There's no such thing as a contraction alkalosis

We recently discussed an excellent paper on the classification of metabolic alkalosis. The three suggested subtypes were primary and secondary stimulation of collecting duct ion transport and exogenous alkali administration. Another interesting editorial was just published in JASN that further expands on the idea that chloride deficiency is central to the maintenance of a metabolic alkalosis.

The traditional view of a contraction alkalosis was that in a volume depleted patient, there would be increased reabsorption of sodium in the proximal tubule. Because this sodium must be reabsorbed with an anion, bicarbonate was also reabsorbed in the proximal tubule along with this in preference to chloride, thus perpetuating the alkalosis. The first challenge to this viewpoint came in the 1960s when it was shown that a chloride deficient alkalosis generated by diuretics or gastric aspiration was corrected by treatment with NaCl or KCl but not with Na or K repletion without Cl. This did not however deal with the issue of volume depletion.

More recently, the authors of the editorial have shown that a chloride deficient alkalosis could be corrected in rats by infusion of a chloride containing solution despite ongoing volume depletion, while restoration of the ECF volume with albumin did not correct the acid-base abnormality. In fact, the urinary excretion of bicarbonate increased in the rats that received chloride while it fell further in those that received volume expansion with albumin alone.

Finally, they treated normal human subjects with a low chloride diet along with furosemide and Na and K supplementation. These subjects developed an alkalosis that was maintained for 5 days and corrected with oral KCl alone without any expansion of plasma volume. This elegantly demonstrated that volume is not the issue in these cases and that it truly is an effect of chloride depletion alone.

So what is the mechanism for the maintenance of the alkalosis? Previous posts have discussed the role of Pendrin, the HCO3-Cl exchanger in the collecting duct. The main stimuli for pendrin activation are decreased distal delivery of chloride and intracellular alkalosis. However, where there is little or no distal Cl delivery, it is not available to exchange with HCO3 and thus the alkalosis is maintained. This also helps explain the alkalosis induced by hypokalemia. Hypokalemia induces intracellular acidosis which inhibits HCO3 excretion by pendrin thus exacerbating the extracellular alkalosis.

Can we now finally get rid of the concept of a contraction alkalosis?

Classification of Metabolic Alkalosis

Dr John Gennari had another typically excellent review of metabolic alkalosis in AJKD in October. He suggests an alternative means of classifying a metabolic alkalosis according to the etiology of the alkalosis along with the physiological basis for the maintenance of the alkalosis once it has occurred. He also goes into some detail explaining the key role that chloride depletion has in the development and maintenance of a metabolic alkalosis.

The 3 subtypes that he suggested are:

1. Secondary stimulation of collecting duct ion transport:

This is the commonest type and results largely from a secondary increase in the activity of ENaC in the distal nephron leading to increased sodium reabsorption and hydrogen ion excretion. The commonest causes are chloride depletion syndromes (GI losses, CF) and the use of thiazide and loop diuretics, with congenital disorders such as Bartter and Gitelman syndrome being rarer. Severe potassium depletion can also precipitate a metabolic alkalosis. The mechanism is complicated but it includes increased proximal tubular hydrogen ion secretion, decreased activity of the Na-2K-Cl transporter in the loop of Henle (with increased NH4 transport in this segment also contributing) and subsequent increased activity of ENaC due to the higher distal delivery of sodium. This form of alkalosis is perpetuated by chloride depletion.

2. Primary stimulation of collecting duct ion transport:

This is almost always due to a pathological increase in sodium reabsorption with consequent hypertension and volume expansion. The commonest cause is primary aldosteronism. Other rarer causes include Cushing’s Syndrome, CAH, Liddle’s Syndrome, 11-hydroxysteroid dehydrogenase inhibition (licorice) or deficiency and exogenous mineralocorticoids.

3. Alkali intake or administration:

This is largely an issue of excess alkali administration in patients who are unable to excrete it rapidly – i.e. patients with abnormal renal function

This paper is highly recommended for anyone wanting to understand more about the pathophysiology of metabolic alkalosis