Pyrazinamide Use in Chronic Kidney Disease
Primary Recommendation
Pyrazinamide can be given at standard doses in patients with chronic kidney disease, including those with moderate to severe impairment and dialysis dependence, but the dosing frequency must be reduced to three times weekly (not daily) when creatinine clearance falls below 30 mL/min or in patients on hemodialysis. 1
Dosing Algorithm by Renal Function
Moderate CKD (eGFR 30–50 mL/min/1.73 m²)
- Standard daily dosing can be used without adjustment 1
- Rifampicin, isoniazid, and pyrazinamide are all given at standard doses in this range of renal impairment 1
- No frequency modification is required at this level of kidney function 1
Severe CKD (eGFR <30 mL/min/1.73 m²) and Dialysis
- Reduce frequency to three times weekly dosing 1
- Dose: 25–35 mg/kg three times per week (not daily) 1
- This represents a shift from daily to intermittent dosing to prevent accumulation of pyrazinamide metabolites 1
- Administer post-dialysis on hemodialysis days to facilitate directly observed therapy and avoid premature drug clearance 1
Pharmacokinetic Rationale
Hepatic Metabolism with Renal Metabolite Clearance
- Pyrazinamide undergoes hepatic metabolism to pyrazinoic acid and 5-hydroxy-pyrazinoic acid 1
- These metabolites may accumulate in renal insufficiency despite the parent drug being hepatically cleared 1
- This metabolite accumulation necessitates the frequency reduction (not dose reduction) in severe CKD 1
Dialysis Clearance
- Pyrazinamide and its metabolites are cleared to a significant degree by hemodialysis 1
- Post-dialysis administration prevents premature drug removal and ensures adequate therapeutic levels 1
Safety Considerations and Monitoring
Known Toxicities in CKD
- Hyperuricemia and arthralgia are dose-dependent adverse effects of pyrazinamide that may be exacerbated in renal impairment 2
- Rare cases of tubulointerstitial nephritis have been reported with pyrazinamide use 2
- Hepatotoxicity risk exists but is not increased by renal impairment per se 1
Clinical Monitoring Requirements
- Baseline and periodic monitoring of renal function is essential throughout treatment 3, 4
- Monitor for signs of hyperuricemia (joint pain, gout flares) which may be more pronounced in CKD patients 2
- Consider serum drug concentration monitoring in patients with borderline renal function or uncertain dialysis adequacy 1
- Measurement at 2 and 6 hours post-dose can assist with optimizing dosages in complex cases 1
Critical Implementation Points
Avoid Common Pitfalls
- Do not reduce the dose per administration—instead, extend the interval between doses to maintain peak concentrations needed for efficacy 1
- Never assume "standard dosing" means daily dosing in severe CKD—the three-times-weekly schedule is the standard for this population 1
- In patients with creatinine clearance between 30–50 mL/min, a 24-hour urine collection may be needed to accurately define renal function before making regimen changes 1
Dialysis-Specific Considerations
- Dialysis affects drug clearance and mandates dose modifications 1
- Post-dialysis timing is mandatory to prevent subtherapeutic levels 1
- Patients on peritoneal dialysis should follow the same three-times-weekly regimen as hemodialysis patients, with serum concentration monitoring to verify adequacy 1
Polypharmacy and Drug Interactions
- CKD patients, especially those with end-stage renal disease, often take multiple medications that may interact or have overlapping toxicities 1
- Careful assessment of the complete medication regimen is required to avoid cumulative nephrotoxic or hepatotoxic effects 4, 5
Comparison with Other First-Line TB Drugs in CKD
No Adjustment Required
- Rifampicin and isoniazid: Standard doses can be used across all stages of CKD, including dialysis 1
Adjustment Required
- Ethambutol: Requires dose reduction and three-times-weekly dosing (20–25 mg/kg three times weekly) when creatinine clearance <30 mL/min 1
- Streptomycin: Requires dose reduction (15 mg/kg 2–3 times weekly) and serum concentration monitoring in renal impairment 1
Evidence Quality and Guideline Authority
The dosing recommendations are derived from the 2016 ATS/CDC/IDSA clinical practice guidelines, which represent the most authoritative and recent guidance on tuberculosis treatment in special populations 1. These guidelines supersede the older 1998 British Thoracic Society recommendations, which provided less specific dosing guidance for pyrazinamide in severe CKD 1. The 2016 guidelines explicitly state that pyrazinamide frequency—not dose per administration—should be modified in severe renal impairment, reflecting updated pharmacokinetic understanding 1.