This form of renal tubular acidosis is a failure of the cortical collecting duct to decrease chloride resorption in response to acidosis.
The defect seems to be in the activity of alpha-intercalated cells of the collecting duct.
There are a few mechanisms discussed in the literature, each of which can result in a diminished urinary acidification, and in a normal anion gap metabolic acidosis.
The key feature of the renal tubular mechanisms involved here is the import of systemic ammonia, as well as the de novo synthesis of ammonia from glutamine within the renal tubule. (This ammonia also leaks out of the kidney into the systemic circulation, but in itself it is not a significant contributor to systemic ammonia levels, in case you are wondering.)
Firstly, one can completely destroy the water-impermeable membranes which separate the peritubular capillary and the tubular lumen. This would lead to an equilibration of bicarbonate and chloride, with the resulting failure to excrete one and retain the other. This is exactly what happens when amphotericin attacks the tubule.
Any interference with NH3 and H+ excretion in the alpha-intercalated cells is another such mechanism.
The ionized NH4+, the combination of excreted NH3 and H+ remains in the lumen of the tubule (where it is trapped by its charge). This positive charge is balanced by the chloride anions, which are already present in the tubule. Any defect of ammonia excretion would therefore decrease the concentration of chloride anions in the tubular fluid. This chloride would have to be retained.
The main defect in this case seems to be a problem with ATP-powered H+ secretion, which is normally an acidity-regulated process. As pH drops, so the activity of this protein should increase, thus increasing the capacity for tubular ammonium trapping and chloride excretion. In distal RTA (particularly the recessive variant) the activity of this protein can remain sluggish even at a low systemic pH.
Another mechanism is the overactivity of a chloride-bicarbonate exchange protein. The kAE1 bicarbonate-chloride exchanger is not a perpetually active protein; rather, it is thought that it is activated by changes in intracellular pH (or perhaps changes in intracellular chloride). An increase in intracellular pH would normally result in an increase in exchanger activity, with resorption and retention of chloride. Conversely, if one is acidotic, one would normally expect this protein to stop working, to facilitate the excretion of chloride and the increase in strong ion difference.
Indeed, this is what seems to happen, at least in perfused rabbit nephrons. The nephrons, when bathed in an acidic solution, demonstrated an acid-induced adaptive decrease in bicarbonate secretion. However, this decrease was not seen after treatment with cyclosporine A, a drug known to cause a distal tubular acidosis.
Apart from rare familiar causes (which are typically gain-of-function mutations in the chloride-bicarbonate exchanger), there are multiple acquired causes of distal RTA.
These are usually either some form of severe renal tubular damage (like the autoimmune causes) or some form of hypercalciuria.
Hypercalciuric conditions which all rely on nephrocalcinosis to kill off the distal tubule
One begins to think about this entity whenever there is somebody with an acidosis, and an absurdly alkaline urine. Specifically, the cut-off is a pH of 5.3 to 5.5.
(If one’s urine is more acidic than this, one cannot claim with a straight face that one has a urinary acidification defect.)
What could be the matter, you think to yourself. Why is this patient not acidifying their urine?
Well. One may wish to calculate the urinary anion gap. Any self-respecting nephron would massively upregulate the renal excretion of ammonium in response to a systemic acidosis, in order to facilitate chloride excretion. Thus, the characteristic finding in distal renal tubular acidosis is a positive urinary anion gap, which demonstrates a failure to upregulate renal ammonium excretion.
A caveat to this is the urinary sodium. If the urinary sodium is lower than 25mmol/L, it begins to impair distal acidification all on its own accord (considering that one needs some significant amount of cations in the urine in order for significant amounts of chloride to be cleared).
So, you may say to yourself; is there a distal tubular failure to excrete acid?
One may be able to test this hypothesis by forcibly acidifying the body fluids. The conventional means of doing so is the administration of an ammonium chloride bolus (NH4Cl).
The immediate renal response to this manoeuvre would be to acidify the urine to a pH below 5.5. In fact, with a large acid load one might expect the urinary pH to drop to its theoretical limits (4.6).
Obviously, if the urinary pH decreases below 5.3, there is no distal tubular acidosis.
Next, one might wish to test one’s hypothesis by giving a large bicarbonate load.
So, lets say you have a normal proximal tubule, with a normal resorption threshold of 26mmol/L.
Lets say your acidosis has resulted in a serum bicarbonate of 10mmol/L.
The bolus of 100mmol of sodium bicarbonate won’t even touch the sides of that bicarbonate deficit.
Thus, in the proximal tubule, the bicarbonate will be completely reabsorbed and the urinary pH will remain unchanged throughout the process.
This, of course, is completely the opposite of what happens to a patient with proximal renal tubular acidosis.
One may rejoice at one’s normal bicarbonate conservation mechanisms. Unlike the Type 2 RTA sufferer, one need not consume entire cupfuls of gluggy citrate. Mere tablespoons will suffice.
In order to restore the serum bicarbonate and pH to a more normal level, around 1-2mmol/kg/day of bicarbonate replacement is required. Again, citrate is the preferred conjugate base for the strong cations, as citrate excretion is relied upon to prevent nephrocalcinosis in distal RTA.
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An excellent overview of the physicochemical approach to RTA can be found in this article from Critical Care.
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