Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis

INTRODUCTION — The approach to therapy in patients with renal tubular acidosis (RTA) is determined by the primary defect in these disorders: decreased distal tubule acidification with distal (type 1) RTA and impaired proximal bicarbonate reabsorption in proximal (type 2) RTA [1]. Correction of the acidosis may have a variety of benefits. In patients with congenital proximal RTA, and young children with acquired RTA, benefits include restoration of normal growth and amelioration of rickets or osteomalacia [2,3]. In distal RTA, acidosis correction diminishes renal potassium wasting and hypokalemia, often stabilizes or reverses nephrocalcinosis, reduces the frequency of calcium kidney stones, and may improve osteoporosis. Adequate therapy of children with congenital distal RTA also improves their growth and kidney function [4]. Adequately treated patients may be asymptomatic, and many can lead a normal life, unless irreversible renal or bone disease has occurred prior to therapy.

The treatment of distal and proximal RTA will be reviewed here. Other issues related to these disorders are discussed separately:

●Pathogenesis of distal and proximal RTA (see "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance")

●Etiology and diagnosis of distal and proximal RTA (see "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis")

DISTAL (TYPE 1) RENAL TUBULAR ACIDOSIS

Management of distal RTA — Alkali therapy is required in patients with distal (type 1) RTA. Correction of the metabolic acidosis has a number of beneficial effects:

●Effects on bone – Correction of the acidosis restores normal growth rates in children [4]. It also diminishes calcium losses associated with bone buffering of some of the retained acid, thereby decreasing the risk of osteopenia in many patients [4].

●Effects on urinary citrate excretion, nephrolithiasis, and nephrocalcinosis – Alkali therapy can also reverse hypercalciuria, reduce the rate of kidney stone formation, and prevent or ameliorate nephrocalcinosis in many patients. (See "Nephrolithiasis in renal tubular acidosis", section on 'Distal (type 1) RTA'.)

Urinary citrate is an important inhibitor of stone formation because it chelates urinary calcium and thereby inhibits the crystallization of calcium with phosphate and oxalate. The citrate excreted into the urine is mainly filtered citrate that has not been reabsorbed by the tubules. Metabolic acidosis increases proximal renal tubule citrate reabsorption, which reduces distal tubule and urinary citrate, thereby increasing the risk for nephrolithiasis and nephrocalcinosis. Thus, in patients with untreated distal RTA, hypercalciuria combined with low urine citrate and an alkaline urine pH augments the formation of calcium phosphate stones and, in some patients, nephrocalcinosis. Correction of the metabolic acidosis decreases proximal citrate reabsorption and increases downstream delivery of citrate.

However, the ingestion of sodium salts (ie, sodium bicarbonate, citrate, or any other sodium salt) can sometimes increase calcium excretion and thereby worsen stone disease. For this reason, potassium bicarbonate or potassium citrate may be more effective than sodium salts in some patients with persistently active calcium stone disease. The reasons why this occurs are discussed elsewhere. (See "Diuretics and calcium balance" and "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Limit sodium intake'.)

●Effects on potassium wasting – Correction of the metabolic acidosis with alkali therapy reduces inappropriate urinary potassium losses, which often corrects the associated hypokalemia [1,3,5-9]. Potassium depletion in these patients is due in part to a reduction in proximal sodium reabsorption induced by metabolic acidosis [10,11]. In some patients with RTA, coordination between the thiazide-sensitive sodium-chloride transporter and the bicarbonate-chloride exchanger (known as pendrin) is disrupted, impairing the ability to maintain normal extracellular fluid volume. The resultant volume depletion activates the renin-angiotensin-aldosterone system. The combination of increased distal sodium delivery and increased aldosterone activity increases renal potassium excretion. Sodium reabsorption from the collecting duct lumen through the electrogenic epithelial sodium channel must be matched by secretion of positive ions into the lumen to maintain electrical neutrality; impaired distal hydrogen ion secretion promotes excess potassium secretion. To the extent the potassium losses are related to extracellular fluid volume contraction, the use of sodium alkali salts may be more effective in reversing this pathology. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance", section on 'Decreased net activity of proton pumps and HCO3 exchangers'.)

●Effects on kidney function – Chronic kidney disease (CKD) occurs frequently in patients with inherited forms of distal RTA, and successful correction of the acidosis may prevent loss of kidney function [4]. In addition to nephrocalcinosis and recurrent nephrolithiasis, the potential mechanisms by which chronic acidosis contributes to kidney disease progression are discussed elsewhere. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease".)

Our approach — The goal of alkali therapy is to achieve a normal serum bicarbonate concentration (22 to 24 mEq/L). A general principal that applies at the initiation of treatment is that the amount of administered bicarbonate must exceed the daily acid load to correct the acidosis; once a normal bicarbonate is achieved, the dose can be reduced to match daily acid production. In addition, patients with hypokalemia should be given potassium either prior to alkali therapy (if severe or symptomatic) or concomitantly with bicarbonate therapy (using a potassium salt of bicarbonate or citrate):

●Dosing of alkali therapy in adults – For adult patients with a serum bicarbonate <16 mEq/L, a reasonable starting dose is 30 mEq of bicarbonate or citrate (which is a bicarbonate precursor) four times daily (120 mEq total per day). If the initial serum bicarbonate is >16 mEq/L, a reasonable starting dose is 40 mEq of bicarbonate or citrate twice daily (80 mEq total per day). There are multiple options for attaining this dose of alkali therapy (table 1). (See 'Dosing options' below.)

The serum bicarbonate should be measured at approximately one week. The dose can then be titrated up or down depending upon the initial response, rechecking the bicarbonate at weekly intervals until a maintenance dose is attained (with a goal serum bicarbonate concentration of 22 to 24 mEq/L). This maintenance dose of bicarbonate (or citrate) is generally between 30 and 50 mEq twice daily.

●Dosing of alkali therapy in children – Children usually require larger doses than adults, often as much as 4 to 10 mEq/kg per day given in divided doses. A dose of 1 mEq/kg four times daily or 2 mEq/kg twice daily is a reasonable starting point in these patients. As with adults, the serum bicarbonate should be measured at approximately one week, and the dose can then be titrated depending upon the response (with a goal serum bicarbonate concentration of 22 to 24 mEq/L). (See 'Dosing options' below.)

As discussed in more detail below, reasons why young children have a larger alkali requirement, per body weight, than adults include a higher fixed urine pH, which results in larger ongoing bicarbonate losses [12]; a rapidly growing skeleton that generates an additional acid load; and ingestion of more calories (and acid-generating foods).

Adults ingesting a typical American or Western European diet generate approximately 1 to 1.5 mEq/kg of nonvolatile acid per day. The anions of these acids are excreted in the urine together with the hydrogen ions in the form of ammonium or titratable acid. This results in acid-base balance, and the serum bicarbonate concentration is maintained at approximately 24 mEq/L. Urine bicarbonate loss is usually negligible in adults with distal RTA as the primary disorder in distal RTA is insufficient bicarbonate regeneration and not reclamation. Thus, the daily alkali requirement of these patients is equal to the amount of hydrogen retained each day plus the small amount of urinary bicarbonate loss obligated by the high urine pH. This urine bicarbonate is a function of the relationship among the urine pH, partial pressure of carbon dioxide (pCO₂), and bicarbonate as expressed by the Henderson-Hasselbalch equation. It does not represent a defect in bicarbonate reabsorption as occurs in proximal RTA. If, for example, the urine pH is 6.4, and the urine carbon dioxide is 40 mmHg, then the urine bicarbonate concentration will be approximately 2 mEq/L. Successful therapy in adults can generally be achieved with administration of 1 to 2 mEq/kg per day of bicarbonate salts or other organic salts that generate bicarbonate when metabolized.

Infants and children below the age of six years generate significantly larger daily acid loads (up to 10 mEq/kg) due to the deposition of alkali in the rapidly growing skeleton and a larger daily dietary caloric intake per body weight compared with older children and adults. In addition, they often have a higher fixed urine pH due to concomitant impairment in bicarbonate reclamation, which results in larger bicarbonate losses [12]. In older children the daily acid load gradually decreases, typically to 2 to 3 mEq/kg [4]. It is imperative that enough alkali salts be given to children to restore normal growth rates and minimize kidney damage [3,4].

Dosing options — There are multiple options for attaining the dose of alkali therapy described above (table 1) (see 'Our approach' above). Commonly used agents include:

●Over-the-counter baking soda contains 27 mEq per 1/2 teaspoon. Dosing should be limited to 1/2 teaspoons at a time in order to avoid uncomfortable gastric gas formation. This is the cheapest and most readily available form of sodium bicarbonate.

●Liquid sodium or potassium citrate formulations, which contain 1 mEq/mL of sodium citrate (equivalent to 1 mEq/mL of bicarbonate).

●Potassium citrate tablets, which contain 5, 10, or 15 mEq of citrate per tablet.

●Sodium bicarbonate tablets, which contain either 3.85 mEq of bicarbonate (the 325 mg tablet) or 7.7 mEq (the 650 mg tablet).

●Potassium bicarbonate tablets, which are available in 1000 mg (11.9 mEq) and 25 mEq sizes.

Alkali therapy can be administered as sodium, potassium, or combination salts. The anion of the salt can be bicarbonate itself or an organic anion that is rapidly metabolized to create bicarbonate within the body. This anion is typically citrate. The per mEq doses of bicarbonate and citrate are equivalent; every 1 mEq of citrate is converted to 1 mEq of bicarbonate. Citrate may be better tolerated than bicarbonate (since there is no gastric gas formation with citrate) and is therefore preferred by many patients. However, sodium bicarbonate powder is the cheapest and most readily available formulation.

Sodium salts have some advantages, but also certain disadvantages, for different patients. They will expand the extracellular fluid, which reverses volume contraction and hyperaldosteronism in some. However, sodium salts can also increase blood pressure and increase urine calcium excretion (the latter may be particularly relevant for patients who also have nephrolithiasis). Potassium salts will improve potassium depletion and hypokalemia and will generally not increase urine calcium excretion.

Severe or symptomatic hypokalemia — All patients with severe or symptomatic hypokalemia should be given potassium prior to alkali therapy, or at least concomitantly with bicarbonate therapy (using a potassium salt of bicarbonate or citrate). In patients who initially present with severe weakness or cardiac arrhythmias, intravenous potassium chloride may be required. In this situation, potassium should be given in a solution that is dextrose free to avoid stimulation of insulin, which can shift potassium into cells and worsen hypokalemia. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Intravenous potassium repletion'.)

Patients with distal RTA may occasionally develop severe hypokalemia and present with paralysis that may progress to respiratory failure. Since metabolic acidosis leads to a shift of potassium from the intracellular to extracellular space, the presence of hypokalemia in patients with distal RTA represents major total body potassium depletion. Correction of metabolic acidosis without first administering potassium can lead to further decreases in serum potassium and precipitate complications such as cardiac arrhythmias and weakness, which can progress to respiratory failure.

After the hypokalemia is corrected, alkali therapy can commence to treat the metabolic acidosis, using a regimen described above. (See 'Our approach' above and 'Dosing options' above.)

Monitoring and adjustment of therapy — Enough alkali salts should be administered to return the serum bicarbonate to the 22 to 24 mEq/L range.

Serum chemistries must be monitored relatively frequently (eg, weekly) when therapy is initiated or doses are adjusted. Once the serum chemistries have been restored to normal, the testing interval can be extended to every few months or longer. However, young children will require more frequent monitoring, since their alkali requirements will change at relatively short intervals.

Correcting the metabolic acidosis with sodium-based alkali therapy typically reduces inappropriate urinary potassium losses, which often corrects the associated hypokalemia. However, some patients may have persistent hypokalemia despite adequate correction of the volume deficit and acidosis. In such cases, potassium citrate, alone or combined with sodium citrate, must be used (table 1).

In addition to metabolic acidosis, many patients with inherited forms of distal RTA also inherit auditory pathology and deafness. Hearing aids and cochlear implants are often necessary [4]. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Genetic causes'.)

PROXIMAL (TYPE 2) RENAL TUBULAR ACIDOSIS

Pretreatment evaluation in proximal RTA — The treatment of proximal RTA varies a great deal depending upon whether the defect is genetic or acquired and whether the acidosis is an isolated disorder or is associated with generalized proximal tubule dysfunction (ie, Fanconi syndrome):

●The cause of proximal RTA should be identified (table 2). (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA' and "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Proximal (type 2) renal tubular acidosis'.)

When the disorder is due to a drug or toxin, the offending agent should be discontinued whenever possible. Proximal RTA due to antiretroviral agents can resolve once the offending drug is removed. By contrast, the defect can be long lasting when it is due to ifosfamide or following exposure to a toxin such as lead. In all cases, therapy should be initiated with the goal of correcting the biochemical abnormalities. The patient should be reassessed over time to determine if improvement in the acidosis has occurred.

●The presence or absence of Fanconi syndrome should be evaluated. In addition to metabolic acidosis, Fanconi syndrome is characterized by a spectrum of proximal tubule defects, including hypophosphatemia (due to phosphaturia) and vitamin D deficiency, both of which require therapy; hypouricemia; and glycosuria (which is revealed when a urine dipstick is positive for glucose despite a serum glucose that is not elevated).

Management of proximal RTA

Patients with Fanconi syndrome — Treatment of the metabolic acidosis is more difficult in proximal RTA than in distal RTA because raising the serum bicarbonate concentration will increase the filtered bicarbonate load above the proximal tubule's reduced reabsorptive capacity, resulting in a marked bicarbonate diuresis. Thus, in contrast to the 1 to 2 mEq/kg per day of alkali therapy required for treatment of distal RTA, alkali doses in proximal RTA are higher. The amount of bicarbonate required will vary in different patients depending upon the extent to which the reclamation process is impaired. As in patients with distal RTA, the goal of therapy is to achieve a normal serum bicarbonate concentration (22 to 24 mEq/L), but this goal is often unattainable. In such cases, raising the serum bicarbonate to as near to normal as possible should be the goal.

We initially prescribe 10 to 15 mEq/kg per day of alkali, given in divided doses, in patients with proximal RTA to overcome urinary bicarbonate losses and raise serum levels [12-15]. The bicarbonaturia generated by alkali therapy also increases urinary potassium losses because increased sodium bicarbonate and water delivery to the distal tubule stimulates potassium secretion [16]. As a result, an empirically determined fraction of the alkali replacement must be given as a potassium salt.

The options for attaining this dose of alkali therapy are the same as those described above for patients with distal RTA (table 1). (See 'Dosing options' above.)

However, in adults and older children, it may be impractical to prescribe sodium bicarbonate tablets or potassium bicarbonate or citrate tablets because of the high pill burden that would be required to provide adequate doses of alkali. Liquid sodium citrate/citric acid (which contains 1 mEq of citrate per mL of solution) can be used instead of or in conjunction with tablets. As an example, initial therapy could consist of 60 mL of liquid sodium citrate/citric acid two to three times daily in combination with three to four sodium bicarbonate tablets two to three times daily.

The alkali dose requirement can be reduced by diminishing the bicarbonate wasting with 12 to 25 mg of hydrochlorothiazide [17,18]. Hydrochlorothiazide enhances bicarbonate reabsorption in the proximal tubule by reducing extracellular volume. However, thiazide diuretics will also increase urine potassium losses. A potassium-sparing diuretic (such as amiloride or spironolactone) can reduce the need for potassium supplements.

The doses of alkali, hydrochlorothiazide, potassium, and potassium-sparing diuretic should be adjusted based on weekly electrolyte measurements until the goals are achieved. As noted above, the precise amount of alkali required will be related to the severity of the impairment in bicarbonate reclamation.

Proximal RTA associated with Fanconi syndrome leads to renal phosphate wasting, hypophosphatemia, and reduced active vitamin D levels; these abnormalities contribute significantly to the development of bone disease. Correction of the acidemia in children with proximal RTA will improve skeletal growth. Correcting vitamin D deficiency and hypophosphatemia will promote healing of rickets or osteomalacia [2,5,7,13,14].

●(See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

●(See "Vitamin D insufficiency and deficiency in children and adolescents".)

●(See "Hypophosphatemia: Evaluation and treatment".)

Patients with isolated proximal RTA — Isolated proximal RTA is not associated with hypophosphatemia and vitamin D deficiency, and therefore there is no need to administer phosphate or vitamin D supplements. Therapy is directed to correcting metabolic acidosis and hypokalemia, as discussed above. These patients generally have only mild skeletal pathology [15]. (See 'Patients with Fanconi syndrome' above.)

Monitoring in proximal RTA — As noted above, the treatment goal is to achieve and maintain a normal serum bicarbonate level (ie, 22 to 24 mEq/L). Frequent monitoring is required, particularly in young children with proximal RTA, because rapid growth can lead to substantial changes in alkali requirement. A reasonable monitoring schedule is to measure electrolytes (including bicarbonate and potassium and, in patients with Fanconi syndrome, phosphate) weekly after initiating alkali therapy. Once the goal bicarbonate level (≥22 mEq/L) has been achieved, these measurements can be performed quarterly. If alkali therapy is modified, or if other drugs are added or discontinued (eg, thiazide or potassium-sparing diuretics), testing should be performed weekly until stable laboratory values are observed.

Proximal RTA may be a transient disorder in some children, in contrast to most childhood forms of distal RTA, which are usually permanent [12,19]. A rise in serum bicarbonate to above normal, thereby prompting a de-escalation of alkali therapy, is a clue that the underlying acidosis may be resolving.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS

●Alkali therapy is required in patients with distal (type 1) renal tubular acidosis (RTA). Correction of the metabolic acidosis has a number of potential beneficial effects, including restoration of normal growth rates in children; prevention of osteopenia, nephrolithiasis, and nephrocalcinosis; correction of potassium wasting and hypokalemia; and prevention of chronic kidney disease (CKD). (See 'Management of distal RTA' above.)

●The goal of alkali therapy in distal RTA is to achieve a normal serum bicarbonate concentration (22 to 24 mEq/L). Patients with hypokalemia should be given potassium either prior to alkali therapy (if severe or symptomatic) or concomitantly with alkali therapy (eg, using a potassium salt of bicarbonate or citrate) (see 'Our approach' above and 'Severe or symptomatic hypokalemia' above):

•For adult patients with distal RTA who have a serum bicarbonate <16 mEq/L, a reasonable starting dose is 30 mEq of bicarbonate or citrate (which is a bicarbonate precursor) four times daily (120 mEq total per day). If the initial serum bicarbonate is >16 mEq/L, a reasonable starting dose is 40 mEq of bicarbonate or citrate twice daily (80 mEq total per day). There are multiple options for attaining these dose of alkali therapy (table 1). (See 'Dosing options' above.)

The serum bicarbonate should be measured at approximately one week. The dose can then be titrated up or down depending upon the response. Maintenance doses of bicarbonate (or citrate) are generally between 30 and 50 mEq twice daily.

•Children with distal RTA usually require larger doses than adults, often as much as 4 to 10 mEq/kg per day given in divided doses. A dose of 1 mEq/kg four times daily or 2 mEq/kg twice daily is a reasonable starting point in these patients. As with adults, the serum bicarbonate should be measured at approximately one week, and the dose can then be titrated depending upon the response. (See 'Dosing options' above.)

●Once the serum chemistries have been restored to normal, the testing interval can be extended to every few months or longer. However, young children with distal RTA will require more frequent monitoring, since their alkali requirements will be changing at relatively shorter intervals. (See 'Monitoring and adjustment of therapy' above.)

●The treatment of proximal RTA varies somewhat depending upon the underlying etiology of the defect and whether the acidosis is an isolated disorder or is associated with generalized proximal tubule dysfunction (ie, Fanconi syndrome) (table 2). When the disorder is due to a drug or toxin, the offending agent should be discontinued whenever possible, and, in some cases, the proximal RTA may resolve. When Fanconi syndrome is present, correction of hypophosphatemia and vitamin D deficiency are needed, in addition to alkali therapy. (See 'Pretreatment evaluation in proximal RTA' above.)

●Treatment of the metabolic acidosis is more difficult in proximal RTA than in distal RTA because raising the serum bicarbonate concentration will increase the filtered bicarbonate load above the proximal tubule's reduced reabsorptive capacity, resulting in a marked bicarbonate diuresis. The amount of bicarbonate or citrate required will vary in different patients depending upon the extent to which the reclamation process is impaired. As in patients with distal RTA, the goal of therapy is to achieve a normal serum bicarbonate concentration (22 to 24 mEq/L), but this goal is often unattainable. In such cases, raising the serum bicarbonate to as near to normal as possible should be the goal. (See 'Patients with Fanconi syndrome' above and 'Patients with isolated proximal RTA' above.)

●We initially prescribe 10 to 15 mEq/kg per day of alkali, given in divided doses, in patients with proximal RTA to overcome urinary bicarbonate losses and raise serum levels. The bicarbonaturia generated by alkali therapy also increases urinary potassium losses because increased sodium bicarbonate and water delivery to the distal tubule stimulates potassium secretion. As a result, an empirically determined fraction of the alkali replacement must be given as a potassium salt. The options for attaining this dose of alkali therapy are the same as those described above for patients with distal RTA (table 1). (See 'Dosing options' above.)

●If the serum bicarbonate concentration cannot be corrected to a value ≥22 mEq/L despite high doses of alkali in patients with proximal RTA, we suggest treatment with a low-dose thiazide diuretic (for example 25 mg hydrochlorothiazide) (Grade 2C). In addition, administration of a potassium-sparing diuretic (such as amiloride or spironolactone) may be required when hypokalemia persists during therapy. (See 'Patients with Fanconi syndrome' above.)

●As with distal RTA, a reasonable monitoring schedule is to measure electrolytes (including bicarbonate and potassium and, in patients with Fanconi syndrome, phosphate) weekly after initiating or modifying alkali therapy. Once the goal bicarbonate level (≥22 mEq/L) has been achieved, these measurements can be performed quarterly. (See 'Monitoring in proximal RTA' above.)