Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin–angiotensin system inhibitors in the community increases the risk of acute kidney injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin–angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin–angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case–control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin–angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25–2.14)) and dual combinations with either renin–angiotensin system inhibitors (1.60 (1.18–2.17)) or diuretics (1.64 (1.17–2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin–angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin–angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought.