi-
tions. The most common category of causes of meta-
bolic alkalosis with hypokalemia are those associated
with volume and chloride depletion: vomiting (or
nasogastric suction) or diuretics. In these conditions,
L.L Hamm, K.S Hering-Smith, and N.L Nakhoul
there is initial loss of both potassium and acid
equivalents via the gastrointestinal or urinary tracts,
but there are frequently additional urinary losses from
increased aldosterone (from volume depletion) and
other intrarenal mechanisms. When volume depletion
or diuretic use is not present, the combination of
metabolic alkalosis and hypokalemia should prompt
consideration of conditions of primary or secondary
hyperaldosteronism. In primary hyperaldosteronism,
the magnitude of the hypokalemia and the metabolic
alkalosis usually correlate.65 Secondary hyperaldoster-
onism would include conditions such as renal artery
stenosis, malignant hypertension, and, rarely, volume
depletion associated with diarrhea.
Primary hyperaldosteronism increasingly is recog-
nized as a relatively common form of severe or
refractory hypertension as discussed extensively by I.
David Weiner in a separate article in this issue (see
page 265).66 The present discussion is restricted to the
effects on acid-base and potassium balance. Some
cases of Cushing syndrome also are accompanied by
an electrolyte pattern mimicking a mineralocorticoid
effect. At least part of the mechanism of this phenom-
enon is that cortisol activates the mineralocorticoid
receptor well. With the usual concentrations of plasma
cortisol, the mineralocorticoid receptor in the distal
nephron is not activated because these cells have the
enzyme 11β-hydroxysteroid dehydrogenase type 2
(11β-HSD), which metabolizes cortisol to inactive
metabolites. When cortisol levels exceed the ability
of this enzyme to fully metabolize excess cortisol,
cortisol will activate the mineralocorticoid receptor,
causing all of the usual effects of aldosterone (sodium
retention, hypertension, acid secretion causing meta-
bolic alkalosis, and increased potassium secretion
causing hypokalemia).
Certain other genetic disorders mimic hyperaldos-
teronism. First, Liddle syndrome with activating muta-
tions of the epithelial sodium channel causes sodium
retention and hypertension; the voltage effects of the
activated sodium channels also drive potassium and
Hþ secretion in the collecting duct. Apparent miner-
alocorticoid excess results from a genetic deficiency of
11β-HSD, causing all the effects of hyperaldosteron-
ism, but secondary to normal levels of circulating
cortisol. Glycyrrhizic acid in certain forms of licorice
inhibits 11β-HSD and produces a similar phenotype.
In most of the conditions described earlier, alkalosis
and hypokalemia occur together in large part as dual
consequences of a mineralocorticoid effect. However,
for the reasons detailed earlier, hypokalemia exacer-
bates the metabolic alkalosis and should be treated to
correct metabolic alkalosis. In rare cases, isolated
severe potassium depletion will be the sole cause of
metabolic alkalosis via the mechanisms described
earlier.
Acid-base and potassium homeostasis
Hypokalemia with Acidosis
In other clinical conditions, there may be coincident
potassium abnormalities and acid-base abnormalities,
but these are not linked by the same direct pathogenic
mechanisms as described earlier. For instance, diarrhea
causes both metabolic acidosis and potassium deple-
tion; however, these result from simultaneous loss of
potassium and loss of alkali in the stool rather than
from a direct interaction. Somewhat similarly, both
type I and type II renal tubular acidosis involve
hyperchloremic metabolic acidosis and hypokalemia.
The acidosis results from defective acid secretion in the
distal and proximal tubule, respectively. The potassium
wasting and hypokalemia in classic distal renal tubular
acidosis (type I RTA) presumably results from a
variety of factors such as the voltage effects of loss
of Hþ secretion (resulting in increased K+ secretion)
and in some cases possibly from tubular damage
causing excessive potassium loss. In proximal RTA
(type II RTA), the hypokalemia presumably results
from excessive potassium secretion because the
capacity of the distal nephron is exceeded with
delivery of solutes out of the proximal tubule. A
variety of other clinical circumstances also can lead
to coincidental potassium and acid-base conditions that
are not necessarily mechanistically linked.
In summary, disorders of potassium and acid-base
balance are commonly linked clinically and/or mech-
anistically. Understanding this linkage and the mech-
anisms involved assists the clinician in the diagnosis of
both common and certain unusual disorders, and in
their management.
REFERENCES
1. Oster JR, Perez GO, Vaamonde CA. Relationship between
blood pH and potassium and phosphorus during acute meta-
bolic acidosis. Am J Physiol. 1978;235:F345-51.
2. Fulop M. Serum potassium in lactic acidosis and ketoacidosis.
N Engl J Med. 1979;300:1087-9.
3. Adrogue HJ, Madias NE. Changes in plasma potassium
concentration during acute acid-base disturbances. Am J Med.
1981;71:456-67.
4. Perez GO, Oster JR, Vaamonde CA. Serum potassium concen-
tration in acidemic states. Nephron. 1981;27:233-43.
5. Wiederseiner JM, Muser J, Lutz T, Hulter HN, Krapf R. Acute
metabolic acidosis: characterization and diagnosis of the dis-
order and the plasma potassium response. J Am Soc Nephrol.
2004;15:1589-96.
6. Aronson PS, Giebisch G. Effects of pH on potassium: new
explanations for old observations. J Am Soc Nephrol. 2011;
22:1981-9.
7. Giebisch G. Renal potassium transport: mechanisms and
regulation. Am J Physiol. 1998;274:F817-33.
8. Kibble JD, Wareing M, Wilson RW, Green R. Effect of barium
on potassium diffusion across the proximal convoluted tubule
of the anesthetized rat. Am J Physiol. 1995;268:F778-83.
9. Wareing M, Wilson RW, Kibble JD, Green R. Estimated
potassium reflection coefficient in perfused proximal
263
convoluted tubules of the anaesthetized rat in vivo. J Physiol.
1995;488:153-61.
10. Hunter M, Kawahara K, Giebisch G. Potassium channels along
the nephron. Fed Proc. 1986;45:2723-6.
11. Filipovic D, Sackin H. Stretch- and volume-activated channels
in isolated proximal tubule cells. Am J Physiol. 1992;262:
F857-70.
12. Kawahara K, Hunter M, Giebisch G. Potassium channels
in Necturus proximal tubule. Am J Physiol. 1987;253:
F488-94.
13. Greger R. Ion transport mechanisms in thick ascending limb of
Henle's loop of mammalian nephron. Physiol Rev. 1985;65:
760-97.
14. Hebert SC, Andreoli TE. Control of NaCl transport in the thick
ascending limb. Am J Physiol. 1984;246:F745-56.
15. Mennitt PA, Wade JB, Ecelbarger CA, Palmer LG, Frindt G.
Localization of ROMK channels in the rat kidney. J Am Soc
Nephrol. 1997;8:1823-30.
16. Giebisch G, Klein-Robbenhaar G, Klein-Robbenhaar J, Rathe-
iser K, Unwin R. Renal and extrarenal sites of action of
diuretics. Cardiovasc Drugs Ther. 1993;7 Suppl 1:11-21.
17. Okusa MD, Unwin RJ, Velazquez H, Giebisch G, Wright FS.
Active potassium absorption by the renal distal tubule. Am J
Physiol. 1992;262:F488-93.
18. Wright FS, Giebisch G. Renal potassium transport: contribu-
tions of individual nephron segments and populations. Am J
Physiol. 1978;235:F515-27.
19. Kaissling B. Structural aspects of adaptive changes in renal
electrolyte excretion. Am J Physiol. 1982;243:F211-26.
20. Madsen KM, Tisher CC. Structural-functional relationship
along the distal nephron. Am J Physiol. 1986;250:F1-15.
21. Giebisch G, Wang W. Potassium transport: from clearance to
channels and pumps. Kidney Int. 1996;49:1624-31.
22. Malnic G, Klose RM, Giebisch G. Micropuncture study of
renal potassium excretion in the rat. Am J Physiol. 1964;206:
674-86.
23. Liu W, Schreck C, Coleman RA, Wade JB, Hernandez Y,
Zavilowitz B, et al. Role of NKCC in BK channel-mediated net
K+ secretion in the CCD. Am J Physiol Renal Physiol.
2011;301:F1088-97.
24. Khuri RN, Strieder WN, Giebisch G. Effects of flow rate and
potassium intake on distal tubular potassium transfer. Am J
Physiol. 1975;228:1249-61.
25. Malnic G, Berliner RW, Giebisch G. Flow dependence of Kþ
secretion in cortical distal tubules of the rat. Am J Physiol.
1989;256:F932-41.
26. Stanton BA, Giebisch G. Effects of pH on potassium transport
by renal distal tubule. Am J Physiol. 1982;242:F544-51.
27. Choe H, Zhou H, Palmer LG, Sackin H. A conserved
cytoplasmic region of ROMK modulates pH sensitivity, con-
ductance, and gating. Am J Physiol. 1997;273:F516-29.
28. Wang WH, Schwab A, Giebisch G. Regulation of small-
conductance Kþ channel in apical membrane of rat cortical
collecting tubule. Am J Physiol. 1990;259:F494-502.
29. Schlatter E, Haxelmans S, Hirsch J, Leipziger J. pH dependence
of Kþ conductances of rat cortical collecting duct principal
cells. Pflugers Arch. 1994;428:631-40.
30. Nakhoul NL, Hering-Smith KS, Abdulnour-Nakhoul SM,
Hamm LL. Ammonium interaction with the epithelial
sodium channel. Am J Physiol Renal Physiol. 2001;281:
F493-F502.
31. Hamm LL, Gillespie C, Klahr S. NH4Cl inhibition of transport
in the rabbit cortical collecting tubule. Am J Physiol. 1985;248:
F631-7.
32. Milton AE, Weiner ID. Intracellular pH regulation in the rabbit
cortical collecting duct A-type intercalated cell. Am J Physiol.
1997;273:t-7.
264
33. Silver RB, Mennitt PA, Satlin LM. Stimulation of apical H-K-
ATPase in intercalated cells of cortical collecting duct with
chronic metabolic acidosis. Am J Physiol. 1996;270:F539-47.
34. Weiner ID, Milton AE. H(þ)-K(þ)-ATPase in rabbit cortical
collecting duct B-type intercalated cell. Am J Physiol.
1996;270:F518-30.
35. Wingo CS. Effect of acidosis on chloride transport in the
cortical thick ascending limb of Henle perfused in vitro. J Clin
Invest. 1986;78:1324-30.
36. Scandling JD, Ornt DB. Mechanism of potassium depletion
during chronic metabolic acidosis in the rat. Am J Physiol.
1987;252:F122-30.
37. Gennari FJ, Cohen JJ. Role of the kidney in potassium
homeostasis: lessons from acid-base disturbances. Kidney Int.
1975;8:1-5.
38. Carlisle EJ, Donnelly SM, Ethier JH, Quaggin SE, Kaiser UB,
Vasuvattakul S, et al. Modulation of the secretion of potassium
by accompanying anions in humans. Kidney Int. 1991;39:
1206-12.
39. Ellison DH, Velazquez H, Wright FS. Mechanisms of sodium,
potassium and chloride transport by the renal distal tubule.
Miner Electrolyte Metab. 1987;13:422-32.
40. Wang WH. Regulation of the hyperpolarization-activated Kþ
channel in the lateral membrane of the cortical collecting duct.
J Gen Physiol. 1995;106:25-43.
41. Adam WR, Koretsky AP, Weiner MW. 31P-NMR in vivo
measurement of renal intracellular pH: effects of acidosis and
Kþ depletion in rats. Am J Physiol. 1986;251:F904-10.
42. Kunau RT Jr, Frick A, Rector FC Jr, Seldin DW. Micro-
puncture study of the proximal tubular factors responsible for
the maintenance of alkalosis during potassium deficiency in the
rat. Clin Sci. 1968;34:223-31.
43. Rector FC Jr, Bloomer HA, Seldin DW. Effect of potassium
deficiency on the reabsorption of bicarbonate in the proximal
tubule of the rat kidney. J Clin Invest. 1964;43:1976-82.
44. Elkjaer ML, Kwon TH, Wang W, Nielsen J, Knepper MA,
Frokiaer J, et al. Altered expression of renal NHE3, TSC,
BSC-1, and ENaC subunits in potassium-depleted rats. Am J
Physiol Renal Physiol. 2002;283:F1376-88.
45. Soleimani M, Bergman JA, Hosford MA, McKinney TD.
Potassium depletion increases luminal Naþ/Hþ exchange and
basolateral Naþ:CO3¼:HCO3- cotransport in rat renal cortex.
J Clin Invest. 1990;86:1076-83.
46. Amlal H, Habo K, Soleimani M. Potassium deprivation
upregulates expression of renal basolateral Na(þ)-HCO(3)()
cotransporter (NBC-1). Am J Physiol Renal Physiol. 2000;279:
F532-43.
47. Soleimani M. Potassium-depletion metabolic alkalosis. In:
Gennari FJ, Adrogue HJ, Galla JH, Madias NE, editors.
Acid-base disorders and their treatment. Boca Raton, FL:
Taylor & Francis; 2005. p.553-84.
48. Silver RB, Soleimani M. Hþ-Kþ-ATPases: regulation and
role in pathophysiological states. Am J Physiol. 1999;276:
F799-811.
49. Capasso G, Jaeger P, Giebisch G, Guckian V, Malnic G. Renal
bicarbonate reabsorption in the rat. II. Distal tubule load
dependence and effect of hypokalemia. J Clin Invest. 1987;80:
409-14.
L.L Hamm, K.S Hering-Smith, and N.L Nakhoul
50. Bailey M, Capasso G, Agulian S, Giebisch G, Unwin R. The
relationship between distal tubular proton secretion and dietary
potassium depletion: evidence for up-regulation of Hþ-
ATPase. Nephrol Dial Transplant. 1999;14:1435-40.
51. Bailey MA, Fletcher RM, Woodrow DF, Unwin RJ, Walter SJ.
Upregulation of Hþ-ATPase in the distal nephron during
potassium depletion: structural and functional evidence. Am J
Physiol. 1998;275:F878-84.
52. Zhou X, Wingo CS. H-K-ATPase enhancement of Rb efflux by
cortical collecting duct. Am J Physiol. 1992;263:F43-8.
53. Silver RB, Breton S, Brown D. Potassium depletion increases
proton pump (H(þ)-ATPase) activity in intercalated cells of
cortical collecting duct. Am J Physiol Renal Physiol. 2000;279:
F195-F202.
54. Nakamura S, Wang Z, Galla JH, Soleimani M. Kþ depletion
increases HCO3- reabsorption in OMCD by activation of
colonic H(þ)-K(þ)-ATPase. Am J Physiol. 1998;274:F687-92.
55. Nakamura S, Amlal H, Galla JH, Soleimani M. Colonic
Hþ-Kþ-ATPase is induced and mediates increased HCO3-
reabsorption in inner medullary collecting duct in potassium
depletion. Kidney Int. 1998;54:1233-9.
56. DuBose TD Jr, Good DW. Effects of chronic hyperkalemia on
renal production and proximal tubule transport of ammonium in
rats. Am J Physiol. 1991;260:F680-7.
57. DuBose TD Jr, Good DW. Chronic hyperkalemia impairs
ammonium transport and accumulation in the inner medulla
of the rat. J Clin Invest. 1992;90:1443-9.
58. Jones JW, Sebastian A, Hulter HN, Schambelan M, Sutton JM,
Biglieri EG. Systemic and renal acid-base effects of chronic
dietary potassium depletion in humans. Kidney Int.
1982;21:402-10.
59. Tizianello A, Garibotto G, Robaudo C, Saffioti S, Pontremoli
R, Bruzzone M, et al. Renal ammoniagenesis in humans with
chronic potassium depletion. Kidney Int. 1991;40:772-8.
60. Nakamura S, Amlal H, Galla JH, Soleimani M. NH4þ secretion
in inner medullary collecting duct in potassium deprivation:
role of colonic Hþ-Kþ-ATPase. Kidney Int. 1999;56:2160-7.
61. Hernandez RE, Schambelan M, Cogan MG, Colman J,
Morris RC Jr, Sebastian A. Dietary NaCl determines severity
of potassium depletion-induced metabolic alkalosis. Kidney Int.
1987;31:1356-67.
62. Young DB, Jackson TE. Effects of aldosterone on potassium
distribution. Am J Physiol. 1982;243:R526-30.
63. Clark BA, Brown RS, Epstein FH. Effect of atrial natriuretic
peptide on potassium-stimulated aldosterone secretion: poten-
tial relevance to hypoaldosteronism in man. J Clin Endocrinol
Metab. 1992;75:399-403.
64. Chan R, Sealey JE, Michelis MF, Swan A, Pfaffle AE, DeVita
MV, et al. Renin-aldosterone system can respond to furosemide
in patients with hyperkalemic hyporeninism. J Lab Clin Med.
1998;132:229-35.
65. Kassirer JP, London AM, Goldman DM, Schwartz WB. On the
pathogenesis of metabolic alkalosis in hyperaldosteronism. Am
J Med. 1970;49:306-15.
66. Gonzaga CC, Calhoun DA. Resistant hypertension and hyper-
aldosteronism. Curr Hypertens Rep. 2008;10:496-503.