What is the relationship between Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Acute Kidney Injury (AKI)?

From the Guidelines

NSAIDs should be avoided in high-risk patients, including the elderly, those with pre-existing kidney disease, heart failure, liver disease, or volume depletion, to prevent acute kidney injury (AKI) 1. To minimize the risk of NSAID-related AKI, it is essential to use the lowest effective dose for the shortest duration possible and monitor kidney function regularly with serum creatinine tests 1. Some key points to consider when managing NSAID-related AKI include:

• Common NSAIDs that can cause AKI include ibuprofen, naproxen, diclofenac, and celecoxib 1
• Ensure patients maintain adequate hydration, especially during illness or hot weather 1
• When NSAID-related AKI occurs, management involves immediate discontinuation of the offending drug, supportive care with intravenous fluids if needed, and monitoring kidney function until recovery 1
• Alternative pain management strategies include acetaminophen, topical analgesics, or non-pharmacological approaches 1 The mechanism of NSAID-induced AKI involves blocking cyclooxygenase enzymes that produce vasodilatory prostaglandins, which normally help maintain renal perfusion during states of decreased effective circulating volume 1. It is crucial to evaluate nephrotoxins as a plausible cause of AKI and determine nephrotoxic causality by assessing the temporal sequence between administration and the onset of injury, other possible causes, response to the removal of a drug, and in some cases the effects of restarting the drug 1. Combining nephrotoxins can result in pharmacodynamic drug interactions, such as the ‘triple whammy’ of NSAIDs, diuretics, and ACE inhibitors or ARBs, which can increase the risk of developing AKI 1. In all phases of acute kidney disease (AKD), selection of a less nephrotoxic drug and/or avoidance of a nephrotoxin should be the goal 1.

From the FDA Drug Label

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly.

NSAID-related Acute Kidney Injury (AKI): The use of NSAIDs, including ibuprofen and naproxen, may increase the risk of AKI, particularly in patients with pre-existing renal impairment, heart failure, or those taking certain medications such as diuretics and ACE inhibitors.

• Key risk factors:
  • Impaired renal function
  • Heart failure
  • Liver dysfunction
  • Use of diuretics and ACE inhibitors
  • Elderly patients
• Recommendation: Use NSAIDs with caution in patients at risk of AKI, and monitor renal function closely. Consider alternative therapies in high-risk patients 2, 3.

From the Research

NSAID-Related Acute Kidney Injury (AKI)

• NSAIDs are a common cause of AKI, with the risk increasing 3- to 5-fold in patients taking renin-angiotensin system inhibitors and diuretics concurrently 4.
• The optimal time of NSAIDs in patients with AKI is unknown, but treatment within 24 hours of AKI onset may be associated with worse outcomes, including increased risk of AKI progression, dialysis, and discharge from dialysis 5.
• NSAID prescribing is positively associated with older age, female sex, greater socioeconomic deprivation, and certain comorbidities, such as diabetes, hypertension, osteoarthritis, and rheumatoid arthritis 6.
• The risk of AKI varies among different NSAIDs, with more selective agents potentially having a lower risk than non-selective NSAIDs 7.
• Initiation of NSAID therapy in hospitalized patients already being treated with diuretics and renin-angiotensin-aldosterone system inhibitors is a risk factor for AKI, with the triple association appearing to have a higher risk than the dual association treatment 8.

Risk Factors for NSAID-Related AKI

• Older age
• Female sex
• Greater socioeconomic deprivation
• Certain comorbidities, such as:
  • Diabetes
  • Hypertension
  • Osteoarthritis
  • Rheumatoid arthritis
  • Chronic kidney disease (CKD)
  • Cardiovascular disease (CVD)
  • Heart failure
• Concurrent use of diuretics and renin-angiotensin-aldosterone system inhibitors

Prevention and Management of NSAID-Related AKI

• Identifying high-risk patients and providing patient and provider education on when to avoid NSAIDs and minimize risk 4.
• Considering medication review and NSAID deprescribing in patients at higher risk of AKI, such as those with CKD and older adults 6.
• Monitoring serum creatinine levels and adjusting NSAID therapy accordingly 8.