Drug use and acute kidney injury: a Drug-Wide Association Study (DWAS) in Denmark and Sweden

Abstract

Background: Knowledge of which medications may lead to acute kidney injury (AKI) is limited, relying mostly on spontaneous reporting in pharmacovigilance systems. We here conducted an exploratory drug-wide association study (DWAS) to screen for associations between dispensed drugs and AKI risk.

Methods: Using two large Danish and Swedish data linkages, we identified AKI hospitalizations occurring between April 1997 and December 2021 in Denmark and between March 2007 and December 2021 in Sweden. We used a case-time control design comparing drug dispensing in the 3 months prior to the AKI with earlier periods for the same patient. Odds ratios (ORs) for the association between each drug and AKI were estimated using conditional logistic regression and adjusting for the presence of comorbidities. We sought replication of signals in both health systems and explored the plausibility of findings through pharmacovigilance system analysis in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, appearance in the RESCUE list of medications that report AKI as a side effect, PubMed evidence review and causality assessment through direct acyclic graphs.

Results: We included 20 622 adults in Denmark and 13 852 in Sweden hospitalized for AKI. In total, 16 unique medications were identified in both cohorts as associated to increased AKI occurrence. Of these, 10 medications had higher reporting ORs in the FAERS database, 9 were listed by RESCUE, and 7 appearing in PubMed. This analysis identified some medications with known AKI risks (i.e. likely true positives such as furosemide, penicillin, spironolactone and omeprazole), medications that may have initiated in response to conditions that lead to AKI (i.e. false positives like metoclopramide provided to treat nausea/vomiting) and other candidates (e.g. opioids) that warrant further evaluation in subsequent studies.

Conclusions: This hypothesis-generating study identifies medications with potential involvement in AKI that require confirmation and validation.

Keywords: AKI; directed acyclic graphs; drug-wide association study; nephrotoxicity; pharmacovigilance.

Graphical Abstract

Figure 1:

Schematic representation of case-time-control design.

Figure 2:

DAG exploring the plausibility of metoclopramide causing AKI. Metoclopramide is a treatment for nausea and vomiting and so it is plausible that AKI is caused by vomiting (confounding by indication). This explanation would be supported by the positive association found between domperidone and AKI in the Danish cohort (this drug was not commercialized in Sweden). Further investigation of data is needed from healthcare systems where other antiemetics (e.g. cyclizine, ondansetron) are commonly used.