1. What is metabolic alkalosis?

The metabolic alkaloses represent a heterogeneous group of disorders that have in common a high concentration of plasma bicarbonate [HCO ₃ ⁻ ] and a low concentration of H ⁺ in plasma. This constellation of findings can be seen in a number of different pathophysiologic entities. Hence metabolic alkalosis is a syndrome of metabolic findings and not a final diagnosis.

As addressed in the chapter on metabolic acidosis, an alkalosis is a process that favors an alkaline blood pH or alkalemia. However, an alkalosis does not guarantee alkalemia, and other processes, such as acidosis, may be concurrent.

2. What are the mechanisms by which metabolic alkaloses develop and persist?

Traditionally, the factors responsible for a rise in [HCO ₃ ⁻ ] have been classified as those that directly raise [HCO ₃ ⁻ ] and those that account for the failure of the kidneys to excrete the excess bicarbonate anions ( Fig. 79.1 ). Six broad mechanisms are recognized. A and B are processes that generate metabolic alkalosis; C to E are contributors to the maintenance of metabolic alkalosis.

Mechanisms that may lead to a rise in the P _HCO3 . ECF, extracellular fluid; GI, gastrointestinal.

Generation:

• A.
  

  The loss of a nonvolatile acid from the extracellular fluid (ECF) compartment (e.g., vomiting)

  
  
• B.
  

  Addition of exogenous alkali (e.g., ingestion of NaHCO ₃ )

  
  
• C.
  

  Loss of NaCl-rich fluid, leading to reabsorption of NaHCO ₃ (e.g., loop and thiazide diuretics)

Maintenance:

• D.
  

  Increased reabsorption of bicarbonate within the proximal tubule

  
  
• E.
  

  Increased regeneration of bicarbonate at the distal nephron

  
  
• F.
  

  Increased bicarbonate produced from the bicarbonate buffer system

With respect to A, the most common clinical example is vomiting or nasogastric suction causing loss of HCl ( Fig. 79.2 ). These are common generators of metabolic alkalosis. Addition of base (B) is also a possible underlying mechanism but a relatively infrequent event, such as ingestion of NaHCO ₃ . A large input of NaHCO ₃ cannot maintain metabolic alkalosis because the kidneys will readily excrete sodium (Na ⁺ ) and HCO _{3 −} or potential HCO ₃ ⁻ (citrate) very quickly, unless reduced kidney function is present. Milk-alkali syndrome is an example in which base administration occurs, and reduced glomerular filtration rate (GFR) accounts for a reduction in the kidney’s ability to excrete the excess base.

Electroneutrality during the deficit of HCl. The stylized structure is the stomach with a parietal cell on its right-hand border. In this cell, CO ₂ + H ₂ O are converted to H ⁺ and HCO ₃ ^– by a reaction catalyzed by carbonic anhydrase (CA) . H ⁺ are secreted into the lumen of the stomach by the H ⁺ /K ⁺ -ATPase, whereas K ⁺ recycle back into the parietal cell (not shown for simplicity). Cl ^– from the extracellular fluid compartment enter parietal cells on the basolateral Cl ^– /HCO ₃ ^– anion exchanger; Cl ^– enter the lumen of the stomach via Cl ^– ion channels. Overall, there is a loss of Cl ^– and a gain of HCO ₃ ^– in the body. Thus there is also electroneutrality in all compartments.

The secrets surrounding direct HCl loss are elaborated in much more detail later.

In the metabolic alkalosis frequently seen with the use of both loop and thiazide diuretics, the urine produced contains mostly NaCl and KCl, removing a portion of plasma that will lead to a higher [HCO ₃ ]. This initial generating phase is termed “contraction” alkalosis. The failure of the kidney to correct the [HCO ₃ ] is due to the ensuing deficiency of both Cl and K, leading to maintenance of the contraction-initiated alkalosis.

Augmentation of proximal bicarbonate reabsorption (D) is considered a perpetuator of alkalosis rather than a trigger. Bicarbonate reabsorption at the proximal convoluted tubule (PCT) is driven largely by angiotensin II and hypokalemia, both of which favor PCT proton excretion, which captures filtered bicarbonate for reabsorption. These processes, which help maintain metabolic alkalosis, are important mediators in states of extracellular volume depletion, or reduced effective arterial blood volume, which stimulate renin and angiotensin II production. When there is a reduction in effective arterial blood volume, reabsorption of sodium predominates over the kidney’s ability to maintain acid-base balance. Angiotensin directly stimulates proximal Na ⁺ /H ⁺ exchange (NHE3), leading to reabsorption of NaHCO ₃ regardless of [HCO ₃ ⁻ ]. Because loss of gastric acid, or the action of diuretics, causes loss of Cl, the reabsorption of Na ⁺ in the PCT must be accompanied by HCO ₃ . Potassium depletion with both vomiting and diuretic effects also contribute to the maintenance process.

Distal bicarbonate regeneration (E) occurs in response to distal sodium delivery and the action of aldosterone. These two prerequisites allow for sodium-proton exchange; the excreted proton leaves the urine as ammonium chloride. Thus hyperaldosteronism is a potential generator of alkalosis. A secret here is that aldosterone promotes the action of the distal proton-ATPase (H ⁺ -ATPase); this protein lies on the luminal side of the distal convoluted tubule and excretes hydrogen ions into the lumen such that bicarbonate is reclaimed. In addition, hypokalemia enhances distal proton-potassium-ATPase (H ⁺ /K ⁺ -ATPase)—a luminal facing hydrogen ion, potassium antiporter—which also leads to bicarbonate absorption. Thus hypokalemia and hyperaldosteronism independently potentiate the magnitude of renal proton excretion (or distal bicarbonate regeneration). Another secret is that chronic elevations of arterial carbon dioxide tension (PaCO ₂ ) up-regulate the expression of distal H ⁺ -ATPase and H ⁺ /K ⁺ -ATPase—the basis for metabolic compensation for chronic respiratory acidosis; note that these processes most appropriately are considered “compensation” rather than “primary metabolic alkalosis.” Stimulation of both distal H ⁺ -ATPase and H ⁺ /K ⁺ -ATPase are associated with enhanced appearance of bicarbonate in the blood as long as the generated protons appear in the urine.

Lastly, bicarbonate can come from underperfused muscle (F). In states with a low effective arterial blood volume and diminished blood flow to muscles, PCO ₂ in capillary blood rises. Because CO ₂ must diffuse from cells to capillaries, it follows that the intracellular PCO ₂ must also be high. As shown in Fig. 79.3 , this high PCO ₂ will drive its conversion to H ⁺ and HCO ₃ ⁻ within skeletal muscle. The H ⁺ binds to proteins in cells while the HCO ₃ ⁻ . exits via the Cl-/HCO ₃ ⁻ anion exchanger. This condition will persist as long as the blood flow rate to muscles remains low.

Generation of new HCO ₃ ⁻ in skeletal muscle when there is a deficit of NaCl. The oval represents a cell membrane containing HCO ₃ ⁻ and protein buffer systems. When the effective arterial blood volume is contracted, the rate of blood flow is reduced. The subsequent extraction of most of the O ₂ from each liter of blood flowing through the capillaries raises both the capillary and the intracellular fluid PCO ₂ (left portion of the figure) . The higher PCO ₂ in the interstitial fluid and in these cells drives the synthesis of H ⁺ and HCO ₃ ⁻ ; the H ⁺ bind to intracellular proteins while the HCO ₃ ⁻ is exported to the extracellular fluid (right portion of the figure) . The net result is a rise in the P _HCO3 . After the infusion of enough saline, there is a decline in capillary and, thereby, the PCO ₂ in cells. When these events are reversed, there will be a fall in the P _HCO3 . DKA, Diabetic ketoacidosis; ECFV, extracellular fluid volume.

3. How does hypokalemia affect the excretion of HCO ₃ ⁻ ?

Loss of potassium from the extracellular space is associated with movement of potassium from the intracellular space to the extracellular space, necessitating movement of protons into cells. The result is lower intracellular pH in cells of the PCT causing activation of the NHE3 in the luminal membrane of this nephron segment. Consequently, there is augmented secretion of H ⁺ , leading to more reabsorption of NaHCO ₃ during hypokalemia, frequently contributing to the maintenance of metabolic alkalosis. Hypokalemia and the associated fall in PCT intracellular pH also stimulate ammoniagenesis, increasing ammonium ion (NH ₄ ⁺ ) production and excretion:

Each ammonium appearing in the urine represents the addition of an HCO ₃ ⁻ to the plasma.

4. Is there a tubular maximum for the renal reabsorption of filtered HCO _{3 −} ?

Under normal conditions, the kidneys reabsorb greater than 90% of filtered HCO ₃ ⁻ in the PCT. As stated earlier, the stimuli for this process are the ambient level of angiotensin II and the usual intracellular pH in cells of the PCT. Consequently, to inhibit this reabsorption of HCO ₃ ⁻ , the effective arterial blood volume must be corrected (e.g., create a positive Na ⁺ balance in cases of reduced total body Na ⁺ content or improve cardiac output in cases of congestive heart failure) to diminish the release of angiotensin II, or the pH in the cells of the PCT must rise. In addition, low GFR is often invoked as a perpetuator of alkalosis because low GFR prevents the high [HCO ₃ ⁻ ] present during alkalosis from exceeding the maximum reabsorption (Tm) of bicarbonate. That is, the low GFR prevents greater HCO ₃ ⁻ filtration from occurring so that Tm is not reached. In that case, there is no bicarbonaturia and systemic alkalosis is maintained. Bearing this in mind, we shall examine the conditions that were present in experimental studies that were interpreted to indicate that there is a renal threshold (Tm) for the reabsorption of HCO ₃ ⁻ by the kidneys.

• •
  

  Data to suggest that there is a renal threshold for the reabsorption of HCO ₃ ⁻ by the kidneys: In the seminal experiments by Pitts et al. in the late 1940s, the infusion of NaHCO ₃ was large enough to expand the ECF volume sufficiently to diminish circulating levels of angiotensin II and to raise the pH in cells of the PCT. Hence the two physiologic stimuli for the proximal reabsorption of HCO ₃ ⁻ were removed. Rather than relate these findings to the changes in physiologic variables, the conclusion was that there is a tubular maximum for the renal reabsorption of HCO ₃ ⁻ .

  
  
• •
  

  Data to suggest that there is not a renal threshold for the reabsorption of HCO _{3 −} : The design of these experiments (e.g., Purkerson et al.) was to avoid a large expansion of the ECF volume while creating a positive balance of NaHCO ₃ . Even though the HCO ₃ ⁻ rose, there was little bicarbonaturia, and hence a tubular maximum for the renal reabsorption of NaHCO ₃ was not observed. In support of this view, the range for the [HCO ₃ ⁻ ] is from 22 to 31 mmol/L in normal subjects consuming a typical Western diet, and there is no appreciable bicarbonaturia at the upper range values for the [HCO ₃ ⁻ ], despite much higher filtered loads for HCO ₃ ⁻ , because the GFR is relatively constant throughout the day.

In summary, the enthusiasm for a T _m for HCO ₃ ⁻ reabsorption in the PCT is based on data from experimental conditions that removed the usual stimuli for the reabsorption of filtered HCO ₃ ⁻ . Furthermore, an infusion of NaHCO ₃ does not represent a normal physiologic occurrence.

Two other points merit emphasis. First, a steady state with metabolic alkalosis can be achieved and maintained when the blood pH rises sufficiently to overcome the stimulatory actions of angiotensin II of the reabsorption of HCO ₃ ⁻ in cells of the PCT. Second, the excretion of potential HCO ₃ ⁻ in the form of organic anions such as citrate is augmented by a high pH in cells of the PCT. Higher intracellular pH inhibits the action of the sodium-dicarboxylate cotransporter in the PCT, leading to excretion of citrate.

5. What other mechanism may lead to a rise in the plasma bicarbonate concentration?

Because concentrations have numerators and denominators, the [HCO ₃ ⁻ ] will rise when there is a net addition of HCO ₃ ⁻ to the ECF compartment and/or when the volume of the ECF compartment declines (see Fig. 79.1 ):

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