Drug-specific risks of acute kidney injury associated with triple whammy therapy: a nationwide self-controlled case series study in Japan.

BACKGROUND: Concomitant use of renin–angiotensin system inhibitors (RASIs), diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs), commonly referred to as the “triple whammy” (TW), is known to increase the risk of acute kidney injury (AKI). However, the relative contribution of each drug component and the influence of their pharmacological subclasses remain unclear. METHODS: A self-controlled case series (SCCS) study was conducted in Japan using a nationwide claims database (April 2014 to January 2024). Patients with at least one AKI episode (the International Classification of Diseases, 10th Edition code N17X) and prescriptions for RASIs, diuretics, or NSAIDs were included. The incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for AKI were estimated using conditional Poisson regression to compare the exposed and unexposed periods within individuals. Sensitivity analyses accounted for the time-varying nephrotoxic exposure to antibiotics, antiviral agents, and iodinated contrast media. RESULTS: Among the 92,880 eligible patients, 109,351 AKI events occurred during 129 million person-days of follow-up. The risk of AKI increased with the number of concomitant drug classes used. Concomitant use of two drug class combinations, that is, diuretics and NSAIDs, conferred the greatest risk, and during TW exposure, the risk was not significantly higher than that observed with diuretics and NSAIDs (IRR 1.01 [0.86–1.19]). The risk of AKI increased with both the number and type of diuretics used, with loop diuretics demonstrating the highest risk. No significant differences were found between angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, and the higher AKI risk observed with nonselective COX inhibitors compared with COX-2-selective agents disappeared after adjustment for time-dependent covariates. CONCLUSIONS: In this nationwide SCCS study, the AKI risk associated with TW therapy was primarily driven by the concomitant use of diuretics and NSAIDs, rather than RASIs. The risk varied according to the number and type of diuretics used, emphasizing the importance of cautious prescription and close renal monitoring during periods of combined use of diuretics and NSAIDs.