METABOLIC ALKALOSIS

Mohamed Abdelhafez SolimanNephrology Specialist

NMGH

METABOLIC ALKALOSIS

• DEFINITION

• BICARBONATE TRANSPORT IN THE KIDNEY

• PATHOPHYSIOLOGY OF METABOLIC ALKALOSIS

• ETIOLOGY

• CLINICAL MANIFESTATIONS

• Approach to the Diagnosis of Metabolic Alkalosis

• TREATMENT

DEFINITION

• 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 (HCO3

−) 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 KIDNEY• 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

filtered HCO3- to produce CO2 and water, removing HCO3

- from the urine.

• 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 excreted.

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− - HCO3− exchanger (pendrin).

• This transporter is activated by alkalemia and requires Cl− 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− - HCO3

− exchanger . suppression of the normally active collecting duct H+-

ATPase.

BICARBONATE TRANSPORT IN THE KIDNEY• Apical membrane ion transporters along the

nephron.

• 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

Alkalosis :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

Chloride Depletion• 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 TransportChloride Depletion

• The metabolic alkalosis induced by gastrointestinal Cl−

losses can be very severe, with serum HCO3− greater

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.

Exogenous Alkali• 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 function.

• If HCO3− excretion is impaired as a result of kidney failure, even minimal daily alkali administration can cause a sustained metabolic alkalosis independent of Cl− intake.

• 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 Inducedby Bicarbonate Retention

• Regardless of the cause, blood pH increases in patients with metabolic alkalosis and elicits secondary hypoventilation, increasing PaCO2.

• 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 .

ETIOLOGY• 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-resistant)

Metabolic Alkalosis 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.

Diuretic Administration• 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 thiazide diuretics.

• Gitelman syndrome becomes clinically apparent later in life and, unlike Bartter syndrome, has hypomagnesemia and hypocalciuria.

Villous adenomas • 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 present.

Cystic fibrosis • 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− responsive.

Metabolic Alkalosis from Primary Stimulation of Ion Transport

Mineralocorticoid excess• Primary hyperaldosteronism:

adenoma, hyperplasia• Cushing syndrome• Corticotropin-secreting tumor• Renin-secreting tumor• Glucocorticoid-remediable

aldosteronism• Adrenogenital syndromes• Fludrocortisone treatment

Apparent mineralocorticoid excess

• Licorice• Carbenoxolone• Liddle syndrome• 11β-Hydroxysteroid

dehydrogenase deficiency

Glucocorticoids (high dose) Methylprednisolone

Mineralocorticoid Excess• 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 metabolic alkalosis.

• 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 in hyperaldosteronism.

• 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.

Alkali Administration

CLINICAL MANIFESTATIONS• Mild to moderate metabolic alkalosis is well tolerated, with few

clinically important adverse effects.• Patients with serum HCO3− 40 mmol/l are usually asymptomatic. • 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

mm Hg• ionized calcium decreases

serum HCO3 − >50 mmol/l seizures, tetany, delirium, or stupor

DIAGNOSIS• Diagnosis of metabolic alkalosis involves three

steps 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.

DIAGNOSISevaluation 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

DIAGNOSIS Determination of the cause.

• In more than 95%, metabolic alkalosis is caused either by diuretic use or by Cl− losses from the GI tract.

• This information is easily obtained from the patient history, and attention can be directed toward the appropriate treatment.

DIAGNOSIS 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 mmol/l).

• 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.

DIAGNOSIS 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 high specificity.

TREATMENTChloride Depletion Alkalosis

In the patient with metabolic alkalosis caused by nasogastric drainage or vomiting

• 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.

TREATMENT• 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−.

TREATMENTCorticosteroid 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 aldosterone secretion.

• 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+ and HCO3−.

• Acetazolamide decreases ECF volume and lowers serum HCO3− but stimulates K+ excretion exacerbating hypokalemia.

• 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.

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