Effects of Nephrotoxic Medication Combinations on Rates of Stage 2/3 AKI

Background: Acute kidney injury (AKI) is common in hospitalized patients and significantly affects clinical outcomes. Previous studies suggest higher nephrotoxin exposure is associated with higher rates of AKI, which may be exacerbated by possible synergistic nephrotoxicity between drug classes. We analyzed AKI rates following exposure to different combinations of nephrotoxins to explore relative rates of nephrotoxicity with combinations of pharmacologic classes. Methods: This single-center retrospective analysis included 9,226 adults admitted from 2014-2022 with a high-nephrotoxin exposure, defined per the current Nephrotoxic Injury Negated by Just-in-Time (NINJA) definition. Combinations of pharmacologic classes were analyzed by sequentially evaluating 2-way interaction terms in a generalized estimating equation (GEE) along with 26 other clinical variables, with stage 2/3 AKI development within 7 days of high-nephrotoxin exposure as the primary outcome. Results: Multiple statistically significant interactions were identified, including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) with or without antibiotics (OR 2.16, 95% CI 1.07-4.37, p=0.03), non-steroidal anti-inflammatory drugs (NSAIDs) with or without antibiotics (OR 2.65, 95% CI 1.12-6.23, p=0.03), and contrast dye with or without NSAIDs (OR 0.45, 95% CI 0.26-0.79, p=0.01), among others. Odds ratios for combinations of medications are shown in Figure 1. Conclusion: Within a database of high-risk patients with simultaneous exposure to multiple nephrotoxins, risks of stage 2/3 AKI associated with a particular drug class differed significantly depending on the presence or absence of other specific medication classes. Synergistic nephrotoxicity is not currently considered in nephrotoxic AKI prevention programs such as NINJA, and future research should examine whether factoring in these interactions improves predictive accuracy.Figure 1. Odds ratios for development of stage 2/3 AKI within the GEE model depending on presence or absence of other specific drug classes.