Mechanisms of triple whammy acute kidney injury

Pharmacol Ther. 2016 Nov:167:132-145. doi: 10.1016/j.pharmthera.2016.07.011. Epub 2016 Aug 1.


Pre-renal acute kidney injury (AKI) results from glomerular haemodynamic alterations leading to reduced glomerular filtration rate (GFR) with no parenchymal compromise. Renin-angiotensin system inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor antagonists (ARAs), non-steroidal anti-inflammatory drugs (NSAIDs) and diuretics, are highly prescribed drugs that are frequently administered together. Double and triple associations have been correlated with increased pre-renal AKI incidence, termed "double whammy" and "triple whammy", respectively. This article presents an integrative analysis of the complex interplay among the effects of NSAIDs, ACEIs/ARAs and diuretics, acting alone and together in double and triple therapies. In addition, we explore how these drug combinations alter the equilibrium of regulatory mechanisms controlling blood pressure (renal perfusion pressure) and GFR to increase the odds of inducing AKI through the concomitant reduction of blood pressure and distortion of renal autoregulation. Using this knowledge, we propose a more general model of pre-renal AKI based on a multi whammy model, whereby several factors are necessary to effectively reduce net filtration. The triple whammy was the only model associated with pre-renal AKI accompanied by a course of other risk factors, among numerous potential combinations of clinical circumstances causing hypoperfusion in which renal autoregulation is not operative or is deregulated. These factors would uncouple the normal BP-GFR relationship, where lower GFR values are obtained at every BP value.

Keywords: ACEI; ARA; Diuretic; NSAID; Pre-renal acute kidney injury; Triple whammy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / epidemiology
  • Acute Kidney Injury / etiology*
  • Acute Kidney Injury / physiopathology
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin Receptor Antagonists / adverse effects
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Blood Pressure / drug effects
  • Blood Pressure / physiology*
  • Diuretics / administration & dosage
  • Diuretics / adverse effects
  • Glomerular Filtration Rate
  • Humans
  • Incidence
  • Models, Theoretical*
  • Renin-Angiotensin System / drug effects
  • Risk Factors


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