Renal Tubular Acidosis



  • Renal tubular acidosis (RTA) is characterized by hyperchloremic metabolic acidosis in the setting of normal or near-normal glomerular filtration rate (GFR).
  • The acidification defect can be localized to the proximal tubule (type II RTA) resulting in incomplete bicarbonate reabsorption or the distal tubule (type I or type IV RTA) resulting in impaired net acid secretion.
  • Type I and II RTA are associated with hypokalemia; type IV is associated with hyperkalemia.
  • Timing of onset and severity of presentation are variable, depending on the underlying cause of the acidification defect.
  • Type I RTA is associated with nephrocalcinosis, osteopenia, rickets, and sometimes hearing loss.
  • Four different types of RTA are recognized:
    • Type I (classic, hypokalemic, distal)
    • Type II (proximal)
    • Type III (characteristics of both proximal and distal RTA, rare inherited disorder associated with mental retardation, osteopetrosis, and cerebral calcification)
    • Type IV (hyperkalemic, distal)
      • Associated with aldosterone deficiency or resistance to its renal effect


RTA is a rare disorder. Increased prevalence is observed in areas where consanguinity is common.


  • Genetic causes of proximal RTA:
    • Mutation in carbonic anhydrase II
    • Mutation in sodium bicarbonate cotransporter
  • Genetic causes of distal RTA (present in up to ~70% of cases):
    • Mutation in anion exchanger 1 (AE1) in α-intercalated cell
    • Mutation in H+-ATPase
    • Mutation in carbonic anhydrase II
  • Genetic causes of Fanconi syndrome/proximal RTA:
    • Lowe syndrome
    • Dent disease
    • Cystinosis
    • Tyrosinemia
    • Galactosemia
    • Hereditary fructose intolerance
    • Wilson disease
    • Fanconi-Bickel syndrome
    • Mitochondrial disorders
  • Acquired causes of proximal RTA:
    • Drugs:
      • Ifosfamide
      • Cisplatin/oxaliplatin
      • Valproic acid
      • Carbonic anhydrase inhibitor (e.g., acetazolamide)
      • Topiramate
      • Aminoglycosides
      • Antiretroviral therapy (tenofovir)
  • Acquired causes of distal RTA type I:
    • Autoimmune disorders
    • Drugs:
      • Lithium toxicity
      • Amphotericin
      • Ifosfamide
  • Acquired causes of distal RTA type IV:
    • Aldosterone resistance/deficiency
      • Diabetic renal disease
      • Obstructive uropathy
      • Adrenal insufficiency
    • Drugs:
      • Nonsteroidal anti-inflammatory medications
      • Heparin
      • Potassium-sparing diuretics
      • Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker
      • Calcineurin inhibitors (e.g., tacrolimus or cyclosporine)
      • Trimethoprim
      • Pentamidine


  • With ingestion of a typical Western diet, healthy adults generate ~1 mEq/kg net acid per day and infants and children ~2 to 3 mEq/kg/day.
  • Under physiologic conditions, the proximal tubule is responsible for reclaiming 85–90% of filtered bicarbonate.
    • Bicarbonate reclamation in the proximal tubule is achieved by a sodium–hydrogen ion antiporter, which secretes hydrogen ion into the urine resulting in generation of bicarbonate within the cell.
    • Cellular bicarbonate is then transported into the bloodstream via an Na-HCO3 transporter on the basolateral membrane.
  • The distal tubule normally reclaims the remaining 10–15% of filtered bicarbonate and secretes a net amount of acid, both via hydrogen ion secretion.
    • In the distal tubule, hydrogen ion secretion occurs primarily via H+-ATPase.
    • Secreted hydrogen ions are buffered in the urinary lumen primarily by ammonia and excreted as ammonium ions.
  • In proximal RTA, mutations in the basolateral sodium bicarbonate cotransporter or in carbonic anhydrase prevent adequate bicarbonate reclamation in the proximal tubule.
    • Unreclaimed bicarbonate enters the distal nephron, which has limited capacity for bicarbonate reclamation, resulting in bicarbonaturia and non–anion gap metabolic acidosis (usually serum bicarbonate does not decrease <16 mEq/L).
  • In distal RTA, mutations in the basolateral anion exchanger or the H+-ATPase prevent bicarbonate transport into the bloodstream and hydrogen ion secretion into the lumen, respectively, resulting in impaired net acid secretion and non–anion gap metabolic acidosis.
  • Proximal RTA is often associated with Fanconi syndrome in which there is general proximal tubular dysfunction leading to bicarbonaturia, glucosuria, phosphaturia, and tubular proteinuria.
  • Distal RTA type I is associated with urine pH >5.5.
  • Distal RTA type IV is associated with either low aldosterone levels or aldosterone resistance and presents with hyperkalemic non–anion gap metabolic acidosis.

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