Approach
The first goal of treatment of RTA, assuming that no reversible cause such as urinary tract obstruction or ongoing drug administration is present, is to give the patient enough alkali to correct the blood pH and bicarbonate to normalize levels.[4][15][141] This is done by giving the patient sodium bicarbonate or a solution of sodium citrate and citric acid (Shohl solution) daily in divided doses. Potassium replacement is also necessary in hypokalemic RTA.
Classic distal RTA (type I)
In classic (type I) distal RTA, alkali replacement therapy is given to correct metabolic acidosis and to maintain serum potassium levels in the normal range.
Treatment with alkali restores normal acid-base balance, prevents the consumption of the skeleton and muscle mass by buffering processes, and restores growth in children.
Potassium deficits may be significant. Administration of bicarbonate drives potassium into cells and can acutely worsen hypokalemia. For this reason, severe potassium deficits should be at least partially corrected before beginning bicarbonate administration. Over time alkali treatment restores extracellular fluid volume, which decreases the stimulus for potassium excretion. Correction of acidosis provides benefits such as prevention of renal failure (especially if the patient has nephrocalcinosis) and decrease in the frequency of nephrocalcinosis.
In distal RTA in adults, the patient may be started with a dose of 1 to 3 mEq/kg of alkali given in divided doses. Shohl solution, K-Shohl solution, or potassium citrate/citric acid solution may be used. In patients with problematic hypokalemia, potassium-containing solutions may be preferable.
The dose of alkali is titrated to raise bicarbonate and pH to normal if possible. In a study of 340 patients with primary distal RTA, alkali treatment achieved normal serum bicarbonate and normocalciuria in 51% of patients. Effective treatment was associated with greater adult height and higher estimated glomerular filtration rate.[53] Unfortunately, alkali treatment does not improve sensorineural hearing loss.[28]
Children with distal RTA require higher doses (up to 5-8 mEq/kg/day in infants) of alkali.[142]
Potassium supplements should also be given as needed. In patients with distal RTA associated with Sjogren syndrome, amiloride has been used to improve hypokalemia with reported good effect.[143]
Proximal RTA (type II)
Patients with proximal RTA usually require doses of at least 10 to 15 mEq/kg/day alkali of Shohl solution or K Shohl solution in divided doses.[144][42] Solutions contain 1 mEq of base per mL of solution.
If enough alkali is given, normal growth may be restored.[145]
The dose is titrated to raise bicarbonate and pH to normal if possible; however, continuing urinary losses make this difficult.
Children with proximal RTA will need aggressive alkali therapy (5-15 mEq/kg/day) to attenuate bone disease and growth retardation.[146]
Potassium-containing citric acid solutions contain either equal amounts of sodium and potassium citrate (K-Shohl solution) or only potassium citrate and citric acid and may be preferable if the patient has problematic hypokalemia.
Potassium supplements should also be given as needed.
Notably, as more alkali is given and bicarbonaturia increases, urinary potassium losses are exacerbated. Hydrochlorothiazide can be used to generate mild volume depletion and increase proximal reabsorption.[4] Theoretically, hydrochlorothiazide can increase proximal bicarbonate reabsorption, but it may worsen potassium losses. Hydrochlorothiazide can be added if bicarbonate fails to increase despite regular use of alkali solutions, but more potassium supplementation will be needed if this is done.
Fanconi syndrome
The single most important aspect of treatment in Fanconi syndrome is the replacement of bicarbonate losses in children (5-15 mEq/kg/day). This is important because of the impact of metabolic acidosis on bone metabolism. The treatment is the same as that for proximal (type II) RTA, and in general all treatment modalities given for proximal RTA apply. Phosphate losses should be accounted for (1-3 g/day of oral phosphate), and vitamin D may be required if levels are inadequate. Carnitine replacement may be useful. Amino acids are lost, but a normal diet is adequate to replace the losses. Hypokalemia, which is a secondary issue, should be treated by supplementation, as in proximal RTA.[23] Description of the specific treatments for the heritable metabolic disorders (e.g., Lowe syndrome, cystinosis, galactosemia) associated with Fanconi syndrome and proximal RTA is beyond the scope of this topic.
Mixed proximal and distal RTA (type III)
Because of the rarity of this type there are no readily available clinical treatment guidelines. The clinician should consider alkali therapy with standard Shohl solution or potassium-containing Shohl solution and supplementary potassium as necessary. There is currently no treatment available to replace the missing carbonic anhydrase enzyme.
Hyperkalemic distal RTA (type IV)
There are two abnormalities requiring treatment in hyperkalemic distal RTA: acidosis and hyperkalemia. Hyperkalemia is often the more acute, obvious, and important problem. Hyperkalemia suppresses ammonia metabolism and thus limits ammonium excretion, in effect causing acidosis; correction of hyperkalemia may relieve the acidosis to a large extent by restoring ammonium excretion to normal.
In type IV RTA, the severity of the hyperkalemia often leads to the decision to begin treatment. Correction of potassium overload may increase ammonia production and excretion to the point that acidosis improves significantly. Drugs known to be associated with hyperkalemia should be discontinued. Patients should avoid salt substitutes containing potassium and should follow a low-potassium diet.
The cause of hyperkalemic distal RTA is often deficiency of aldosterone. In patients with this etiology of RTA, fludrocortisone may be given as replacement. Dietary potassium restriction is advised.
Patients with hyperkalemic distal RTA who are resistant to aldosterone should be treated by potassium restriction. Patients with aldosterone resistance (sometimes said to have true type IV RTA) do not respond to fludrocortisone. They should be given furosemide or other loop diuretic while being maintained on a liberal salt diet.
Patients with hyperkalemic distal RTA may be given Shohl solution. Use of K-Shohl solution and other forms of citric acid preparations that include the potassium salt should be avoided.
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