How should the standard four‑drug tuberculosis regimen (isoniazid, rifampin, pyrazinamide, ethambutol) be dosed in an adult with chronic kidney disease, including adjustments for different eGFR levels and dialysis?

HRZE Dosing in Chronic Kidney Disease

In adults with CKD, rifampin and isoniazid require no dose adjustment at any eGFR level or on dialysis, while pyrazinamide and ethambutol must be reduced to three-times-weekly dosing (not daily) when creatinine clearance falls below 30 mL/min or the patient is on dialysis. 1

Drug-Specific Adjustments by Renal Function

Rifampin (R) – No Adjustment Required

• Standard dose of 600 mg once daily (or 600 mg three times weekly for intermittent regimens) is safe at all levels of renal impairment, including hemodialysis. 2, 1
• Rifampin undergoes almost exclusive hepatic metabolism with minimal renal clearance; renal impairment does not affect drug exposure. 2
• The drug is not removed by hemodialysis due to high protein binding (>80%), extensive tissue distribution, and rapid hepatic metabolism. 2
• Administer after hemodialysis sessions on dialysis days to facilitate directly observed therapy and maintain consistent timing with other anti-TB drugs. 2

Isoniazid (H) – No Adjustment Required

• Standard dose of 300 mg once daily (or 900 mg three times weekly) requires no modification in severe CKD or dialysis. 1
• Hepatic metabolism predominates and dialysis removal is negligible. 1
• All CKD patients receiving isoniazid should receive prophylactic pyridoxine 25–50 mg daily to prevent peripheral neuropathy. 1

Pyrazinamide (Z) – Requires Interval Extension

• For CrCl <30 mL/min or dialysis: give 25–35 mg/kg three times weekly (Monday/Wednesday/Friday), NOT daily. 3, 1
• Although the parent drug is hepatically cleared, toxic metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) accumulate in renal failure and cause hyperuricemia and hepatotoxicity. 1
• Daily dosing in severe CKD leads to dangerous metabolite accumulation. 1

Ethambutol (E) – Requires Interval Extension

• For CrCl <30 mL/min or dialysis: give 20–25 mg/kg three times weekly (Monday/Wednesday/Friday), NOT daily. 3, 1
• Approximately 80% of ethambutol is renally cleared; daily dosing in renal impairment causes drug accumulation with high risk of irreversible optic neuropathy. 1
• The 2016 ATS/CDC/IDSA guidelines increased the thrice-weekly dose from 15 mg/kg to 20–25 mg/kg to achieve adequate peak concentrations. 1

Dosing Algorithm by eGFR Level

eGFR ≥70 mL/min (Mild CKD)

• Use standard daily HRZE regimen: Rifampin 600 mg, Isoniazid 300 mg, Pyrazinamide 25–40 mg/kg, Ethambutol 15–20 mg/kg, all given once daily. 3, 4

eGFR 30–69 mL/min (Moderate CKD)

• Rifampin 600 mg daily and Isoniazid 300 mg daily: no change. 2, 1
• Ethambutol requires dose modification when CrCl <70 mL/min: reduce to 15–20 mg/kg three times weekly. 4
• Pyrazinamide: expert opinion recommends standard daily doses for CrCl 30–50 mL/min, but consider therapeutic drug monitoring (TDM) with serum concentrations at 2 h and 6 h post-dose to optimize exposure and avoid toxicity. 1

eGFR <30 mL/min or Hemodialysis (Severe CKD/ESRD)

• Rifampin 600 mg: continue daily or three times weekly, no adjustment. 2, 1
• Isoniazid 300 mg: continue daily or 900 mg three times weekly, no adjustment. 1
• Pyrazinamide 25–35 mg/kg: three times weekly ONLY (Monday/Wednesday/Friday). 3, 1
• Ethambutol 20–25 mg/kg: three times weekly ONLY (Monday/Wednesday/Friday). 3, 1
• Administer all medications after hemodialysis sessions on dialysis days to prevent premature drug removal. 1

Peritoneal Dialysis

• Apply the same hemodialysis dosing recommendations (thrice-weekly pyrazinamide and ethambutol) and verify adequacy with serum concentration monitoring, as specific peritoneal dialysis data are lacking. 1

Rationale for Interval Extension vs. Dose Reduction

The preferred strategy is to extend dosing intervals rather than reduce individual doses, preserving peak serum concentrations (Cmax) essential for efficacy of concentration-dependent drugs such as ethambutol and pyrazinamide. 1

• Dose reduction would lower Cmax and may compromise treatment success, especially for ethambutol where efficacy correlates directly with peak levels. 1
• Extended-interval dosing with full doses maintains bactericidal activity while allowing time for drug clearance between doses. 1
• Rifampin is an exception: its pharmacokinetics do not require interval extension or dose reduction regardless of renal function. 2, 1

Critical Safety Monitoring

Baseline Assessment

• Calculate creatinine clearance using the Cockcroft-Gault equation or 24-hour urine collection rather than relying on serum creatinine alone, because low muscle mass in CKD can mask severe renal impairment. 2, 1

Ethambutol Toxicity Prevention (Most Critical)

• Ethambutol accumulation is the most hazardous toxicity in renal failure; daily dosing can cause irreversible optic neuropathy. 1
• Mandatory visual monitoring: baseline visual acuity and red-green color discrimination testing before starting therapy, then monthly repeat testing. 4
• Discontinue ethambutol immediately at the first sign of visual changes. 4
• Never use standard daily doses when CrCl <70 mL/min. 4

Pyrazinamide Toxicity Prevention

• Pyrazinamide metabolites accumulate in renal failure, leading to hyperuricemia and hepatotoxicity; thrice-weekly regimen mitigates this risk. 1
• Monitor liver function tests and uric acid levels regularly. 1

Therapeutic Drug Monitoring (TDM)

• Consider TDM for ethambutol, pyrazinamide, and rifampin in patients with borderline renal function (CrCl 30–50 mL/min) or uncertain dialysis adequacy to ensure therapeutic exposure without toxicity. 1
• Measure serum concentrations at 2 h and 6 h post-dose. 1

Hepatic Monitoring

• Baseline liver function tests are mandatory before initiating rifampin, isoniazid, and pyrazinamide. 2, 1
• Monitoring schedule: weekly for the first 2 weeks, every 2 weeks during the first 2 months, then monthly thereafter. 1
• Regular liver-function testing is essential because rifampin is hepatically metabolized and can be hepatotoxic, particularly when combined with isoniazid and pyrazinamide. 2

Drug-Drug Interactions

• Vigilant monitoring for drug-drug interactions is required in ESRD patients who often receive phosphate binders, immunosuppressants, and cardiovascular drugs that may alter anti-tuberculosis pharmacokinetics. 2, 1
• Rifampin induces hepatic enzymes that reduce the efficacy of oral contraceptives; alternative contraception should be offered. 4
• Double the maintenance dose of corticosteroids when co-administered with rifampin because rifampin accelerates steroid clearance. 4

Common Pitfalls to Avoid

• Do not use daily pyrazinamide or ethambutol when CrCl <30 mL/min—this is the most common and dangerous error. 1
• Do not withhold ethambutol in renal impairment; instead, apply the renal-adjusted thrice-weekly dosing. 4
• Do not neglect monthly visual monitoring in patients with renal disease receiving ethambutol. 4
• Do not use ethambutol doses >30 mg/kg in renal impairment, as toxicity risk rises dramatically. 4
• Do not assume rifampin requires dose adjustment—it does not, regardless of renal function. 2, 1
• Do not administer medications before hemodialysis—always give after dialysis sessions. 2, 1