Mechanism of Ethambutol-Induced Renal Injury
Ethambutol primarily causes renal injury through accumulation of the parent drug and its metabolites in patients with impaired renal function, leading to direct tubular toxicity. 1, 2
Pharmacokinetic Factors Contributing to Nephrotoxicity
- Ethambutol is primarily cleared by the kidneys, with approximately 50% of the initial dose excreted unchanged in urine within 24 hours 2
- An additional 8-15% appears in the form of metabolites, with the main metabolic pathway involving oxidation of alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid 2
- In patients with normal renal function, no drug accumulation occurs with consecutive daily doses of 25 mg/kg 2
- However, marked accumulation has been demonstrated in patients with renal insufficiency, leading to prolonged elimination half-life and decreased total body clearance 3
Mechanisms of Renal Injury
- Ethambutol can cause direct tubular toxicity through accumulation of the parent drug and its metabolites in renal tubular cells 4, 5
- The drug's metabolites may contribute to nephrotoxicity through oxidative stress and mitochondrial dysfunction in renal tubular epithelial cells 5, 6
- Prolonged exposure to high concentrations of ethambutol due to impaired clearance can lead to structural damage to renal tubules 3, 6
Risk Factors for Ethambutol-Induced Renal Injury
- Pre-existing renal insufficiency significantly increases the risk of ethambutol nephrotoxicity 1
- Higher doses (>30 mg/kg/day) increase the risk of toxicity, including renal effects 1
- Concomitant use of other nephrotoxic medications can potentiate ethambutol's renal effects 4, 5
- Advanced age and dehydration may further increase the risk of nephrotoxicity 4, 6
Clinical Implications and Management
- Ethambutol dosage must be adjusted in patients with renal insufficiency to prevent accumulation and toxicity 1
- For patients with end-stage renal disease, ethambutol should be administered at a dose of 15-20 mg/kg three times a week after dialysis 1
- Regular monitoring of renal function is essential during ethambutol therapy, especially in patients with pre-existing renal impairment 1, 4
- The terminal phase elimination rate constant correlates significantly with creatinine clearance and the reciprocal of serum creatinine, making these parameters useful predictors for a patient's capacity to eliminate ethambutol 3
Relationship Between Renal Impairment and Other Toxicities
- Renal insufficiency increases the risk of ethambutol's other adverse effects, particularly optic neuritis 1, 7
- In patients with end-stage renal disease on hemodialysis, ethambutol-induced optic neuritis can be severe and potentially irreversible 7
- The risk of optic toxicity is higher in patients receiving higher doses and those with renal insufficiency 1, 7