Renal tubular acidosis (RTA) refers to a collection of renal transport defects in the reabsorption of bicarbonate or the secretion of hydrogen ion, or both, resulting in a hyperchloremic, non-anion gap metabolic acidosis. RTA may be an isolated disorder or one feature of a more complex disorder, disease, or syndrome. Because RTA can present with nonspecific symptoms such as failure to thrive, constipation, vomiting, and lethargy, recognizing, diagnosing, and managing these disorders is essential for inpatient management.

RTA is categorized into three types, depending on the location of the tubular dysfunction. Proximal, or type II, RTA refers to disorders involving bicarbonate reabsorption at the proximal tubule. Distal, or type I, RTA encompasses syndromes of defective hydrogen ion transport in the distal convoluted tubule. Type IV RTA also involves the distal tubule but is related to defects in the aldosterone response; it is often referred to as hyperkalemic RTA. What was once called type III RTA is now believed to be a combination of types I and II.

PATHOPHYSIOLOGY

A normal functioning kidney maintains acid–base homeostatsis by two principle processes: reabsorption of filtered bicarbonate (HCO₃⁻) at the proximal tubule and excretion of acid through ammonium (NH₄⁺) at the distal nephron. Under normal circumstances, the kidney excretes acid at the same rate that metabolic processes generate acid; usually about 1 to 3 mEq/kg per day in children.¹ In RTA, this acid-excreting mechanism is disrupted, resulting in a net surplus of acid. Calculating the blood anion gap should be done in patients presenting with acidosis. The equation for calculating the anion gap is as follows:

The normal range of the anion gap is 12 ± 4 mEq/L.²

In RTA, the retained acid is in the form of hydrogen ions (H⁺) paired with chloride; therefore the serum chloride is elevated to the same degree that the serum bicarbonate is diminished.³ Accordingly, the anion gap remains within normal limits.

Renal acidification at the proximal tubule is driven by hydrogen (H⁺) secretion at the luminal membrane and bicarbonate reabsorption at the basolateral membrane (Figure 116-1). About 85% of tubular reabsorption of bicarbonate occurs in the proximal tubule. Therefore if there are any defects in this process, a large amount of bicarbonate is wasted in the urine, resulting in a net retention of acid, as in proximal type II RTA.⁴

Renal acidification at the distal collecting tubule is characterized by hydrogen ion secretion. H⁺ is secreted into the lumen, paired with ammonia (NH₃) to make ammonium (NH₄⁺) and then excreted in the urine (Figure 116-2). In a similar fashion, hydrogen ions are paired with other ions, referred to as titratable acids, for excretion.² Generally, this process is prompted by the hormone aldosterone. In distal type I RTA, the mechanism of hydrogen delivery to the lumen is defective.¹ In hyperkalemic, or type IV, RTA, there is a defect in the hormonal message initiating this distal acid excretion—that is, aldosterone is not sent or received correctly.

Proximal Renal Tubular Acidosis (Type II RTA)

In the proximal tubule, intraluminal and intracellular carbonic anhydrase facilitates bicarbonate reclamation. This process is supported by a Na⁺-H⁺ exchanger (NHE-3), which in turn is regulated by Na⁺/K⁺-ATPase (Figure 116-1). Any of these three components can be defective in proximal RTA.¹ Proximal RTA can be primary or secondary. The primary form can be either sporadic or genetically inherited in an autosomal dominant or autosomal recessive manner.¹ Sporadic proximal RTA is usually transient in nature, whereas the inherited forms require lifelong treatment.² The secondary forms of proximal RTA are numerous and can be associated with other inherited tubulopathies (e.g. Fanconi syndrome, hereditary fructose intolerance, cystinosis, galactosemia, Wilson disease), drugs and toxins (e.g. ifosfamide, 6-mercaptopurine, valproic acid, carbonic anhydrase inhibitors, outdated tetracycline), and other miscellaneous disorders (e.g. amyloidosis, hyperparathyroidism, vitamin D deficiency, tetralogy of Fallot, osteopetrosis)⁵ (Table 116-1). The prognosis of secondary proximal RTA depends on the underlying condition.

In proximal RTA, the threshold for bicarbonate reabsorption is reset at a lower level than in normal individuals. In normal children, this setpoint keeps serum bicarbonate around 22 mEq/L, whereas in those with proximal RTA, the setpoint is around 15 mEq/L.² Patients waste bicarbonate until they reach this new threshold, and then the proximal tubule begins reabsorbing bicarbonate again. Therefore at the outset of the illness, bicarbonate is wasted in the urine in large amounts, resulting in alkalotic urine (pH >5.5).⁶ However, once the serum bicarbonate has reached the new threshold, the proximal tubule begins reabsorbing bicarbonate again, and the urine is acidified distally as normal.⁶ Thus a feature that distinguishes proximal from distal RTA is the ability to make acidic urine (pH <5.5) in the setting of severe acidosis.⁵

Patients with proximal RTA often have hypokalemia because the increased delivery of bicarbonate and sodium to the distal tubule results in increased aldosterone-mediated potassium excretion.^1,5 This phenomenon is aggravated by treatment with alkali supplements, so patients must receive potassium supplementation concurrently.²

Distal Renal Tubular Acidosis (Type I RTA)

In the distal tubule, hydrogen ion secretion is mediated by the H⁺-ATPase pump on the luminal aspect of the intercalated cells¹ (Figure 116-2). This function can be impaired in three distinct ways: pump failure, back-diffusion of the ions due to increased permeability of the luminal membrane, and inadequately negative lumen charge (also known as voltage-dependent distal RTA).² As a result, a lesser amount of ammonium and titratable acids is excreted, and there is a net acidosis due to accumulation of H⁺ ions. This acidosis is progressive and can be profound. Unlike in proximal RTA, the urine cannot be acidified to less than 5.5, even in the face of severe systemic acidosis.¹