CJASN ePress. Published on June 25, 2020 as doi: 10.2215/CJN.

16041219

Metabolic Alkalosis
A Brief Pathophysiologic Review

Michael Emmett

Abstract
Metabolic alkalosis is a very commonly encountered acid-base disorder that may be generated by a variety of
exogenous and/or endogenous, pathophysiologic mechanisms. Multiple mechanisms are also responsible for Divisions of Internal
the persistence, or maintenance, of metabolic alkalosis. Understanding these generation and maintenance Medicine and
Nephrology,
mechanisms helps direct appropriate intervention and correction of this disorder. The framework utilized in
Department of
this review is based on the ECF volume-centered approach popularized by Donald Seldin and Floyd Rector in Medicine, Baylor
the 1970s. Although many subsequent scientific discoveries have advanced our understanding of the University Medical
pathophysiology of metabolic alkalosis, that framework continues to be a valuable and relatively Center at Dallas,
straightforward diagnostic and therapeutic model. Dallas, Texas
CJASN 15: ccc–ccc, 2020. doi: https://doi.org/10.2215/CJN.16041219
Correspondence:
Dr. Michael Emmett,
Department of
Medicine, Baylor
Introduction profile, or Gamblegram (Figure 2), shows why the University Medical
Metabolic alkalosis is a primary acid-base disorder increased [HCO32] must be accompanied by a re- Center at Dallas, 3500
that increases the serum bicarbonate concentration duction of [Cl2] (independent of [Na1]), a reduction Gaston Avenue, Room
[HCO32] (this is usually approximated by its surro- of the [AG2], or both (7,8). In fact, metabolic alkaloses H-102, Dallas, TX
75246-2096. Email:
gate the venous total [CO2]) above 30 meq/L (1), reproducibly increase the [AG2] to a small degree,
Michael.Emmett@
causing the arterial blood [H1] to fall, i.e., the arterial mostly owing to increased negative charge density of BSWHealth.org
blood pH increases into the alkaline range (.7.45). plasma proteins (9,10). Therefore, the relative [Cl2]
Metabolic alkalosis is a very common disorder, espe- decrease must be even greater.
cially in ICU settings (2). The diagnostic criteria and a However, an identical electrolyte pattern, increased
pathophysiologic approach to differential diagnosis [HCO32] and reduced [Cl2], is also generated by
and treatment on the basis of dissection of the etiology compensation for chronic respiratory acidosis. Clini-
and dominant maintenance mechanisms are reviewed. cal assessment and arterial blood pH measurement
will point toward the correct diagnosis—the blood pH
is high-normal/overtly alkaline with metabolic alka-
Respiratory Compensation losis and low-normal/overtly acid with chronic re-
Uncomplicated metabolic alkalosis rapidly (minutes spiratory acidosis. Venous blood pH, although less
to hours) generates hypoventilatory compensation definitive than arterial, can also differentiate these
that elevates the pCO2. Compensation reduces the disorders—add 0.03 pH units to the venous pH to
arterial pH, but it generally remains .7.45. Although approximate the arterial pH (11).
the magnitude of the hypoventilatory response is
proportional to the [HCO32] increase, the response is
very variable (Figure 1) (3–6, M.A. Fallahzadeh, et al., Pathogenesis: Generation and Maintenance
unpublished observations). Seldin and Rector published a classic review “The
Generation and Maintenance of Metabolic Alkalosis”
in 1972 (12). Although many subsequent discoveries
Serum Chloride Concentration and have expanded our understanding of the complex
Metabolic Alkalosis systemic neurohormonal, kidney, cellular, and para-
Hyper- or hypochloremia can reflect water/hydration cellular mechanisms participating in the development
disorders, acid/base disorders, or both. When an and maintenance of this acid-base disorder, the
abnormal [Cl2] is secondary to a water/hydration Seldin/Rector extracellular fluid (ECF) volume-
disorder, there is a proportional degree of hyper- or centered approach continues to be an extremely useful
hyponatremia. Thus the abnormal [Cl2] coexists with and relatively easy-to-understand diagnostic and ther-
an abnormal [Na1] in a 1:1.4 ratio. This relationship is apeutic framework for the metabolic alkaloses. Some
disrupted in acid-base disorders such as metabolic experts believe the “ECF volume-centered” approach
alkalosis. The elevated [HCO32 ] with metabolic should be replaced by a chloride-depletion model
alkalosis is generally associated with a reciprocally and cite experimental animal models to support their
reduced [Cl2] independent of [Na1]. The electrolyte position (13–16). However, others challenge these

www.cjasn.org Vol 15 November, 2020 Copyright © 2020 by the American Society of Nephrology 1
2 CJASN

Figure 1. | Respiratory compensation for metabolic alkalosis. Simultaneous pCO2 and [HCO3] data points derived from a recent compre-
hensive literature review showing the best-fit linear regression line (*M.A. Fallahzadeh, et al., unpublished observations). Also shown are several
commonly published relationship equations with adjacent references. The following very simple and easy to remember and utilize relationship:
pCO2 5 [HCO3]110 (dashed line), to be very similar to the best-fit regression line in the HCO3 range between 30 and 50 meq/L. If the [HCO32]
exceeds 55 mmol/L, the pCO2 may increase markedly. This is likely because of the development of a coexisting respiratory muscle weakness
generated by almost inevitable severe hypokalemia. Therefore, respiratory acidosis often complicates extreme metabolic alkalosis. pCO2, partial
pressure of carbon dioxide; 1 TORR, 133.32 Pascal (Pa).

experimental results and their interpretation (17,18).
This review uses the traditional “ECF volume-centered”
classification.
Figure 2. | The three major serum electrolytes in a normal patient and
a patient with metabolic alkalosis, visualized using a Gamblegram.
Note, when the HCO32 concentration increases and the anion gap
also increases slightly (this occurs with most forms of metabolic al-
kalosis), then the [Cl2] must fall and the Cl:Na ratio must fall below its
normal 1:1.4 ratio.
Normal HCO32 Reclamation, Regeneration, and Generation
Nonvolatile acids are generated by metabolism of ingested
foods and oxidation of endogenous substrates. A typical
Western European/American diet generates 80–100 meq/d of
nonvolatile strong acids (mainly sulfuric, phosphoric, and
hydrochloric). These acids release H1 that mainly reacts
with HCO32 to form H2CO3, which rapidly dehydrates to
CO2 and H2O. Thus, serum [HCO32] falls and is “replaced”
by the anions of the generated strong acids, i.e., Cl2, SO422,
HPO422, etc. Acid-base homeostasis is restored by the
kidney, which filters and secretes the acid anions mainly
with Na1, then the tubules reabsorb the Na1 in exchange
for H1, and finally the anions are excreted together with an
equal quantity of H1, in the form of titratable acid (largely
H2PO42) and NH41. In this way, 80–100 meq of H1 are
“buffered” and excreted in the urine and 80–100 meq of
HCO32 are regenerated and added back to the body fluids.
However, before the kidney can secrete/excrete the daily
required load of acid and thereby regenerate the decomposed
HCO32, all the filtered HCO32 must first be reclaimed and
returned to the body. About 85%–90% of the normal filtered
HCO32 load (4000–4500 meq/d) is reclaimed by the proximal
tubules via H1 secretion. A large fraction of proximal Na1
reabsorption occurs via the Na-H exchanger 3 (NHE3)
in the luminal membrane. This exchange is energized by
basolateral membrane Na-K ATPase, which reduces in-
tracellular Na1 and generates a negative intracellular charge.
This creates a strong inward (lumen into cell) electrochemical
Na1 gradient. Additionally, ATP-energized H1 pumps in
the lumenal membrane contribute a smaller fraction (about
CJASN 15: ccc–ccc, November, 2020 Metabolic Alkalosis, Emmett 3

Figure 3. | Proximal tubule: The major proximal tubule cellular and

luminal events that participate in HCO32 reclamation. Intracellular
H2O combines with CO2 to generate H2CO3 that rapidly dissociates to
H1 and HCO32 ions. These reactions are catalyzed by the cytoplasmic
enzyme carbonic anhydrase II (CAII). Na-K ATPase in the basolateral
membrane creates a steep Na1 electrochemical gradient that ener-
gizes Na1 reabsorption via the Na1-H1 antiporter exchanger (NHE3).
When H1 moves into the lumen, it reacts with filtered HCO32 to form
H2CO3. The H2CO3 dehydrates to H2O and CO2, a reaction catalyzed
by intraluminal carbonic anhydrase IV (CAIV) (tethered to the luminal
membrane). Generated CO2 flows into the cell, largely via the aquaporin 1
channel. The HCO32 ions generated within the cells move into the peri-
tubular capillary, primarily via a Na1-3HCO32 cotransporter (the elec-
trogenic NBCe1-A transporter; a product of the Solute Carrier Family 4
Member A4 or SLC4A4 gene). The net effect of the secretion of one H1
molecule and reabsorption of one Na1 molecule is the addition of one
molecule of NaHCO3 to the extracellular fluid and the disappearance of
one NaHCO3 molecule from the lumen. In addition, a smaller component Figure 4. | Principal cellsa and type A and type B intercalated cells
of proximal tubule H1 secretion (HCO32 reclamation) is accomplished via are located in the late distal convoluted tubule, the connecting tu-
a V-type H1-ATPase pump complex. About 85%–90% of the filtered bule, and cortical collecting duct. Principal cell transport is energized
NaHCO3 is reclaimed in the proximal tubule. primarily by electrogenic Na1-K1 ATPase pumps in the basolateral
membrane. The resulting low intracellular [Na1 ] and negative in-
tracellular potential difference combine to create a large gradient
30%) of proximal H 1 secretion. Each secreted H1 for Na1 to move from the lumen into these cells. Flow occurs mainly
generates a HCO32 molecule that is added to the ECF and through the epithelial sodium channel (ENaC; which is composed of
causes the disappearance of an HCO32 molecule from the a, b, and g subunits, each a product of a different gene). Inward flow
lumen. Major aspects of proximal tubule Na1 reabsorption/H1 of Na1 ions is more rapid than the sum of outward movement of K1
secretion are shown in Figure 3. The 10%–15% of HCO32 (mainly through the renal outer medullary potassium channel
that escapes proximal reclamation is reclaimed in the [ROMK]) and inward flow of Cl2 (mainly via the paracellular space).
distal tubules/collecting ducts, as shown in Figure 4. Therefore, the Na1 influx generates a negative potential difference
(PD of about 240 mv) in the lumen. The secretion of H1 by the type A
After HCO32 has largely disappeared from the distal
intercalated cells initially reacts with HCO32 in the lumen, which
tubules/collecting ducts, continued H1 secretion regen-
represents HCO32 reclamation. As the luminal pH falls, additional
erates decomposed ECF HCO32. If dietary and metabolic secreted H1 combines with buffers such as HPO422 and NH3to
acids have produced 80–100 meq/d of nonvolatile acids, generate urine titratable acid and NH42, which creates equimolar
then 80–100 meq/d of H1 must be excreted by the kidneys. quantitates of systemic HCO32. See Figure 5 for a description of in-
This regenerates the HCO32 that reacted with H1derived tercalated cell ion transport.
from nonvolatile acids and thereby decomposed or “dis-
appeared.” Also, any HCO32 lost in stool must be regerated. Figure 4 shows the major distal kidney transport mech-
As HCO32 disappears from the tubular fluid, the fluid pH anisms for HCO32 reclamation, regeneration, and gener-
falls. The minimum achievable urine pH is about 4.5, which ation (all linked to H1 secretion) and also HCO32 secretion
represents only 0.03 meq/L of free [H1]. Therefore, virtually (by type B intercalated cells).
the entire excreted H1 load must be bound to urine buffers:
HPO422 (titrated to H2PO42) represents most of the titratable
acid, and NH3 binds to H1 to form NH41. These buffered Metabolic Alkalosis—Source of Excess HCO32
H1 charges are electrically balanced by acid anions such as Usually metabolic alkalosis indicates an accumulation
SO42 and Cl2 in the urine. of “excess” HCO32. The source of excess HCO32 can be
4 CJASN

Table 1. Metabolic alkalosis: Mechanisms of generation

Ingest and absorb or infuse NaHCO3 or NaHCO3 precursors (i.e., Na acetate, Na citrate, Na gluconate)
Distal renal tubule HCO3 generation through enhanced H1 secretion
Generous delivery of NaCl (or other Na salts such as Na2SO4 or Na penicillin) to distal tubules/collecting ducts, which are actively
reabsorbing Na1
K depletion (shifting H1 into cells)
1

Remove HCl from body (vomiting/nasogastric suction/chloride-rich diarrhea)

exogenous, endogenous, or both. Exogenous sources are
Na1 or K1 HCO32 salts or salts of precursors (organic
anions such as lactate, acetate or citrate, which generate
HCO32 when completely oxidized). These salts can be
ingested/absorbed or infused (Table 1).
The two potential endogenous sources of large
amounts of HCO32 are (1) the stomach and (2) the
kidneys. Net endogenous HCO32 generation requires H1
removal from the body. HCO32 is generated when HCl is
secreted into gastric lumen, but net HCO32 accumulation in
the ECF requires the HCl to be lost externally, usually as a
result of vomiting and/or suction (see section on gas-
tric alkalosis).
Normally, kidney H1 excretion into the urine (as NH41
and/or titratable acid) generates HCO32 to replace the
quantity decomposed by nonvolatile H1 derived from
dietary intake and metabolism and any HCO32 lost in
alkaline stool. To the extent kidney HCO32 generation
exceeds this requirement, “excess” HCO32is generated.
This generally occurs when the following conditions
coexist: (1) the kidney tubules/ducts beyond the early
distal tubule are avidly reabsorbing Na1 (for example,
aldosterone activity is high and (2) the delivery of salt and
volume to these sites is relatively large.
Clinical examples of kidney bicarbonate overproduc-
tion are:
1. Primary hyperaldosteronism (especially when a high-salt
diet is ingested) and other mimics of primary hyper-
aldosteronism (Table 2).
2. Loop and/or thiazide diuretics and several inherited syn-
dromes that have diuretic like manifestations (i.e., Bartter
and Gitelman syndromes).
3. The infusion of Na1 salts of poorly absorbed anions (PO4,
SO4, penicillin, etc.) if distal tubule Na1 reabsorption is
stimulated by mineralocorticoids and/or volume contrac-
tion (19,20).
Another endogenous source of HCO32 is the movement
of K1 from within cells into the ECF. In response to

Table 2. The metabolic alkaloses

ECF volume contracted: urine chloride concentration <20 meq/L

Gastric alkalosis: vomiting/nasogastric suction
Chloride-rich diarrhea (congenital chloridorrhea)
Status/postchronic hypercapnia (acute reversal of chronic respiratory acidosis)
Cystic fibrosis with major sweating
Thiazide or loop diuretics after renal tubule diuretic effect has dissipated
Some villous adenomas
ECF volume expanded: urine chloride concentration >20 meq/L
Primary hyperaldosteronism (unilateral adenoma/bilateral hyperplasia/glucocorticoid-sensitive hyperaldosteronism)
Severe Cushing syndrome (especially because of ectopic ACTH)
Exogenous mineralocorticoids
Reduced 11-b (OH) steroid dehydrogenase activity
Chronic licorice/carbenoxolone ingestion
Congenital AME syndrome (11-b HSD type 2 inactivating mutation)
Renin-secreting tumors
Some forms of congenital adrenal hyperplasia
11-b hydroxylase deficiency
17-a hydroxylase deficiency
Liddle syndrome
ECF volume contracted: but urine chloride concentration >20 meq/L (generally indicates a renal tubule reabsorptive defect)
Thiazide or loop diuretics actively working
Bartter syndrome (defective Na reabsorption in loop of Henle, furosemide-like lesion)
Gitelman syndrome (defective Na reabsorption at the thiazide-sensitive site)
Metabolic alkalosis: other
Severe potassium deficiency
Milk (calcium) alkali syndrome
NaHCO3 loads with markedly reduced GFR
Refeeding after fasting

ECF, extracellular fluid; ACTH, adrenocorticotropic hormone; AME, apparent mineralocorticoid excess; HSD, hydroxysteroid
dehydrogenases
CJASN 15: ccc–ccc, November, 2020
hypokalemia, K1 exit is partially balanced by movement of
H1 into cells and this generates ECF HCO32 (21,22). ECF
[HCO32] can also increase when the ECF volume contracts
around a fixed quantity of HCO32 (23) (see section on
gastric alkalosis).
Maintenance of Metabolic Alkalosis
The various mechanisms responsible for the maintanence
of metabolic alkalosis are shown in Table 3. If metabolic
alkalosis develops and the GFR is not markedly reduced,
correction of the alkalosis should be relatively straightfor-
ward: merely excrete a large fraction of the filtered HCO32
(which should be supranormal because of the higher
serum/filtered [HCO32 ]). A brisk HCO32 diuresis would
then reduce the [HCO32 ] and restore normal acid-base
status. This obviously has not occurred when metabolic
alkalosis persists. Why does the kidney not excrete
HCO32 and rapidly restore normal acid-base status?
The answer to this question varies, depending on the
underlying cause, and the precise explanations continue
to be refined and debated.
Normal individuals ingesting up to 1000 meq/d of
NaHCO3 for several weeks are able to efficiently excrete
this load with a minimal increase in their serum [HCO32]
(24). Consequently, when metabolic alkalosis develops and
persists despite a relatively normal GFR, this indicates the
kidney is reclaiming HCO32 at a supranormal rate.
Most patients with metabolic alkalosis have developed
increased proximal HCO32 reabsorption. The major stim-
ulatory factors responsible are reduced intravascular, or
effective arterial, blood volume, and hypokalemia (12).
Metabolic acidosis and chronic respiratory acidosis also
increase proximal tubule HCO32 reabsorption, but these
disorders are not relevant to the current discussion.
Metabolic alkalosis is also usually associated with
accelerated distal HCO32 reabsorption and generation.
Generous distal Na1 delivery, combined with avid distal
Na1 reabsorption (for example, because of high aldoste-
rone levels) accelerates distal H1 and K1 secretion. This
occurs, in part, because distal Na1 reabsorption, mainly via
the epithelial sodium channel (ENaC) in principal cells,
generates a lumen negative electric potential (potential
difference [PD]5240 mv), which drives paracellular and
transcellular anion (mostly Cl2) reabsorption and enhances
the secretion of H1 and K1. Also, many neurohormonal
stimuli of distal Na1 absorption increase type A interca-
lated cell activity (25) (Figure 4).
Figure 5 shows three types of intercalated cells. The type
B intercalated cell secretes HCO 3 2 in exchange for Cl 2 ,
and can therefore contribute to the correction of meta-
bolic alkalosis. However, generous distal delivery of
Cl 2 is required to enable this cell to secrete major
quantities of HCO 3 2 . Recent studies show that interca-
lated cells also play an important role in NaCl reab-
sorption and volume regulation (25–31) (discussed in
the legend for Figure 5).
When the GFR is markedly reduced, metabolic acidosis
usually develops. However, occasionally, metabolic alka-
losis occurs and then the HCO32 load cannot be excreted
because of the reduced GFR. Kidney dysfunction contrib-
utes to the maintenance of metabolic alkalosis in several
Metabolic Alkalosis, Emmett 5
Table 3. Metabolic alkalosis: Mechanisms of maintenance
Increased proximal renal tubule HCO3 reclamation
Extracellular fluid contraction
K1 depletion
Continuous or intermittent generation of new HCO3
In distal kidney tubules and collecting ducts
Gastric HCl losses
Exogenous alkali
Reduced HCO3 filtration: reduced GFR/kidney failure
syndromes, including milk-alkali or calcium-alkali syn-
drome (35) and bicarbonate ingestion or vomiting by
patients with severe kidney dysfunction (36).
The Metabolic Alkaloses: Etiology on the Basis of ECF
Volume Status
The generation, maintenance, and resolution of “classic”
examples of metabolic alkalosis in each ECF volume status
category is described below.
ECF Volume Contracted
Classic Example: Gastric Alkalosis.
Generation. Gastric fluid osmolality is about 300 mosm/L
with a [Cl2] of about 150 meq/L and total cations of about
150 meq/L. The [H1 ] typically varies between 40 and
140 meq/L, [K1] varies between 10 and 15 meq/L, and [Na1]
makes up the balance (37). Secretion of HCl (via gastric type
H1/K1 ATPase) into the gastric lumen generates equimolar
addition of HCO3 to the ECF. Normally, gastric HCl secretion
does not produce metabolic alkalosis because the acid is not
lost from the body. The HCl leaves the stomach and enters
the small bowel, where H1 is neutralized by HCO32 mainly
secreted by the pancreas (with a smaller component from
bile and intestinal epithelium). This generates CO2 and water.
The secretion of HCO32 adds H1 to the body fluids. Because
the quantity of HCO32 secreted into the small bowel equals the
quantity of H1 delivered from the stomach, these two
processes neutralize one another. However, removal of the
gastric HCl from the body, by vomiting or tube suction,
prevents the HCl from reaching the small bowel. Conse-
quently, HCO32 is not secreted into the intestinal lumen so
that a gastric-derived HCO32 bolus is added to the ECF
and an equal quantity of Cl2 is removed from the body.
Later in the development of gastric alkalosis, a K1/H1 cell
shift also generates additional HCO32 (described below).
Maintenance. Initially, much of the HCO32 added to
the ECF (after vomiting or gastric suction) is filtered and
excreted by the kidneys largely as NaHCO3. The loss of
gastric fluid combines with kidney loss of NaHCO3 and
fluid to generate ECF volume contraction: GFR falls and
kidney salt and fluid retention are stimulated. Distal delivery
of Na1 and HCO32, linked with secondary hyperaldosteron-
ism, increases the fraction of HCO32 excreted as KHCO3 (40).
Hypokalemia shifts K1 out of, and H1 into, cells generating
ECF HCO32 (21,22). The resulting intracellular acidifica-
tion of kidney tubule cells stimulates HCO32 reclamation
and generation. Hypokalemia also reduces pendrin activ-
ity and type B intercalated cell density, which further
limits HCO32 secretion (30,31).
6 CJASN
Figure 5. | Intercalated cells: Three different intercalated cell types
have been identified: type A intercalated cells, type B intercalated
cells, and non–type A/non–type B intercalated cells. Each is rich in
carbonic anhydrase II and is capable of generating abundant HCO32
and H1 from H2CO3. Type A intercalated cells: H1 is secreted into the
lumen mainly via V-type H1 ATPase and to a smaller extent via H1-K1
ATPase. The generated cytoplasmic HCO32 moves into the peritubular
capillary in exchange for Cl2, via anion exchanger 1 (AE1; a product of
the Solute Carrier Family 4 Member 1 or SLC4A1 gene). This trans-
porter is also called the “erythrocyte membrane protein band 3” in red
blood cells. Type B intercalated cells: H1 is secreted into the peri-
tubular capillary by V-type H1 ATPase in the basolateral membrane
(the same proton transporter as found in type A intercalated cells, but in
the opposite, or luminal, membrane). The HCO32 generated in this
cell is secreted into the lumen via an anion exchanger named Pendrin
(a product of the Solute Carrier Family 26 Member A4 or SLC26A4
gene) that exchanges one HCO32 for one Cl2. Pendrin is a distinct and
different exchanger than the AE1 in the type A cells that is present in the
basolateral membrane. A Na1/3HCO32 cotransporter AE4 (a product
of the Solute Carrier Family 4 Member A4 or SLC4A4 gene) is present
in the basolateral membrane. These cells also have the sodium-driven
ECF contraction generates proximal and distal Na1
reabsorption and HCO32 reclamation. Distally, Na1 reabsorp-
tion increases H1 and K1 secretion. K1 depletion also increases
H1 secretion by type A intercalated cells via both H1 ATPase
and H/K ATPase pumps (see Figures 3 and 4), and increases
kidney NH3 generation and excretion (38,39).
During the maintenance phase, the urine electrolyte
pattern fluctuates. Generally, filtered Na1, K1, HCO32,
Cl2, and water are avidly reabsorbed, generating concen-
trated, electrolyte-poor, and relatively acid (denoted as
“paradoxical aciduria” because metabolic alkalosis exists)
urine. However, intermittently (for example, immediately
after loss of a large bolus of gastric fluid), the serum
[HCO32] acutely increases, and for a period of time, the
larger load of filtered HCO32 cannot be completely re-
claimed despite the multiple stimulatory factors described
previously. When this occurs, the urine [HCO32], [Na1],
[K1], and pH all temporarily increase. Subsequently, the
serum [HCO32] declines, the ECF volume contracts further,
and filtered NaHCO3 is completely reclaimed. Urine
electrolyte concentrations and pH again fall. However, it
is important to note that throughout these cyclic variations,
the urine [Cl2] remains low. Thus, a low urine [Cl2] (,20
meq/L) generally indicates the kidney’s ongoing response
to reduced ECF volume or intra-arterial blood volume.
Resolution. The factors responsible for kidney HCO32
retention are reversed by adequate ECF volume expansion
(NaCl infusion) and KCl repletion. Adequate restoration
of ECF volume is signified by rising urine [Cl2] and the
development of a NaHCO3 diuresis. K1 replacement
moves K1 into, and H1 out of, cells into the ECF,
simultaneously reducing the [HCO32] and increasing in-
tracellular pH. The urine electrolyte profiles discussed
above presume relatively intact kidney tubule function and
the absence of diuretic activity.
The term “contraction alkalosis” has been used to
describe several different disorders in which the ECF
“contracts” around a relatively fixed quantity of HCO32 .
Figure 5. | Continued. bicarbonate chloride exchanger (NDBCE; a
product of the Solute Carrier Family 4 Member A8 or SLC4A8 gene) in the
luminal membrane (see discussion below). Non–type A/non–type B
intercalated cells: this is the third type of intercalated cell. Both a V-type
H1 ATPase, pumping H1, and Pendrin, exchanging HCO32 for Cl2,
coexist in the lumen membrane. The anion exchanger AE4 (a product of
the Solute Carrier Family 4 Member A4 or SLC4A4 gene) is a major Na1/3
HCO32 transporter in the basolateral membrane, moving these ions into
the peritubular capillary. Although intercalated cells were originally
identified as major kidney acid base–regulating cells, it is now clear that
these cells also play an important role in salt and volume regulation
(32,33). The sodium-driven bicarbonate chloride exchanger (NDBCE)
in the luminal membrane of the type B intercalated cells is an elec-
trically neutral ion exchanger moving one Na1 and two HCO32 ions
into the cell while moving one Cl2 into the lumen. The net effect of two
Pendrin cycles (two HCO32 ions enter the lumen in exchange for
uptake of two Cl2 ions) and one NDBCE cycle (two HCO3 ions and one
Na1 ion enter the cell and one Cl2 ion enters the lumen) has the net
effect of the reabsorption on one molecule of NaCl. These acid-base
and salt reabsorption interactions of intercalated cells may explain
why some patients with Pendred syndrome, a genetic defect of Pen-
drin, develop severe salt depletion and metabolic alkalosis when
treated with thiazide diuretics (34).
CJASN 15: ccc–ccc, November, 2020
Although gastric alkalosis is an ECF volume-“contracted”
condition and the ECF contraction contributes impor-
tantly to both its pathogenesis and maintenance, the major
cause of the blood [HCO32 ] increase is not shrinkage of
the ECF per se, but rather generation of HCO32 owing
to gastric HCl loss and cellular H1 -K1 shifts (21–23,40).
Conversely, although expansion of the ECF with NaCl does
dilute the ECF [HCO32] to a small degree, its correcting action
in these patients is mainly a result of kidney HCO32 excretion.
Reducing or stopping the loss of gastric HCl is of course
critical for reversing the process at its initiation point.
However, if the gastric fluid losses cannot be stopped, then
reducing the gastric fluid [HCl] concentration with an H2
blocker or proton pump inhibitor can be helpful (41).
Table 2 lists the most common forms of ECF volume-
contracted metabolic alkalosis. The urine [Cl2] is typically
reduced to ,20 meq/L.
ECF Volume Expanded
Classic Example: Primary Mineralocorticoid Excess
Syndromes. Primary hyperaldosteronism is a condition of
autonomous, or inappropriately upregulated, aldosterone
secretion. This generates ECF volume expansion, hyper-
tension, hypokalemia, and metabolic alkalosis. A unilateral
adrenal adenoma secreting aldosterone is the prototypical
cause of this disorder, but many conditions can mimic the
electrolyte and acid-base pathophysiology of primary hy-
peraldosteronism (Table 2).
ECF Volume Regulation of Renin and Aldosterone
(Normal Physiology). The reabsorption of Na1 in late distal
tubules/collecting ducts is mainly accomplished by principal
cells (Figure 4) through ENaC pores in the luminal mem-
branes. When these pores are open, the electrochemical
gradient favors reabsorption of Na1. This generates a lumen
negative electrical potential (240 mv) that drives both
chloride reabsorption and secretion of K1 and H1.
ECF volume contraction in normal individuals reduces
the GFR and sharply increases the reabsorption of NaCl
and NaHCO3 in the proximal tubules. Volume contraction
also generates secondary hyperaldosteronism (high aldo-
sterone activity driven by high renin and angiotensin II
activity). The result of these coordinated actions is that the
potent aldosterone-driven stimulus to reabsorb Na1 in the
distal/collecting tubules is coordinated with increased
proximal reabsorption, which sharply reduces distal salt
and water delivery. Consequently, reduced Na1 delivery
to aldosterone-sensitive sites blunts the magnitude of Na1
reabsorption and the indirectly linked secretion of K1 and
H1. The opposite occurs in response to ECF volume
expansion in normal individuals—the GFR increases,
proximal salt and water reabsorption fall, and generous
distal salt and water delivery ensues. Simultaneously, renin
angiotensin II and aldosterone levels fall. Now despite
generous distal salt and water delivery, low aldosterone
levels downmodulate distal Na1 reabsorption, and indirectly
linked K1 and H1 secretion. This describes the normal
reciprocal physiologic balance that exists between the mag-
nitude of distal delivery of salt and water and neuro-
hormonal stimulation of distal Na1 reabsorption and K1
and H1 secretion. This exquisite reciprocal balance is
disrupted by autonomous aldosterone secretion (12,42).
Metabolic Alkalosis, Emmett 7
Generation. Autonomous hyperaldosteronism increases
distal Na1 reabsorption, expanding the ECF. This expansion
raises the GFR and reduces proximal tubule salt and water
reabsorption. Generous distal salt and water delivery ensue.
This results in inappropriately high aldosterone activity
combining with generous distal tubule salt and water delivery.
This combination represents pathophysiology and high rates
of Na1 reabsorption, and indirectly linked K1 and H1
secretion ensue. Excretion of K1 and H1 exceeds physiologic
requirements, generating hypokalemia and metabolic alkalo-
sis. The development of hypokalemia and K1 depletion
contribute importantly to HCO32 generation when K1
shifts out of cells in exchange for H1 (22), and kidney H1
secretion and ammonia excretion increases. Additionally,
hypokalemia increases proximal tubule HCO32 reclaimation
and H 1 /K1 ATPase activity in type A intercalated
cells (25,27).
Maintenance Phase. Usually, expansion of the ECF
reduces proximal salt reabsorption and HCO32 reclama-
tion and simultaneously reduces renin, angiotensin II, and
aldosterone levels. Consequently, distal Na1 reabsorption
and K1 and H1 secretion remain modest despite high
delivery rates. However, when autonomous aldosterone
secretion combines with generous distal salt delivery, in-
appropriately high levels of distal Na1 reabsorption and K1
and H1 excretion develop. As hypokalemia and K1 depletion
ensue, they contribute importantly to both additional HCO32
generation and kidney HCO32 reclamation via systemic K1/
H1 cell shifts and acidification of kidney tubule cells. Hypo-
kalemia also increases H1/K1-ATPase activity in type A
intercalated cells (Figures 4 and 5) (25,27). Furthermore,
aldosterone also increases salt reabsorption via a sequence
of pendrin-related events (Figure 5) (28). During the
maintenance phase of autonomous hyperaldosteronism,
the urine electrolytes reflect the patient’s salt intake. Thus,
the urine [Cl2] will generally be .20 meq/L.
Recovery Phase. Successful resection of an adrenal
aldosterone secreting adenoma generally reverses the
entire syndrome. However, if hypertension has existed
for a long period of time, it may persist because of
structural vascular pathology. In lieu of surgery, drugs
that block the action of aldosterone can be very helpful. The
physical and biochemical manifestations of primary hyper-
aldosteronism can also be ameliorated by ingestion of a
very-low-salt diet, which reduces distal salt delivery,
blunting H 1 and K1 loss. Conversely, the physical
findings and electrolyte abnormalities are exacerbated by a
high-salt diet (42,43). Analagously, other mineralocorticoid
excess syndromes and mineralocorticoid excess-like syndromes
can sometimes be reversed or cured at their source and/or
treated by blocking downstream pathophysiology.
ECF Volume Contracted: Diuretic and
Diuretic-Like Etiologies
Classic Example: Thiazide and/or Loop Diuretics. Thiazide
and/or loop diuretics very frequently generate hypokale-
mia and metabolic alkalosis. Despite development of a
relatively contracted ECF, or effective arterial blood vol-
ume, the generation and maintenance mechanisms of this
condition has many similarities to the ECF volume-expanded
condition of primary hyperaldosteronism (42). That is because
increased distal salt and volume delivery (due to the diuretics)
8 CJASN
combine with activation of the renin angiotensin II-
aldosterone axis.
Generation. Inhibition of the Na/K/2Cl cotransporter
(NKCC2) in the thick limb of Henle by loop diuretics and/or
inhibition of the neutral Na/Cl cotransporter (NCC) in the
diluting segment by thiazide diuretics increases NaCl and
volume delivery to more distal sites. Diuretics also generally
increase renin, angiotensin II, and aldosterone levels,
generating a state of secondary hyperaldosteronism. In
the absence of diuretics, secondary hyperaldosteronism is
typically associated with reduced distal salt and volume
delivery, which limits the magnitude of distal Na1
reabsorption (and thereby H1 and K1 secretion). How-
ever, diuretics generate a state of secondary hyperaldoster-
onism linked with generous distal tubule Na1 and volume
delivery. Therefore, enhanced distal Na1 reabsorption via
principal cell ENaCs occurs together with generous distal
Na1 and volume delivery, accelerating distal H1 and K1
secretion and generating metabolic alkalosis and hypoka-
lemia. Hypokalemia also generates additional ECF HCO32
via cellular H1/K1 exchange, which also stimulates distal
H1 secretion. During periods of diuretic activity, urine
[Na1] and [Cl2] are both high. However, diuretic action is
generally intermittent, and periods of diuretic activity cycle
with periods of inactivity and recovery. During the “off-
diuretic” phases, avid kidney salt reabsorption markedly
reduces distal NaCl delivery, limiting principal cell Na1
reabsorption and distal K1 and H1 secretion. Now, urine
[Cl2] and [Na1] fall to low levels, reflecting the relative
ECF-contracted state. Thus, the urine [Cl2] and [Na1] cycle
up and down depending on the level of diuretic activity. In
contrast, diuretic-mimicking disorders such as Bartter and
Gitelman syndromes are characterized by persistent, high
urine [Cl2] because they never develop an “off-diuretic-
like” period.
Maintenance. Again, many similarities to the mainte-
nance mechanisms described for primary hyperaldoster-
onism exist. Hypokalemia increases both proximal and
distal tubule H 1 and NH 4 1 secretion. ECF and/or
effective intra-arterial volume is reduced, generating a
neurohormonal cascade that increases proximal tubule
NaCl and HCO32 reclamation. Periods of diuretic activity
deliver salt and volume to distal segments that are
responding to hyperaldosteronism. These generation
and maintenance phases cycle as diuretic activity
waxes and wanes.
Recovery Phase. Stopping the diuretic markedly reduces
distal delivery of salt and volume so that HCO32 gener-
ation ceases. However, metabolic alkalosis will not resolve
unless potent stimuli that accelerate proximal and distal
salt reabsorption can be reduced or eliminated. Therefore, if
diuretics were initiated to treat avid salt retention gener-
ated by heart failure or cirrhosis, the metabolic alkalosis
generally persists until the underlying disorder can be
ameliorated. Reversing hypokalemia and K1 depletion is
also important. If the clinical situation mandates continu-
ing diuretics despite severe metabolic alkalosis, the addi-
tion of potassium sparing (triamterene, spironolactone, etc.)
or “acidifying” (acetazolamide) diuretics can be helpful.
Note, however, that acetazolamide often generates marked
K1 wasting, so aggressive K1 supplementation is gener-
ally required (44).
All three types of intercalated cells located in the distal
tubule/collecting ducts not only play a major role in
acid/base regulation, but also participate in volume
regulation and NaCl balance (32,33). These cells may be
especially important in moderating the development of
metabolic alkalosis in patients receiving thiazide diuretics
(34) (see Figure 5).
Diagnostic Approach. When the cause of metabolic
alkalosis is not readily apparent from the history and
physical examination, then it is very helpful to categorize
the disorder on the basis of the patient’s kidney function
and volume status. If the GFR is markedly reduced and
major acidic gastrointestinal fluid losses do not exist, a
source of exogenous bicarbonate loading should be sought.
If the GFR is not markedly reduced, then carefully assess
volume status with history, physical examination, and a
spot urine [Cl2] measurement. A urine [Cl2] ,20 meq/L is
consistent with a reduced ECF or effective intra-arterial
volume, whereas a urine [Cl2 ] .20 meq/L suggests an
expanded state. Consider the diagnoses in Table 2.
However, recognize that diuretic-generated metabolic
alkaloses are characterized by cyclic changes in urine
[Cl2 ] as the diuretic effect waxes and wanes. In general,
widely varying urine [Cl2 ] changes indicate diuretic use
(which some patients may deny).
Metabolic alkalosis is a very common disorder. This
brief review provides a diagnostic and therapeutic
framework using an ECF volume-oriented physiologic
approach to the generation, maintenance, and resolution
of this disorder. Space limitations preclude in-depth
discussion of many fascinating clinical metabolic alkalosis
syndromes and a number of recent physiologic and path-
ophysiologic discoveries that enhance our understanding of
this disorder.
Disclosures
The author has nothing to disclose.
Funding
None.
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