Mechanisms of Piperacillin/Tazobactam Nephrotoxicity: Piperacillin/Tazobactam-Induced Direct Tubular Damage in Mice

Abstract

Piperacillin/tazobactam (PT) is one of the most commonly prescribed antibiotics for critically ill patients in intensive care. PT has been reported to cause direct nephrotoxicity; however, the underlying mechanisms remain unknown. We investigated the mechanisms underlying PT nephrotoxicity using a mouse model. The kidneys and sera were collected 24 h after PT injection. Serum blood urea nitrogen (BUN), creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and renal pathologies, including inflammation, oxidative stress, mitochondrial damage, and apoptosis, were examined. Serum BUN, creatinine, and NGAL levels significantly increased in PT-treated mice. We observed increased IGFBP7, KIM-1, and NGAL expression in kidney tubules. Markers of oxidative stress, including 8-OHdG and superoxide dismutase, also showed a significant increase, accompanied by mitochondrial damage and apoptosis. The decrease in the acyl-coA oxidase 2 and Bcl2/Bax ratio also supports that PT induces mitochondrial injury. An in vitro study using HK-2 cells also demonstrated mitochondrial membrane potential loss, indicating that PT induces mitochondrial damage. PT appears to exert direct nephrotoxicity, which is associated with oxidative stress and mitochondrial damage in the kidney tubular cells. Given that PT alone or in combination with vancomycin is the most commonly prescribed antibiotic in patients at high risk of acute kidney injury, caution should be exercised.