What are the pediatric subtypes of renal tubular acidosis, their pathophysiology, clinical features, and management?

Pediatric Renal Tubular Acidosis Subtypes

Classification and Pathophysiology

Pediatric RTA is classified into three major subtypes: Type 1 (distal), Type 2 (proximal), and Type 4 (hyperkalemic distal), each with distinct pathophysiology and clinical presentations. 1, 2

Type 1 (Distal) RTA

• Defective hydrogen ion excretion in the distal tubule and collecting duct causes inability to acidify urine below pH 5.3, resulting in persistently alkaline urine (pH >5.5) despite systemic acidosis. 3, 4

• Genetic mutations in ATP6V1B1, ATP6V0A4, or SLC4A1 encode subunits of the vacuolar H⁺-ATPase or anion exchanger 1, accounting for most hereditary cases. 3

• Hyperchloremic metabolic acidosis with hypokalemia (serum K⁺ typically <3.5 mEq/L) and hypercalciuria are hallmark features. 3, 5

• Medullary nephrocalcinosis and calcium phosphate kidney stones develop from the combination of alkaline urine, hypercalciuria, and low urinary citrate. 3, 4

Type 2 (Proximal) RTA

• Impaired bicarbonate reabsorption in the proximal tubule leads to bicarbonate wasting when serum levels exceed the reduced reabsorptive threshold (typically 15-18 mEq/L). 2

• Fanconi syndrome frequently coexists, presenting with glycosuria, phosphaturia, aminoaciduria, and uricosuria in addition to acidosis. 2

• Urine can be acidified to pH <5.3 once serum bicarbonate falls below the reabsorptive threshold, distinguishing it from distal RTA. 2

Type 4 (Hyperkalemic Distal) RTA

• Aldosterone deficiency or resistance causes impaired distal sodium reabsorption and potassium/hydrogen secretion. 1

• Hyperkalemia with mild metabolic acidosis (bicarbonate typically 17-22 mEq/L) distinguishes this from other RTA types. 1

• Less common in children than Types 1 and 2, but may occur with obstructive uropathy, medications, or adrenal insufficiency. 1

Clinical Features by Subtype

Type 1 (Distal) RTA Presentation

• Severe growth failure and failure to thrive are the most common presenting features in untreated children, with height frequently below -2 standard deviation score. 3, 5

• Refractory rickets with bone pain, proximal muscle weakness, widened wrists, and genu valgum result from chronic acidosis and hypophosphatemia. 5

• Polyuria and polydipsia occur due to nephrogenic diabetes insipidus from hypercalciuria and nephrocalcinosis. 5

• Sensorineural hearing loss develops in ATP6V1B1 mutations (present in 5 of 6 patients in one series), while ATP6V0A4 mutations rarely cause childhood hearing loss. 3

• Two-thirds of patients initially present with proximal tubular dysfunction, mimicking Fanconi syndrome, which resolves after acidosis correction. 3

• Medullary cysts may develop in approximately one-third of patients without apparent clinical consequences. 3

Type 2 (Proximal) RTA Presentation

• Infancy presentation with polyuria, growth retardation, and hypotonia is typical. 2

• Rickets requiring phosphate and vitamin D supplementation occurs when Fanconi syndrome is present. 2

• Hypokalemia is common but typically less severe than in distal RTA. 2

Diagnostic Approach

Type 1 (Distal) RTA Diagnosis

• Measure arterial or venous blood gas showing hyperchloremic metabolic acidosis (pH <7.35, bicarbonate <20 mmol/L, normal anion gap). 5, 4

• Simultaneously check urine pH; values >5.5 in the presence of systemic acidosis confirm distal RTA. 5, 4

• Perform ammonium chloride loading test (100 mg/kg orally) if baseline urine pH is equivocal; failure to acidify urine below pH 5.3 confirms the diagnosis. 4

• Measure serum potassium (expect <3.5 mEq/L in complete distal RTA). 3, 5

• Obtain renal ultrasound to detect medullary nephrocalcinosis, present in most untreated cases. 3, 5

• Check 24-hour urine for calcium and citrate; hypercalciuria with hypocitraturia is characteristic. 4

• Measure urinary calcium-creatinine ratio as a screening test for hypercalciuria. 6

• Order genetic testing for ATP6V1B1, ATP6V0A4, and SLC4A1 to confirm hereditary forms and guide prognosis. 3

• Perform audiometry in all confirmed cases to detect sensorineural hearing loss. 3

Type 2 (Proximal) RTA Diagnosis

• Document hyperchloremic metabolic acidosis with serum bicarbonate typically 12-18 mEq/L. 2

• Measure fractional excretion of bicarbonate (>15% when serum bicarbonate is raised above threshold confirms proximal defect). 2

• Screen for Fanconi syndrome with urinalysis for glucose, urine amino acids, phosphate, and uric acid. 2

• Verify ability to acidify urine to pH <5.3 when serum bicarbonate is low. 2

Type 4 (Hyperkalemic Distal) RTA Diagnosis

• Confirm hyperkalemia (K⁺ >5.0 mEq/L) with mild metabolic acidosis (bicarbonate 17-22 mEq/L). 1

• Check plasma renin and aldosterone levels to distinguish aldosterone deficiency from resistance. 1

Management Strategies

Type 1 (Distal) RTA Treatment

• Initiate oral alkali therapy immediately with potassium citrate as the mainstay of treatment, targeting serum bicarbonate >22 mEq/L. 3, 4

• Dose potassium citrate at 1-3 mEq/kg/day divided into 3-4 doses, adjusting based on serum bicarbonate and potassium levels. 4

• Expect dramatic catch-up growth with 10 cm height gain and 5 kg weight gain within 6 months of adequate alkali therapy. 5

• Monitor serum bicarbonate, potassium, and chloride monthly until stable, then every 3-6 months. 3

• Repeat renal ultrasound every 12-24 months to monitor nephrocalcinosis progression. 7

• Perform annual audiometry in patients with ATP6V1B1 mutations to detect progressive hearing loss. 3

• Supplement additional potassium chloride if hypokalemia persists despite adequate citrate therapy. 4

• Avoid sodium bicarbonate as sole therapy because it does not correct hypokalemia and may worsen urinary calcium excretion. 4

Type 2 (Proximal) RTA Treatment

• Administer high-dose alkali therapy (5-15 mEq/kg/day) divided into multiple doses because bicarbonate wasting requires larger replacement. 2

• Add thiazide diuretics to reduce bicarbonate wasting by inducing mild volume contraction. 2

• Supplement potassium chloride to maintain serum potassium >3.5 mEq/L. 2

• Provide phosphate (20-60 mg/kg/day) and calcitriol (0.25-2 mcg/day) when Fanconi syndrome with rickets is present. 2

Type 4 (Hyperkalemic Distal) RTA Treatment

• Restrict dietary potassium to <2-3 g/day as first-line therapy. 8

• Administer loop diuretics (furosemide 1-2 mg/kg/day) to enhance renal potassium excretion. 8

• Provide sodium bicarbonate (1-2 mEq/kg/day) to correct acidosis and promote intracellular potassium shift. 8

• Consider fludrocortisone (0.05-0.2 mg/day) only when documented aldosterone deficiency exists, monitoring closely for hypertension. 8

Common Pitfalls and Caveats

• Do not dismiss distal RTA based on normal serum bicarbonate alone; incomplete distal RTA presents with normal bicarbonate but persistent alkaline urine and nephrocalcinosis. 4

• Recognize that proximal tubular dysfunction in distal RTA mimics Fanconi syndrome; follow proximal tubular function after acidosis correction to establish the correct diagnosis. 3

• Never use potassium bicarbonate or potassium citrate in Type 4 RTA; these worsen metabolic alkalosis—use only potassium chloride. 8

• Avoid potassium-sparing diuretics in Type 4 RTA; they catastrophically worsen hyperkalemia. 8

• Do not delay genetic testing; molecular diagnosis guides prognosis, audiologic surveillance, and family counseling. 3

• Ensure adequate alkali dosing; underdosing perpetuates growth failure and bone disease despite treatment. 5

• Monitor for medullary cyst development with serial ultrasounds, though cysts rarely cause clinical consequences. 3