Non-steroidal anti-inflammatory drugs, renin-angiotensin system blockade or diuretics and risk of acute kidney injury: A case-crossover study

Background: Aging-related physiological changes, such as decline in renal function, not only exacerbates preexisting comorbidities but also escalate the susceptibility to adverse events. Previous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI), and the concomitant use of renin-angiotensin system blockade or diuretics may further potentiate the risk. However, studies evaluating the risk of AKI associated with NSAIDs (including routes, concomitant use of different NSAIDs, categories (traditional NSAIDs or COX -2 inhibitors), and cumulative doses of NSAIDs) are limited, particularly the risk of AKI associated with the dual or triple combination of NSAIDs with reninangiotensin system blockade (RAS blockades) and/or diuretics. Methods: A case-crossover study utilized two sets of longitudinal data from Taiwan 's National Health Insurance Research Database (NHIRD). Newly admitted patients with a primary AKI diagnosis were included, with the index date defined as the first admission date. The 1 -7 days and 181 -187 days prior to the index date served as the case and control periods. Exposure to NSAIDs and co-exposures of RAS blockade and/or diuretics were assessed in both periods. Multivariable conditional logistic regression models, adjusting for potential confounders, estimated adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) for AKI associated with NSAIDs, dual, or triple combinations. Sensitivity analyses explored result robustness by varying case and control period lengths. Results: The study included 1,284 newly diagnosed AKI patients. NSAIDs showed a 3.55-fold increased risk of AKI (aOR: 3.55; 95 % CI 2.70 -4.65), with similar risks for traditional NSAIDs and COX -2 inhibitors. Use of multiple NSAIDs, parenteral dosage forms, and higher cumulative doses increased AKI risk. Dual combination with either RAS blockade or diuretics resulted in a 2.90-fold (aOR: 2.90; 95 %CI 1.47 -5.70) and 12.68-fold (aOR: 12.68; 95 %CI 6.15 -26.12) risk, respectively. The highest risk occurred with triple combination (aOR: 29.22; 95 %CI 12.82 -66.64). Conclusions: NSAIDs, including both non-selective NSAIDs and COX2 inhibitors, elevate the risk of AKI. Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the risk, with the latter associated with the highest risk of AKI.