Distal Renal Tubular Acidosis

March

Etiology and Pathogenesis

This condition primarily results from impaired acidification in the distal renal tubules. It can be classified into primary and secondary forms based on the underlying cause:

Primary distal renal tubular acidosis (dRTA)

This is due to congenital functional defects in the distal renal tubules and is more common in children. Most cases follow an autosomal dominant inheritance pattern, while a minority are autosomal recessive. It may also be associated with hereditary spherocytosis and sensorineural hearing loss.

Secondary dRTA

This is more common in adults and is often secondary to autoimmune diseases such as Sjögren's syndrome and systemic lupus erythematosus, as well as hepatitis virus infections and pyelonephritis. Nephrotoxic substances, such as aristolochic acid, are also significant causes of secondary dRTA.

The acid secretion function of the distal renal tubules is primarily carried out by type A intercalated cells. Carbon dioxide (CO₂) combines with water (H₂O) under the action of carbonic anhydrase II to form carbonic acid (H₂CO₃), which dissociates into hydrogen ions (H⁺) and bicarbonate ions (HCO₃^-). The H⁺ ions are transported into the tubular lumen via H⁺-ATPase, while HCO₃^- ions are transported back into the blood via the Cl^-/HCO₃^- exchanger AE₁. In the tubular lumen, H⁺ combines with phosphate and ammonia (NH₃); with hydrogen phosphate (HPO₄^2-) to form dihydrogen phosphate (H₂PO₄^-); with NH₃ to form ammonium (NH₄⁺), which is actively reabsorbed and dissociates into H⁺ and NH₃. The H⁺ ions serve as substrates for H⁺-ATPase, while NH₃ diffuses into the tubular lumen. Defects in H⁺ secretion in the distal nephron lead to reduced urine acidification and decreased NH₄⁺ secretion. This results in the inability to establish and maintain a steep hydrogen ion gradient between the tubular lumen and the surrounding fluid. During acidosis, the urine fails to acidify, with a urinary pH > 5.5 and reduced total acid excretion.

Figure 1 Pathogenesis of Type I renal tubular acidosis (RTA)

Clinical Manifestations

General Symptoms

Patients may present with fatigue, nocturia, flaccid paralysis, and polyuria with polydipsia. Hypokalemia can cause flaccid paralysis, arrhythmias, and even respiratory distress or respiratory muscle paralysis.

Renal Involvement

Prolonged hypokalemia can lead to hypokalemic nephropathy, characterized by impaired urine concentrating ability, manifesting as nocturia. Some patients may develop nephrogenic diabetes insipidus, which further exacerbates hypokalemia. In dRTA, reduced calcium reabsorption in the renal tubules leads to hypercalciuria, which can result in kidney stones and nephrocalcinosis.

Skeletal System Involvement

Hypercalciuria and hypocalcemia can induce secondary hyperparathyroidism, leading to hyperphosphaturia and hypophosphatemia. Children may exhibit growth retardation and rickets, while adults may experience bone pain, skeletal deformities, osteomalacia, or osteoporosis.

Laboratory Tests

Key investigations include routine urinalysis, blood and urine electrolyte measurements, urine acidification tests, imaging studies, anion gap (AG) calculation, ammonium chloride loading tests, bicarbonate reabsorption tests, and tests to identify the underlying cause.

Diagnosis

The diagnosis of dRTA can be established based on the patient's history, clinical manifestations, and laboratory findings:

Normal anion gap (AG) hyperchloremic metabolic acidosis.
Hypokalemia (serum K⁺ < 3.5 mmol/L) with concurrent hyperkaluria (urinary K⁺ > 25 mmol/L when serum K⁺ < 3.5 mmol/L).
Urinary pH remains > 5.5 even in the presence of severe acidosis.
Significant reductions in total urinary acid and ammonium excretion (total urinary acid < 10 mmol/L, NH₄⁺ < 25 mmol/L).

For cases of suspected incomplete dRTA with normal arterial blood pH, an ammonium chloride loading test (or calcium chloride loading test in patients with liver disease) may be performed. A marked reduction in blood pH and bicarbonate levels, with a urinary pH > 5.5, supports the diagnosis of dRTA.

Treatment

For secondary dRTA, the primary disease should be treated. Specific treatments for dRTA include the following:

Hypokalemia is a prominent feature of dRTA. Since most patients also have hyperchloremia, potassium chloride should be avoided for potassium supplementation. Potassium citrate is recommended, and intravenous potassium administration may be required in cases of severe hypokalemia.

Potassium citrate solution (containing citrate, potassium citrate, and sodium citrate) is recommended to correct acidosis. Oral sodium bicarbonate tablets may also be used to treat metabolic acidosis, with intravenous sodium bicarbonate reserved for severe cases.

Oral potassium citrate can increase the solubility of calcium in urine, thereby preventing kidney stones and nephrocalcinosis. Neutral phosphate preparations may be used to correct hypophosphatemia. For patients with bone disease, calcium supplementation (e.g., calcium citrate in cases of hypercalciuria) and calcitriol can be cautiously administered.