Heterogeneity in the definition of major adverse kidney events: a scoping review

Abstract

Acute kidney injury (AKI) is associated with persistent renal dysfunction, the receipt of dialysis, dialysis dependence, and mortality. Accordingly, the concept of major adverse kidney events (MAKE) has been adopted as an endpoint for assessing the impact of AKI. However, applied criteria or observation periods for operationalizing MAKE appear to vary across studies. To evaluate this heterogeneity for MAKE evaluation, we performed a systematic scoping review of studies that employed MAKE as an AKI endpoint. Four major academic databases were searched, and we identified 122 studies with increasing numbers over time. We found marked heterogeneity in applied criteria and observation periods for MAKE across these studies, with some even lacking a description of criteria. Moreover, 13 different observation periods were employed, with 30 days and 90 days as the most common. Persistent renal dysfunction was evaluated by estimated glomerular filtration rate (34%) or serum creatinine concentration (48%); however, 37 different definitions for this component were employed in terms of parameters, cut-off criteria, and assessment periods. The definition for the dialysis component also showed significant heterogeneity regarding assessment periods and duration of dialysis requirement (chronic vs temporary). Finally, MAKE rates could vary by 7% [interquartile range: 1.7-16.7%] with different observation periods or by 36.4% with different dialysis component definitions. Our findings revealed marked heterogeneity in MAKE definitions, particularly regarding component assessment and observation periods. Dedicated discussion is needed to establish uniform and acceptable standards to operationalize MAKE in terms of selection and applied criteria of components, observation period, and reporting criteria for future trials on AKI and related conditions.

Keywords: Acute kidney injury; Composite endpoint; Dialysis dependence; Major adverse kidney events.

Fig. 1

Flow chart showing the selection process. MAKE major adverse kidney events

Fig. 2

Number of articles using MAKE as endpoints. This bar histogram shows the annual number of articles using MAKE as an endpoint from each year, with bars representing the number of articles and colored by study design. Data are presented from full calendar years except 2023, which includes articles through November 3rd. Cluster randomized controlled trials are included under Randomized controlled trials and crossover trials are included under Prospective cohort studies

Fig. 3

Variation in observation periods for MAKE evaluation according to study type. This bar plot describes the variation in observation periods in articles that used single period evaluation. MAKE major adverse kidney events, RCT randomized controlled trial

Fig. 4

Variation in the criteria used to describe persistent renal dysfunction in MAKE. This bar chart illustrates the criteria used to describe the persistent renal dysfunction component of MAKE. AKI acute kidney injury, eGFR estimated glomerular filtration rate, MAKE major adverse kidney events

Fig. 5

Variation in definitions for dialysis component. This alluvial plot illustrates the heterogeneity in the criteria and assessment window applied to evaluate the dialysis component of MAKE across study publications. Each flow represents publications applying a criterion for dialysis component in terms of RRT modality and assessment window, with flow color indicating the observation period for MAKE evaluation and flow width representing the number of publications. Publications evaluating MAKE at multiple observation periods are represented repeatedly in the plot, comprising 122 publications with 146 observation periods. MAKE definitions varied substantially across studies. Articles with observation periods of ≤ 30 days more often applied a criterion for this component as any use of RRT at any time until the study endpoint (66.7%) rather than chronic dialysis or RRT dependence at the endpoint (14.6%). In contrast, for articles with > 30 days observation periods or employing Time-to-MAKE analyses, a higher proportion used criteria of chronic dialysis or RRT dependence at the final assessment endpoint (44.4% and 60.0%, respectively) rather than any RRT until that endpoint (33.3% and 10.0%). Additionally, 10.7% of articles did not describe the RRT modality and 18.9% did not describe the assessment window. One article employed combined criteria of chronic and temporary dialysis that could not be distinctly classified within the categories shown, and was thus excluded from this visualization. ICU intensive care unit, MAKE major adverse kidney events, RRT renal replacement therapy