Use of proton pump inhibitors and macrolide antibiotics and risk of acute kidney injury: a self-controlled case series study

Abstract

Background: Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal disorders such as peptic ulcer disease and dyspepsia. However, several studies have suggested that PPI use increases the risk of acute kidney injury (AKI). PPIs are often concomitantly used with antibiotics, such as macrolides and penicillins for Helicobacter pylori eradication. Although macrolide antibiotics are considered to have relatively low nephrotoxicity, they are well known to increase the risk of AKI due to drug-drug interactions. In this study, we aimed to investigate the association between PPI use and the development of AKI. We also evaluated the effect of concomitant use of PPIs and macrolide antibiotics on the risk of AKI.

Methods: This self-controlled case series study was conducted using electronic medical records at Kyoto University Hospital. We identified patients who were prescribed at least one PPI and macrolide antibiotic between January 2014 and December 2019 and underwent blood examinations at least once a year. An adjusted incident rate ratio (aIRR) of AKI with PPI use or concomitant use macrolide antibiotics with PPIs was estimated using a conditional Poisson regression model controlled for the estimated glomerular filtration rate at the beginning of observation and use of potentially nephrotoxic antibiotics.

Results: Of the 3,685 individuals who received PPIs and macrolide antibiotics, 766 patients with episodes of stage 1 or higher AKI were identified. Any stage of AKI was associated with PPI use (aIRR, 1.80 (95% confidence interval (CI) 1.60 to 2.04)). Stage 2 or higher AKI was observed in 279 cases, with an estimated aIRR of 2.01 (95% CI 1.57 to 2.58, for PPI use). For the period of concomitant use of macrolide antibiotics with PPIs compared with the period of PPIs alone, an aIRR of stage 1 or higher AKI was estimated as 0.82 (95% CI 0.60 to 1.13).

Conclusions: Our findings added epidemiological information for the association between PPI use and an increased risk of stage 1 or higher AKI. However, we did not detect an association between the concomitant use of macrolide antibiotics and an increased risk of AKI in PPI users.

Keywords: Acute kidney injury; Macrolide antibiotics; Proton pump inhibitor; Self-controlled case series study.

Fig. 1

Study design and definition of exposure. A In analysis 1, we aimed to investigate the association between proton pump inhibitor (PPI) use and the development of acute kidney injury (AKI). The start of the observation was defined as the earliest date of the first serum creatinine measurement or PPI prescription. The end of observation was defined as the latest data of the last serum creatinine measurement, 30 days after the end of last administration of a PPI, or date of death. PPI exposure period (risk period) was defined as the period from the start of PPI administration to 30 days after the end of administration. B In analysis 2, we evaluated the effect of concomitant use of macrolide antibiotics on the risk of AKI only during the initial PPI exposure period. The exposure period of macrolide antibiotics (risk period) was defined as the period from the start of macrolide antibiotics administration to 14 days after the end of its administration

Fig. 2

Identification of cases eligible for the analysis. eGFR, estimated glomerular filtration rate