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Designing acute kidney injury clinical trials

Nature Reviews Nephrology volume 20, pages 137–146 (2024)Cite this article

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Abstract

Acute kidney injury (AKI) is a common clinical condition with various causes and is associated with increased mortality. Despite advances in supportive care, AKI increases not only the risk of premature death compared with the general population but also the risk of developing chronic kidney disease and progressing towards kidney failure. Currently, no specific therapy exists for preventing or treating AKI other than mitigating further injury and supportive care. To address this unmet need, novel therapeutic interventions targeting the underlying pathophysiology must be developed. New and well-designed clinical trials with appropriate end points must be subsequently designed and implemented to test the efficacy of such new interventions. Herein, we discuss predictive and prognostic enrichment strategies for patient selection, as well as primary and secondary end points that can be used in different clinical trial designs (specifically, prevention and treatment trials) to evaluate novel interventions and improve the outcomes of patients at a high risk of AKI or with established AKI.

Key points

  • Acute kidney injury (AKI) is a very heterogeneous syndrome; therefore, enrichment strategies are required to reduce heterogeneity within the study patient cohort and to reduce sample size. Several factors, including risk scores, biomarkers and clinical features, can be used for prognostic and predictive enrichment.

  • Careful selection of end points is crucial for any trial. Different end points are required for phase II and phase III trials, and for prevention, attenuation and treatment trials.

  • The occurrence of AKI is a key end point in prevention or attenuation trials and is mainly assessed based on current AKI definitions (based on serum creatinine and urine output) but biomarkers can be used as surrogate end points in phase II trials.

  • Major adverse kidney events cannot be used in prevention trials, but different components in this composite end point should always be reported when used in treatment trials.

  • The trajectory of AKI is an important outcome in intervention trials, because clinical measures or drugs might influence the course of AKI and subsequently influence the mortality rate.

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Fig. 1: General consideration of designing a trial.
Fig. 2: Overview of the timing of the intervention, patient population and relevant outcomes.

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Acknowledgements

A.Z. received funding from the German Research Foundation (KFO 342/2, ZA428/18-2, and ZA428/21-1 to A.Z.).

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Authors and Affiliations

  1. Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, Münster, Germany

    Alexander Zarbock

  2. Outcomes Research Consortium, Cleveland, OH, USA

    Alexander Zarbock

  3. Department of Critical Care, Royal Surrey Hospital Foundation Trust, Guildford, UK

    Lui G. Forni

  4. School of Medicine, Faculty of Health Sciences, University of Surrey, Guildford, UK

    Lui G. Forni

  5. Department of Intensive Care, King’s College London, Guy’s & St Thomas’ Hospital, London, UK

    Marlies Ostermann

  6. Department of Medicine, University of Padova, Padua, Italy

    Claudio Ronco

  7. International Renal Research Institute of Vicenza, Vicenza, Italy

    Claudio Ronco

  8. Department of Nephrology, San Bortolo Hospital, Vicenza, Italy

    Claudio Ronco

  9. Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton, Alberta, Canada

    Sean M. Bagshaw

  10. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Ravindra L. Mehta

  11. Department of Critical Care, University of Melbourne, Parkville, Victoria, Australia

    Rinaldo Bellomo

  12. Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia

    Rinaldo Bellomo

  13. Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia

    Rinaldo Bellomo

  14. Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Rinaldo Bellomo

  15. The Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    John A. Kellum

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Contributions

A.Z., L.G.F., R.B. and J.A.K. designed and conceptualized the review. All authors contributed to writing of the manuscript and reviewed and/or edited the manuscript before submission.

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Correspondence to Alexander Zarbock.

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Competing interests

A.Z. has received consulting fees from Astute-bioMérieux, Baxter, Bayer, Novartis, Guard Therapeutics, AM Pharma, Paion, Fresenius, research funding from Astute-bioMérieux, Fresenius, Baxter, and speakers fees from Astute-bioMérieux, Fresenius, Baxter; L.G.F. has received research support and lecture fees from Ortho Clinical Diagnostics, Baxter, Exthera and bioMérieux and consulting fees from La Jolla Pharmaceuticals and Paion; M.O. received research funding from Baxter, Fresenius Medical, bioMérieux and La Jolla Pharma. She also received speaker honoraria from Baxter, Fresenius Medical, bioMérieux and Gilead, which was used for research purposes in the institution; C.R. has been on the advisory boards or speaker’s bureau for Asahi, Aferetica, Baxter, bioMérieux, Cytosorbents, B. Braun, GE, Medica, Medtronic, Jafron and AstraZeneca; S.M.B. is a scientific adviser for Baxter, BioPorto, Novartis, exerts clinical adjudication for BioPorto, is on the DSMB of the I-SPY-COVID trial, and is supported by a Canada Research Chair in Critical Care Outcomes and Systems Evaluation; R.L.M. has consulting/advisory relationships with Baxter, AM Pharma, bioMérieux, Intercept, Mallinckrodt, GE Healthcare; Medtronic, CHF Solutions, Sphingotec, Abiomed, Nova Biomed, Sanofi, Renasym, Alexion, Fresenius, Abbott and Renibus; R.B. has received grant money, speaker’s fees, and advisory board fees from Baxter Acute Care, Jafron Biomedical, CSL Behring, AM Pharma and Paion; J.A.K. has received grant support and consulting fees from Astute Medical and Alere, unrelated to the current study.

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Nature Reviews Nephrology thanks S. Gaudry, C. Parikh, S. Vaara, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Endotype

An endotype is a subtype of a condition, which is defined by a distinct pathobiological or functional mechanism. Patients with a specific endotype present within phenotypic clusters of diseases.

Phenotype

A phenotype is an observable characteristic or trait of a disease, such as physiological or biochemical properties, without any implication of a mechanism. A clinical phenotype is the presentation of a disease in a given individual.

Win ratio

The win ratio is a new method for examining composite end points that accounts for the relative priorities of its components and allows the components to be different types of outcomes.

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Zarbock, A., Forni, L.G., Ostermann, M. et al. Designing acute kidney injury clinical trials. Nat Rev Nephrol 20, 137–146 (2024). https://doi.org/10.1038/s41581-023-00758-1

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