• BICARBONATE TRANSPORT IN THE KIDNEY
• PATHOPHYSIOLOGY OF METABOLIC ALKALOSIS
• CLINICAL MANIFESTATIONS
• Approach to the Diagnosis of Metabolic Alkalosis
• Metabolic alkalosis is a primary acid–base
disturbance due to either loss of acid (H) or gain of
HCO3 in the ECF.
• The blood has a pH of >7.4 and plasma HCO of
>26–28 mEq/L .
• The increase in pH that results from the elevation in
−) induces hypoventilation, producing a secondary
increase in arterial CO2 tension (PaCo2).
• Thus, metabolic alkalosis is characterized by
coexisting elevations in serum HCO3
− , arterial pH,
and PaCO2 .
• Metabolic alkalosis occurs in half of all patients
hospitalized with acid–base disorder .
• A direct relationship between mortality and blood pH
exists when the blood pH is >7.48.
• Mortality rates of 45% and 80% have been noted at blood
pH levels of 7.55 and 7.65, respectively .
• Major adverse effects of alkalemia are frequently seen
when blood pH is ≥7.6 .
BICARBONATE TRANSPORT IN THE
• Bicarbonate ions are freely filtered across the glomerulus .
• Under normal conditions must be completely reabsorbed from the
tubule urine to conserve body alkali stores.
• Acid excretion must occur to regenerate any HCO3− consumed in
buffering of endogenously produced acids.
• Both tasks are accomplished by secretion of hydrogen ions (H+)
into the renal tubules.
• Bicarbonate ions are reabsorbed when secreted H+ combines with
- to produce CO2 and water, removing HCO3
- from the
• Acid excretion occurs in the collecting duct when secreted H+
combines with filtered phosphate, converting HPO4 to H2PO4, or
with ammonia (NH3) to form ammonium (NH4
+), and these ions are
BICARBONATE TRANSPORT IN THE KIDNEY
• Excretion of excess bicarbonate is facilitated by
secretion of HCO3
into the tubule in the cortical
collecting duct through apical membrane Cl
• This transporter is activated by alkalemia and requires
reabsorption in exchange for secreted HCO3.
• The HCO3−secreted into the urine by this transporter
can be recaptured again by H+ secretion further along
in the collecting duct .
• So excretion of excess alkali requires both :
stimulation of the Cl
suppression of the normally active collecting duct H+-
BICARBONATE TRANSPORT IN THE KIDNEY
• Apical membrane ion transporters along the
• Bicarbonate ions (HCO3)
are recaptured by H secretion
Throughout the renal tubules.
• Bicarbonate secretion occurs in
the distal tubule and cortical collecting duct
under conditions of alkalemia through
Cl−-HCO3linked exchanger (pendrin).
PATHOPHYSIOLOGY OF METABOLIC ALKALOSIS
• Pathophysiologic Classification of Causes of Metabolic
1. Primary stimulation of collecting duct ion transport
(Na+ uptake , H+ and K+ secretion)
2. Secondary stimulation of collecting duct ion transport
(Na+ uptake, H+ and K+ secretion)
Extrarenal Cl– losses and secondary K+ losses
Renal Cl– losses and secondary K+ losses
a - Pharmacologic (diuretics)
b - Inactivating gene mutations of Cl–-linked Na+ cotransporters
3. Alkali administration in settings in which HCO3− excretion is
impaired (e.g kidney failure)
Secondary Stimulation of Collecting Duct Ion Transport
• The most common clinical presentation of metabolic
alkalosis is generated by Cl− depletion.
• Selective Cl− depletion, induced by vomiting or nasogastric
suction, increases serum HCO3
• The degree of alkalosis generated is greater when H+ loss
also occurs .
• In either setting, maintenance of the metabolic alkalosis
depends on sustained depletion of body Cl− stores.
• Serum HCO3
− returns to normal when sufficient Cl− is given
to replenish losses.
• Chloride-depletion metabolic alkalosis always causes
concomitant K+ depletion through renal K+ losses, but Cl−
administration can correct the alkalosis.
Secondary Stimulation of Collecting Duct Ion Transport
• The metabolic alkalosis induced by gastrointestinal Cl−
losses can be very severe, with serum HCO3
than 60 mmol/l.
• A less severe Cl−-dependent metabolic alkalosis, without
evident H+ loss :
by thiazide or loop diuretics administration
Bartter and Gitelman syndromes
two genetic abnormalities in Cl− reabsorption
Pathophysiology of Chloride-Responsive Metabolic Alkalosis
• Chloride depletion stimulates H+ and K+ secretion into the collecting duct (CD)
as a result of disproportionate distal Na+ delivery and reabsorption.
• The resultant K+ depletion further stimulates H+ secretion and promotes ammonium(NH4+)
production and excretion, as well as down regulating Na+ reabsorption in Henle loop.
• These events all contribute to a sustained increase in serum [HCO3−].
• Chloride depletion also reduces glomerular filtration rate (GFR) and therefore HCO3 −
filtration, reducing potential alkali losses.
Primary Stimulation of Collecting Duct Ion Transport
• Metabolic alkalosis produced by primary stimulation of collecting duct ion
transport is less than 1% of the clinical incidence of this disorder, and the
most common cause is primary hyperaldosteronism.
• Primary hyperaldosteronism is characterized by persistently high and
unregulated aldosterone secretion, which activates both the epithelial
sodium channel (ENaC) and H+-ATPase, regardless of body fluid volume
and acid-base status .
• As a result, Na+ reabsorption and H+ secretion are increased directly, and
K+ secretion is increased secondarily, depleting body K+ stores.
• The resultant K+ depletion promotes NH4 + production and activates
H+,K+-ATPase activity, further facilitating acid excretion.
• Sodium retention leads to hypertension and also ensures continued Na+
delivery to the collecting duct, sustaining the cycle of increased
reabsorption and increased K+ and H+ secretion.
• As a result of all these events, metabolic alkalosis is sustained despite
normal Cl− intake.
• The kidney responds rapidly to excess alkali by
increasing HCO3− excretion, and sustained metabolic
alkalosis does not occur unless massive amounts are
administered in individuals with normal kidney
• If HCO3− excretion is impaired as a result of kidney
failure, even minimal daily alkali administration can
cause a sustained metabolic alkalosis independent of
• End-stage renal disease is the ultimate model of
impaired HCO3− excretion, and any added alkali
remains in the body until it is consumed by buffering
the strong acids produced by protein metabolism
(endogenous acid production).
Secondary Response to Alkalemia Induced
by Bicarbonate Retention
• Regardless of the cause, blood pH increases in patients with
metabolic alkalosis and elicits secondary hypoventilation,
• The response is a potent one, occurring despite the
concomitant development of hypoxemia.
• the predicted PCO2 for any given serum [HCO3−] in metabolic
alkalosis can be calculated as follows:
PCO2 (mmHg) = 40 + 0.7 × (HCO3−mmol/l) − 24)
• Variations of up to 5 to7 mm Hg between the observed and
calculated PCO2 may occur.
• When serum [HCO3−] exceeds 60 mmol/l,the formula is not a
reliable predictor of the respiratory response.
• Upper line in the graph illustrates the relationship between
arterial pH and serum[HCO3−] in the absence of adaptive
hypoventilation (PCO2 maintained at40 mm Hg).
• Lower line shows the relationship when PCO2 is increased
by the expected level of hypoventilation .
• The major causes of metabolic alkalosis are subdivided into three
groups based on pathophysiology .
• The most common causes are induced and sustained by chloride
depletion resulting from abnormal losses from the gut or the kidney.
• The second subgroup, much rarer, includes the metabolic alkalosis
induced by excess corticosteroids, or by collecting duct transport
abnormalities that mimic excess mineralocorticoid activity.
• The third subgroup includes the causes of metabolic alkalosis due to
alkali administration or ingestion.
• This newer classification replaces the traditional separation of causes
based on treatment response (chloride-responsive and chloride-
from Secondary Stimulation of Ion Transport
Vomiting or Nasogastric Drainage :
• Loss of chloride from the upper gastrointestinal
(GI) tract, accompanied by concomitant H+
losses, produces a metabolic alkalosis that is
sustained until body Cl− stores are replenished .
• With continued emesis or nasogastric suction
and without replacement of Cl− losses, serum
HCO3− may rise to extremely high levels.
• The thiazides and metolazone inhibit the Na+-Cl−
cotransporter in the early distal tubule
• The loop diuretics inhibit the Na+-K+-2Cl−
cotransporter in the TAL .
• These agents all impair Cl− reabsorption, causing
selective Cl− depletion, and stimulate K+ excretion
by increasing Na+ delivery to the collecting duct.
• The alkalosis produced is typically mild (serum
HCO3− <38 mmol/l)
• Hypokalemia caused by K+ depletion is more
prominent and is the major management problem.
Genetic Impairment of Cl−-Linked Na+Transport
Bartter and Gitelman
• hereditary disorders manifested by metabolic alkalosis and
hypokalemia without hypertension.
• Bartter syndrome the effect of impeding Cl−-associated Na+
reabsorption in TAL through Na+-K+-2Cl− cotransporter .
• Patients usually ill early in life with metabolic alkalosis and
volume depletion, features similar to those seen in individuals
abusing loop diuretic agents.
• Gitelman syndrome inactivate the thiazide-sensitive Na+-Cl−
cotransporter in the early distal tubule , leading to
hypokalemia and metabolic alkalosis similar to that caused by
• Gitelman syndrome becomes clinically apparent later in life
and, unlike Bartter syndrome, has hypomagnesemia and
• occur in the distal colon and typically secrete 1
to3 L/day of fluid that is rich in Na+, Cl−, and K+.
• Because the volume of secreted fluid is relatively
low, metabolic alkalosis usually mild when
• characterized by high sweat [Cl−] and, with
excessive sweating, Cl− losses can be large
enough to cause metabolic alkalosis.
• In children and adolescents, this acid-base
disorder can be the presenting symptom.
Severe Potassium Deficiency
• In patients with severe K+ depletion (serum
[K+] <2 mmol/l), metabolic alkalosis can be
sustained despite Cl− administration.
• Chloride resistance in this setting is probably
caused by impairment of renal Cl−
reabsorption induced by K+ depletion.
• Partial repletion of K+ stores rapidly reverses
this problem and makes the alkalosis Cl−
• Aldosterone and other mineralocorticoids cause metabolic alkalosis by
directly stimulating both the H+-ATPase and the ENaC in the collecting
duct, promoting Na+ retention, K+ loss, and metabolic alkalosis .
• The metabolic alkalosis is typically mild (serum HCO3 − 30 to 35 mmol/l)
and is associated with more severe hypokalemia (K+ <3 mmol/l) than
observed with Cl− depletion alkalosis.
• Primary hyperaldosteronism is the most common cause of this form of
• Glucocorticoid-remediable aldosteronism (GRA) is caused by a mutation
that results in stimulation of aldosterone secretion by adrenocorticotropic
hormone (ACTH) rather than by angiotensin.
• The oral mineralocorticoid fludrocortisone can induce metabolic alkalosis
if used inappropriately.
• Corticosteroids, when administered in high doses, increase renal K+
excretion nonspecifically and produce a mild increase in serum [HCO3−].
Apparent Mineralocorticoid Excess Syndromes
• Inherited abnormalities produce a metabolic alkalosis that is clinically
indistinguishable from hyperaldosteronism but without measurable aldosterone .
• Liddle syndrome a genetic mutation prevents the removal of ENaCs from the
urinary membrane of collecting duct epithelial cells . As a result, Na+
reabsorption cannot be downregulated, causing the same cascade of events seen
• Because continuous stimulation of Na+ reabsorption expands ECF volume,
however, aldosterone levels are low.
• 11β-hydroxysteroid dehydrogenase deficiency , an enzyme adjacent to
mineralocorticoid receptor that converts cortisol to cortisone.
• When this enzyme is inactivated, cortisol activates the receptor, stimulating
Na+ reabsorption and K+ secretion and producing metabolic alkalosis and
hypertension with low aldosterone levels.
• Glycyrrhizic acid (a component of natural licorice), carbenoxolone , and
gossypol (an agent that inhibits spermatogenesis) inhibit the activity of 11β-
hydroxysteroid dehydrogenase and can cause the same clinical picture.
• Mild to moderate metabolic alkalosis is well tolerated,
with few clinically important adverse effects.
• Patients with serum HCO3− 40 mmol/l are usually
• The adverse effect of most concern is hypokalemia, which
increases the likelihood of cardiac arrhythmias in patients
with coronary heart disease.
• With more severe metabolic alkalosis (serum HCO3− >45
mmol/l), arterial oxygen tension (PaO2) often falls to less
than 50 mm Hg (<6.6 kP) secondary to hypoventilation,
and ionized calcium decreases (due to alkalemia).
• Patients with serum HCO3 −greater than 50 mmol/l may
develop seizures, tetany, delirium, or stupor.
• These changes in mental status are probably multifactorial
in origin, resulting from alkalemia, hypokalemia,
hypocalcemia, and hypoxemia.
serum HCO3− 40 mmol/l asymptomatic
serum HCO3− >45 mmol/l
• PaO2 falls to less than 50
• ionized calcium decreases
serum HCO3 − >50 mmol/l
seizures, tetany, delirium, or
• Diagnosis of metabolic alkalosis involves three
The first step Detection based on elevated
venous [total CO2].
The second step is evaluation of the secondary
response (hypoventilation), excluding the
possibility that a respiratory acid-base
abnormality is also present.
This step requires measurement of arterial pH and Paco2.
The third step is Determination of the cause.
evaluation of the secondary response
• A major deviation in PaCO2 from the expected
value indicates the presence of a complicating
respiratory acid-base disorder, either respiratory
acidosis or respiratory alkalosis .
• The anion gap, [Na+]− ([Cl−] + [HCO3−]), is not
increased in mild to moderate metabolic alkalosis
• but it can be increased by 3 to 5 mmol/l when
alkalosis is severe.
• If the anion gap is more than 20 mmol/l,
metabolic alkalosis is most likely complicated by
superimposed metabolic acidosis
Determination of the cause.
• In more than 95%, metabolic alkalosis is caused
either by diuretic use or by Cl− losses from the GI
• This information is easily obtained from the
patient history, and attention can be directed
toward the appropriate treatment.
Determination of the cause
• If the cause is unclear from the history, measurement of urine Cl− can help.
• Unless the patient has recently taken a diuretic agent, urine [Cl−] should be less
than 10 mmol/l if the metabolic alkalosis is caused by Cl− depletion.
• A confounding problem can be self-induced vomiting (bulimia)
or surreptitious use of diuretics
which presents the greater diagnostic dilemma because continued diuretic-
induced Cl− excretion may lead one to undertake an extensive workup for rarer
forms of metabolic alkalosis.
Urinary screens for specific diuretic compounds may be necessary to establish
the correct diagnosis.
In bulimic patients, urine Cl− excretion should be low (spot urine [Cl−] <10
• If the cause is not apparent from this analysis, rarer forms of metabolic alkalosis
caused by tubule transport abnormalities should be considered. In these forms
of metabolic alkalosis, urine [Cl−] is typically greater than 30 mmol/l.
Determination of the cause
• In the patient with hypertension and adequate chloride
intake who is not taking a diuretic agent, the most common
cause of metabolic alkalosis is primary hyperaldosteronism.
• Measurement of serum renin and serum or urine
aldosterone levels can distinguish mineralocorticoid excess
syndromes from the rarer syndromes of apparent
mineralocorticoid excess .
• In the normotensive or hypotensive patient who is not
taking a diuretic agent, and who has metabolic alkalosis
despite adequate chloride intake, the diagnosis of Bartter
or Gitelman syndrome should be considered.
• Familial genetic studies can establish these diagnoses with
Chloride Depletion Alkalosis
In the patient with metabolic alkalosis caused by nasogastric drainage or
• Administration of intravenous NaCl will correct both the alkalosis and
the volume depletion. Potassium losses should also be replaced by oral
or intravenous KCl.
• Typically the K+ deficit is 200 to 400 mmol in patients with mild to
moderate metabolic alkalosis induced by Cl− losses in the upper GI tract.
• When nasogastric drainage must be continued, H+ and Cl− losses can be
reduced by drugs that inhibit gastric acid secretion.
• In contrast to patients with GI losses, NaCl administration is not usually
required in patients with metabolic alkalosis caused by diuretics, unless
clinical signs of volume depletion are present.
• Potassium chloride supplements should be
given to minimize K+ depletion and decraese
the severity of the metabolic alkalosis.
• The addition of a potassium-sparing diuretic,
such as amiloride, triamterene, spironolactone
can assist in minimizing these abnormalities.
• A mild metabolic alkalosis is well tolerated,
with no clinically significant adverse effects.
• If possible, the diuretic should be
discontinued; the disorder then will resolve as
long as the diet contains adequate K+ and Cl−.
Corticosteroid and Apparent Corticosteroid- Induced Metabolic Alkalosis
• If the alkalosis is caused by an adrenal adenoma, the disorder is
corrected by surgical removal of the tumor .
• In other forms of primary hyperaldosteronism, the alkalosis can be
minimized by dietary NaCl restriction and by aggressive replacement of
body K+ stores with supplemental KCl. Spironolactone or eplerenone,
competitive inhibitors of aldosterone, can also correct the disorder.
• In patients with GRA, the disorder is corrected by dexamethasone
administration, which suppresses ACTH secretion and thereby reduces
• In the hereditary forms of apparent mineralocorticoid excess (Liddle
syndrome and 11β-hydroxysteroid dehydrogenase deficiency),
amiloride is the most effective treatment.
Management of metabolic alkalosis in patients
with severe congestive heart failure
• In patients with congestive heart failure and fluid
overload who still have adequate kidney function,
acetazolamide can be used to reduce serum[HCO3−].
• This carbonic anhydrase inhibitor blocks H+-linked
Na+ reabsorption, leading to excretion of both Na+
• Acetazolamide decreases ECF volume and lowers
serum HCO3− but stimulates K+ excretion
• When use acetazolamide should be accompanied by
aggressive K+ replacement therapy.
Management of metabolic alkalosis in
patients with renal failure
• Continuous venovenous hemofiltration can remove 20 to 30 l/day of an
ultrafiltrate of plasma, and a bicarbonate free replacement solution can
be used to reduce serum HCO3 and increase serum Cl−.
• Serum HCO3− can also be lowered by continuous slow , low-efficiency
dialysis, with the dialysate HCO3
− adjusted to 23 mmol/l.
• Standard hemodialysis or peritoneal dialysis is less useful because these
treatments are designed to add alkali to the blood, and the alkali
concentration in the dialysate is set at 35 to 40 mmol/l.
• However, newer machines allow adjustment of the dialysate HCO3− to
as low as 30 mmol/l, and this form of treatment has been used to
successfully treat patients with severe metabolic alkalosis.