How does Azetazolamide (carbonic anhydrase inhibitor) cause renal injury?

Mechanism of Acetazolamide-Induced Renal Injury

Acetazolamide causes renal injury primarily through inhibition of carbonic anhydrase in the proximal tubule, leading to metabolic acidosis, electrolyte imbalances, and in severe cases, acute kidney injury. 1

Primary Mechanisms of Renal Injury

1. Direct Effects on Renal Function

• Inhibition of Proximal Tubular Reabsorption
  • Acetazolamide inhibits carbonic anhydrase in the proximal tubule, reducing sodium bicarbonate reabsorption by approximately 80% in superficial nephrons 2
  • This leads to increased urinary bicarbonate excretion and subsequent metabolic acidosis
  • Causes a significant 18% decline in glomerular filtration rate (GFR) 3

2. Metabolic Derangements

• Severe Metabolic Acidosis

  • Acetazolamide can produce severe lactic acidosis with increased lactate-to-pyruvate ratio 4
  • Inhibition of mitochondrial carbonic anhydrase V disrupts the tricarboxylic acid cycle by limiting bicarbonate availability to pyruvate carboxylase 4
  • This metabolic acidosis is particularly dangerous in elderly patients with reduced renal function 1

• Electrolyte Imbalances

  • Causes hyponatremia and hypokalemia due to increased renal excretion of these electrolytes 1
  • Creates a urinary organic acid profile similar to pyruvate carboxylase deficiency 4

Risk Factors for Acetazolamide-Induced Renal Injury

• High-Risk Populations:
  • Elderly patients (due to age-related decline in renal function) 1
  • Patients with pre-existing renal dysfunction 1
  • Patients with liver disease or cirrhosis (contraindicated) 1
  • Diabetic patients 1
  • Patients with impaired alveolar ventilation 1
  • Patients on concomitant medications like high-dose aspirin 1

Monitoring and Prevention

• Laboratory Monitoring

  • Baseline and regular monitoring of serum electrolytes (particularly sodium and potassium) 1
  • Regular assessment of acid-base status 1
  • Monitoring of renal function parameters (BUN, creatinine) 1

• Preventive Measures

  • Avoid concomitant use with other carbonic anhydrase inhibitors 1
  • Use caution when administering with other medications that affect electrolyte balance 1
  • Ensure adequate hydration to prevent dehydration-induced renal injury 5
  • Consider citrate as a potential prophylaxis in high-risk patients 4

Clinical Implications

• Therapeutic Considerations

  • Acetazolamide is contraindicated in patients with marked kidney disease or dysfunction 1
  • Should be used with caution in patients with impaired glucose tolerance or diabetes mellitus due to potential effects on blood glucose levels 1
  • Discontinue if significant electrolyte imbalances or worsening renal function occurs 1

• Potential Adverse Effects

  • Renal calculus formation (especially when used with sodium bicarbonate) 1
  • Bone marrow suppression in severe cases 4
  • Hyperchloremic metabolic acidosis 1

Special Considerations

• In heart failure patients, acetazolamide may be used for diuresis but requires careful monitoring of renal function 6
• When used for enhanced decongestion in heart failure, acetazolamide may increase the risk of impaired kidney function similar to other diuretics 6
• The drug is eliminated primarily by the kidneys, so impaired renal function can lead to drug accumulation and increased toxicity 1

By understanding these mechanisms, clinicians can better anticipate, monitor for, and manage potential renal complications associated with acetazolamide therapy.