(122) Multisource Overview on Proton Pump Inhibitors-Associated Acute Kidney Injury

Background: Proton pump inhibitors (PPI) are widely prescribed to treat indications like peptic ulcer disease or gastroesophageal reflux disease and were considered to be safe for a long time. However, recent evidence suggests that prolonged use of PPIs may be associated with acute kidney injury (AKI). Thus, there is an ongoing controversy surrounding the association between PPIs and AKI.

Objectives: To obtain evidence on PPI-associated AKI by creating a comprehensive resource which combines and provides expert contextualisation on data from a spontaneous reporting system (SRS) database, a drug information database (DID) and an expert consensus study.

Methods: The study focusses on five approved PPIs in the Netherlands, obtaining information from EudraVigilance (EV) individual case safety reports (ICSRs) between 2012 and 2022 for disproportionality analyses, Micromedex for average AKI-related adverse drug event (ADE) frequencies and a 29-expert consensus study assessing the AKI potential of 195 medications. AKI was identified in ICSRs using terms from standardised Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) v26.0 for Acute Renal Failure. We included ICSRs submitted by healthcare professionals, reported in the European Economic Area, and about drugs administered via systemic routes. We excluded paediatric or combination drugs ICSRs. The reporting odds ratio (ROR) and the 95% confidence intervals (CIs) were computed. When the ROR's lower 95% CI bound is >1, then there is a strong association with AKI. In Micromedex, for each PPI, all reported AKI-related ADE frequencies were mapped to MedDRA Preferred Terms, standardised into 1 to 5 frequency categories and subsequently averaged.

Results: Out of a total of 20,625 PPI ICSRs, 921 (4.5%) were AKI-related. PPI RORs (95% CI) were, in descending order: esomeprazole 1.7 (1.9, 1.5), pantoprazole 1.6 (1.9, 1.5), omeprazole 1.4 (1.7, 1.3), rabeprazole 1.4 (2.1, 0.9) and lansoprazole 1.2 (1.5, 0.9). Micromedex shows variable average AKI-related ADE frequencies, being infrequent for esomeprazole (i.e., 0.1 to 1%) and rare for lansoprazole (i.e., 0.01 to 0.1%). No frequencies are provided for omeprazole, pantoprazole and rabeprazole AKI-related ADEs. Finally, expert consensus indicates a ‘possible’ AKI potential for PPIs.

Conclusions: In EV, we identify AKI associations for esomeprazole, omeprazole and pantoprazole. Yet Micromedex reports variable but generally low AKI-related ADE frequencies and expert consensus indicates a possible yet not definite potential for AKI. This multisource overview on PPI-associated AKI shows variability across data sources, highlighting the need for further validation and causality studies to clarify this association.