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A Large Animal Model for Acute Kidney Injury by Temporary Bilateral Renal Artery Occlusion
Published on: February 2, 2021
Determining risk factors for triple whammy acute kidney injury
Jessica Leete1, Carolyn Wang2, Francisco J López-Hernández3
1Computational Biology and Bioinformatics Program, Duke University, Durham, NC, USA.
Abstract:
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.
Insights
The "triple whammy" of diuretics, renin-angiotensin system inhibitors, and NSAIDs significantly raises acute kidney injury risk. Low water intake and specific physiological responses may increase susceptibility to this drug interaction.
Area of Science:
- Nephrology
- Pharmacology
- Computational Biology
Background:
- Concurrent use of diuretics, renin-angiotensin system (RAS) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs) is common, particularly in hypertensive patients.
- This drug combination, termed "triple whammy," significantly elevates the risk of acute kidney injury (AKI).
- Understanding the underlying mechanisms and individual susceptibility factors for triple whammy AKI is crucial for patient safety.
Purpose of the Study:
- To investigate the mechanisms contributing to acute kidney injury caused by the "triple whammy" drug combination.
- To identify physiological factors that may predispose individuals to developing triple whammy AKI.
- To utilize sex-specific computational models to simulate and analyze these effects.
Main Methods:
- Development and application of sex-specific computational models of long-term blood pressure regulation.
- Inclusion of detailed physiological variables: cardiovascular system, kidney function, nephron reabsorption, and the RAS.
- Modeling hypertension as overactive renal sympathetic nervous activity, with models parameterized for male and female physiology.
Main Results:
- Model simulations indicate that low water intake, the myogenic response, and drug sensitivity are potential predisposing factors for triple whammy AKI.
- Simulated triple treatment (ACE inhibitor, furosemide, NSAID) resulted in blood pressure levels comparable to dual treatment (ACE inhibitor and furosemide).
- Sex-specific models showed similar responses in most scenarios, with notable differences observed in the ACE inhibitor and NSAID dual treatment condition.
Conclusions:
- Physiological factors such as hydration status, myogenic response, and individual drug sensitivity play a role in triple whammy AKI.
- Computational modeling provides valuable insights into the complex interactions leading to drug-induced kidney injury.
- Further research into sex-specific responses may refine understanding and management of triple whammy AKI.
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