Description

• 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

Epidemiology

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

Etiology

• 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

Pathophysiology

• 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.