Renal Tubular Acidosis: Types, Channels, and Causes
Classification Overview
Renal tubular acidosis comprises four major types based on the site of tubular dysfunction and the specific transport defect, each with distinct ion channel abnormalities and clinical presentations. 1, 2
Type 1 RTA (Distal RTA)
Pathophysiology and Channels
- Defective hydrogen ion secretion in the distal nephron (collecting duct) causes inability to acidify urine below pH 5.5 despite systemic acidosis 1, 3
- The primary defect involves impaired function of H+-ATPase pumps and H+/K+-ATPase in alpha-intercalated cells of the collecting duct 2, 4
- Mutations affect genes encoding the B1 subunit of H+-ATPase (ATP6V1B1) or the a4 subunit (ATP6V0A4) in hereditary forms 3, 4
- The anion exchanger AE1 (SLC4A1) mutations also cause distal RTA by impairing basolateral bicarbonate exit 4
Causes
- Primary (hereditary): Autosomal dominant or recessive mutations in ATP6V1B1, ATP6V0A4, or SLC4A1 genes, typically diagnosed in infancy or childhood 3, 4
- Secondary (acquired): Autoimmune diseases (Sjögren syndrome, lupus), hypercalciuria, nephrocalcinosis, medications (amphotericin B, lithium), and obstructive uropathy 1, 3
Key Clinical Features
- Severe hypokalemia leading to paralysis, rhabdomyolysis, and cardiac arrhythmias 5
- Hypercalciuria with nephrocalcinosis and kidney stones 3, 2
- Normal anion gap metabolic acidosis (anion gap 8-12 mEq/L) 6
- Growth retardation in children, osteomalacia in adults 2, 4
Type 2 RTA (Proximal RTA)
Pathophysiology and Channels
- Impaired bicarbonate reabsorption in the proximal tubule due to defective Na+/H+ exchanger (NHE3) or basolateral Na+/HCO3- cotransporter (NBCe1) 2, 4
- The threshold for bicarbonate reabsorption is reduced from normal ~24-26 mEq/L to 15-18 mEq/L 2
- Mutations in SLC4A4 gene encoding NBCe1 cause hereditary proximal RTA with ocular abnormalities 4
Causes
- Primary: Isolated hereditary forms (SLC4A4 mutations) or as part of Fanconi syndrome 5, 4
- Secondary: Multiple myeloma, heavy metal toxicity (lead, cadmium), medications (acetazolamide, topiramate, tenofovir), vitamin D deficiency, and tyrosinemia type 1 1, 4
Key Clinical Features
- Associated Fanconi syndrome features: aminoaciduria, glucosuria, phosphaturia, and uricosuria 5, 2
- Hypokalemia (though typically less severe than Type 1) 1
- Rickets in children due to phosphate wasting 5
- Normal anion gap metabolic acidosis 6, 1
Type 3 RTA (Mixed)
Pathophysiology
- Extremely rare form combining features of both proximal and distal RTA 1
- Historically described but now recognized that most cases represent severe forms of Type 1 or Type 2 RTA 7
Type 4 RTA (Hyperkalemic Distal RTA)
Pathophysiology and Channels
- Aldosterone deficiency or resistance causes impaired potassium and hydrogen ion secretion in the collecting duct 1, 2
- Defective epithelial sodium channel (ENaC) function reduces the electrochemical gradient needed for K+ and H+ secretion 2, 4
- Mutations in genes encoding ENaC subunits (SCNN1A, SCNN1B, SCNN1G) cause pseudohypoaldosteronism type 1 4
- Mutations in mineralocorticoid receptor (NR3C2) also cause aldosterone resistance 4
Causes
- Aldosterone deficiency: Hyporeninemic hypoaldosteronism (diabetic nephropathy, chronic kidney disease), adrenal insufficiency, medications (NSAIDs, heparin, ACE inhibitors, ARBs) 8, 1
- Aldosterone resistance: Pseudohypoaldosteronism, medications (potassium-sparing diuretics, trimethoprim, pentamidine), tubulointerstitial disease 1, 4
- Most common in adults with chronic kidney disease stages 3-5 8
Key Clinical Features
- Hyperkalemia is the dominant feature (distinguishes from other RTA types) 1, 2
- Mild metabolic acidosis with normal anion gap 6, 1
- Risk of cardiac arrhythmias from hyperkalemia 8
- Absence of nephrocalcinosis or hypercalciuria 2
Critical Diagnostic Distinctions
Laboratory Patterns
- All RTA types present with normal anion gap (8-12 mEq/L) metabolic acidosis, distinguishing them from high anion gap acidoses like diabetic ketoacidosis 6
- Urine pH >5.5 in Type 1 RTA despite acidemia; urine pH can be <5.5 in Type 2 and Type 4 RTA 1, 2
- Fractional excretion of bicarbonate >15% during bicarbonate loading confirms Type 2 RTA 2
- Serum potassium: low in Types 1 and 2, high in Type 4 1, 7
Common Pitfall
- Do not confuse RTA with Bartter syndrome, which presents with similar hypokalemic metabolic alkalosis but has elevated fractional chloride excretion (>0.5%) and is a salt-losing rather than acid-handling disorder 9