This study investigated the relationship between NSAIDs and kidney function by using long-term data from patients with AS. The correlation between NSAIDs intake score and eGFR change was not significant at intervals of 6 months, 1 year, 2 years, 3 years, 5 years, and 10 years. Our data provides evidence for the safety of long-term NSAID use in patients with AS without deterioration of kidney function. However, the results should be interpreted with consideration of the characteristics of AS, which is more prevalent at a young age [15].
In AS patients, more patients with impaired kidney function than in the general population may be found due to various factors, such as the presence of comorbidities such as hypertension and nephrotoxic medication. The prevalence rate of AS in patients with decreased eGFR is approximately 0.1–5.4% [19–21]. In a retrospective cohort, CKD was found in 2.5% of men and 1.6% of women, which was higher than that in men (1.5%) and women (1.2%) in the general population [19]. A single center study among patients with AS in China reported that 5.4% of the patients had reduced eGFR [20]. The risk of renal impairment or CKD seems to be reported differently depending on the definition of kidney disease, methods of kidney function evaluation, and sex and age of the study population. Our data revealed that 2.69% of patients had a decreased eGFR (< 60 ml/min/m2) at least once during the follow-up period. The kidney function of our patients was similar to that of other AS study participants and patients encountered in general medical settings. However, it is worth noting that very few patients showed a sustained decrease in eGFR (< 60 ml/min/m2).
NSAIDs have been widely used as first-line treatment for symptom relief in patients with various types of arthritis. In rheumatoid arthritis (RA), a chronic inflammatory disease, long-term treatment with NSAIDs is often required to control symptoms. Previous studies among patients with RA have reported a relationship between the long-term use of NSAIDs and renal impairment. In a prospective cohort study, chronic NSAID use in patients with RA was an independent predictor of accelerated kidney function decline in patients with an eGFR < 30 ml/min/1.73 m2 [22]. In a population-based cohort study of patients with RA, patients using NSAIDs for more than 90 days had a double risk of CKD compared to non-users [23].
Considering that many patients have been prescribed NSAIDs for a substantial period, the literature regarding the correlation between kidney function and NSAIDs intake in patients with AS is limited. In a single-center cohort study, the use of NSAIDs in patients with AS did not differ between CKD and non-CKD patients [20]. However, this study was insufficient to explain the safety of kidney function in patients with AS requiring long-term treatment with NSAIDs. One age- and sex-matched study of AS reported that the group that used NSAIDs for more than 48 months had a lower rate of kidney dysfunction than those who took NSAIDs for less than 48 months [24]. The authors suggested that these results may be due to AS itself and not to NSAIDs induced nephropathy. However, there was a limitation in that it was difficult to generalize the results because the number of cases (40 cases) was too small.
It is difficult to explain the long-term safety of NSAIDs because of conflicting results on the relationship between NSAIDs and kidney function. However, the subgroup analysis provided reasonable results regarding the stability of NSAIDs in the selected patients. In a cohort study, there was a significant correlation between the cumulative NSAID dose and a decrease in eGFR in elderly patients [25]. Another study reported an increased risk of ibuprofen-associated renal impairment in elderly patients and in patients with coronary artery disease [26]. Among active young and middle-aged adults, modest but significant associations were observed between exposure to high doses of NSAIDs and incident kidney disease [11]. Summarizing those results, caution is warranted with the long-term use of NSAIDs in patients of old age or with comorbidities. Patients at risk are susceptible to nephrotoxicity owing to their low cardiac output, volume-contracted state, or other conditions that lead to impaired renal perfusion [10]. Considering the age of onset of patients with other arthritic diseases in previous studies, relatively young patients with AS were less likely to have conditions that were more susceptible to NSAIDs-induced nephrotoxicity than patients with other arthritic diseases. We believe that this is why there may have been no association between kidney function and NSAID dose in patients with AS in this study. Therefore, we need to focus on patients with decreased kidney function in the present study. Although their number was small, it is necessary to identify factors that may affect kidney function during long-term NSAID treatment.
In this study, the NSAID intake score was used to unify the prescriptions of various NSAIDs into one indicator. Although the defined daily dose system (DDD) was also used to determine the dose of an NSAID in several studies [25, 27, 28], the NSAID intake score was simple and easy to understand. Interestingly, some patients had NSAID intake scores greater than 100. They may have been prescribed more than the regular dose of NSAIDs, or they may have been prescribed two or more overlapping NSAIDs. However, the eGFR change in most patients was less than 20 at all intervals.
The present results should be interpreted in the light of some limitations. First, the long-term use of NSAIDs was calculated by integrating the effects of various NSAIDs into the NSAID intake score. Differences in action between NSAIDs, such as the selectivity of COX, were ignored. Second, in patients with AS, there are patients who take NSAIDs when they need them, so it is possible that they were prescribed and did not take the full dose. This was an inevitable limitation of the EMR study, in which compliance was not collected. Third, there were no data on comorbidities such as cardiovascular diseases and diabetes and their associated drugs that directly affect kidney function. Fourth, since most patients with AS were diagnosed at a young age, data on older patients are relatively scarce.
We found that long-term NSAID use was not associated with a decline in kidney function, even at 10-year intervals. Moreover, there was no correlation between the duration of NSAIDs use and kidney function among the age groups. These findings suggest that long-term NSAIDs may be safe for kidney function in patients with AS. Further studies are needed to evaluate older patients or those with preexisting conditions, particularly CKD, in a larger patient population.