From a nephrology perspective, how should the standard RIPE (rifampin, isoniazid, pyrazinamide, ethambutol) anti‑tuberculosis regimen be dosed in patients with chronic kidney disease or on dialysis (eGFR < 50 mL/min)?

Anti-Tuberculosis Medication Dosing in Chronic Kidney Disease and Dialysis

For patients with CKD (eGFR <30 mL/min) or on hemodialysis, rifampin and isoniazid require no dose adjustment, while pyrazinamide and ethambutol must be switched from daily to three-times-weekly dosing with weight-based doses given after dialysis sessions. 1

Core Dosing Strategy by Drug

Rifampin and Isoniazid: No Adjustment Required

• Rifampin 600 mg once daily or 600 mg three times weekly – hepatically metabolized with minimal renal clearance, standard dosing is safe even in severe CKD and dialysis 1
• Isoniazid 300 mg once daily or 900 mg three times weekly – hepatically metabolized, no dose reduction needed regardless of renal function 1
• Neither drug is significantly removed by hemodialysis due to rifampin's high protein binding and rapid hepatic metabolism, and isoniazid's minimal dialysis clearance 1, 2

Pyrazinamide: Frequency Reduction Mandatory

• 25–35 mg/kg three times weekly (NOT daily) for CrCl <30 mL/min or dialysis patients 1
• Although hepatically metabolized, pyrazinamide's metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) accumulate in renal failure and cause toxicity 1
• Pyrazinamide is significantly removed by hemodialysis (45% dialysate recovery), requiring post-dialysis administration to avoid premature drug loss 2

Ethambutol: Frequency Reduction Mandatory

• 20–25 mg/kg three times weekly (NOT daily) for CrCl <30 mL/min or dialysis patients 1
• Approximately 80% renally cleared, making accumulation and optic neurotoxicity a major risk with daily dosing in renal impairment 1
• The 2016 ATS/CDC/IDSA guidelines increased the recommended dose from 15–25 mg/kg to 20–25 mg/kg for thrice-weekly regimens to ensure adequate peak concentrations 1

Critical Dosing Principles

Extend Intervals, Don't Reduce Doses

• The fundamental principle is increasing dosing intervals rather than decreasing individual doses to maintain adequate peak serum concentrations while avoiding accumulation 1
• Reducing doses compromises peak concentrations (Cmax) and treatment efficacy, particularly for concentration-dependent drugs like ethambutol 1

Post-Dialysis Administration

• All anti-tuberculosis medications should be administered after hemodialysis sessions on dialysis days to prevent premature drug removal and facilitate directly observed therapy (DOT) 1
• This timing is especially critical for pyrazinamide, which undergoes significant dialytic clearance 2

Borderline Renal Function (CrCl 30–50 mL/min)

• Standard daily doses are used by experts for patients with CrCl 30–50 mL/min, as insufficient data exist to guide specific adjustments in this range 1
• Therapeutic drug monitoring (TDM) with serum concentrations at 2 and 6 hours post-dose should be considered to optimize dosing and avoid toxicity, particularly for ethambutol and pyrazinamide 1

Common Pitfalls and How to Avoid Them

Don't Trust Serum Creatinine Alone

• Calculate actual creatinine clearance using Cockcroft-Gault or 24-hour urine collection before making dosing decisions, as "normal" serum creatinine can mask severe renal impairment in elderly or low-muscle-mass patients 1, 3
• A patient with CrCl <30 mL/min may have serum creatinine of only 1.5 mg/dL if they have minimal muscle mass 1

Ethambutol Optic Neurotoxicity Risk

• Ethambutol accumulation in renal failure is the most dangerous toxicity – daily dosing in dialysis patients can cause irreversible optic neuropathy 1, 4
• If ethambutol must be used, serum concentration monitoring is strongly recommended, and patients should be counseled on vision changes requiring immediate drug discontinuation 1

Pyrazinamide Metabolite Accumulation

• Even though pyrazinamide itself is hepatically cleared, toxic metabolites accumulate in renal failure, causing hyperuricemia and hepatotoxicity 1
• The three-times-weekly regimen prevents metabolite accumulation while maintaining efficacy 1

Peritoneal Dialysis Patients

• Begin with hemodialysis dosing recommendations (three-times-weekly regimens for pyrazinamide and ethambutol) and verify adequacy using serum concentration monitoring, as no specific data exist for peritoneal dialysis 1

Second-Line Agents in Renal Failure

Fluoroquinolones

• Levofloxacin 750–1000 mg three times weekly for CrCl <30 mL/min or dialysis, as 80% undergoes renal clearance 1, 5, 3
• Moxifloxacin 400 mg once daily requires no adjustment due to primarily hepatic metabolism, making it preferable in severe CKD 1, 5

Injectable Aminoglycosides

• Streptomycin, kanamycin, amikacin, and capreomycin: 15 mg/kg two to three times weekly (NOT daily) for CrCl <30 mL/min or dialysis 1
• These drugs are almost entirely renally cleared and exhibit concentration-dependent killing, requiring extended intervals with full doses rather than dose reduction 1

Monitoring Recommendations

• Baseline and periodic renal function assessment throughout treatment, particularly in patients with borderline function or multiple nephrotoxic medications 1
• Consider therapeutic drug monitoring for ethambutol, pyrazinamide, and levofloxacin in dialysis patients to ensure adequate exposure without toxicity 1
• Monitor for drug interactions, as ESRD patients typically receive multiple medications (phosphate binders, immunosuppressants, cardiovascular drugs) that may alter anti-tuberculosis drug pharmacokinetics 1