Renal Tubular Acidosis

Group of hyperchloraemic acidoses secondary to renal tubular disease that:

• Are characterised by impaired renal acid clearance
  Inappropriately high urinary pH.
  • HCO₃^- elimination is inappropriately ↑
  • Cl^- reabsorption is inappropriately ↑
    To maintain electroneutrality.
• May only become apparent in presence of an acid load
  Incomplete disease may leave enough reserve to clear normal daily acid production.
• Are subclassified by mechanism into:
  • Type 1
    ↓ H⁺ secretion in the DCT.
    • May have ↓ HCO₃^- reabsorption in the PCT
      If reabsorption is intact, the requirement for alkali supplementation is significantly ↓.
    • Causes failure to maximally acidify urine
  • Type 2
    Isolated ↓ HCO₃^- reabsorption in the PCT.
    • DCT is able to secrete ammonia, which limits the degree of acidaemia and alkaluria
  • Type 4
    ↓ H⁺ and K⁺ clearance in the DCT.

Functionally:

• Type 2 is the effect of acetazolamide - there is an alkaline diuresis
• Type 4 is the effect of hypoaldosteronism - there is ↓ Na⁺ reabsorption and ↑ H⁺ and K⁺ retention

Type 3 RTA was initially defined as both type 1 (↓ DCT H⁺ secretion) and type 2 (↓ PCT HCO₃^- reabsorption), but has been merged into a subtype of type 1.

Pathophysiology

Type 1:

RTA differ from the acidosis of renal failure as:

• The pathology is in the tubule, rather than the glomerulus
  • GFR may be normal
• There is a NAGMA, rather than a HAGMA

• Impaired H⁺ ATPase
  Failure to ↑ activity in response to ↓ blood pH.
• Destruction of H⁺ pump
• Destruction of tubular membrane
  Allows equilibration of HCO₃^- and Cl^-.

Type 2:

• Impaired HCO₃^- reabsorption in PCT
• ↑ Cl^- reabsorption to maintain electroneutrality

Type 4:

• ↓ Na⁺ reabsorption causes ↓ K⁺ elimination
• ↑ K⁺ causes ↓ NH₄⁺ elimination
  The mechanism of this is somewhat complex:
  • Normally, NH₄⁺ is excreted in the PCT
  • Excreted NH₄⁺ is reabsorbed in the thick ascending limb
    • Absorption uses the Na⁺-K⁺-2Cl^- cotransporter, where NH₄⁺ may substitute for K⁺
    • Reabsorption concentrates NH₄⁺ in the renal medulla
      This drives the counter-current multiplier, facilitating urinary concentration.
  • An ↑ in luminal K⁺ competes with NH₄⁺, ↓ reabsorption
• ↓ Ammonia elimination results in ↑ Cl^- reabsorption

Clinical Features

Comparison of Renal Tubular Acidoses

Feature	Type 1	Type 2	Type 4
Plasma HCO3-	<15mmol/L Severe acidosis.	Usually >15mmol/L
Urinary pH	>5.5 Inappropriately high, despite ↓ plasma pH.	Generally >5.5 Can achieve <5.5 under acid load	<5.5
Plasma K+	Low	Low-normal	High
Unique Features	Positive urinary AG Indicates failure to ↑ ammonia elimination. Intact HCO3- reabsorption Following a HCO3- bolus: Blood pH ↑ Urinary pH unchanged	Negative urinary AG Ammonia elimination intact. Failure of HCO3- reabsorption ↑ Urinary pH following a HCO3- bolus in the setting of acidaemia.	Hyperkalaemia
Causes	Genetic Autoimmune Hypercalciuria: Stones damage DCT. Hyperparathyoridism Sarcoid Vitamin D intoxication Drugs: Amphotericin B Cyclosporin Ifosphamide Toluene inhalation	Genetic Vitamin D deficiency Amyloid Cystic kidney disease Heavy metals: Lead Cadmium Mercury Copper Drugs: Acetazolamide Topiramate Tenofovir Aminoglycosides Ifosfamide	Aldosterone deficiency Renin interruption: A2RB ACE-I NSAIDs Heparin Primary Critical illness Calcineurin inhibitors Aldosterone antagonists Calcineurin inhibitors Spironolactone Aldosterone-sensitive channel failure Drugs Amiloride Pentamide Trimethoprim

Management

• Treat cause
• Replace potassium
• Alkali supplementation

Specific therapy:

• Pharmacological
  • Alkali supplementation
    Citrate preferred to avoid precipitating renal stones.
    • Type 1
      1-2mmol/kg/day of HCO₃^-.
    • Type 2 10-20mmol/kg/day of HCO₃^-.
      • Add thiazide
        Volume depletion ↑ Na⁺ reabsorption, ↑ SID, and ↓ acidosis.
  • Fludrocortisone
    For Type 4.

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References

1. Brandis, K. Acid-base pHysilogy. 2015.
2. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg. 1 Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders. 5th ed. New York, NY: McGraw-Hill; 2001.