How should the Anti-Tuberculosis Drug (ATD) regimen be adjusted in patients with Chronic Kidney Disease (CKD) and Impaired Renal Function?

ATD Regimen Adjustment in Chronic Kidney Disease

For patients with CKD requiring anti-tuberculosis drugs, reduce the dosing frequency to 2-3 times weekly while maintaining the full milligram dose at 12-15 mg/kg per dose for injectable agents, rather than reducing the dose amount, to preserve concentration-dependent bactericidal activity. 1

General Dosing Principles by CKD Severity

Mild CKD (GFR 60-89 mL/min/1.73m²)

• No dose adjustment needed - use standard national guideline regimens for all first-line anti-TB drugs 2
• Continue standard dosing frequencies and amounts 2

Moderate CKD (GFR 30-59 mL/min/1.73m²)

• Begin implementing frequency adjustments for renally-cleared drugs 1
• Maintain standard doses but extend intervals for injectable agents 1

Severe CKD (GFR <30 mL/min/1.73m²) and End-Stage Renal Disease

• Mandatory dose adjustments required for most anti-TB medications 1, 2
• This is the critical threshold where regimen modification becomes essential 2

Drug-Specific Adjustments in Renal Impairment

Injectable Aminoglycosides (Streptomycin, Amikacin, Kanamycin)

Dosing strategy: Reduce frequency to 2-3 times weekly, maintain dose at 12-15 mg/kg per administration 1

• For patients >59 years: reduce daily dose to 10 mg/kg (750 mg maximum) 1
• Critical principle: Smaller doses reduce drug efficacy - never compromise the milligram amount 1, 3
• Administer after hemodialysis to facilitate directly observed therapy and prevent premature drug removal 1
• Mandatory therapeutic drug monitoring to avoid ototoxicity and nephrotoxicity 1

Capreomycin

• Reduce frequency to 2-3 times weekly, maintain 12-15 mg/kg per dose 1
• Carries 20-25% risk of significant nephrotoxicity requiring discontinuation 1
• Monitor potassium and magnesium monthly in addition to standard renal monitoring 1
• Give after dialysis 1

Fluoroquinolones

Levofloxacin: Reduce to 3 times weekly in reduced renal function 1

Moxifloxacin: No dose adjustment needed 1

Pyrazinamide

• Reduce frequency to 3 times weekly in renal impairment 1
• Maintain dose at 25-40 mg/kg per administration 1

Cycloserine/Terizidone

• Start with 250 mg daily and verify with therapeutic drug monitoring in renal disease 1
• This drug requires particularly careful monitoring due to CNS toxicity risk 1

Drugs Requiring NO Adjustment

The following can be continued at standard doses: 1

• Bedaquiline - no change needed
• Linezolid - no change needed
• Moxifloxacin - no change needed
• Ethionamide/Prothionamide - no change needed
• p-Aminosalicylic acid - no change needed
• High-dose isoniazid - no change needed

Ethionamide

• For creatinine clearance <30 mL/min or hemodialysis: reduce to 250-500 mg/day 1
• No adjustment needed for mild-moderate impairment 1

Carbapenems (Imipenem-cilastatin, Meropenem)

• May reduce dosing frequency in renal impairment 1
• Maintain dose strength while extending interval 4

Delamanid

• Mild to moderate renal insufficiency: no change 1
• Severe insufficiency: limited data, use with caution 1

Critical Monitoring Requirements

Baseline Assessment

• Audiogram and vestibular testing for injectable agents 1
• Serum creatinine and calculated GFR 1
• Liver function tests 1
• Electrolytes (potassium, magnesium) for capreomycin 1

Ongoing Monitoring

• Monthly renal function assessment for all patients on nephrotoxic agents 1
• Monthly questioning about auditory/vestibular symptoms 1
• Serum drug concentration monitoring for aminoglycosides and capreomycin 1
• Repeat audiogram if symptoms of eighth nerve toxicity develop 1

Common Pitfalls and How to Avoid Them

Pitfall #1: Reducing Dose Amount Instead of Frequency

The mistake: Lowering the milligram dose of concentration-dependent drugs like aminoglycosides 1, 3

Why it matters: This compromises bactericidal activity and treatment efficacy 1, 3

Correct approach: Extend the dosing interval (e.g., from daily to 2-3 times weekly) while keeping the full 12-15 mg/kg dose 1, 3

Pitfall #2: Timing Injectable Drugs Before Dialysis

The mistake: Administering aminoglycosides or capreomycin before hemodialysis sessions 1

Why it matters: Premature drug removal reduces efficacy 1

Correct approach: Always give after dialysis 1

Pitfall #3: Failing to Adjust for Age

The mistake: Using standard 15 mg/kg dosing in elderly patients (>59 years) with renal impairment 1

Why it matters: Elderly patients have increased ototoxicity and nephrotoxicity risk 1

Correct approach: Reduce to 10 mg/kg per day (750 mg maximum) for patients >59 years 1

Pitfall #4: Inadequate Therapeutic Drug Monitoring

The mistake: Not monitoring serum drug levels in CKD patients on aminoglycosides 1

Why it matters: CKD patients have unpredictable pharmacokinetics and higher toxicity risk 1, 5, 6

Correct approach: Mandatory serum concentration monitoring to guide dosing and prevent toxicity 1

Clinical Outcomes and Safety Considerations

Evidence on efficacy: Renal function-based dosage adjustments achieve similar therapeutic outcomes (78% sputum conversion at 2 months) compared to non-CKD patients when guidelines are followed 5

Adverse event risk: Despite appropriate dose adjustments, CKD patients experience significantly higher rates of adverse drug reactions (48% vs 13.7% in non-CKD patients), with more severe reactions 6

Most common ADRs in CKD: 6

• Hepatobiliary (30.6% vs 8.9%)
• Neuropsychiatric (10.6% vs 1.2%)
• Renal (5.3% vs 0.4%)
• Gastrointestinal (6.6% vs 1.9%)

Severe CKD as risk factor: Severe CKD stage independently predicts regimen change due to adverse events (OR 5.92,95% CI 1.08-32.5) 5

Special Population: Hemodialysis Patients

For patients on hemodialysis with multidrug-resistant TB: 7

• Use directly observed treatment short-course (DOTS) strategy
• Implement strict renal-dose adjustments
• Administer all renally-cleared drugs post-dialysis
• Intensify monitoring for drug-induced hepatitis and cutaneous reactions
• Consider therapeutic drug monitoring protocols to reduce mortality risk