NSAID Kidney Risk Underestimated in Young, Active Adults

Diana Phillips

February 15, 2019

The risks of incident and chronic renal disease associated with regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) in active young and middle-age adults may be greater than previously estimated, new research has shown.

In a retrospective study of a large military population, individuals with the highest levels of dispensed NSAIDS had a 20% increased risk of both acute kidney injury (AKI) and chronic kidney disease (CKD), researchers report in an article published online today in JAMA Network Open.

Although modest, the statistically significant associations indicate there is a need for greater patient education about risks and benefits of higher doses of NSAIDs. The findings also point to the need for more research into alternative pain management options in this population, write D. Alan Nelson, MPAS, PhD, of the Division of Primary Care and Population Health in the Department of Medicine at Stanford University, California, and colleagues.

The researchers undertook this study to address an evidence gap. "Most epidemiologic research on the association of NSAIDs and incident kidney disease has involved older persons and/or those with chronic and serious conditions," they write, noting that evidence about the overall risks of NSAIDs and their renal effects in younger, healthy individuals is relatively sparse.

The researchers chose to investigate these associations in a large cohort of US Army soldiers because previous research has suggested that routine NSAID use in this population is widespread. In addition, they explain, this population engages in endurance exercise, which is thought to exacerbate the risk of kidney disease among NSAID users because of diminished renal blood flow during strenuous activity.

The retrospective cohort study included longitudinal data on 764,228 active-duty US Army soldiers collected from January 1, 2011, to December 31, 2014. Most of the participants (86%) were men, and the mean age was 28.6 years.

During the observation period, 1,630,694 distinct NSAID prescriptions were dispensed to participants. Ibuprofen and naproxen were the most common, accounting for 72.4% of all prescriptions. Most of the ibuprofen prescriptions (78.3%) were for 800-mg tablets and most (88.4%) allowed for three or more daily doses. Similarly, nearly all of the naproxen prescriptions (95.7%) were for 500-mg or stronger tablets, and most (93.8%) allowed for at least twice-daily use, the authors report.

More than half of the soldiers (66%) did not receive prescription NSAIDs in the prior 6 months, while nearly 18% received 1 to 7 mean total defined daily doses (DDDs) per month and approximately 16% received more than 7 DDDs per month.

Of 763,752 participants eligible for analysis, 2356 (0.3%) experienced incident AKI events. And of 763,654 individuals eligible for the CKD analysis, 1634 (0.2%) experienced incident CKD.

Some significant differences were observed between individuals with and without NSAID exposure. The proportion of women increased from 12.5% of those without NSAID use to 18.3% of those in the highest use group. In addition, obesity, history of diabetes, and history of hypertension were each twice as prevalent in the highest vs lowest NSAID use category. Finally, African American participants were more highly represented among those who received the highest level of prescription NSAIDs than those who received none, according to the authors.

In the adjusted regression models for AKI and CKD analyses, 7 or more DDDs per month was associated with a 20% higher risk for each outcome (AKI: adjusted hazard ration [aHR], 1.2; 95% confidence interval [CI], 1.1 - 1.4 and CKD: aHR, 1.2; 95% CI, 1.0 - 1.3).

Subsequent risk computations indicate associations between the highest NSAID exposure level and 17.6 excess AKI cases per 100,000 exposed individuals and 30.0 excess CKD cases per 100,000. "These potentially preventable cases are of particular concern in a population in which medical readiness is a foundation of national security," the authors write.

The risk for one or both kidney outcomes associated with highest NSAID exposure was even higher among individuals with other medical conditions.


Table. Risk of kidney disease with high NSAID exposure and comorbid condition

Baseline condition

AKI, aHR (95% CI)

CKD, aHR (95% CI)


1.5 (1.3 - 1.7)

1.6 (1.3 - 1.8)


1.2 (1.1 - 1.4)

1.1 (1.0 - 1.3)


3.2 (2.9 - 3.6)

4.5 (4.0 - 5.1)


2.9 (1.9 - 4.7)

2.7 (1.7 - 4.4)


1.8 (1.4 - 2.4)

1.8 (1.4 - 2.2)


"To address the issue of whether the selected medical condition covariates might interact with NSAID use, we conducted a formal test of the statistical significance of each such interaction," the authors write, noting that the only statistically significant association was the interaction between hypertension and NSAIDs in the CKD analysis (aHR, 0.7; 95% CI, 0.5 - 0.9). "This finding provides some evidence that, in this population, the association between NSAIDs and CKD is significantly weaker among those with prior hypertension than those without," they state.

Additional significant associations with kidney outcomes in the high-dose NSAID population include male sex (AKI: aHR, 2.3; 95% CI, 2.0 - 2.7; CKD: aHR, 1.6; 95% CI, 1.4 - 1.9); African American ethnicity compared with white (AKI: aHR, 1.6; 95% CI, 1.4 - 1.7; CKD: aHR, 2.3; 95% CI, 2.0-2.5); and Hispanic compared with other ethnicities (AKI: aHR, 0.8; 95% CI, 0.6 - 0.9; CKD: aHR, 1.0; 95% CI, 0.8 - 1.2).

Age also influences the risk of kidney disease associated with high-dose NSAIDs. Specifically, participants older than 22 years of age had a higher adjusted risk for each outcome than younger participants. "The association with age was strongest in the CKD analysis," the authors report. Participants aged 42 to 49 years were five times more likely to experience CKD (aHR, 5.0; 95% CI, 3.5 - 7.1), and those aged 50 years and older had a 7.1-fold increase (95% CI, 4.8 - 10.4).

The increased risks of renal outcomes were observed only among the participants who received relatively high NSAID doses. "No significant elevation in risk was observed among soldiers prescribed between 1 and 7 DDDs of NSAIDs per month," the authors stress.

"While recognizing that the pain burden in such active populations must be managed using the best-available measures, given the relatively high mean DDD per prescription we observed, providing lower doses is one approach to those with pain and/or inflammation," the authors suggest. "The increases in kidney disease risk that we observed for modifiable factors, such as body mass index and hypertension, reinforce the established importance of managing these conditions, regardless of patient age."

The study was funded by the National Heart, Lung, and Blood Institute in collaboration with the Uniformed Services University of the Health Sciences. The authors have disclosed no relevant financial relationships.

JAMA Network Open. Published online February 15, 2019. Abstract

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