Acute kidney injury associated with nephrotoxic drugs in critically ill patients: a multicenter cohort study using electronic health record data

Background. Nephrotoxic drugs frequently cause acute kidney injury (AKI) in adult intensive care unit (ICU) patients. However, there is a lack of large pharmaco-epidemiological studies investigating the associations between drugs and AKI. Importantly, AKI risk factors may also be indications or contraindications for drugs and thereby confound the associations. Here, we aimed to estimate the associations between commonly administered (potentially) nephrotoxic drug groups and AKI in adult ICU patients whilst adjusting for confounding. Methods. In this multicenter retrospective observational study, we included adult ICU admissions to 13 Dutch ICUs. We measured exposure to 44 predefined (potentially) nephrotoxic drug groups. The outcome was AKI during ICU admission. The association between each drug group and AKI was estimated using etiological cause-specific Cox proportional hazard models and adjusted for confounding. To facilitate an (independent) informed assessment of residual confounding, we manually identified drug group-specific confounders using a large drug knowledge database and existing literature. Results. We included 92 616 ICU admissions, of which 13 492 developed AKI (15%). We found 14 drug groups to be associated with a higher hazard of AKI after adjustment for confounding. These groups included established (e.g. aminoglycosides), less well established (e.g. opioids) and controversial (e.g. sympathomimetics with alpha- and beta-effect) drugs. Conclusions. The results confirm existing insights and provide new ones regarding drug associated AKI in adult ICU patients. These insights warrant caution and extra monitoring when prescribing nephrotoxic drugs in the ICU and indicate which drug groups require further investigation. LAY SUMMARY Acute kidney injury (AKI) is a common problem in adult intensive care unit (ICU) patients and is often caused by nephrotoxic drugs. However, due to a lack of large pharmaco-epidemiological studies investigating the associations between drugs and AKI, our knowledge on the nephrotoxicity of drugs is limited. This hampers our ability to improve medication safety in the ICU. Using real-world data from 13 ICUs on 92 616 ICU admissions, we estimated the associations between 44 (potentially) nephrotoxic drug groups and AKI whilst adjusting for confounding. In total, 14 groups were associated with a higher hazard of AKI. Our approach confirms existing knowledge and provides new insights and directions for current ICU practice and follow-up research regarding AKI associated with drugs.