BACKGROUND: Potentially nephrotoxic drugs play an important role in acute kidney injury (AKI) in children. In the previous pharmacovigilance study, we found a statistical correlation between diazepam and AKI in children, but the causality needs to be further verified. METHODS: An observational cohort study was conducted to investigate the association between diazepam exposure and the risk of AKI in hospitalized children. The exposed group received diazepam while the control group did not. The outcome was AKI in accordance with the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Logistic regression was used to explore the association between diazepam exposure and the risk of AKI in children after adjusting for covariates. RESULTS: A total of 3018 hospitalized children were included, 148 in the diazepam group and 2870 in the control group. After adjusting for covariates, diazepam exposure was associated with an increased risk of AKI in children (OR = 1.85, 95%CI: 1.11-3.09, P = 0.019). Multivariate logistic regression showed that age (P <
0.002), low baseline serum creatinine (P <
0.002), chronic kidney disease (P = 0.039), diuretics (P = 0.009), Non-steroidal anti-inflammatory drugs (NSAIDs, P = 0.046), proton pump inhibitors (P = 0.007) and vasoactive drugs (P = 0.007) were risk factors for diazepam-associated AKI in children. CONCLUSIONS: The use of diazepam in children is associated with an increased risk of AKI. The risk factors for diazepam-associated AKI in children included age, low baseline serum creatinine, chronic kidney disease, diuretics, NSAIDs, proton pump inhibitors, and vasoactive drugs. TRIAL REGISTRATION: ChiCTR2400085281 2024-06-04 (retrospectively registered).