What dose adjustments are needed for anti-tuberculosis (TB) treatment in patients with impaired renal function?

Dose Adjustment of Anti-TB Treatment in Kidney Disease

For patients with creatinine clearance <30 mL/min or on hemodialysis, increase the dosing interval to three times weekly for pyrazinamide (25-35 mg/kg/dose), ethambutol (15-25 mg/kg/dose), and all injectable aminoglycosides (streptomycin, amikacin, kanamycin, capreomycin at 12-15 mg/kg/dose), while maintaining standard daily dosing for isoniazid and rifampin. 1

Core Principle: Extend Intervals, Not Reduce Doses

The fundamental approach differs from typical renal dosing adjustments. Instead of decreasing the dose, increase the dosing interval to maintain adequate peak serum concentrations while avoiding toxicity. 1 Reducing doses may compromise efficacy by producing subtherapeutic peak levels, particularly problematic for concentration-dependent bactericidal drugs like aminoglycosides. 1

Specific Drug Adjustments by Renal Function

Creatinine Clearance ≥30 mL/min

• No dose adjustment required for any first-line anti-TB drugs 1
• Standard regimens should be used, though serum concentration monitoring should be considered to avoid toxicity 1

Creatinine Clearance <30 mL/min and Hemodialysis Patients

These two groups are managed identically: 1

No adjustment needed:

• Isoniazid: 300 mg once daily or 900 mg three times weekly 1
• Rifampin: 600 mg once daily or 600 mg three times weekly 1
• Both are hepatically metabolized with minimal renal clearance 1

Require interval extension (three times weekly dosing):

• Pyrazinamide: 25-35 mg/kg per dose three times weekly (not daily) 1

  • Although hepatically metabolized, metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) accumulate in renal insufficiency 1
  • Significantly removed by hemodialysis 1

• Ethambutol: 15-25 mg/kg per dose three times weekly (not daily) 1, 2

  • Approximately 80% renally cleared 1
  • 50% excreted unchanged in urine within 24 hours 2
  • Marked accumulation occurs in renal insufficiency 2

Injectable aminoglycosides (all require adjustment):

• Streptomycin: 12-15 mg/kg per dose two or three times weekly 1
• Amikacin: 12-15 mg/kg per dose two or three times weekly 1
• Kanamycin: 12-15 mg/kg per dose two or three times weekly 1
• Capreomycin: 12-15 mg/kg per dose two or three times weekly 1
• All are almost exclusively renally cleared 1
• Approximately 40% removed by hemodialysis when given before dialysis 1
• Critical: Maintain the mg/kg dose to preserve concentration-dependent bactericidal activity; smaller doses reduce efficacy 1

Second-line agents:

• Levofloxacin: 750-1,000 mg per dose three times weekly 1
• Cycloserine: 250 mg once daily or 500 mg three times weekly 1
  • Primarily renally excreted and 56% cleared by hemodialysis 1
• Ethionamide: 250-500 mg daily (no adjustment) 1
  • Not renally cleared or removed by hemodialysis 1
• p-Aminosalicylic acid (PAS): 4 g twice daily (no adjustment) 1
  • Modestly cleared by hemodialysis (6.3%), but metabolite acetyl-PAS substantially removed 1

Hemodialysis-Specific Considerations

Administer all anti-TB drugs after hemodialysis to avoid premature drug removal and facilitate directly observed therapy. 1 This timing is critical even for drugs not significantly dialyzed.

Supplemental dosing is not required for isoniazid, rifampin, or ethambutol after dialysis. 1 If pyrazinamide is given after hemodialysis, supplemental dosing is also unnecessary. 1

Rifampin is not cleared by hemodialysis due to high molecular weight, wide tissue distribution, high protein binding, and rapid hepatic metabolism. 1

Monitoring Requirements

For aminoglycosides in renal insufficiency:

• Baseline audiogram, vestibular testing, Romberg testing, and serum creatinine 1
• Monthly renal function assessment and questioning about auditory/vestibular symptoms 1
• Serum drug concentration monitoring to avoid toxicity 1
• Repeat audiogram and vestibular testing if eighth nerve toxicity symptoms develop 1

For capreomycin specifically:

• Additional baseline and monthly serum potassium and magnesium measurements 1

Critical Safety Warnings

Aminoglycosides carry increased risk of both ototoxicity and nephrotoxicity in renal impairment. 1 Capreomycin causes significant renal toxicity requiring drug discontinuation in 20-25% of patients. 1

Ethambutol accumulation in renal failure increases optic neuritis risk, making interval extension essential. 1

Common pitfall: Reducing aminoglycoside doses rather than extending intervals compromises their concentration-dependent killing and may lead to treatment failure. 1

Clinical Outcomes Evidence

A retrospective study of 241 pulmonary TB patients (including 154 with CKD) demonstrated that guideline-based renal dosing adjustments achieved similar therapeutic outcomes (78% sputum conversion at 2 months, 5.8% TB-related mortality) across all CKD severity groups compared to non-CKD patients. 3 However, severe CKD was a significant risk factor for regimen change due to adverse events (OR 5.92,95% CI 1.08-32.5). 3