Clinical Trial Endpoints in Acute Kidney Injury

Abstract

The development and use of consensus criteria for acute kidney injury (AKI) diagnosis and the inclusion of recently identified markers of renal parenchymal damage as endpoints in clinical trials have improved the ability of physicians to compare the incidence and severity of AKI across patient populations, provided targets for testing new treatments, and may increase insight into the mechanisms of AKI. To date, these markers have not consistently translated into important clinical outcomes. Is that because these markers of renal injury/dysfunction are measurements of process of care (and not indicative of persistently impaired renal function), or is it because patients do actually recover from AKI? Physicians currently have limited ability to measure renal function reserve, and the ultimate consequence of a case of AKI on long-term morbidity remains unclear. There is little doubt that groups of patients who develop AKI have worse outcomes than groups of patients who do not, but investigators are now realizing the value of measuring clinically meaningful renal endpoints in all subjects enrolled in AKI clinical trials. Important examples of these outcomes include persistently impaired renal function, new hemodialysis, and death. We propose that these major adverse kidney events (MAKE) be included in all effectiveness clinical trials. Adaptation of the MAKE composite assessed 30, 60, or 90 days following AKI (i.e., MAKE30 or MAKE90) will improve our capacity to understand and treat AKI and may also provide a consensus composite to allow comparison of different interventions. Primary endpoints for phase I and II clinical trials, on the other hand, should continue to use continuous markers of renal injury/dysfunction as well as ‘hard' clinical outcomes in order to generate meaningful data with limited subject exposure to untested treatments. By doing so, investigators may assess safety without requiring large sample sizes, demonstrate treatment effect of an unknown therapeutic, and power subsequent studies. In contrast, phase III trials should include consensus AKI criteria and more important subsequent clinical outcomes, such as MAKE90, as primary endpoints.

Journal

Journal ID (publisher-id): NEC

Journal ID (nlm-ta): Nephron Clin Pract

Journal ID (doi): 10.1159/issn.1660-2110

Title: Nephron Clinical Practice

Publisher: S. Karger AG

ISSN (Electronic): 1660-2110

Publication date Subscription-year: 2014

Publication date (Print): September 2014

Publication date (Electronic): 24 September 2014

Volume: 127

Issue: 1-4

Pages: 89-93

Affiliations

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tenn., USA

Author notes

*Frederic T. Billings IV, MD, MSc, 1211 21st Avenue South, Suite 526, Nashville, TN 37212 (USA)

Article

Publisher ID: 363725 Pmcid ID: PMC4480222 Other ID: Nephron Clin Pract 2014;127:89-93

DOI: 10.1159/000363725

PMC ID: PMC4480222

PubMed ID: 25343828

Copyright statement: © 2014 S. Karger AG, Basel

License:

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Page count

Tables: 1, Pages: 5

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Categories

Subject: Review