Use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the United States in both prescription and over-the-counter forms is widespread; more than 70 million prescriptions for NSAIDs are written each year. NSAID use in 2010 was estimated at more than 29 million US adult regular users; an increase of 41% from 2005. Self-reports of over-the-counter and prescription NSAID use revealed that 90% of users of ibuprofen took it regularly, 37% took a second NSAID in combination with ibuprofen, and 11% exceeded the recommended daily limit of ibuprofen.
There are adverse renal effects associated with both selective and nonselective NSAIDs through prostaglandin-related effects. Adverse events can include impaired renal blood flow as well as clinically significant cytotoxic effects. Hypertension and edema, while infrequent, may also be related to NSAID use and can complicate management of blood pressure.
The majority of previous studies on the association between NSAID use and incident kidney disease have focused on older persons and/or those with chronic and serious comorbidities. There are limited data on kidney disease and NSAID use among younger healthy individuals. Researchers, led by D. Alan Nelson, MPAS, PhD, recently conducted a retrospective longitudinal cohort study to examine associations between dispensed NSAIDs and incident acute kidney injury (AKI) and chronic kidney disease (CKD) in a large cohort of patients derived from deidentified medical and administrative data on active-duty US army soldiers. Results of the study were reported online in JAMA Internal Medicine[doi:10.1001/jamaneworkopen.2018.7896].
The cohort included 764,228 participants; 85.8% (n=655,392) were men, mean age was 28.6 years, median age was 27.0 years, and 31.2% (n=238,168) were new to the military during 2011-2014. During the total observation period, there were a total of 1,630,694 distinct NSAID prescriptions dispensed, for a mean of 2.1 total prescriptions per person.
In the 6 months prior to the observation period, 65.8% of participants (n=502,527) were not prescribed prescription NSAIDs, 17.9% (n=137,108) were dispensed one to seven mean total agent-specific World Health Organization-defined daily doses (DDDs) per month, and 16.3% (n=124,594) received more than seven DDDs per month. The mean DDD per prescription was 1.6. The most commonly prescribed preparations were ibuprofen and naproxen; together they accounted for 72.4% (n=1,180,549) of dispensed NSAIDs. There were 804,471 prescriptions for ibuprofen; of those, 78.3% were for 800-mg tablets and 88.4% allowed for three or more doses per day. Of the 376,078 prescriptions for naproxen, 95.7% were for 500-mg or stronger tablets and 93.8% allowed for at least twice daily dosing.
The analysis for AKI included 763,752 participants. Of those, 0.3% (n=2356) experienced incident AKI events. Among the AKI outcomes, 0.6% (n=13) were detected from eProfile data rather than diagnoses in the electronic health record. There were 763,654 individuals eligible for the CKD analysis. Of those, 0.2% (n=1634) experienced incident CKD, including nine cases detected solely from the eProfile data.
Fewer than 1% of participants had a history of diabetes or rhabdomyolysis; hypertension was more prevalent at up to 8.8%. There were statistically significant differences in the distribution of biomedical and demographic factors comparing groups with and without NSAID use. The proportion of women increased from 12.5% in the group without NSAID use to 18.3% of those in the group with the highest NSAID use.
Those who received the greatest NSAID volumes were twice as likely to be obese; 23.6% of those in the highest use category and 12.4% of those in the lowest use category were obese. Those in the highest use group were nearly twice as likely to have hypertension than those in the lowest use group (8.8% vs 3.6%, respectively) and diabetes (0.9% vs 0.3%, respectively). African American participants were more highly represented in the group with the highest use of NSAIDs than in the group without NSAID use (22.9% vs 19.6%).
There were also statistically significant differences for each of the military-specific factors. There was an association between increasing duration of military service and increased use of NSAIDs. Those with >12 years of service made up 19.4% of the no NSAID use group and 30.4% of the highest NSAID use group.
There was an association between NSAID exposure of seven or more DDDs per month and significant increases in the adjusted hazard rates (aHRs) of AKI (aHR, 1.2; 95% confidence interval [CI], 1.1-1.4) and CKD (aHR, 1.2; 95% CI, 1.0-1.3). Based on postregression-adjusted risk computations, there was an association between the highest NSAID exposure level and annual case excesses per 100,000 exposed individuals of 17.6 cases for AKI and 30.0 cases for CKD. There were associations between mean NSAID exposure of one to seven DDDs and smaller, nonsignificant hazard increases.
There was an association between obesity and significant increases in the hazard of each outcome (AKI, aHR, 1.5; 95% CI, 1.3-1.7; CKD, aHR, 1.6; 95% CI, 1.3-1.8); there was also a modest, significant increase in the hazard of AKI with overweight status (aHR, 1.2; 95% CI, 1.1-1.4). There were associations between histories of hypertension and rhabdomyolysis and greater than 2-fold increases in the adjusted hazard of both AKI and CKD; diabetes conferred smaller increases.
There was an association between male sex and more than twice the adjusted hazard of AKI and a smaller but significant increase in the hazard of CKD. Compared with white participants, African American participants had more than twice the hazard of CKD and a smaller, significant increase in the hazard of AKI.
The authors cited some limitations to the analysis, including the limitations of diagnosis coding, relatively short follow-up times, possible misclassification of AKI as CKD and vice versa, and lack of a mechanism to observe the details of individual NSAID use.
In summary, the researchers said, “We have identified modest but statistically significant associations between the highest levels of observed NSAID exposure and incident AKI and CKD among active, largely healthy adults in the military. 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 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.”
Takeaway Points
- Researchers conducted a retrospective longitudinal cohort study to examine the association between dispensed nonsteroidal anti-inflammatory drugs (NSAIDs) and incident acute kidney injury (AKI) and chronic kidney disease (CKD).
- The cohort included 764,228 active-duty US army soldiers serving between January 1, 2011, and December 31, 2014.
- There were associations between prescriptions of more than seven daily defined doses of NSAIDs and modest but significant increases in the adjusted hazard ratios of AKI and CKD.
