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

Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis
Authors:
Michael Emmett, MD
Biff F Palmer, MD
Section Editor:
Richard H Sterns, MD
Deputy Editor:
John P Forman, MD, MSc
Literature review current through: Dec 2022. | This topic last updated: Sep 08, 2021.

INTRODUCTION — Distal (type 1) and proximal (type 2) renal tubular acidosis (RTA) are uncommon disorders, particularly in adults. Proximal RTA is characterized by a reduction in proximal bicarbonate reabsorptive capacity that leads to bicarbonate wasting in the urine until the serum bicarbonate concentration has fallen to a level low enough to allow all of the filtered bicarbonate to be reabsorbed. By comparison, the primary defect in distal RTA is impaired distal acidification. These different pathogenetic mechanisms result in different clinical manifestations, but some degree of hypokalemia is commonly present with most forms of distal and proximal RTA (table 1).

The etiology and diagnosis of distal and proximal RTA will be reviewed here. The pathogenesis of the different forms of RTA, the treatment of these disorders, the impact they have on potassium balance, and an overview of RTA are discussed separately:

(See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

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

The hyperkalemic forms of RTA include type 4 RTA is another form of RTA in which the primary problem is either decreased aldosterone secretion or aldosterone resistance or a voltage defect. These patients typically have a mild metabolic acidosis (serum bicarbonate concentration above 17 mEq/L) with the major manifestation being hyperkalemia. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

Although initially used to describe a transiently severe form of distal RTA in infants, the term "mixed (type 3) RTA" is most often applied to a rare autosomal recessive syndrome (resulting from carbonic anhydrase II deficiency) with features of both proximal and distal RTA [1,2]. In addition to RTA, affected patients suffer from osteopetrosis, cerebral calcification, and intellectual disability. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Mixed (type 3) RTA'.)

ETIOLOGY — The different forms of renal tubular acidosis (RTA), which lead to a hyperchloremic (normal anion gap) metabolic acidosis, can be caused by a wide variety of disorders, most of which are rare [3]. The most frequent causes vary with the type of RTA.

Distal (type 1) RTA — The major causes of new-onset distal RTA in adults are autoimmune diseases (eg, Sjögren's syndrome and rheumatoid arthritis) and hypercalciuria (which is the primary defect in some families) (table 2) [1,3-8]. Distal RTA may be the presenting manifestation of autoimmune diseases such as Sjögren's syndrome. Thus, adults with seemingly idiopathic distal RTA should be evaluated for Sjögren's syndrome. (See "Kidney disease in primary Sjögren syndrome" and "Diagnosis and classification of Sjögren's syndrome".)

By comparison, hereditary distal RTA is most common in children. Genetic mutations in the basolateral chloride-bicarbonate exchanger (SLC4A1 gene) and in the apical hydrogen-ATPase (ATP6V0A4 and ATP6V1B1 genes) have been identified as major causes of hereditary distal RTA. Mutations in other genes, including ATP6V1C2 and the forkhead transcription factor FOXI1, may be responsible for other cases [9,10]. Mutations in the ATP6V0A4 and ATP6V1B1 genes lead to autosomal recessive distal RTA and are often accompanied by sensorineural hearing impairment [11]. Mutations in the SLC4A1 (AE1) gene can cause distal RTA and are most commonly inherited in an autosomal dominant fashion. These patients do not exhibit hearing defects. An autosomal recessive mutation in AE1 has also been described, which is accompanied by hemolytic anemia. The mechanisms whereby mutations in these genes produce distal RTA are discussed separately. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

Ifosfamide, a chemotherapeutic agent that is an analog of cyclophosphamide, is a cause of both distal and proximal RTA in children and adults. Other drugs have also been implicated, and there are multiple case reports of distal, and less commonly proximal, RTA as a complication of ibuprofen alone or in combination with codeine [12-14]. (See "Ifosfamide nephrotoxicity", section on 'Clinical manifestations'.)

Toluene inhalation due to glue sniffing had been considered a relatively common cause of distal RTA in recreational drug abusers. However, metabolism of toluene to benzoic and hippuric acid is a more important cause of the acidosis than RTA in this disorder. Affected patients usually present with a normal anion gap because the hippurate is both filtered and secreted into the tubular lumen and then rapidly excreted in the urine with sodium, potassium, or ammonium [15]. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis", section on 'D-lactic acidosis and toluene inhalation' and "Urine anion and osmolal gaps in metabolic acidosis".)

Proximal (type 2) RTA — Proximal RTA occurs rarely as an isolated defect of proximal bicarbonate reabsorption and more commonly in association with other defects in proximal tubular function that impair reabsorption of other solutes such as phosphate, glucose, uric acid, and amino acids. Such patients can present with hypophosphatemia, renal glucosuria (glucosuria with a normal serum glucose concentration), hypouricemia, and/or aminoaciduria. Generalized proximal tubule dysfunction is called the Fanconi syndrome (table 3).

A major cause of proximal RTA in adults is proximal tubular toxicity related to increased excretion of monoclonal immunoglobulin light chains due to monoclonal gammopathies that are otherwise latent [16]. The light chains that produce renal tubule toxicity appear to have unique biochemical characteristics such as a variable domain that is resistant to degradation by lysosomal proteases in the proximal tubular cells [17,18]. Accumulation of the variable domain fragments is presumably responsible for the impairment in tubular function. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Light chain proximal tubulopathy'.)

Proximal RTA in adults may also result from carbonic anhydrase inhibitors such as acetazolamide and topiramate, which impair proximal bicarbonate reabsorption without affecting the reabsorption of other proximal tubule solutes [19]. However, inhibition of carbonic anhydrase usually also impairs distal tubule acidification. Nephrotoxic drugs, such as tenofovir and ifosfamide, and inflammatory disorders, such as Sjögren's syndrome, can produce a Fanconi syndrome (table 3) [20-22]. (See "Ifosfamide nephrotoxicity", section on 'Clinical manifestations'.)

In children, idiopathic RTA, ifosfamide therapy, and cystinosis are the most common causes of proximal RTA [23-26]. Although most children present with Fanconi syndrome, some have isolated proximal RTA. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children" and "Ifosfamide nephrotoxicity" and "Cystinosis".)

Isolated proximal RTA can be due to inherited defects in the genes that direct synthesis of the transmembrane transporters responsible for proximal acidification. Mutations in the gene (SLC4A4) that directs the synthesis of NBCe1, the basolateral sodium bicarbonate transporter, result in autosomal recessive proximal RTA with short stature and ocular abnormalities [27-31].

In addition, some families have a pure proximal RTA transmitted as an autosomal dominant trait. The molecular basis for this form of familial proximal RTA is unclear, and it is not due to a defect in genes that are known to be involved in proximal bicarbonate reabsorption [32]. One possibility is a mutation in the basolateral, inwardly rectifying potassium subchannel called Kir4.2, encoded by KCNJ15. Dysfunction of this potassium channel leads to depolarization of the proximal tubular cell (ie, a decrease in electronegativity of the cell). This change results in less bicarbonate exit coupled to sodium ions via NBCe1 since this co-transporter caries a net negative charge and is driven by intracellular electronegativity. The net effect is increased cell pH and downregulation of proteins involved in ammoniagenesis, resulting in features of a proximal RTA in the absence of generalized tubular dysfunction [33]. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance", section on 'Proximal (type 2) RTA'.)

DIAGNOSIS — The presence of distal or proximal renal tubular acidosis (RTA) should be considered in any patient with an otherwise unexplained normal anion gap (hyperchloremic) metabolic acidosis [3]. Metabolic compensation for respiratory alkalosis produces an electrolyte pattern that is identical to that seen in a normal anion gap metabolic acidosis. Thus, the first step in the diagnosis of a patient with a reduced serum bicarbonate and elevated chloride concentration is to confirm that metabolic acidosis is present by measuring the blood pH. (See "Approach to the adult with metabolic acidosis", section on 'Physiologic interpretation of the serum anion gap'.)

When a normal anion gap acidosis is confirmed, a variety of disorders other than RTA must be considered (table 4). These include the loss of bicarbonate and/or "potential" bicarbonate (eg, lactate, acetate or butyrate, which can be metabolized to bicarbonate) in the stool due to diarrhea due to a malfunctioning urinary bladder reconstruction or diversion, due to recovery from ketoacidosis, or due to toluene inhalation (usually from spray paint or glue sniffing, which may be denied by the patient). (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis", section on 'D-lactic acidosis and toluene inhalation'.)

Thus, the next steps in the diagnosis of possible RTA in patients who have a normal anion gap metabolic acidosis are measurement of the urine pH and measurement or estimation of urinary ammonium excretion. (See 'Urine pH' below and 'Urine ammonium excretion' below.)

Urine pH — Patients with normal kidney function and normal renal acidification mechanisms who develop metabolic acidosis usually have a urine pH of 5.3 or less. An exception to this general rule can occur in patients with chronic metabolic acidosis who also have hypokalemia, as may be seen with diarrhea [34,35]. In such patients, potassium moves out of the cells, and electroneutrality is maintained by the entry of hydrogen and sodium into the cells. In the kidney, the resulting intracellular acidosis stimulates both hydrogen secretion and ammonia production [36,37]. Ammonia (NH3) in the tubular lumen combines with hydrogen ions to form ammonium (NH4+). The reduction in the free hydrogen ion concentration elevates the urine pH. Depending upon the chronicity of the acidosis and the degree of hypokalemia, the urine pH may be 5.5 or higher, incorrectly suggesting a diagnosis of distal RTA. The urine pH is also generally higher than 5.5 in patients with a normal anion gap due to toluene inhalation in whom urinary ammonium excretion is also increased. (See "Hypokalemia-induced kidney dysfunction", section on 'Increased ammonia production'.)

In most cases of distal RTA, the urine pH is persistently 5.5 or higher, reflecting the primary defect in distal acidification, and a urine pH below 5.5 generally excludes distal (but not proximal) RTA. However, the urine pH can be reduced below 5.5 in occasional patients (2 of 17 in one study) with distal RTA [38-41]. A possible mechanism is that the rate of hydrogen ion secretion is impaired more than the ability to lower the urine pH. This disorder has been called "rate-dependent" RTA [41] and may be more common in children [40]. The pathogenesis of the different types of distal RTA is discussed separately. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance", section on 'Distal (type 1) RTA'.)

In contrast to the persistently elevated urine pH in distal RTA, the urine pH is variable in proximal RTA, a disorder characterized by diminished proximal bicarbonate reabsorption. The urine pH will be inappropriately elevated if patients with proximal RTA are treated with alkali, increasing the serum bicarbonate concentration enough to produce a filtered bicarbonate load that exceeds the reduced proximal reabsorptive capacity; this most commonly occurs when alkali is given for the diagnosis or treatment of this disorder. By contrast, once the serum bicarbonate concentration has fallen sufficiently so that all of the filtered bicarbonate can be reabsorbed, the distal nephron functions normally and can reduce the urine pH to 5.3 or less. Such untreated patients have metabolic acidosis but are able to excrete the daily acid load and are in acid-base balance.

In patients presenting with a normal anion gap metabolic acidosis, several scenarios can produce a misleading elevation in the urine pH that incorrectly suggests the presence of RTA:

Chronic metabolic acidosis, usually accompanied by hypokalemia, can markedly increase renal ammonium excretion and thereby raise the urine pH above 5.5.

Urinary tract infections with urea-splitting organisms may increase the urine pH because urea is converted to ammonia and bicarbonate. Thus, assessment of the urine pH should include a urinalysis and, if indicated, a urine culture.

Severe volume depletion (which indirectly and reversibly limits hydrogen ion secretion by reducing distal sodium delivery) can impair urine acidification [34,42]. Thus, reliable interpretation of an inappropriately high urine pH requires that the urine sodium concentration be greater than 25 mEq/L.

Urine ammonium excretion — A urine pH of 5.5 or higher in patients with a normal anion gap acidosis is characteristic of distal RTA. However, as mentioned in the preceding section, it can also occur in patients with intact distal acidification who have a normal anion gap metabolic acidosis, hypokalemia, and increased urinary ammonium excretion as a result of disorders such as diarrhea and toluene inhalation (glue sniffing). By contrast, urine ammonium excretion is reduced in distal RTA (see 'Urine pH' above). Thus, either direct measurement or indirect estimation of the urine ammonium concentration can be helpful in establishing the correct diagnosis.

Urinary ammonium concentration cannot be directly measured in most clinical laboratories. However, an indirect estimate of urine ammonium concentration can be obtained by calculating the urine anion gap and/or the urine osmolal gap (calculator 1 and calculator 2 and calculator 3). These calculations are discussed in detail elsewhere. (See "Urine anion and osmolal gaps in metabolic acidosis".)

Estimation of ammonium excretion is not useful in patients with proximal RTA. As mentioned in the preceding section, untreated patients are in acid-base balance at a lower-than-normal serum bicarbonate concentration since bicarbonate wasting has ceased. They will excrete "normal" quantities of ammonium. Patients treated with alkali will have a urine pH of 5.5 or higher due to bicarbonate wasting.

Distal versus proximal RTA — Once a diagnosis of RTA has been established, distal and proximal RTA must be distinguished from one another:

In distal RTA, there is an inability to excrete the daily acid load. In the absence of alkali therapy, this results in progressive hydrogen ion retention. The serum bicarbonate concentration usually stabilizes at a level greater than 10 mEq/L. To make a diagnosis of distal RTA, the urine pH should be persistently 5.5 or higher, the urine sodium concentration should be above 25 mEq/L (since lower levels can impair distal acidification in the absence of RTA), and the urine ammonium excretion should be reduced. The urine ammonium concentration can be estimated by calculating a urine anion gap or urine osmolal gap. Because the urine anion gap may be misleading in certain situations (hypovolemia, high urinary excretion of unmeasured anions such as hippurate or ketoacid anions), the urine osmolal gap generally provides a better estimate of urinary ammonium excretion. (See "Urine anion and osmolal gaps in metabolic acidosis", section on 'Limitations of the UAG'.)

Proximal RTA is caused by a reduced capacity to reclaim filtered bicarbonate in the proximal tubule. Consequently, bicarbonate wasting occurs when the serum bicarbonate concentration is raised above the diminished bicarbonate reabsorptive threshold. The more distal renal tubule segments have substantial bicarbonate reabsorptive capacity but cannot replace the function of the proximal tubule. The serum bicarbonate concentration in untreated patients with proximal RTA is usually between 12 and 20 mEq/L. When the serum bicarbonate is low, most of the filtered bicarbonate can be reabsorbed and distal acidification then proceeds normally. The urine pH will then be appropriate for the patient's diet. After an acid load, the urine pH can be normally reduced to 5.3 or less. (See 'Proximal (type 2) RTA' above.)

Proximal RTA can occur as an isolated defect in bicarbonate reabsorption or in association with other defects in proximal tubular function, such as impaired reabsorption of phosphate, glucose, uric acid, and/or amino acids (called the Fanconi syndrome). Such patients can present with hypophosphatemia, renal glucosuria (glucosuria with a normal serum glucose concentration), hypouricemia, and/or aminoaciduria. These features are not found in distal RTA. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Fanconi syndrome'.)

The diagnosis of proximal RTA can be established by raising the serum bicarbonate concentration toward normal (18 to 20 mEq/L) with an intravenous infusion of sodium bicarbonate at a rate of 0.5 to 1 mEq/kg per hour [3]. The urine pH, even if initially acid, will rise rapidly once the reabsorptive threshold for bicarbonate (which is abnormally diminished) is exceeded. As a result, the urine pH will increase above 7.5 and the fractional excretion of bicarbonate (FEHCO3) will exceed 15 to 20 percent. The latter can be determined from simultaneous urine and serum specimens using a formula similar to that for the fractional excretion of sodium, where U and S refer to the urine and serum concentrations of bicarbonate (HCO3) and creatinine (Cr) (calculator 4 and calculator 5):

                       UHCO3  x  SCr
 FEHCO3  =  —————————  x  100
                       SHCO3  x  UCr

By contrast, raising the serum bicarbonate concentration to 18 to 20 mEq/L in patients with distal RTA has little effect on bicarbonate excretion since there is no defect in proximal reabsorptive capacity. As a result, the urine pH will remain stable (though elevated) and the fractional excretion of bicarbonate will remain less than 3 percent.

Incomplete distal RTA — The term "incomplete distal RTA" refers to a disorder in which impaired urinary acidification and an inability to reduce the urine pH to 5.3 or below with an acid load exists, but net acid excretion is maintained at a rate equal to acid generation. This is achieved by an increase in ammonium excretion that offsets the reduction in titratable acid excretion caused by the high urine pH. Thus, patients with this disorder are able to maintain a normal serum bicarbonate concentration [3,43]. Some patients with incomplete distal RTA progress to overt distal RTA, and some have a family history of RTA. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance", section on 'Incomplete distal RTA'.)

Patients with incomplete distal RTA have reduced urine citrate levels and may present with or develop calcium stone disease, typically calcium phosphate stones [44,45]. Urine citrate excretion is increased, and the frequency of stone formation is decreased, by correcting the metabolic acidosis with exogenous bicarbonate or bicarbonate precursor salts such as potassium citrate or potassium bicarbonate [46].

Patients with distal RTA are often hypercalciuric and may develop otherwise unexplained osteoporosis [47,48], although not all studies support this conclusion [49]. (See "Nephrolithiasis in renal tubular acidosis", section on 'Treatment' and "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Low urine citrate'.)

Patients with recurrent calcium stones (particularly calcium phosphate stones), a normal serum bicarbonate concentration, and a urine pH that is persistently 5.5 or higher should be evaluated for incomplete distal RTA. The diagnosis should also be considered in patients with a family history of distal RTA and perhaps in those with unexplained osteoporosis. This evaluation typically includes measurement of urinary citrate excretion, which is reduced in this condition [50]. However, a fasting morning urine pH <5.3 and a serum potassium >3.8 excludes nearly all patients with incomplete distal RTA (negative predictive value of 98 percent) [45].

The gold standard for the diagnosis of incomplete RTA is an ammonium chloride acidification test, although this is not commonly performed. The ammonium chloride acidification test is usually done with a single oral dose of ammonium chloride (0.1 g/kg) [3,43,48]. Serum bicarbonate concentration and urine pH are measured several times over the subsequent six hours, ideally at two, four, and six hours [48]. The urine pH must be measured with a pH meter. Collection of the urine under mineral oil is not necessary [51,52]. The serum bicarbonate concentration should fall by more than 3 mEq/L. Failure of the urine pH to fall to 5.3 or less is consistent with incomplete distal RTA.

Some patients with suspected incomplete RTA cannot tolerate the ammonium chloride because of gastric irritation, nausea, and vomiting, which occur commonly. An alternative acidification test employs the simultaneous oral administration of furosemide (40 mg) and fludrocortisone (1 mg), followed by hourly urine collections for eight hours. Normal subjects can reduce their urine pH below 5.3, and patients with distal RTA cannot [45,53].

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

Distal (type 1) and proximal (type 2) renal tubular acidosis (RTA) are uncommon disorders. Proximal RTA is characterized by a reduction in proximal bicarbonate reabsorptive capacity that leads to bicarbonate wasting in the urine. Distal RTA is characterized by impaired distal acidification. Hypokalemia is commonly present in both. (See 'Introduction' above.)

Causes of distal RTA in adults include autoimmune diseases (eg, Sjögren's syndrome and rheumatoid arthritis) and hypercalciuria (table 2). Hereditary distal RTA is more commonly diagnosed in children. Drugs such as ifosfamide and amphotericin cause distal RTA in adults and children. (See 'Distal (type 1) RTA' above.)

Causes of proximal RTA in adults include light chain-induced proximal tubular toxicity in multiple myeloma and other monoclonal gammopathies, and carbonic anhydrase inhibitors such as acetazolamide or topiramate (table 3). Causes of proximal RTA in children include inherited mutations (eg, cystinosis) and ifosfamide therapy. (See 'Proximal (type 2) RTA' above.)

The diagnosis of RTA requires measurement of the urine pH and estimation of urinary ammonium excretion. The urine pH is persistently 5.5 or higher in patients with distal RTA. The urine pH is variable in proximal RTA: it will be elevated if the filtered bicarbonate load exceeds the reduced proximal reabsorptive capacity, which is most often due to alkali therapy, and it will be appropriately 5.3 or less if the filtered bicarbonate load is reduced and can be completely reabsorbed, which most often occurs in untreated patients. (See 'Urine pH' above.)

Urinary ammonium excretion may distinguish patients with distal RTA from those who have a normal anion gap metabolic acidosis and hypokalemia resulting from other causes (such as diarrhea or toluene inhalation). Although urinary ammonium excretion cannot be directly measured in most clinical laboratories, an estimate can be obtained by determination of the urine anion gap and/or urine osmolal gap. (See 'Urine ammonium excretion' above.)

Distal and proximal RTA may be distinguished from one another by demonstrating changes in the urine pH in response to changes in the serum bicarbonate concentration (see 'Distal versus proximal RTA' above):

To make a diagnosis of distal RTA, the urine pH should be 5.5 or higher regardless of the serum bicarbonate concentration, the urine sodium concentration should be above 25 mEq/L (since lower levels can impair distal acidification in the absence of RTA), and the urine anion gap and urine osmolal gap should be consistent with a low urine ammonium concentration.

In proximal RTA, the urine pH may be 5.3 or less if the filtered bicarbonate load (which is directly related to the serum bicarbonate concentration) is below the bicarbonate reabsorptive threshold, which most often occurs in untreated patients. The diagnosis of proximal RTA can be established by raising the serum bicarbonate concentration toward normal (18 to 20 mEq/L) with an intravenous infusion of sodium bicarbonate at a rate of 0.5 to 1 mEq/kg per hour. The urine pH, even if initially acid, will rise rapidly once the reabsorptive threshold for bicarbonate is exceeded, resulting in a urine pH above 7.5 and a fractional excretion of bicarbonate (FEHCO3) exceeding 15 to 20 percent.

The term "incomplete distal RTA" refers to patients who have impaired urinary acidification and an inability to reduce the urine pH to 5.3 or below but who are able to maintain net acid excretion at a rate equal to acid generation and to maintain a normal serum bicarbonate concentration via an increase in ammonium excretion. Such patients may present with calcium stone disease or unexplained osteoporosis. (See 'Incomplete distal RTA' above.)

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Topic 2328 Version 28.0

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