Major adverse kidney events as an endpoint in acute kidney injury trials: is it time for a RE-MAKE?

A scoping review of the criteria used for major acute kidney events (MAKE) by Maeda and colleagues, published in Intensive Care Medicine highlights the need for a “RE-MAKE” [1]. The composite outcome of death, dialysis, and worsened kidney function, MAKE, was first introduced into the literature 13 years ago [2]. MAKE endpoint utilization in clinical research is growing, with a current PubMed search revealing over 350 investigations in the last 5 years. Maeda et al. show that significant heterogeneity exists when and how its components are applied across studies [1]. Notably, although the constituents of MAKE align with patient-centered principles, they do not differentiate the relative clinical significance of each component. As we now recognize the crucial role of including the perspectives of persons with lived experiences (PWLE) in defining endpoints in acute kidney injury (AKI) trials [3], we propose re-evaluating how we operationalize MAKE with two adaptions.

The use of hierarchical composite endpoints (HCE), based on the concept of a “win ratio” (WR), allows for the assessment of individual events based on clinical relevance and importance to PWLE. We suggest that the WR method prioritizes clinical components of MAKE and evaluates events in pre-specified order of importance, comparing patients in the intervention group with those in the control group [4]. While it is attractive to have one clearly defined composite outcome for AKI trials, it may be that different combinations of hierarchical endpoints may be advantageous which warrants future exploration.

We propose an alternative four-component MAKE employing the WR method, termed RE-MAKE, including in suggested order of importance to PWLE: (1) death, (2) AKI, (3) non-recovery from AKI, including dialysis dependency, and (4) slope of glomerular filtration rate (GFR). Importantly, applicable to preventative studies, severe AKI (stages 2 or 3, including receipt of acute renal replacement therapy) was not included with the original MAKE components. After 13 years of studies since the introduction of MAKE, the evidence has grown, supporting the association of severe AKI with significant morbidity and its inclusion in a composite outcome of kidney health. Strikingly, Maeda et al. revealed 37 definitions of “persistent renal dysfunction” across 122 studies [1]. Growing evidence shows that the GFR slope is a strong surrogate endpoint for kidney disease progression, primarily in the setting of chronic kidney disease. It may be an alternative endpoint to persistent renal dysfunction. We suggest that future investigations validate and explore the use of GFR slope in the setting of acute changes in GFR using methods, such as a two-slope mixed-effects model [5].

The proposed RE-MAKE framework, with its prioritized components, aims to provide a more comprehensive and meaningful measure of AKI endpoints, addressing the evolving understanding of kidney health outcomes. Importantly, there is a crucial need for prospective validation of our proposed RE-MAKE, including establishing an optimal time span for defining renal recovery. Of paramount importance is inclusion of PWLE in all aspects of the design and implementation of studies assessing AKI endpoints. This refined approach promises to improve the precision of clinical research and ensures that the outcomes measured truly reflect patient priorities.

Data availability

A data availability statement is not applicable as no data was used for this correspondence.

Declarations

Conflicts of interest

SMB has received fees for scientific advisory from Baxter, bioMerieux, BioPorto, Novartis, Sea Star Medical, SphingoTec.; SLG has received grant support from BioPorto Diagnostics, Baxter, NuWellis, ExThera Medical, SeaStar Medical, Roche, Otsuka and consulting fees from BioPorto Diagnostics, Baxter, NuWellis, SeaStar Medical, Talphera, Otsuka, Calcimedica, Fresenius. He has ownership interest in MediBeacon Inc. and receives licensing revenues from RAIDAR Health; the remaining authors declare no potential competing interests.