Review of the Diagnostic Evaluation of Renal Tubular Acidosis

Distal RTA

Distal RTA, also known as type 1 RTA, is most commonly observed in children as a primary genetic defect.¹ Depending on the gene mutation, children can present with mild or severe disease. Severe forms of heritable distal RTA manifest as vomiting and profound dehydration, obtundation, restricted skeletal growth, and rickets. Such cases are usually detected in infancy. Milder disease presents later in childhood, and complaints may include weakness or polyuria, although many patients remain asymptomatic. A relatively frequent first manifestation—typically during adolescence—of mild forms of distal RTA is nephrolithiasis owing to altered renal calcium handling.²

Acquired deficits usually manifest in adults and are most typically associated with autoimmune conditions or nephrotoxins. However, secondary distal RTA may evolve at any age depending on the cause of kidney disease.¹ In addition to the signs specific to RTA, patients may present with features of their underlying disorder, such as discoid rash in patients with systemic lupus erythematosus.

Proximal RTA

Proximal RTA is also known as type 2 RTA. Its demography is similar to the patient demographics of distal RTA in that most cases are discovered in children with heritable mutations.¹ As with distal RTA, proximal RTA has a spectrum of disease severity. The clinical manifestations of mild disease are usually limited to short stature and lethargy. In severe cases, patients present with respiratory distress, vomiting, and feeding difficulties.

Most cases of proximal RTA occur as a component of generalized tubular dysfunction, referred to as Fanconi syndrome.³ Fanconi syndrome is a malabsorptive state of the proximal convoluted tubules, while proximal RTA refers only to the deficiency in HCO₃⁻ retention. As with RTA, Fanconi syndrome may be hereditary or acquired. Patients with Fanconi syndrome experience added nutritional deficiencies, and clinical sequelae are more common in patients with Fanconi syndrome than in patients with isolated proximal RTA. Typical signs include failure to thrive, volume depletion, rickets, and constipation.³ Several rare genetic disorders are associated with Fanconi syndrome and may be suggested by malformations such as ocular abnormalities, tooth deformities, and intellectual impairment.⁴

Both isolated proximal RTA and Fanconi syndrome can also arise as acquired lesions in children or adults. Extrarenal manifestations may reveal underlying conditions, such as Wilson disease or obstructive uropathy.

The physical and biochemical changes of hereditary isolated proximal RTA are often transient. Normal tubular function is generally restored after 3-5 years, although any delays experienced in physical development may be irreversible. The relatively infrequent progression of hereditary proximal RTA contrasts with the natural history of distal RTA, which is a lifelong disease. Patients with Fanconi syndrome have a variable duration of illness. When a secondary cause is present, morbidity is often dictated more by the underlying illness than by RTA or Fanconi syndrome per se.

Hyperkalemic RTA

The hyperkalemic RTA subtype is also commonly known as type 4 RTA. The manifestations of hyperkalemic RTA are a consequence of the effects of aldosterone deficiency or insensitivity. Biochemical findings are routinely the only detectable change in these patients.¹ Potential symptoms include postural hypotension and lethargy. In many patients, the clinical manifestations are directed by the secondary disease rather than by RTA.

Hyperkalemic RTA occurs more frequently in adults than children and is usually an acquired rather than a heritable defect.⁵ The potential causes are broad because virtually any renal insult can produce this condition. Patients should therefore be examined for signs of secondary renal disease, including stigmata of diabetes mellitus or reports of nephrotoxic medication consumption.

Serum Biochemistry and Acid-Base Balance

The defining feature of most cases of RTA is impaired renal acid-base buffering and the development of non–anion gap metabolic acidosis. Many cases are detected inadvertently upon the discovery of this unexplained acid-base disturbance during routine investigations for other purposes. The first step in diagnosing RTA of any type is confirmation of a persisting hyperchloremic metabolic acidosis. Unreported chronic diarrhea must be excluded in this context because it is the most common reason for hyperchloremic acidosis.

RTA is a process limited to malfunction of pertinent acid-base mechanisms; renal performance is otherwise satisfactory. RTA is one of many conditions included within the ambit of chronic kidney disease (CKD) and may be simultaneously accompanied by other renal pathology. The GFR in isolated true RTA should be normal or only mildly reduced.

Other forms of renal insufficiency are known to induce both anion gap and non–anion gap acidosis through various separate processes. In CKD, acid retention generally occurs largely because of impaired ammonium (NH₄⁺) excretion facilitated by inadequate generation of ammonia buffer.⁶ This process is in contradistinction to distal RTA in which the fault lies with NH₄⁺ transport. In CKD, acidosis worsens and anion gap widens as the number of functional nephrons declines, as measured by GFR.^7,8 Late in the disease course, refractory RTA may be gradually accompanied by declining GFR.¹

RTA is associated with abnormal potassium (K⁺) distribution in the kidney. K⁺ derangement is also a frequent finding in RTA and can guide evaluation and treatment. Hypokalemia is characteristic of distal RTA and proximal RTA, while hyperkalemia is indicative of hyperkalemic RTA.

Some patients with proximal RTA may also have findings indicative of Fanconi syndrome. Nutritional deficiencies typical of Fanconi syndrome include hypophosphatemia, hyponatremia, and rarely, hypoglycemia or hypoproteinemia.

Urine Biochemistry

Urine composition is important for the diagnosis of RTA. Patients with normal renal function and intact urinary acidification mechanisms who are exposed to metabolic acidosis will usually produce a urine pH ≤5.3 in attempt to restore the plasma pH. Under normal conditions in individuals with a normal acid-base status, the average urinary pH is 5-6.⁹

In patients with hyperchloremic metabolic acidosis and alkaline urine, considered in this context as urine pH >5.5, RTA of some type is strongly suggested. However, urinary pH alone is a poor diagnostic tool. In several circumstances, pH can lead to false diagnosis. Both intravascular volume depletion and urinary tract infection by urea-splitting organisms can elevate urinary pH while simultaneously causing non–anion gap metabolic acidosis, mimicking the appearance of RTA. Additionally, urinary pH is often <5.5 in cases of distal and hyperkalemic RTA.

Elevated urinary calcium is prevalent in distal RTA. This elevation explains the proclivity for nephrocalcinosis and stone formation in patients with distal RTA.

Confirmatory Testing

Definitive testing to confirm the diagnosis of RTA is complex and primarily involves urinary measurement of indices of acid and HCO₃⁻ secretion. Before explaining such tests, revisiting the basic mechanisms of acid-base imbalance in the different forms of RTA will be helpful. Knowledge of the expected physiologic disturbance will guide the clinician in selecting an appropriate provocation test.

Patients with distal RTA have a distal tubular defect characterized by the inability to excrete hydrogen (H⁺). Patients with proximal RTA have a problem with proximal tubular HCO₃⁻ reabsorption that results in a decline of serum HCO₃⁻ and pH. Finally, hyperkalemic RTA is typified by hypoaldosteronism. Hypoaldosteronism in this context refers to the effects of reduced aldosterone activity that may be a consequence of low aldosterone secretion from primary or secondary adrenal insufficiency or a result of renal insensitivity to aldosterone. Hyperkalemic RTA is said to be present once this condition upsets the acid-base balance and is accompanied by a normal anion gap metabolic acidosis. The acidosis is thought to be induced by hyperkalemia that retards urinary NH₄⁺ excretion.^5,10,11

The distinction between hyperkalemic RTA and distal and proximal RTA is relatively straightforward. Hyperkalemic RTA is readily diagnosed by hyperkalemia and serum aldosterone measurements in the presence of near-normal GFR. Serum aldosterone may be high or low depending on the reason for hypoaldosteronism. Distinguishing between proximal and distal RTA requires different methods.

An HCO₃⁻ loading test (Sidebar) is used to confirm proximal RTA.^12,13 The principle is that in patients with acidemia, low plasma HCO₃⁻ concentration, and intact proximal tubule function, administering HCO₃⁻ should not alter urine HCO₃⁻ levels because the HCO₃⁻ is avidly reabsorbed from the urine. In patients with proximal RTA, urinary HCO₃⁻ concentration will rise following HCO₃⁻ infusion because of impaired reabsorption.

In patients with clearly low serum HCO₃⁻ and metabolic acidosis, a single urinary measurement of the fractional excretion of HCO₃⁻ can sometimes confirm proximal RTA without the need for an HCO₃⁻ loading test. If serum HCO₃⁻ is low, under normal circumstances urinary reabsorption is expected to be vigorous and to be accompanied by an allowed fractional excretion <5%. A single inappropriately basic urine pH is also suggestive. In patients with equivocal readings, the HCO₃⁻ loading test is the gold standard for diagnosis.

On the other hand, definitive diagnosis of distal RTA is best reached with an NH₄⁺ loading test (Sidebar).^14,15 Administration of an acid load in the form of ammonium chloride (NH₄Cl) should acidify urine in a normally functioning kidney in an effort to buffer blood pH. In patients with distal RTA and impaired urinary H⁺ and NH₄⁺ secretion, urinary pH will not decrease as expected. In contrast to the HCO₃⁻ loading test used to diagnose proximal RTA, NH₄⁺ concentration cannot be directly measured in urine. The urine anion gap (UAG) is used as a surrogate marker of NH₄⁺ secretion.

The UAG is positive under normal circumstances, similar to the serum anion gap. It is derived by subtracting urine chloride (Cl⁻), which is an anion, from urinary cations, specifically sodium (Na⁺) and K⁺. The usual UAG ranges from 20-90 mEq/L. The kidneys acidify urine by secreting NH₄⁺, which is usually secreted coupled to Cl⁻. Therefore, urinary Cl⁻ provides an indirect measurement of NH₄⁺ secretion. In a properly functioning nephron, the UAG becomes less positive and eventually becomes negative following administration of an NH₄Cl load because increased NH₄⁺ secretion is accompanied by increased urinary Cl⁻. Patients with impaired NH₄⁺ excretion maintain an inappropriately positive UAG.

For diagnosis of distal RTA, the NH₄⁺ loading test is the gold standard test, but it may occasionally be bypassed in patients with obvious hyperchloremic metabolic acidosis and inappropriately high urine pH. In these cases, a single UAG measurement may be sufficient to verify the diagnosis of distal RTA (Figure 1).¹⁶ Because the purpose of NH₄⁺ loading is to generate acidosis, the test is unnecessary and possibly unsafe in patients who are already acidemic. The test must be undertaken cautiously because adverse effects, including nausea and vomiting or dysrhythmia, may occur.

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Figure 1.

Suggested algorithm for suspected renal tubular acidosis (RTA) in patients with non–anion gap metabolic acidosis and hypokalemia. HCO₃⁻, bicarbonate; UAG, urine anion gap.

The UAG also helps differentiate between diarrhea and distal RTA as the culprit for hyperchloremic metabolic acidosis. Patients with diarrhea and intact urinary acidification should be expected to produce a negative UAG. However, this result must be interpreted carefully in patients with volume depletion. Hypovolemia associated with a urine Na⁺ concentration <20 mEq/L alters Cl⁻ reabsorption and may falsely raise the UAG.¹⁷

Type 3 RTA

A fourth subtype, known as type 3 RTA, is rarely seen in clinical practice but deserves mentioning. This mixed syndrome has diagnostic findings characteristic of both distal and proximal RTA. Type 3 RTA manifests with debilitating congenital syndromes in children and is principally associated with carbonic anhydrase II deficiency.¹⁸

Type 3 RTA was formerly thought to be more widespread when it was first identified in 1972.¹⁹ Infants with distal RTA were routinely found to possess coexisting significant urinary HCO₃⁻ wasting.¹⁶ It is now acknowledged that most young children with distal RTA experience an initial transient phase of bicarbonaturia as part of the syndrome's natural history, and this reference to type 3 RTA is no longer in use.

Voltage-Dependent RTA

A small number of patients with distal RTA express hyperkalemia rather than hypokalemia. This variety of distal RTA is known as voltage-dependent RTA. Impaired acid secretion is a result of reduced distal tubular Na⁺ delivery or poor reabsorption, in contrast to the primary defect in H⁺ transport observed in classic distal RTA.²⁰ A favorable transepithelial voltage gradient cannot be maintained, forcing retention of both K⁺ and H⁺. Voltage-dependent distal RTA may be confused with hyperkalemic RTA, as hyperkalemia is often accompanied by slight elevations in aldosterone. The entities are distinct because patients with type 4 hyperkalemic RTA maintain their ability to acidify urine in response to acidemia.³ Although the electrochemical mechanism and serum K⁺ differ, the causes and laboratory findings of voltage-dependent RTA are essentially the same as for classic distal RTA (Figure 2). Amiloride, a K⁺-sparing diuretic, is an important exception that generates voltage-dependent RTA but does not induce classic distal RTA.²¹

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Figure 2.

Suggested algorithm for suspected renal tubular acidosis (RTA) in patients with non–anion gap metabolic acidosis and hyperkalemia.³