How should proximal renal tubular acidosis (type 2 renal tubular acidosis) be diagnosed and managed?

Proximal Renal Tubular Acidosis: Diagnosis and Management

Diagnosis

Proximal RTA (Type 2) should be diagnosed when there is normal anion-gap metabolic acidosis with bicarbonate wastage in urine (fractional excretion of bicarbonate >15% during bicarbonate loading), typically presenting with serum bicarbonate <18 mmol/L, and must be distinguished from Fanconi syndrome by assessing for concurrent glucosuria (with normal serum glucose), aminoaciduria, phosphaturia, and hypophosphatemia. 1, 2

Key Diagnostic Features

• Isolated proximal RTA presents with impaired bicarbonate reabsorption in the proximal tubule without other tubular defects, though this is rare 1, 3
• Fanconi syndrome-associated proximal RTA is far more common and includes urinary wastage of phosphate, uric acid, glucose, amino acids, and low-molecular-weight proteins alongside bicarbonate 1, 2
• The constellation of glucosuria with normal serum glucose, aminoaciduria, and metabolic acidosis is the classic presentation of Fanconi syndrome 4

Biochemical Confirmation

• Measure serum bicarbonate, electrolytes, and calculate anion gap (should be normal) 5
• Exclude metabolic acidosis, hypercalciuria, and renal Fanconi syndrome features by measuring serum bicarbonate levels and urinary excretion of calcium, amino acids, glucose, and low-molecular-weight protein markers 6
• Assess urinary bicarbonate excretion: fractional excretion of bicarbonate >15% during bicarbonate loading confirms proximal defect 1, 2
• Check for hypophosphatemia and measure urinary phosphate excretion (elevated in Fanconi syndrome) 4, 2

Genetic Testing

• Genetic testing should be pursued to identify mutations in SLC4A4 (encoding NBCe1, the basolateral sodium-bicarbonate cotransporter) for isolated proximal RTA 1, 3
• Autosomal recessive proximal RTA with ocular abnormalities is associated with SLC4A4 mutations 3
• Autosomal dominant proximal RTA may involve SLC9A3 (NHE3) mutations 3
• Recent studies have identified EHHADH and HNF4A gene mutations causing Fanconi syndrome 2

Etiologic Workup

• Drug-induced causes are most common: screen for ifosfamide, valproic acid, tenofovir (especially with ritonavir or didanosine), and carbonic anhydrase inhibitors 1, 2
• Carbonic anhydrase inhibitors cause isolated proximal RTA, while other drugs typically cause Fanconi syndrome 1
• Evaluate for systemic diseases: cystinosis (most common inherited cause), tyrosinemia type 1, Wilson disease, and multiple myeloma 2
• In infants with hypophosphatemia and frontal bossing, consider Fanconi-Bickel syndrome (GLUT2 deficiency) which presents with hepatomegaly and fasting hypoglycemia 4

Management

Treatment of proximal RTA requires alkali therapy with sodium bicarbonate or potassium citrate at doses of 10-20 mEq/kg/day (often requiring very high doses due to ongoing bicarbonate wastage), combined with phosphate supplementation when Fanconi syndrome is present, and addressing the underlying cause when identified. 7, 5

Alkali Therapy

• Target serum bicarbonate >22 mmol/L in adults 7
• Pediatric patients may require more aggressive treatment to optimize growth and bone health 6, 7
• Spread electrolyte supplements throughout the day to maintain consistent levels 7
• Do not aim for serum bicarbonate exceeding the upper limit of normal and monitor to ensure treatment does not adversely affect blood pressure, serum potassium, or fluid status 6, 7
• Very high doses of alkali (10-20 mEq/kg/day) are typically required because bicarbonate is wasted in urine until the serum level falls below the reduced renal threshold 5

Treatment of Fanconi Syndrome Components

• Phosphate supplementation is essential for rickets and bone disease when Fanconi syndrome is present 7, 4
• Monitor for and treat rickets with vitamin D supplementation 4
• Replace other lost electrolytes as needed 4

Addressing Underlying Causes

• In tyrosinemia type 1 patients with secondary RTA, NTBC therapy with dietary phenylalanine/tyrosine restriction reverses tubulopathy within weeks 7
• Discontinue offending medications when possible (tenofovir, ifosfamide, valproic acid) 1, 2
• Treat underlying systemic diseases (cystinosis, Wilson disease, multiple myeloma) 2

Special Considerations and Pitfalls

• Avoid citrate-containing alkali salts in CKD patients exposed to aluminum salts, as citrate increases aluminum absorption 7
• Use gastric acid suppressants with nonselective COX inhibitors to prevent gastrointestinal complications; switch to H2 blockers or COX-2 selective agents if proton pump inhibitors cause hypomagnesemia 7
• Sporadic isolated proximal RTA is often transient and alkali therapy can be discontinued after several years, unlike autosomal dominant or recessive forms which require lifelong treatment 3
• Monitor treatment to ensure it does not result in metabolic alkalosis or worsen fluid status 6, 7