Mechanism of Pyrazinamide-Induced Renal Toxicity
Pyrazinamide causes renal toxicity primarily through inhibition of renal tubular uric acid secretion, leading to hyperuricemia and, rarely, tubulointerstitial nephritis, though the latter mechanism remains poorly understood. 1
Primary Mechanism: Inhibition of Uric Acid Excretion
Pyrazinamide's most common renal effect involves disruption of normal uric acid handling in the kidney:
The drug inhibits renal tubular secretion of uric acid, resulting in decreased uric acid clearance and subsequent hyperuricemia in 81-84% of patients. 1, 2
Studies demonstrate that pyrazinamide suppresses the uric acid clearance to creatinine clearance ratio (Cua/Ccr) to as low as 2.3%, indicating near-complete blockade of tubular uric acid secretion. 3
This effect manifests within 2 weeks of treatment initiation, with serum uric acid rising from baseline levels of approximately 4.4 mg/dL to 9.8 mg/dL, while uric acid clearance drops from 8.8 mL/min to 3.5 mL/min per 1.73 m². 2
The hyperuricemic effect is reversible, returning to baseline values within 2 months after pyrazinamide discontinuation, with no permanent impairment of renal function (serum creatinine and creatinine clearance remain unchanged). 2
Rare Mechanism: Tubulointerstitial Nephritis
A second, uncommon mechanism involves direct tubular injury:
Pyrazinamide can cause acute tubulointerstitial nephritis, though this is rare and the exact pathophysiologic mechanism remains unclear. 4
Case reports document renal failure with fever, arthritis, and arthralgia during pyrazinamide therapy, with renal biopsy confirming tubulointerstitial nephritis that improved upon drug withdrawal while continuing other antituberculous agents. 4
This suggests an idiosyncratic or hypersensitivity reaction rather than a dose-dependent toxic effect. 4
Clinical Implications in Dialysis Patients
For patients already on dialysis, the renal toxicity concerns are modified:
The FDA label notes that only 17% of pyrazinamide is excreted via the kidneys, suggesting that renal impairment may not dramatically alter drug disposition, though clinical significance in end-stage renal disease remains uncertain. 5
Guidelines recommend reducing pyrazinamide dosing to 25-35 mg/kg three times weekly (not daily) for creatinine clearance <30 mL/min, though this applies to patients with residual renal function rather than those on dialysis. 6
Patients on dialysis do not require dose reduction for hyperuricemia prevention since they lack functional renal tubular secretion mechanisms, though monitoring for the rare tubulointerstitial nephritis remains prudent. 1
Important Caveats
The hyperuricemic effect, while common, is not considered true "renal toxicity" by most guidelines, as it represents an expected pharmacologic effect without adverse clinical consequences in the absence of symptomatic gout. 6, 7
Pre-existing gout is a contraindication to pyrazinamide use, as acute gouty arthritis can be precipitated in these patients. 5, 6
Asymptomatic hyperuricemia does not require treatment or drug discontinuation. 6, 7