What are the dosing recommendations for antitubercular (anti-tuberculosis) drug therapy in patients with Chronic Kidney Disease (CKD)?

Antitubercular Drug Dosing in Chronic Kidney Disease

For patients with CKD and creatinine clearance <30 mL/min or on hemodialysis, isoniazid and rifampin require no dose adjustment, while pyrazinamide and ethambutol should be dosed three times weekly (not daily) at 25-35 mg/kg and 20-25 mg/kg respectively, with all medications administered post-dialysis. 1

Core First-Line Agents

Isoniazid (INH)

• No dose adjustment needed regardless of renal function severity, including ESRD and dialysis 1
• Standard dosing: 300 mg once daily or 900 mg three times weekly 1
• Metabolized hepatically, not renally cleared 1

Rifampin (RIF)

• No dose adjustment required in any stage of CKD or dialysis 1, 2
• Standard dosing: 600 mg once daily or 600 mg three times weekly 1
• The CDC explicitly states fixed-dose combination products containing rifampin may be used without adjustment in renal insufficiency 2
• Hepatic metabolism with no renal clearance; not removed by hemodialysis 1

Pyrazinamide (PZA)

• Requires dosing interval change (not dose reduction) in severe CKD 1
• For CrCl <30 mL/min or hemodialysis: 25-35 mg/kg three times weekly (never daily) 1
• Maximum 3 grams per dose should not be exceeded 3
• Although hepatically metabolized, its metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) accumulate in renal insufficiency, necessitating interval extension 1
• Significantly cleared by hemodialysis 1

Ethambutol (EMB)

• Requires dosing interval change in severe CKD 1
• For CrCl <30 mL/min or hemodialysis: 20-25 mg/kg three times weekly (never daily) 1
• Approximately 80% renally cleared, leading to accumulation in renal insufficiency 1
• Partially cleared by hemodialysis 1

Critical Timing Consideration

All antitubercular medications should be administered post-dialysis to facilitate directly observed therapy (DOT) and prevent premature drug clearance, particularly for pyrazinamide which is significantly dialyzed 1

Second-Line Agents (When Needed)

Fluoroquinolones

• Levofloxacin: Requires interval adjustment to 750-1000 mg three times weekly (not daily) for CrCl <30 mL/min due to significant renal clearance 1
• Moxifloxacin: No adjustment needed (400 mg once daily) as it undergoes minimal renal clearance 1

Injectable Agents

• Streptomycin and Capreomycin: Dose 15 mg/kg 2-3 times weekly (not daily) for CrCl <30 mL/min 1

Other Second-Line Drugs

• Cycloserine: 250 mg once daily or 500 mg three times weekly for CrCl <30 mL/min 1
• Ethionamide: No adjustment (250-500 mg daily) 1
• Para-aminosalicylic acid: No adjustment (4 g twice daily) 1

Patients with Borderline Renal Function (CrCl 30-60 mL/min)

For patients with CrCl >30 mL/min but <60 mL/min, insufficient data exist to guide specific dosing recommendations 1. Expert consensus suggests:

• Use standard doses 1
• Consider 24-hour urine collection to accurately define degree of renal insufficiency before making changes 1
• Therapeutic drug monitoring at 2 and 6 hours post-dose can optimize dosing 1

Clinical Outcomes and Safety Considerations

Efficacy with Dose Adjustment

• Renal function-based dosage adjustments maintain therapeutic efficacy comparable to non-CKD patients, with similar sputum culture conversion rates at 2 months (78.0%) and TB-related mortality 4

Adverse Event Risk

• CKD patients experience significantly more frequent and severe adverse drug reactions (48.0% vs 13.7% in normal renal function, p<0.0001) despite appropriate dose adjustments 5
• CKD is an independent predictor for ADRs (OR 4.96,95% CI: 2.79-8.82) 5
• Most common ADRs in CKD: hepatobiliary (30.6%), neuropsychiatric (10.6%), renal (5.3%), and gastrointestinal (6.6%) 5
• Severe CKD stage is a significant risk factor for regimen change due to ADRs (OR 5.92,95% CI: 1.08-32.5) 4

Monitoring Requirements

• Close clinical and pharmacological monitoring is essential in ESRD patients who often take multiple interacting medications 1
• Therapeutic drug monitoring may be necessary, particularly for borderline renal function 1
• Enhanced vigilance for hepatotoxicity and cutaneous reactions, which significantly increase regimen change risk 4

Common Pitfalls to Avoid

1. Do not reduce the dose of pyrazinamide or ethambutol—instead extend the dosing interval to three times weekly 1
2. Avoid pre-dialysis dosing which can lead to premature drug clearance 1
3. Do not use estimated GFR alone in borderline cases; obtain 24-hour urine collection for accurate creatinine clearance 1
4. Never assume hepatically metabolized drugs are safe without considering active metabolite accumulation (as with pyrazinamide) 1