Determining risk factors for triple whammy acute kidney injury

Math Biosci. 2022 May:347:108809. doi: 10.1016/j.mbs.2022.108809. Epub 2022 Apr 4.


Concurrent use of a diuretic, a renin-angiotensin system (RAS) inhibitor, and a non-steroidal anti-inflammatory drug (NSAID) significantly increases the risk of acute kidney injury (AKI). This phenomenon is known as "triple whammy". Diuretics and RAS inhibitors, such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker, are often prescribed in tandem for the treatment of hypertension, whereas some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common. The goals of this study are to better understand the mechanisms underlying the development of triple whammy AKI and to identify physiological factors that may increase an individual's susceptibility. To accomplish these goals, we utilize sex-specific computational models of long-term blood pressure regulation. These models include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron and the RAS and are parameterized separately for men and women. Hypertension is modeled as overactive renal sympathetic nervous activity. Model simulations suggest that low water intake, the myogenic response, and drug sensitivity may predispose patients with hypertension to develop triple whammy-induced AKI. Triple treatment involving an ACE inhibitor, furosemide, and NSAID results in blood pressure levels similar to double treatment with ACEI and furosemide. Additionally, the male and female hypertensive models act similarly in most situations, except for the ACE inhibitor and NSAID double treatment.

Keywords: Blood pressure; Diuretics; Hypertension; NSAID; Renin-angiontensin system; Sex differences.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury* / etiology
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Diuretics / adverse effects
  • Female
  • Furosemide / adverse effects
  • Humans
  • Hypertension* / complications
  • Male
  • Risk Factors


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