Review

. 2024 Mar 21;28(1):92.

doi: 10.1186/s13054-024-04877-4.

Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials

Matthieu Legrand¹, Sean M Bagshaw², Pavan K Bhatraju^{3

4}, Azra Bihorac^{5

6}, Ellen Caniglia⁷, Ashish K Khanna^{8

9

10}, John A Kellum¹¹, Jay Koyner¹², Michael O Harhay¹³, Fernando G Zampieri², Alexander Zarbock¹⁴, Kevin Chung¹⁵, Kathleen Liu¹⁶, Ravindra Mehta¹⁷, Peter Pickkers¹⁸, Abigail Ryan¹⁹, Juliane Bernholz²⁰, Laura Dember²¹, Martin Gallagher²², Patrick Rossignol^{23

24

25}, Marlies Ostermann²⁶

Affiliations

¹ Division of Critical Care Medicine, Department of Anesthesia and Perioperative Care, UCSF, 521 Parnassus Avenue, San Francisco, CA, 94143, USA. Matthieu.Legrand@ucsf.edu.
² Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton, Canada.
³ Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, USA.
⁴ Kidney Research Institute, University of Washington, Seattle, USA.
⁵ Department of Medicine, University of Florida, Gainesville, FL, USA.
⁶ Intelligent Critical Care Center (IC3), University of Florida, Gainesville, FL, USA.
⁷ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
⁸ Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁹ Outcomes Research Consortium, Cleveland, OH, USA.
¹⁰ Perioperative Outcomes and Informatics Collaborative, Winston-Salem, NC, USA.
¹¹ Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
¹² University Section of Nephrology, Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
¹³ Clinical Trials Methods and Outcomes Lab, Department of Biostatistics, Epidemiology, and Informatics, PAIR (Palliative and Advanced Illness Research) Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Hospital Münster, Münster, Germany.
¹⁵ SeaStar Medical, Denver, CO, USA.
¹⁶ Divisions of Nephrology and Critical Care Medicine, Departments of Medicine and Anesthesia, University of California San Francisco, San Francisco, CA, USA.
¹⁷ Department of Medicine, University of California, San Diego, USA.
¹⁸ Intensive Care Medicine, Radboudumc, Nijmegen, The Netherlands.
¹⁹ Chronic Care Policy Group, Division of Chronic Care Management, Center for Medicare and Medicaid Services, Center for Medicare, Baltimore, MD, USA.
²⁰ AM-Pharma, Stadsplateau 6, 3521 AZ, Utrecht, The Netherlands.
²¹ Renal-Electrolyte and Hypertension Division, Department of Medicine, Department of Biostatistics, Epidemiology and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²² The George Institute for Global Health, University of New South Wales, Sydney, Australia.
²³ FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
²⁴ INSERM CIC-P 1433, CHRU de Nancy, INSERM U1116, Université de Lorraine, Nancy, France.
²⁵ Medicine and Nephrology-Hemodialysis Departments, Monaco Private Hemodialysis Centre, Princess Grace Hospital, Monaco, Monaco.
²⁶ Department of Critical Care, King's College London, Guy's & St Thomas' Hospital, London, UK.

PMID: 38515121
PMCID: PMC10958912
DOI: 10.1186/s13054-024-04877-4

Review

Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials

Matthieu Legrand et al. Crit Care. 2024.

. 2024 Mar 21;28(1):92.

doi: 10.1186/s13054-024-04877-4.

Authors

Affiliations

¹ Division of Critical Care Medicine, Department of Anesthesia and Perioperative Care, UCSF, 521 Parnassus Avenue, San Francisco, CA, 94143, USA. Matthieu.Legrand@ucsf.edu.
² Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton, Canada.
³ Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, USA.
⁴ Kidney Research Institute, University of Washington, Seattle, USA.
⁵ Department of Medicine, University of Florida, Gainesville, FL, USA.
⁶ Intelligent Critical Care Center (IC3), University of Florida, Gainesville, FL, USA.
⁷ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
⁸ Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁹ Outcomes Research Consortium, Cleveland, OH, USA.
¹⁰ Perioperative Outcomes and Informatics Collaborative, Winston-Salem, NC, USA.
¹¹ Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
¹² University Section of Nephrology, Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
¹³ Clinical Trials Methods and Outcomes Lab, Department of Biostatistics, Epidemiology, and Informatics, PAIR (Palliative and Advanced Illness Research) Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Hospital Münster, Münster, Germany.
¹⁵ SeaStar Medical, Denver, CO, USA.
¹⁶ Divisions of Nephrology and Critical Care Medicine, Departments of Medicine and Anesthesia, University of California San Francisco, San Francisco, CA, USA.
¹⁷ Department of Medicine, University of California, San Diego, USA.
¹⁸ Intensive Care Medicine, Radboudumc, Nijmegen, The Netherlands.
¹⁹ Chronic Care Policy Group, Division of Chronic Care Management, Center for Medicare and Medicaid Services, Center for Medicare, Baltimore, MD, USA.
²⁰ AM-Pharma, Stadsplateau 6, 3521 AZ, Utrecht, The Netherlands.
²¹ Renal-Electrolyte and Hypertension Division, Department of Medicine, Department of Biostatistics, Epidemiology and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²² The George Institute for Global Health, University of New South Wales, Sydney, Australia.
²³ FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
²⁴ INSERM CIC-P 1433, CHRU de Nancy, INSERM U1116, Université de Lorraine, Nancy, France.
²⁵ Medicine and Nephrology-Hemodialysis Departments, Monaco Private Hemodialysis Centre, Princess Grace Hospital, Monaco, Monaco.
²⁶ Department of Critical Care, King's College London, Guy's & St Thomas' Hospital, London, UK.

PMID: 38515121
PMCID: PMC10958912
DOI: 10.1186/s13054-024-04877-4

Abstract

Acute kidney injury (AKI) often complicates sepsis and is associated with high morbidity and mortality. In recent years, several important clinical trials have improved our understanding of sepsis-associated AKI (SA-AKI) and impacted clinical care. Advances in sub-phenotyping of sepsis and AKI and clinical trial design offer unprecedented opportunities to fill gaps in knowledge and generate better evidence for improving the outcome of critically ill patients with SA-AKI. In this manuscript, we review the recent literature of clinical trials in sepsis with focus on studies that explore SA-AKI as a primary or secondary outcome. We discuss lessons learned and potential opportunities to improve the design of clinical trials and generate actionable evidence in future research. We specifically discuss the role of enrichment strategies to target populations that are most likely to derive benefit and the importance of patient-centered clinical trial endpoints and appropriate trial designs with the aim to provide guidance in designing future trials.

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Conflict of interest statement

SMB has received fees for scientific advisory from Baxter, BioMerieux, BioPorto, Novartis, Sea Star Medical, SphingoTec. SMB is an editor of the journal. RM has received fees for scientific advisory from Baxter, AM Pharma, BioMerieux, Mallinckrodt, GE Healthcare; Sanofi; Abiomed; NovaBiomed; Novartis; Renasym; Fresenius; and Guard and had received grant support from Fresenius; Fresenius-Kabi. AZ has received fees for scientific advisory from Baxter, SphingoTec, BioMerieux, AM Pharma, Guard Therapeutics, Bayer, Novartis, Renibus, Paion and has received grant support from Fresenius, Baxter and BioMerieux. MO has been awarded research funding from Baxter, BioMerieux, Fresenius Medical and LaJolla Pharma. The funding was received by the institution. LD has received compensation from the National Kidney Foundation for her role as Deputy Editor of the American Journal of Kidney Diseases, consulting fees from AstraZeneca, Cara Therapeutics, and Merck, and compensation for serving on Data and Safety Monitoring Boards for the National Institute of Diabetes and Digestive and Kidney Diseases, and Data Monitoring Committees for CSL Behring and Vertex Pharmaceuticals. JAK is a full-time employee of Spectral Medical and has received consulting fees and grant support from BioMerieux/Astute Medical. KC is an employee of SeaStar Medical. IHS contributed to this manuscript in her personal capacity. The opinions expressed in this paper do not necessarily reflect those of the National Institute of Diabetes, Digestive and Kidney Diseases, the National Institutes of Health, the Department of Health and Human Services, and the government of the USA.

Figures

**Fig. 1**
Areas identified as potential candidates to improve sepsis-associated AKI outcomes and to be considered as priorities for testing in clinical trials

**Fig. 2**
Visual representation of sub-phenotypes (classifying patients based on clinical and physiological characteristics), endotypes (classifying patients based on mechanistic pathways underlying the phenotypes) and treatable traits that would lead to targeted therapies to be tested in randomized trials. Of note, overlap can exist between different phenotypes, endotypes and treatable traits

**Fig. 3**
Visual representation of key outcomes to be considered in clinical trials investigating interventions in sepsis-associated AKI

**Fig. 4**
Critical features of an intervention under investigation when designing a more pragmatic or exploratory trial. More pragmatic trials enroll a broader population and tend to increase the generalizability of the trial while more exploratory trials enroll enriched population, at the cost of lower generalizability

See this image and copyright information in PMC

References

1. Schulman IH, Chan K, Der JS, et al. Readmission and mortality after hospitalization with acute kidney injury. Am J Kidney Dis. 2023;S0272–6386(23):00067–77. doi: 10.1053/j.ajkd.2022.12.008. - DOI - PMC - PubMed
1. Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe investigators. Intensive Care Med. 2015;41:1549–1560. doi: 10.1007/s00134-015-3822-1. - DOI - PubMed
1. Kellum JA, Chawla LS, Keener C, et al. The effects of alternative resuscitation strategies on acute kidney injury in patients with septic shock. Am J Respir Crit Care Med. 2016;193:281–287. doi: 10.1164/rccm.201505-0995OC. - DOI - PMC - PubMed
1. Legrand M, Rossignol P. Cardiovascular consequences of acute kidney injury. N Engl J Med. 2020;382:2238–2247. doi: 10.1056/NEJMra1916393. - DOI - PubMed
1. Chawla LS, Bellomo R, Bihorac A, et al. Acute kidney disease and renal recovery: consensus report of the acute disease quality initiative (ADQI) 16 workgroup. Nat Rev Nephrol. 2017;13:241–257. doi: 10.1038/nrneph.2017.2. - DOI - PubMed

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Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials

Affiliations

Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous