Discussion
AKI, death, designStrengths, nephrotoxic
ACUTE INTERSTITIAL NEPHRITIS
This pragmatic, randomized trial of medication-targeted electronic alerts for AKI found that alerts had a significant impact on reducing exposure to the medications of interest, but no significant effect on the primary outcome of progression of AKI, dialysis, or death. However, the alert was associated with clinical benefit among individuals receiving PPI at the time of randomization; PPI-exposed individuals comprised the majority of the study cohort.Prior research into the efficacy of alerting for AKI has shown mixed results. In part, this is due to the variety of study designs employed to evaluate AKI alerts (which range from retrospective before/after analyses, to stepped-wedge designs, to individual-level randomized trials)Several studies show that AKI alerts have substantial promise when executed appropriately. A stepped-wedge trial by Selby et al. showed that AKI alerts coupled to a care bundle and an educational AKI package led to a significantly reduced hospital length of stay, but no change in overall mortalityWe were surprised to see no clinical benefit of alerts in the NSAID subgroup. We targeted this class of medications given the broad consensus and international guidelines that suggest discontinuing NSAIDs in the setting of AKI given their known potent adverse biological effects on kidney healthOur observation that alerts reduced the primary outcome among those treated with PPIs has several potential explanations. Although this was a pre-specified subgroup analysis, there is the possibility that this signal is due to chance. Alternatively, there may be a causal link between PPI-use and AKI which is ameliorated by cessation in the context of alerting. Prior research, predominantly observational, has elucidated associations between PPI and AKI, and particularly acute interstitial nephritisWe were also intrigued to examine the data surrounding the alert targeting those on RAASi. Substantial debate exists about the utility of stopping these agents during AKI. RAASi reduce glomerular hydrostatic pressure and thus GFR which may lead to harm by decreasing clearance of uremic byproductsLimitations of this study include the fact that only three medication classes were targeted. There are many other medications, including aminoglycoside antibiotics, certain types of chemotherapy, and others that are potentially nephrotoxic. However, we designed this trial not only to inform the benefit of alerting for AKI in the setting of medication exposures, but to evaluate the impact of cessation of key often-used medication classes in the setting of AKI. This has allowed us to conduct careful sub-group analyses that suggest that, for example, cessation of PPI may be reasonable among those with AKI. Other limitations include the fact that this trial was randomized at the patient level, which introduces the possibility of contamination, as providers who receive alerts may learn how better to care for AKI patients over time. Alternative designs, such as cluster-randomized or stepped-wedge designs might ameliorate this, but simulation studies have shown that, in the setting of potential contamination, statistical power is maximized through inflation of sample size (as done here) more efficiently than by conversion to a cluster or stepped-wedge designStrengths of this study include its sample size, which was adequate to detect a clinically meaningful impact of alerting, its use of a clinical outcome, focus on agents commonly used in the inpatient setting, randomization, and diverse patient mix.In conclusion, this pragmatic, randomized trial of automated, electronic alerting for individuals with AKI exposed to common kidney-relevant medications suggests that there is unlikely to be broad-based benefit to all patients, but those exposed to PPIs may benefit.