The results of the meta-analysis showed that current exposure to NSAIDs was associated with an approximately 1.5-fold increase in the odds of developing AKI in the general population and in people with CKD. Since AKI is a rare NSAIDs associated adverse outcome, odds ratios will approximate to relative risks. There was considerable heterogeneity between studies, particularly in the general population group and so the pooled estimates should be interpreted with caution. The limited numbers of studies eligible for inclusion precluded meta-regression, so subgroup analyses were conducted in order to try to explore and explain heterogeneity. Results were consistent with and similar to the main findings. Older people who were prescribed NSAIDs had a somewhat higher (2-fold) risk of developing AKI, but there was no strong evidence that greater COX-2 selectivity was associated with lower AKI risk. NSAIDs with high COX-2 selectivity (≥5-fold) had a lower association with AKI than NSAIDs with COX-2 selectivity <5-fold, and heterogeneity in the subgroups was reduced compared to the overall results consistent with some of the heterogeneity being due to differences in the age of the population studies and the type of NSAIDs examined. Five studies included individual NSAID usage in their analyses in which only Lafrance and Schneider compared dose effect in Rofecoxib, Celecoxib, Naproxen and Meloxicam (Lafrance only) [9, 32, 34, 35, 37]. Dose response cannot be easily stratified as higher dosage will be associated with a higher risk of effect compared to lower dosage but the exposure window is not under control. However, other differences in population and in AKI definition were substantial and likely accounts for much of the observed heterogeneity. Overall, all analyses showed a statistically significant, modestly increased risk of AKI from exposure to NSAIDs, and the magnitude of the increased risk of AKI was rather similar among all sub-groups with mostly overlapping confidence intervals.

The study strengths include careful study selection and the use of a structured quality assessment tool to ensure that only high quality studies were included [21]. The observed associations were consistent across subgroups, but the study has several limitations. As with all systematic reviews, the findings depend on the quality of the included studies. We chose to review and meta-analyse observational studies because an initial literature search identified that trials of NSAIDs rarely report renal outcomes (the focus of this study) and exclude people with CKD (a key topic of interest) and other comorbidities as well as older people and minority groups [18, 39]. However, observational studies are vulnerable to residual confounding by measured and unmeasured variables. An example is confounding by indication, which in this context is likely to occur if prescribers avoid NSAIDs in people they perceive to be at higher risk of NSAID toxicity including AKI, which would lead to an underestimation of AKI risk if present. There were also large differences between studies in the population examined and the way in which AKI was measured, both of which likely contributed to the observed moderate to large heterogeneity between studies. It is also important to recognise that the estimate of the risk of NSAIDs in the general population is adjusted for potential confounders, but the estimate in people with CKD is not because only one study reported an adjusted estimate [33]. Other limitations include that we only included studies published in English, that there were a relatively small number of studies suitable for inclusion which made meta-regression to explore heterogeneity unfeasible, and that the rate of concomitant use of OTC NSAID use could not be assessed in the populations studied. Seven of the included studies [6, 8, 31, 32, 34, 35, 37] addressed that OCT NSAID use may have caused exposure misclassification. But all of the studies believed that due to reasons such as financial incentives, the proportion of OCT NSAID users is expected to be small and nondifferential with respect to the NSAID categories the populations studied. Consequently, it would bias the results toward the null. As most of the studies confirmed eligible cases then selected controls according to a certain proportion, non-response rate was not given in the majority of the included studies. Since cases and controls of these studies were derived from the same databases, were examined for the same exposure and followed up in the same way, then non-response rate is not considered to be a problem and therefore it is unlikely there would be missing data bias. We were unable to access publication bias because of the extensive statistical heterogeneity. For many of the methodological qualities assessed there was an unclear risk of bias as studies did not provide explicit detail to make an informed judgement.

To our knowledge, this study is the first meta-analysis to examine associations between NSAID exposure and AKI in the general community-dwelling population and people with CKD. A previous systematic review which was conducted in 2014 included five observational studies and reported risk of AKI by individual NSAID exposure, finding a statistically significant elevated AKI risk among most of the traditional NSAIDs but did not achieve a statistical significance for COX-2 inhibitors or traditional NSAIDs with higher COX-2 selectivity (meloxicam and diclofenac) [40]. Our study used a more comprehensive search and included additional studies, and found a similar estimate of pooled risk but statistically significantly increased risk irrespective of COX-2 selectivity. Another systematic review specifically focused on myocardial, vascular and renal risks of COX-2-selective meloxicam allowed a broad definition of renal outcomes and it did not find a significantly increased renal risk [41]. A third systematic review examined the risk of CKD progression associated with NSAID use, finding that high (but not standard) dose NSAID use was associated with an increased risk of CKD progression [42].