Type 2 renal tubular acidosis and acetazolamide

This form of renal tubular acidosis decreases the strong ion difference by interfering with bicarbonate resorption in the proximal tubule; the mechanism is analogous to the action of acetazolamide.

Bicarbonate handling in the proximal tubule

Behold, the familiar activity of carbonic anhydrase in the proximal tubule.

Carbonic anhydrase converts the filtered bicarbonate into easily resorbed CO₂, and then traps it again inside the cell. The filtered bicarbonate is essentially completely reabsorbed. The concentration of chloride in the tubule is therefore expected to increase- if the bicarbonate has been reabsorbed,  more chloride must remain in the tubule to maintain electroneutrality.

However, the failure of carbonic anhydrase results in bicarbonate remaining trapped in the urine. This, of course, means that electroneutrality of the tubule is maintained without the excretion of any further chloride.

Chloride retention results.

Thus, the chloride which would otherwise be excreted, is retained.

There is an excellent article which discusses the mechanisms of chloride retention in acetazolamide-intoxicated patients with metabolic alkalosis. Particularly, it contains a graph of urinary strong ion diference over time, after the administration of 500mg of acetazolamide. It looks a little like this:

Causes of proximal renal tubular acidosis

Isolated congenital Type 2 RTA is very rare, and would likely form a part of of a syndrome, being associated with a series of other tubular defects, or forming a part of a whole-proximal-tubule problem like Fanconi syndrome.
Anong the elderly, a new onset of Type 2 RTA without any new medication changes can be due to a monoclonal gammopathy, where ligh chains selectively damage the proximal tubule. Similarly, amyloidosis can produce tubule damage which results in Type 2 RTA, as a part of its many manifestations. Additionally, Vitamin D deficiency and rickets are associated with Type 2 RTA, and hyperparathyroidism is implicated as a cause, but the mechanism is poorly understood, and the only article which sheds light on this is trapped behind a pay wall.

However, the most common cause is drugs.

The following drugs cause a proximal renal tubular acidosis:

• Acetazolamide: by inhibiting carbonic anhydrase
• Topiramate: by inhibiting carbonic anhydrase
• Tenofovir: in toxicity, by causing a Fanconi syndrome among a host of hideous nephrotoxic effects
• Ifosfamide: in toxicity, by causing a Fanconi syndrome
• Aminoglycosides: in toxicity, as a part of overall nephrotoxicity
• Lead, cadmium, mercury and copper poisoning (by forming covalent complexes with proximal tubule proteins)

Diagnosis of proximal renal tubular acidosis

The chief problem, at least according to the classical definition, is the tendency to excrete more bicarbonate than one ought to (to be more specific, the fractional excretion of 15% from a given dose of bicarbonate). The normal bicarbonate resorption threshold (26-27 mmol/L) is decreased to something around 20mmol/L.   

So, you test the bicarbonate resorption threshold by trying to return the serum bicarbonate to a more normal level, knowing that in a normal proximal tubule all that bicarbonate will be reabsorbed. Let us say that your 1mmol/Kg/Hr bicarbonate infusion  increases the patients serum bicarbonate from 20mmol/L to 25mmol/L.

Under normal circumstances, this should result in no change whatsoever to the urinary pH – after all, 25mmol/L is below the normal resorption threshold. However, in Type 2 RTA the  urinary pH will rise, demonstrating that the bicarbonate resorption threshold is decreased. This absurd alkaline urine in response to an alkali load is the characteristic of Type 2 RTA.

If one is trying to differentiate this disorder from the distal (type 1 ) renal tubular acidosis, one may calculate the urinary anion gap. The anion gap will be negative, demonstrating that distal ammonium excretion mechanisms are still working. This is similar to the urinary anion gap result of somebody with completely normal kidneys, who has a normal anion gap metabolic acidosis due to gastrointestinal losses. Haque et al (2012) points out a study by Brenez & Sanchez  (1993) who loaded a bunch of patients with ammonium chloride for three days (they had a mixture of proximal RTA patients and normal patients). For the first two days, the excretion of NH₄⁺  was the same in all patients, i.e. the urinary anion gaps would have been negative even in proximal RTA patients receiving an acid load. Only on the third day did the RTA patients have a diminished rate of NH₄⁺ clearance. What can we learn from this? The urinary anion gap in RTA patients is probably negative, but it may not be as negative as in normal people with metabolic acidosis. This contrasts with distal RTA, where the urinary anion gap is consistently and predictably positive.

Management of proximal renal tubular acidosis

Of course, the administration of more and more bicarbonate in this setting will result in the loss of more and more bicarbonate, and one will not get anywhere. Soriano mentions daily bicarbonate requirements of 10-20 mmol/kg/day, or 700-1400mmol per day for a 70kg person. This “bicarbonate” is usually administered in the form of sodium and potassium citrate.

On one hand, we can say (from a “classical” interpretation of acid-base balance) that the citrate is consumed in Krebs cycle, thereby absorbing a hydrogen ion and decreasing whole-body acidity.

On the other hand, the physicochemical explanation would be that the administration of sodium citrate is the administration of a strong cation and a weak anion; the weak anion perishes in the metabolic furnace, and the strong cation remains, increasing the strong ion difference and thereby decreasing the acidity of the body fluids.

So, say you have to eat 1 mole of sodium citrate every day. What does that look like?

Well. The commonly available oral trisodium citrate has a molar mass of 294g. Thus, one would need to consume about one full cup of this feral-tasting gloop in order to stay ahead of renal bicarbonate losses. Sodium bicarbonate is only slightly better- there is only 84g of it to consume.  Unfortunately, it has the unpleasant tendency to fizz in contact with stomach acid, thereby creating an obscene excess of eructation. Additionally, apart from measuring out and eating 84 of raw cooking-grade sodium bicarbonate, one has no convenient way of consuming it. The gentle reader is reminded that each Sodibic capsule contains only 10mmol of sodium bicarbonate, and thus through the course of one day we would be expecting the patient to eat 100 of these capsules.

This, patently, is insane. But the addition of a thiazide diuretic sometimes helps to reduce the bicarbonate dose. Diuresis results in some volume depletion and thus an increase in sodium resorption in the proximal tubule (and the collecting duct) increasing the amount of strong cation retained, and thereby increasing the strong ion difference. The downside is that this volume depletion stimulates the activity of aldosterone, which leads to potassium depletion.