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

Kidney Int. 2015 Aug;88(2):396-403. doi: 10.1038/ki.2015.101. Epub 2015 Apr 15.


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.

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / epidemiology*
  • Aged
  • Aged, 80 and over
  • Angiotensin Receptor Antagonists / adverse effects*
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Case-Control Studies
  • Cohort Studies
  • Diuretics / adverse effects*
  • Drug Therapy, Combination / adverse effects
  • Female
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Risk Assessment
  • Risk Factors
  • United Kingdom / epidemiology


  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Anti-Inflammatory Agents, Non-Steroidal
  • Diuretics