AKI—A Relevant Safety End Point?

Abstract

Acute kidney injury (AKI) is a common outcome evaluated in clinical studies, often as a safety end point in a variety of cardiovascular, kidney disease, and other clinical trials. AKI end points that include modest increases in serum creatinine levels from baseline may not associate with patient-centered outcomes such as initiation of dialysis, sustained decline in kidney function, or death. Surprisingly, data from several randomized controlled trials have suggested that in certain settings, the development of AKI may be associated with favorable outcomes. AKI safety end points that are nonspecific and may not associate with patient-centered outcomes could result in beneficial therapies being inappropriately withheld or never developed for commercial use. We review several issues related to commonly used AKI definitions and suggest that future work in AKI use more patient-centered AKI end points such as major adverse kidney events at 30 days or other later time points.

Optimizing the Design and Analysis of Future AKI Trials

“…Here, we offer a few summary comments. First, although AKI diagnosis on the basis of changes in serum creatinine may not be ideal in some settings, it may be a reasonable choice as a key safety end point or an exploratory secondary end point (giving an indication of the mechanistic aspects of an intervention), such as in the RELIEF trial 38 , 39 . Patient-centered outcomes, like all-cause mortality, require a robust effect size and a large sample size because of the low proportion of mortality that can be attributed directly to AKI.…”

Overcoming barriers in the design and implementation of clinical trials for acute kidney injury: a report from the 2020 Kidney Disease Clinical Trialists meeting

“…This raises important questions regarding the selection of clinical endpoints (See "Optimizing Outcome Selection" section below). Endpoints like all-cause mortality are of particular importance when there is improved survival despite impaired renal function, as has been observed in the setting of heart failure (15). While AKI may be a suitable endpoint for safety analysis or preventive studies, it does not represent a patient-centered outcome (PCO) and may even be dissociated from important PCOs like survival in patients with established AKI.…”

Changing the Trajectory of Heart Failure and Kidney Disease

“…Additionally, the inappropriate use of terms, such as "AKI," to describe the functional decrease in eGFR due to therapeutic hemodynamic changes creates fear of harm, especially with the concomitant use of therapies such as renin-angiotensin system inhibitors, SGLT2i, and MRAs. To this end, improving affordability and access to SGLT2i with joint lobbying across specialty organizations and guidance from specialty societies on specific terminology to differentiate true kidney injury from benign fluctuations in kidney biomarkers, such as serum creatinine or cystatin C, would go far in effectively implementing these agents (10). Finally, educating patients and their caregivers about the benefits of SGLT2i that are incurred even within weeks of initiation is key to promoting adherence while actively engaging in strategies to reduce polypharmacy and deprescribing less effective agents.…”