Hyperchloraemic Acidosis
(Normal anion gap acidosis)

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Normal pH regulation
Causes of hyperchloraemic alkalosis
Proximal RTA
Distal RTA
Hypoaldosteronism & RTA
Differential Diagnosis


The confusion in the literature about this topic reflects our ignorance about the normal physiology of pH regulation in the kidney. The body's main long-term defence mechanisms against metabolic acidosis reside in the kidney. Conditions where production or ingestion of vast amounts of acidic substances (for example, salicylate ingestion or diabetic ketoacidosis) compromise this mechanism will generally present with a high anion gap and a normal serum chloride. Conversely, if the anion gap is normal and the serum chloride is raised, then acidosis is likely to be due to compromise of the renal defence mechanism itself. Such acidosis may on occasion be due to an overwhelming stress on the kidney (for example, ongoing massive intestinal bicarbonate loss) but is far more likely to be related to impairment of the renal mechanisms themselves.

Normal pH regulation in the kidney

Where does acid normally come from?

A major source of hydrogen ions is the metabolism of sulphur-containing amino acids, and phosphorylated moieties such as phosphoserine. This is normally in the order of 50 mEq/day. Production of carbonic acid from CO2 made during aerobic respiration is not normally a substantial source, as the CO2 is excreted via the lungs. Other potential sources of acid are organic acids either produced or ingested. These will be considered when we discuss acidosis with an elevated anion gap.

How does the kidney get rid of acid (H+ ions)?

The kidney has several mechanisms of acidifying the urine. Acidification of the urine occurs in both proximal and distal tubules: The minimum urinary pH that the kidney can achieve is about 4.5. Although this is about a thousand times more hydrogen ion than is normally present in blood (a pH of 7.4 corresponds to a hydrogen ion concentration of about 4 * 10-8, 4.5 to about 3 * 10-5), as total quantities go, this is a trivial amount of acid. The kidney needs a better way of getting rid of hydrogen ions. It has two:

The first method is an important mechanism for getting rid of hydrogen ions (about 10-40 mmol/24 hours, or up to double this if required), but when the kidney is presented with an extra acid load above and beyond normal H+ production, the second, ammonium-based mechanism comes into prominence. Normally the ammonium mechanism removes 30(+) mmol/24 hours, but this may increase to 200mmol or more if required. We can measure the buffering provided by monobasic phosphate quite simply - just add alkali until the pH of the urine rises to physiological pH (7.4) and this is a measure of the amount of hydrogen ion buffered. Unsurprisingly, we call this the "titratable acidity" of the urine. Measuring the contribution made by ammonium ion is a bit more tricky!

Where does the ammonium ion in the urine come from?

The main source is removal of ammonia (NH3) from the amino acid glutamine, which is turned into glutamate. The enzyme glutaminase, abundantly present in renal tubular cells, catalyses the reaction. The glutamate in turn can give up another ammonia molecule, to form alpha-ketoglutarate. Ever cunning, the kidney then can metabolise the alpha-ketoglutarate, using two hydrogen ions in the process! All in all, this is a smart way of getting rid of ammonia, and removing hydrogen ions. Note that the glutamate comes mainly from the liver, which thus participates indirectly in acid-base balance. Note that for the reaction:

NH3 + H+ <==> NH4+

the pK' is 9.0, in other words, only at a pH of 9.0 will equal concentrations of ammonia and ammonium be present at equilibrium. The lower the pH, the higher the concentration of ammonium ion relative to that of ammonia. This is a wonderful mechanism for concentrating ammonium ion in the urine - the renal cells make ammonia which diffuses into the urine, hydrogen ions in the urine bind the ammonia to make ammonium, and more ammonia can therefore diffuse passively across the renal cells into the urine, to be snapped up in turn! As they often do, physiologists have complicated things by labelling this simple process - they call it "nonionic diffusion".

How can we determine the amount of ammonium ion in urine?

Ammonium concentration can be directly determined in the laboratory, but a convenient 'trick' is to estimate it by calculating the urine net charge, often referred to rather less accurately as the "urinary anion gap". This is:

Urine net charge = [Na+]U + [K+]U - [Cl-]U

It is easy to see how if there is a high concentration of ammonium in the urine, the chloride concentration will usually be far higher than the sum of the Na and K concentrations - the extra chloride goes into balancing the positive charge provided by the NH4+. Thus, with lots of ammonium, the urine net charge will be negative - this is the normal compensation for metabolic acidosis.

Causes of Hyperchloraemic Acidosis

Acidosis of this type is often both initiated and perpetuated by renal tubular dysfunction, hence the term "renal tubular acidosis" (RTA). There are however other causes of "normal anion gap acidosis". If you look at the standard textbooks, you'll probably see something resembling the following list:

Note that in the above list, most of the non-renal causes are self evident, and would have to be persistent, or otherwise a normally functioning kidney would compensate for the acidosis. We will therefore concentrate on renal causes, so called "Renal Tubular Acidosis". RTA excludes people with severe renal dysfunction, where acidosis is often associated with a moderately raised anion gap, and is due to overall renal dysfunction with inability to clear hydrogen ions. Regarding RTA, different authors have radically different classifications, and some have even tried to abandon the concept of "proximal" and "distal" RTA. This latter approach does not at present seem to have much utility, and we have thus used the more traditional approach. Also note that "Type III" RTA doesn't exist - previously, people used it to (for example) categorise cases where there seemed to be a mixture of type I and type II.

Proximal RTA
(Type II RTA)

This disorder often appears milder in its presentation, but is more difficult to treat than distal RTA. This is because the cause is proximal tubular wasting of bicarbonate - diminished bicarbonate resorption results in loss of bicarbonate in the urine, until the serum bicarbonate level drops to a level where equilibrium is reached (usually at about 15-17 mmol/l). Whenever the serum level rises, the more bicarbonate is simply lost in the urine. Many cases of type II RTA are associated with generalised proximal tubular dysfunction, presenting as the "Fanconi syndrome" (proximal RTA together with proximal tubular loss of glucose, amino acids and phosphate). Presentation may be with features of the underlying disease, or with features of acidaemia and hypokalaemia. Bone disease is fairly common. We can conveniently classify causes as follows:

Causes of Proximal RTA:

Treatment of Proximal RTA

This is difficult. Orally administered alkali is simply lost in the urine. Always remember to identify and treat (if possible) the underlying cause! One management strategy is to restrict sodium intake (and possibly even administer a thiazide diuretic!) This resets glomerulotubular balance, with increased proximal tubular resorption of sodium and bicarbonate, and less bicarbonate wasting.

Distal RTA
(Type I RTA)

This is often a far more serious disorder than type II RTA, not only with acidosis and hypokalaemia, but also with frequent nephrolithiasis and progression to nephrocalcinosis in a large proportion of cases. The response to treatment with oral alkali is however good.

Causes of distal RTA
There are several distinct types of distal RTA:

Treatment of distal RTA

The mainstay of treatment is provision of oral alkali, for example Shohl's solution (sodium citrate + citric acid), in a dose of 1-4 mmol/kg/day (in an adult, about 30ml QID is often sufficient).

Hypoaldosteronism & RTA
(Type IV RTA)

This disorder has a number of causes, including:

Pathogenesis is probably complex, including decreased stimulation of proton secretion due to the absence of aldosterone effect, a mild voltage gradient defect, and hyperkalaemia (which interferes with ammonia production and transport). Urinary acidification is normal (pH can drop below 5).

Treatment of RTA consequent on hypoaldosteronism

Again, identifying and treating the cause is important. Management of the hyperkalaemia is vital, and will often result in resolution of the acidosis. Select cases may benefit from mineralocorticoid administration, or even use of loop diuretics (furosemide).

Distinguishing between RTA Types

  1. First we have to establish whether RTA is present. If the patient has hyperchloraemic metabolic acidosis, then one should check the urinary pH, and more importantly, the urine net charge. If the urine net charge is negative, then ammonium production is appropriately high, and RTA types I and IV are unlikely. It is possible that the patient has proximal RTA, and if other causes of hyperchloraemic acidosis with a negative urine net charge are not present (intestinal bicarbonate loss, administration of acidic salts or ammonium chloride, use of acetazolamide) then the diagnosis of proximal RTA can be made by administering bicarbonate, and calculating the fractional excretion of filtered bicarbonate. If this is over 15%, the diagnosis is made. (Speak to your laboratory about determining the fractional excretion of filtered bicarbonate). Other clues to the presence of proximal RTA might be other features of the Fanconi syndrome. Alternatively, one could try administration of Shohl's solution, and if the response is poor, strongly suspect type II RTA!

  2. If urine net charge is positive, types I or IV RTA are likely. Check the serum potassium. Secretory distal RTA will be associated with hypokalaemia (or sometimes, normokalaemia), and respond well to administration of alkali (e.g. Shohl's solution). Note that with classical type I RTA (gradient- limited secretory distal RTA) the urine pH will tend to be over 5.5, while with rate-limited secretory distal RTA, pH is often below 5.5. Be cautious in using urinary pH - urea-splitting organisms present in urine might raise pH, and any cause of volume or potassium depletion will also raise it remarkably).

    One problem that can be confused with rate-limited secretory distal RTA is defective NH3 production. These can be distinguished by giving bicarbonate and checking the urinary PCO2. If there is a distal defect in hydrogen ion secretion, the urine PCO2 minus the blood PCO2 will be abnormally low (under 3.3kPA). Normally, alkalinisation of the urine to a pH of over 7.0 by NaHCO3 administration results in bicarbonaturia, and this bicarbonate binds distally secreted hydrogen ions to form H2CO3. The H2CO3 in turn breaks down to form CO2 and H2O, resulting in a urinary PCO2 of over 3.3kPa.
    Amphotericin B toxicity may resemble gradient-limited secretory distal RTA, but here again, urine PCO2 - blood PCO2 will be normal, in contrast to the low value found in gradient-limited secretory distal RTA.

    If you are still unsure about the presence or absence of distal RTA, ammonium chloride loading has been used to distinguish between distal RTA (where urine pH fails to drop below 5.5) on the one hand, and proximal or type IV RTA on the other (where the pH drops). In rate- limited distal RTA, the pH should also drop. Avoid this test.

  3. If there is hyperkalaemia, suspect type IV RTA, or voltage-distal RTA. In voltage distal RTA, the urine pH tends to be over 5.5, while with hypoaldosteronism, the pH is often under 5.5. It may be necessary to determine serum aldosterone levels (low with aldosterone deficiency, high-ish with resistance), although often the clinical context will tell you what to expect.


Date of Last Update: 1998-09-12
Web page author: jo@anaesthetist.com