May 12, 2022
Patients who mix a diuretic and renin-angiotensin system (RAS) inhibitor with a nonsteroidal anti-inflammatory drug (NSAID) could face a higher risk of developing acute kidney injury (AKI), a new analysis confirms.
The study also looked at risk factors associated with the effect of triple therapy with these agents, which has been called "triple whammy" AKI.
"It's not that everyone who happens to take this combination of drugs is going to have problems," Anita Layton, PhD, University of Waterloo, Ontario, Canada, said in a statement. "But the research shows it's enough of a problem that you should exercise caution."
The study was published online April 4 in Mathematical Biosciences.
In an earlier study, triple therapy with a diuretic, RAS inhibitor, and NSAID was associated with a 31% increased risk for AKI, relative to diuretic and RAS inhibitor therapy only.
However, the factors that predispose some patients to develop "triple whammy" AKI are unclear.
To better understand the mechanism by which triple therapy increases risk for AKI, Layton and colleagues used computational models to gauge interactions between concurrent use of a diuretic, a RAS inhibitor, and an NSAID.
They identified dehydration and high sensitivity to drug treatment as key contributing factors to the development of triple whammy AKI.
Their model simulations suggested that low water intake, the myogenic response (that is, the reflex response of arteries and arterioles to changes in blood pressure to maintain consistent blood flow), and drug sensitivity "may predispose patients with hypertension to develop triple whammy-induced AKI," they write.
"We hypothesize that individuals with an impaired myogenic response may be particularly susceptible to triple whammy AKI. Additionally, increased drug sensitivity or low water intake can predispose patients to triple whammy AKI," they add.
In the absence of additional risk factors, there was no indication of an elevated risk for AKI when an angiotensin-converting-enzyme (ACE) inhibitor and NSAID are combined, the study team says.
In contrast, when an ACE inhibitor, diuretic, and NSAID are combined, critical blood pressure and glomerular filtration rate (GFR) regulatory mechanisms are simultaneously interrupted, they report.
"Perhaps not unexpectedly, model simulations indicate that triple treatment reduces GFR more than single or double treatments in all individuals. However, under triple treatment, urine volume and GFR have not been predicted to fall sufficiently far to indicate AKI," they write. "This result is consistent with the fact that only a fraction of individuals develop AKI following triple treatment."
They expect, therefore, that hypertensive patients who are otherwise healthy will be able to withstand triple treatment, in the absence of these aggravating factors, the researchers conclude.
Nonetheless, it's wise to "always be careful when mixing medications," Layton told theheart.org | Medscape Cardiology.
She noted that "triple whammy AKI is known among kidney researchers and nephrologists. To what extent nonspecialists are aware, it isn't clear."
"More importantly," Layton said, "NSAIDs can be obtained over the counter, and triple whammy AKI isn't common knowledge outside of the medical community."
This research was supported by the Canada 150 Research Chair program and by the Natural Sciences and Engineering Research Council of Canada. The authors have declared no conflicts of interest.