renal tubular acidosis IV

[Ingersoll]

did not see it addressed in any other thread, so...

can someone explain to me why hypoaldosteronism ---> (hyperkalemia) --> decreased secretion of ammonia(ium). I don't understand the mechanism of decreased NH3 excretion, so I will never be able to "learn" it. Hopefully it's easy, but does not seem to be addressed by books I have.

thanks fellas and ladies.

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[airmonkey84]

Hypoaldosteronism will result in a decreased secretion of H+ ions. NH3 combines with H+ to be excreted as polar NH4+. Thus, if less H+ is secreted in RTA IV, there will be less NH4+ produced, and NH3 (non polar) will be resorbed.

 

[Ingersoll]

yep. figured it would be that simple. but it makes all the difference in the world. thanks.

 

[medstylee]

potassium concentration regulates the production of NH3 from glutamine in the kidney. hyperkalemia causes decreased synthesis of NH3. so, if you are hyperkalemic (due to hypoaldosteronism in this case), then you produce less NH3 and thus you cannot secrete as much H+ as titratable acid (NH4+). that's the mechanism for acidosis in type IV tubular acidosis. i hope that makes some sense.

 

[airmonkey84]

potassium concentration regulates the production of NH3 from glutamine in the kidney. hyperkalemia causes decreased synthesis of NH3. so, if you are hyperkalemic (due to hypoaldosteronism in this case), then you produce less NH3 and thus you cannot secrete as much H+ as titratable acid (NH4+). that's the mechanism for acidosis in type IV tubular acidosis. i hope that makes some sense.

How does potassium regulate ammonia production from glutamine?

 

[medstylee]

How does potassium regulate ammonia production from glutamine?

i have no idea. it was in my physiology textbook and i didn't really look into the mechanism any further than that. (maybe it has some sort of effect on glutaminase?). anyway, i think the take home message is that hyperkalemia causes decreased production of NH3 and vice versa with hypokalemia. this is reiterated in Costanzo's BRS book - I'm using the 3rd edition and it's on p.194-195. i'm sure just knowing that is more than sufficient for step 1. (i hope, at least).

 

[medstylee]

http://www.uphs.upenn.edu/renal/renal%20curr%20pdfs/k%20and%20acid%20base.pdf

look at the top right part of the first page. i'm sure the mechanism is in the pdf file somewhere - i didn't have the will-power to look through to find it. hope that helps.

on a side note - i definitely did not know this mechanism before reading up on it. i read the OP's question and realized i didn't really know the mechanism for type IV rta either, so i looked it up. in my perfect universe, i will not have any kidney questions on step 1, heh.

 

[airmonkey84]

http://www.uphs.upenn.edu/renal/renal curr pdfs/k and acid base.pdf

look at the top right part of the first page. i'm sure the mechanism is in the pdf file somewhere - i didn't have the will-power to look through to find it. hope that helps.

on a side note - i definitely did not know this mechanism before reading up on it. i read the OP's question and realized i didn't really know the mechanism for type IV rta either, so i looked it up. in my perfect universe, i will not have any kidney questions on step 1, heh.

Looking at the document it seems that the bigger issue at hand is diffusion of NH3 versus NH4+ trapping. The whole kalemia thing plays a role but not as definitive based on the explanation in the document.

 

[stop2stop]

Looking at the document it seems that the bigger issue at hand is diffusion of NH3 versus NH4+ trapping. The whole kalemia thing plays a role but not as definitive based on the explanation in the document.

I know this is a really old thread, but is there anyway someone could elaborate on this mechanism/know if it has been updated recently? I notice that FA 2016 says that NH3 synthesis is decreased. How is hyperkalemia leads to decreased synthesis/if it does at all?

 

[DoctorInTheMaking14]

I know this is a really old thread, but is there anyway someone could elaborate on this mechanism/know if it has been updated recently? I notice that FA 2016 says that NH3 synthesis is decreased. How is hyperkalemia leads to decreased synthesis/if it does at all?

It says that BRS too but doesn't explain further. I'm stumped as well.

 

[Jabbed]

I know this is a really old thread, but is there anyway someone could elaborate on this mechanism/know if it has been updated recently? I notice that FA 2016 says that NH3 synthesis is decreased. How is hyperkalemia leads to decreased synthesis/if it does at all?

The basic principle is that ammoniagenesis in the PCT is a reaction to either 1) acidosis or 2) activation of RAAS. With that in mind, the ↓ammoniagenesis in type IV RTA is due to two reasons:

1. ↓aldosterone → ↓ammoniagenesis
2. ↑[K] → H/K exchange → intracellular alkalosis → ↓ammoniagenesis

We all tend to fixate on the RAAS mechanism because it is conceptually easier to understand, but the role of potassium is equally important to conceptualize as it helps explain why we often see hyperkalemia/acidemia and hypokalemia/alkalemia in tandem. Note that even though hypoaldosteronism will directly lead to less H secretion in the collecting duct, the principle mechanism of the acidosis is due to the decrease in ammoniagenesis. This is why type IV RTA is the only RTA that is actually associated with an acidic urine (i.e., you're still able to secrete H ions, but you have a net decrease in buffering capacity).

 

[worldbeater]

Type 4 RTA is due to an infarcted J-G apparatus -> no renin -> no Aldo -> high k. Can be due to DM, NSAIDs, ACE-I, Heparin.

This is why type IV RTA is the only RTA that is actually associated with an acidic urine

Respectfully disagree, Type II RTA definitely has acidic urine (pH of 2).

 

[thehundredthone]

Note that even though hypoaldosteronism will directly lead to less H secretion in the collecting duct, the principle mechanism of the acidosis is due to the decrease in ammoniagenesis. This is why type IV RTA is the only RTA that is actually associated with an acidic urine (i.e., you're still able to secrete H ions, but you have a net decrease in buffering capacity).

Careful. The urine pH is lower in RTA4, and appropriately so in response to the acidosis, i.e. <5.5. However, RTA1 and 2 also have "acidic" urine, just that the pH tends to be higher >5.5 (at least initially). This is because RTA4 still has a functional distal tubule with H+ secretory function in response to the tubular acidosis.

Proximal RTA (RTA2) tends to have relatively HCO3- rich urine, but only while serum [HCO3-] is above 15-18 mEq/L. This is because proximal bicarbonate reabsorption is defective, and the distal reabsorption is inadequate. If the serum bicarbonate is low enough, there isn't much being filtered, hence the distal tubule can and does reabsorb enough bicarbonate, leading to more profound (or, perhaps, appropriate?) aciduria. This is achieved in diagnostic testing by acid loading with NH4Cl.

RTA1, due to a distal tubule defect in H+ secretion will have alkalinuria despite severe acidemia. Even acid loading with NH4Cl will not change the urine pH because H+ just doesn't get secreted adequately. This is where one can differentiate RTA1 and 2.

 

[Jabbed]

Careful. The urine pH is lower in RTA4, and appropriately so in response to the acidosis, i.e. <5.5. However, RTA1 and 2 also have "acidic" urine, just that the pH tends to be higher >5.5 (at least initially). This is because RTA4 still has a functional distal tubule with H+ secretory function in response to the tubular acidosis.

Proximal RTA (RTA2) tends to have relatively HCO3- rich urine, but only while serum [HCO3-] is above 15-18 mEq/L. This is because proximal bicarbonate reabsorption is defective, and the distal reabsorption is inadequate. If the serum bicarbonate is low enough, there isn't much being filtered, hence the distal tubule can and does reabsorb enough bicarbonate, leading to more profound (or, perhaps, appropriate?) aciduria. This is achieved in diagnostic testing by acid loading with NH4Cl.

RTA1, due to a distal tubule defect in H+ secretion will have alkalinuria despite severe acidemia. Even acid loading with NH4Cl will not change the urine pH because H+ just doesn't get secreted adequately. This is where one can differentiate RTA1 and 2.

Thank you for the correction. In my mind I thought of the urine pH in RTA 4 as "appropriately" low and RTA 1/2 as "inappropriately" high (acidic vs alkalotic was an over-simplification on my part).

Your explanations of the urine pH changes in type II RTA and acid loading test were very helpful for clarifying that concept.

 

[thehundredthone]

Thank you for the correction. In my mind I thought of the urine pH in RTA 4 as "appropriately" low and RTA 1/2 as "inappropriately" high (acidic vs alkalotic was an over-simplification on my part).

It did look from your post that it was probably just a terminology issue than a conceptual issue. The way you're thinking about it is correct.

 

[ray656712]

Low aldo > hyperkalemia

H shifts from ICF to ECF, and K comes from ECF to ICF to maintain K balance

Low H inside INSIDE of the cell > nothing to combine with NH3 > no NH4 secreted




Acetzolamide causes decreased NH4 secretion in a similar way..inhibition of CAI INSIDE the cell > less H inside > nothing to combine with NH3

 

[Oh_Gee]

can someone please explain what the NH3 has to do with RTA type 4? i read the whole thread (and others on SDN) but am still utterly confused

 

[68PGunner]

can someone please explain what the NH3 has to do with RTA type 4? i read the whole thread (and others on SDN) but am still utterly confused

There's a lot of mechanisms at play that will explain the decrease of NH3 when it comes to RTA Type 4. However, you just need to remember the role for the secretion of NH3, and everything will make complete sense. Remember that NH3 is secreted into the tubules to act as a buffer against excess H+ in order to convert to NH4+ by trapping the H+ in the tubules for secretion and also to push the pH higher toward the physiological tolerable range.

RTA Type 4 is due to hypoaldosteronism, which will lead to less excretion of H+ and K+ resulting in metabolic acidosis and hyperkalemia. Therefore, less secreted H+ into the tubules will naturally require less secreted NH3 as a buffer in the tubules.

 

[Oh_Gee]

There's a lot of mechanisms at play that will explain the decrease of NH3 when it comes to RTA Type 4. However, you just need to remember the role for the secretion of NH3, and everything will make complete sense. Remember that NH3 is secreted into the tubules to act as a buffer against excess H+ in order to convert to NH4+ by trapping the H+ in the tubules for secretion and also to push the pH higher toward the physiological tolerable range.

RTA Type 4 is due to hypoaldosteronism, which will lead to less excretion of H+ and K+ resulting in metabolic acidosis and hyperkalemia. Therefore, less secreted H+ into the tubules will naturally require less secreted NH3 as a buffer in the tubules.

but how does NH3 affect pH? and what part of the nephron secretes NH3? i thought NH3 was filtered through the glomerulus

 

[68PGunner]

but how does NH3 affect pH? and what part of the nephron secretes NH3? i thought NH3 was filtered through the glomerulus

NH3 is a buffer, so naturally its main role against excess H+ is to alkalize the pH to its physiological tolerable range in the tubules.

The secretion of NH3 comes from the paracellular space at the PCT, which actually comes from the splitting of NH4 to H+ and NH3. NH4 is created from the glutamine splitting to form NH4 and glutamate. Here's a picture:

Most pics and textbooks will show the NH3 combining w/ H in the PCT cells to form NH4 and then exchange it for sodium. However, there's another mechanism involved in which NH3 is leaking out of the PCT in order to buffer against excess H+. The following pics best explain my point:

NH3 isn't filtered through the glomerulus.

 

[68PGunner]

But, the previous points that I have mentioned in depth are ridiculous low yield points that even my nephrologist doesn't give a damn. You need to know that RTA IV = hypoaldosteronism

Aldosteronism pisses out excess H+ and K+. Therefore, hypoaldosteronism will result in metabolic acidosis and hyperkalemia. Since there's less secreted H+ in the renal tubules, less NH3 will be secreted in order to trap the H+ into NH4 and also buffer against the high acidic level associated with excess H+ in the renal tubules. The conversion of H+ and NH3 will help you piss out more H+. H+ by itself can certainly diffuse back to the renal epithelial cells and blood supply.

 

[Oh_Gee]

But, the previous points that I have mentioned in depth are ridiculous low yield points that even my nephrologist doesn't give a damn. You need to know that RTA IV = hypoaldosteronism

Aldosteronism pisses out excess H+ and K+. Therefore, hypoaldosteronism will result in metabolic acidosis and hyperkalemia. Since there's less secreted H+ in the renal tubules, less NH3 will be secreted in order to trap the H+ into NH4 and also buffer against the high acidic level associated with excess H+ in the renal tubules. The conversion of H+ and NH3 will help you piss out more H+. H+ by itself can certainly diffuse back to the renal epithelial cells and blood supply.

which is why spironolactone and eplerenone can cause RTA IV, right?

 

[68PGunner]

which is why spironolactone and eplerenone can cause RTA IV, right?

One of the possible side effects of K+ sparing diuretics is RTA IV bc they block the aldosterone receptors for the downstream actions of aldosterone. Therefore, no pissing out K+ and H+ = metabolic acidosis + hyperkalemia.