Acetazolamide --> normal anion-gap acidosis. Why?

[Phloston]

Why does acetazolamide lead to normal anion-gap acidosis (chloride must be high, but what is the actual mechanism (i.e. which specific transporters are we dealing with and where are they?)? Be specific.

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[Thing1]

Doesn't it just cause HCO3- excretion, therefore leading to normal anion gap? The only way you get high anion gap acidosis is if the primary metabolite abnormality is due to an unmeasured anion (eg lactate). Serum chloride concentration increases in order to make up for the loss of HCO3- in order to preserve electroneutrality. Not sure there is only one specific transporter that is responsible for this (Wikipedia says there are approximarely 13 poorly understood Cl- channels. I'm guessing a few of these are responsible).

 

[withrye]

It's a carbonic anhydrase inhibitor, so you trap HCO3 in the lumen. HCO3 and Cl are generically in an inverse balance with each other, so trapped luminal bicarb leads to increased Cl reabsorption. I don't think the specific Cl pathway is known.

The carbonic anhydrase part doesn't use a transporter; the CO2 made by CA diffuses into the cell before being broken back into H+ and HCO3.

 

[Thing1]

It's a carbonic anhydrase inhibitor, so you trap HCO3 in the lumen. HCO3 and Cl are generically in an inverse balance with each other, so trapped luminal bicarb leads to increased Cl reabsorption. I don't think the specific Cl pathway is known.

The carbonic anhydrase part doesn't use a transporter; the CO2 made by CA diffuses into the cell before being broken back into H+ and HCO3.

I agree with this explanation, in case my previous explanation was unclear.

 

[Phloston]

A need a bit of a deeper mechanism though.

 

[withrye]

How much deeper do you want? A CA inhibitor causes a buildup of HCO3 in the PCT. This buildup is offset electrochemically by myriad Cl transporters in the PCT. I don't think anyone knows how many and which Cl transporters offset the HCO3 buildup.

 

[Belleza156]

Anion Gap = serum Na+ - (serum Cl- + serum HCO3-) = 12 mEq/L +/- 2
-----the 12 mEq/L represents the anions not in the formula, ex. phosphate, albumin, sulfate

If AG is > 12 there must be additional anions outside of those represented by the 12mEq/L that aren't supposed to be there. ex. lactate, salicylate, acetoacetate, Beta-hydroxybutyrate

These unwanted outsiders come as acids with H+ ions, which HCO3- buffers. So now we have decreased HCO3-. But we can't have an imbalance in electroneutrality so the anions of the acid that HCO3- just buffered are there to counterbalance the loss of HCO3- and maintain electroneutrality. So in the equation decreased HCO3- leads to a larger number indicating we have anions present that are neither Cl-,HCO3-, phosphate, albumin, sulfate.

Now if we take acetazolamide which inhibits carbonic anhydrase, reclamation of HCO3- back to the blood can't occur in the PCT because HCO3- will stay as HCO3- in the PCT lumen and not form H2CO3 because the Na+/H+ pump won't be driven to exchange H+ for Na+ (because the Carbonic anhydrase is also inhibited inside the renal tubular cell) and leads to HCO3- to be excreted along with Na+ (Na+HCO3-). So we are losing HCO3-, we can't regenerate it or reclaim it. But electroneutrality has to be maintained at all times so Cl- comes to the rescue and increases to counterbalance the loss of HCO3-.

Anion Gap = serum Na+ - (increased serum Cl- + decreased serum HCO3-) = 12 mEq/L +/- 2

So now we have hyperchloremic NORMAL anion gap metabolic acidosis because within the equation the proportions stayed the same, unlike what happens in increased AG metabolic acidosis where the anions from outside those in the equation offset the loss of HCO3- which doesnt lead to maintenance of the proportions within the equation.

There aren't really any specific transporters to help understand the concept because it's just based on an equation which only represents Na+, Cl-, HCO3, phosphate, albumin, and sulfate.

 

[Phloston]

How much deeper do you want? A CA inhibitor causes a buildup of HCO3 in the PCT. This buildup is offset electrochemically by myriad Cl transporters in the PCT. I don't think anyone knows how many and which Cl transporters offset the HCO3 buildup.

If you look at the early renal chapter in FA, you'll see the electrolytes in two columns: hyper- and hypo-states. For chloride, high levels are seen in Addison's disease and low ones in Conn's. Aldosterone and acetazolamide are strongly interconnected, given that acetazolamide-use induces hypokalaemia secondary to an aldosterone-induced attempt to reclaim Na+ at the principal cell. I know if no one comes up with an answer, I'll have to do the dirty work, which is what I feel like always happens.

There aren't really any specific transporters to help understand the concept because it's just based on an equation which only represents Na+, Cl-, HCO3, phosphate, albumin, and sulfate.

Belleza, thanks for the anion-gap review

 

[withrye]

What specific question(s) are you still looking to have answered?

 

[Boardz]

Why does acetazolamide lead to normal anion-gap acidosis (chloride must be high, but what is the actual mechanism (i.e. which specific transporters are we dealing with and where are they?)? Be specific.

There's a Cl-/HCO3- exchange transporter in the intercalated cell in the collecting duct.

No HCO3- to exchange for Cl- in the serum = hyperchloremia.

 

[Phloston]

There's a Cl-/HCO3- exchange transporter in the intercalated cell in the collecting duct.

No HCO3- to exchange for Cl- in the serum = hyperchloremia.

Interestingly, there are both alpha- and beta-intercalated cells. Alpha secrete protons (under the influence of aldosterone) and beta secrete bicarbonate. Therefore, acetazolamide induces a net zero effect at the intercalated cells, since CA is inhibited in both.

 

[withrye]

Interestingly, there are both alpha- and beta-intercalated cells. Alpha secrete protons (under the influence of aldosterone) and beta secrete bicarbonate. Therefore, acetazolamide induces a net zero effect at the intercalated cells, since CA is inhibited in both.

This also ignores the fact that with a CA inhibitor, the lumen has plenty of HCO3, rendering the point about the distal nephron not seeing HCO3 moot.

 

[Boardz]

This also ignores the fact that with a CA inhibitor, the lumen has plenty of HCO3, rendering the point about the distal nephron not seeing HCO3 moot.

The chloride/bicarb exchange pump is on the basolateral side. But, whatever. I guess I just said something ******ed.

 

[DrizzyDrake]

Anion Gap = serum Na+ - (serum Cl- + serum HCO3-) = 12 mEq/L +/- 2
-----the 12 mEq/L represents the anions not in the formula, ex. phosphate, albumin, sulfate

If AG is > 12 there must be additional anions outside of those represented by the 12mEq/L that aren't supposed to be there. ex. lactate, salicylate, acetoacetate, Beta-hydroxybutyrate

These unwanted outsiders come as acids with H+ ions, which HCO3- buffers. So now we have decreased HCO3-. But we can't have an imbalance in electroneutrality so the anions of the acid that HCO3- just buffered are there to counterbalance the loss of HCO3- and maintain electroneutrality. So in the equation decreased HCO3- leads to a larger number indicating we have anions present that are neither Cl-,HCO3-, phosphate, albumin, sulfate.

Now if we take acetazolamide which inhibits carbonic anhydrase, reclamation of HCO3- back to the blood can't occur in the PCT because HCO3- will stay as HCO3- in the PCT lumen and not form H2CO3 because the Na+/H+ pump won't be driven to exchange H+ for Na+ (because the Carbonic anhydrase is also inhibited inside the renal tubular cell) and leads to HCO3- to be excreted along with Na+ (Na+HCO3-). So we are losing HCO3-, we can't regenerate it or reclaim it. But electroneutrality has to be maintained at all times so Cl- comes to the rescue and increases to counterbalance the loss of HCO3-.

Anion Gap = serum Na+ - (increased serum Cl- + decreased serum HCO3-) = 12 mEq/L +/- 2

So now we have hyperchloremic NORMAL anion gap metabolic acidosis because within the equation the proportions stayed the same, unlike what happens in increased AG metabolic acidosis where the anions from outside those in the equation offset the loss of HCO3- which doesnt lead to maintenance of the proportions within the equation.

There aren't really any specific transporters to help understand the concept because it's just based on an equation which only represents Na+, Cl-, HCO3, phosphate, albumin, and sulfate.

thank you

 

[navigator]

I think the reason for this is not that Cl- is reabsorbed through a particular Cl- transporter but rather that high tubular HCO3- causes electrical repulsion of other anions, indirectly inducing paracellular reabsorption of Cl- in DCT and CD. The same mechanism is what causes reabsorption of Mg2+ and Ca2+ from net positive electric potential (caused by back-diffusion of K+) in TAL.

Just a guess, but curious to know if anyone came across a different explanation