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

Abstract

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 α- and β-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.

Keywords: acute kidney injury; adverse drug events; confounding; drugs; intensive care units.

Figure 1:

Illustration of our approach to investigate the association between each (potentially) nephrotoxic drug group and AKI. The crude association between a drug group and AKI can be confounded. A confounder is a factor that both (indirectly) affects the administration of the group under investigation and (indirectly) affects AKI risk. The collection of all confounders may include (1) acute AKI risk factors (e.g. sepsis), (2) chronic AKI risk factors (e.g. liver disease), (3) demographics (e.g. sex) and (4) other nephrotoxic drugs, illustrated by the boxes with dotted outlines. For each investigated drug group, we identified the group-specific confounders. In addition, we identified age, sex, the SCr baseline, the APACHE IV predicted mortality probability and known nephrotoxic drugs as confounders for all groups. We measured exposure to each drug group from ICU admission until the outcome (i.e. AKI, discharge or death) and estimated the association between each group and AKI independent of the confounders using cause-specific Cox proportional hazard models. See Supplementary data, Fig. S4.1 for group-specific examples of confounding by indication and confounding by contraindication. (p)ND: (potentially) nephrotoxic drug.

Figure 2:

Overview of included and excluded admissions with corresponding exclusion criteria.