Chloride responsiveness and metabolic alkalosis

[ChessMaster3000]

I am grappling with how chloride deficiency is related to metabolic alkalosis and likewise how infusing saline can result in a met. acidosis. In the alpha-intercalated cell of the collecting tubule there is a bicarb-chloride transporter, which causes retention of bicarb and excretion of chloride. I would thing that infusion chloride would increase the activity of this transporter leading to even more bicarb retention. Of course that's not the case--anyone have an idea why?

thanks in advance

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[Myxedema]

There is another type of intercalated cell called β-intercalated cell, which is in essence a mirror image of the α-intercalated cell:

Right side shows α-intercalated cell, which secretes H+ ions to the urine while absorbing HCO3- into the interstitium in exchange for Cl-. β-intercalated cell, as it is shown in the left side, has the same co-transporters, but on the reverse side. Its luminal Cl-/HCO3- co-transporter allows secretion of HCO3- into the urine in exchange for Cl-.
In metabolic alkalosis, there's excess HCO3-. Now, if there's adequate Cl- in the urine, then it is possible to absorb that Cl- and excrete HCO3- in return. Indeed, if HCO3- excess occurred as a result of volume contraction (like you'd see in loop diuretics), then giving saline to such a patient would result Cl- to be filtered in the urine, which then can be exchanged for HCO3-. This type of metabolic alkalosis is saline responsive, and due to the kidney exchanging Cl- for HCO3-, urine Cl is < 10 mEq/L. However, metabolic alkalosis may also seen in pathologies with volume excess, such as hyperaldosteronism. In such cases, there will be excess H+ secretion (rather than increased HCO3- absorption as seen with volume contraction). H+ secretion is accompanied by passive Cl- secretion (not shown in the figure above). That is why in such cases, urine Cl- is found to be increased (>20 mEq/L).
In metabolic acidosis, you'd want increased HCO3- reabsorption.

 

[ChessMaster3000]

There is another type of intercalated cell called β-intercalated cell, which is in essence a mirror image of the α-intercalated cell:

Right side shows α-intercalated cell, which secretes H+ ions to the urine while absorbing HCO3- into the interstitium in exchange for Cl-. β-intercalated cell, as it is shown in the left side, has the same co-transporters, but on the reverse side. Its luminal Cl-/HCO3- co-transporter allows secretion of HCO3- into the urine in exchange for Cl-.
In metabolic alkalosis, there's excess HCO3-. Now, if there's adequate Cl- in the urine, then it is possible to absorb that Cl- and excrete HCO3- in return. Indeed, if HCO3- excess occurred as a result of volume contraction (like you'd see in loop diuretics), then giving saline to such a patient would result Cl- to be filtered in the urine, which then can be exchanged for HCO3-. This type of metabolic alkalosis is saline responsive, and due to the kidney exchanging Cl- for HCO3-, urine Cl is < 10 mEq/L. However, metabolic alkalosis may also seen in pathologies with volume excess, such as hyperaldosteronism. In such cases, there will be excess H+ secretion (rather than increased HCO3- absorption as seen with volume contraction). H+ secretion is accompanied by passive Cl- secretion (not shown in the figure above). That is why in such cases, urine Cl- is found to be increased (>20 mEq/L).
In metabolic acidosis, you'd want increased HCO3- reabsorption.

Wow that was phenomenal, thanks. So this exact explanation also applies to why giving saline produces a non-gap met acidosis?

 

[Myxedema]

Wow that was phenomenal, thanks. So this exact explanation also applies to why giving saline produces a non-gap met acidosis?

I don't think giving a healthy person some normal saline would cause metabolic acidosis. The only connection I can make here is distinguishing between the two main causes of non-anion gap metabolic acidosis: diarrhea and RTAs. Obviously, the treatment of diarrhea is with volume supplementation (i.e. saline), whereas you'd treat RTAs with bicarbonate (type I), bicarbonate and volume contraction [i.e. thiazides] (type II) and fludrocortisone (type IV). To distinguish between those two etiologies, urine anion gap can be calculated, which is UAG = Urine Na - Urine Cl. In diarrhea, since the kidneys are working correctly, there would be excretion of excess H+ via the α-intercalated cells. As I've mentioned above, Cl- follows H+, which means urine chloride would be increased. Thus, in diarrhea, UAG will be negative. In RTAs, since the problem lies within the kidney, this mechanism won't work, Cl- won't be secreted, and UAG will be positive. So, you'd give saline if UAG is negative, and give the appropriate treatment (based on further testing) if UAG is positive.

 

[ChessMaster3000]

I don't think giving a healthy person some normal saline would cause metabolic acidosis. The only connection I can make here is distinguishing between the two main causes of non-anion gap metabolic acidosis: diarrhea and RTAs. Obviously, the treatment of diarrhea is with volume supplementation (i.e. saline), whereas you'd treat RTAs with bicarbonate (type I), bicarbonate and volume contraction [i.e. thiazides] (type II) and fludrocortisone (type IV). To distinguish between those two etiologies, urine anion gap can be calculated, which is UAG = Urine Na - Urine Cl. In diarrhea, since the kidneys are working correctly, there would be excretion of excess H+ via the α-intercalated cells. As I've mentioned above, Cl- follows H+, which means urine chloride would be increased. Thus, in diarrhea, UAG will be negative. In RTAs, since the problem lies within the kidney, this mechanism won't work, Cl- won't be secreted, and UAG will be positive. So, you'd give saline if UAG is negative, and give the appropriate treatment (based on further testing) if UAG is positive.

Fair enough. So for the only way for this all to make sense, there would be little to no chloride in the urine as it is entering the collecting tubules, correct? Also, does that only apply to type 1 and 4 RTA? Because in that disorder there is an issue with H+ and therefor Cl- secretion from the tubules. From what I understand your reasoning would not apply to type 2 RTA, right?