In an adult with chronic kidney disease on dialysis, should pyrazinamide be dose‑reduced, and what liver‑function and serum uric‑acid monitoring is required?

Pyrazinamide Dosing in Chronic Kidney Disease and Dialysis

In adults with chronic kidney disease on dialysis, pyrazinamide should be dose-reduced to 25-35 mg/kg administered three times weekly (not daily) and given after dialysis sessions. 1

Dose Adjustment Strategy

For Patients with CrCl <30 mL/min or on Hemodialysis

• Reduce dosing frequency from daily to three times weekly at 25-35 mg/kg per dose 1
• Administer pyrazinamide immediately after hemodialysis on dialysis days to facilitate directly observed therapy and avoid premature drug clearance 1
• The 2005 IDSA guidelines suggest 50-100% of full dose daily for CrCl <10 mL/min, or 25-30 mg/kg after dialysis 1, but the more recent 2016 ATS/CDC/IDSA guidelines supersede this with the three-times-weekly recommendation 1

Rationale for Dose Reduction

Pyrazinamide metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) accumulate in renal insufficiency despite hepatic metabolism of the parent drug. 1 Hemodialysis clears pyrazinamide and its metabolites to a significant degree, necessitating post-dialysis administration. 1

For Patients with CrCl 30-50 mL/min

• Standard daily doses are used by experts 1
• Consider measuring serum concentrations at 2 and 6 hours post-dose to optimize dosing and avoid accumulation 1

Monitoring Requirements

Liver Function Monitoring

Baseline liver function tests (ALT/SGPT and AST/SGOT) are mandatory before initiating pyrazinamide. 2 The FDA label explicitly requires this baseline assessment. 2

• Perform periodic liver function testing during therapy, particularly if clinical signs or symptoms develop (fever, loss of appetite, malaise, nausea, vomiting, dark urine, jaundice) 2
• Patients with ESRD often have multiple comorbidities and concomitant medications that increase hepatotoxicity risk, warranting closer monitoring 1
• Recent evidence from a 2024 phase 3 trial (n=2,255) demonstrated that hepatotoxicity was associated with pyrazinamide exposure, establishing therapeutic windows of 231-355 mg·h/L 3

Serum Uric Acid Monitoring

Baseline uric acid levels must be obtained prior to therapy. 2 Pyrazinamide inhibits renal excretion of urates, frequently causing hyperuricemia. 2

• Monitor uric acid periodically during treatment 2
• If hyperuricemia is accompanied by acute gouty arthritis, discontinue pyrazinamide 2
• Asymptomatic hyperuricemia alone does not require discontinuation 2

Therapeutic Drug Monitoring Considerations

• Serum drug concentration monitoring should be considered in ESRD patients to ensure adequate absorption without excessive accumulation and to assist in avoiding toxicity 1
• The 2019 ATS/CDC/ERS/IDSA guidelines note that for severely decreased kidney function including dialysis, consultation with a nephrologist is advised 1
• Pyrazinamide displays sevenfold exposure variability (151-1,053 mg·h/L) even in patients with normal renal function 3

Critical Clinical Pitfalls

Common Errors to Avoid

• Do not continue daily dosing in dialysis patients—this leads to metabolite accumulation and increased toxicity risk 1
• Do not administer pyrazinamide before dialysis—the drug will be prematurely cleared, compromising efficacy 1
• Do not assume weight-based dosing alone is sufficient—body weight is not a clinically relevant predictor of pyrazinamide clearance in the context of renal dysfunction 3

Special Populations

For patients with both renal and hepatic dysfunction, extreme caution is warranted with intensified monitoring, as pyrazinamide metabolites accumulate renally while the parent drug undergoes hepatic metabolism. 1