Feasibility Assessment of a Biomarker-Guided Kidney-Sparing Sepsis Bundle: The Limiting Acute Kidney Injury Progression In Sepsis Trial

Hernando Gómez; Alexander Zarbock; Stephen M Pastores; Gyorgy Frendl; Sven Bercker; Pierre Asfar; Steven A Conrad; Jaques Creteur; James Miner; Jean Paul Mira; Johan Motsch; Jean-Pierre Quenot; Thomas Rimmelé; Peter Rosenberger; Christophe Vinsonneau; Bob Birch; Fabienne Heskia; Julien Textoris; Luca Molinari; Louis M Guzzi; Claudio Ronco; John A Kellum

doi:10.1097/CCE.0000000000000961

Feasibility Assessment of a Biomarker-Guided Kidney-Sparing Sepsis Bundle: The Limiting Acute Kidney Injury Progression In Sepsis Trial

Crit Care Explor. 2023 Aug 21;5(8):e0961. doi: 10.1097/CCE.0000000000000961. eCollection 2023 Aug.

Authors

Hernando Gómez¹, Alexander Zarbock^{2

3}, Stephen M Pastores⁴, Gyorgy Frendl⁵, Sven Bercker⁶, Pierre Asfar⁷, Steven A Conrad⁸, Jaques Creteur⁹, James Miner¹⁰, Jean Paul Mira¹¹, Johan Motsch¹², Jean-Pierre Quenot^{13

14

15}, Thomas Rimmelé¹⁶, Peter Rosenberger¹⁷, Christophe Vinsonneau¹⁸, Bob Birch¹⁹, Fabienne Heskia²⁰, Julien Textoris^{20

21}, Luca Molinari²², Louis M Guzzi²³, Claudio Ronco²⁴, John A Kellum¹

Affiliations

¹ Program for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.
² Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.
³ Outcomes Research Consortium, Cleveland, OH.
⁴ Department of Anesthesiology and Critical Care Medicine, Critical Care Center, Memorial Sloan Kettering Cancer Center, New York, NY.
⁵ Department of Anesthesiology, Surgical ICU Translational Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
⁶ Department of Anesthesia and Intensive Care Medicine, University Hospital of Leipzig, Leipzig, Germany.
⁷ Medical Intensive Care Department, University Hospital of Angers, Angers, France.
⁸ Departments of Medicine, Emergency Medicine and Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA.
⁹ Department of Intensive Care, Cliniques Universitaires de Bruxelles-Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgique.
¹⁰ Department of Emergency Medicine, Hennepin Health and University of Minnesota, Minneapolis, MN.
¹¹ Medical Intensive Care Unit, Cochin University Hospital, Groupe Hospitalier Paris Centre, AP-HP, Paris Cite University, Paris, France.
¹² Department of Anesthesiology, University Clinics Heidelberg, Heidelberg, Germany.
¹³ Department of Intensive Care, Burgundy University Hospital, Dijon, France.
¹⁴ Lipness Team, INSERM Research Center LNC-UMR1231 and LabEx LipSTIC, University of Burgundy, Dijon, France.
¹⁵ INSERM CIC 1432, Clinical Epidemiology, University of Burgundy, Dijon, France.
¹⁶ Anesthesiology and Intensive Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
¹⁷ Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Hoppe-Seyler-Straße, Tübingen, Germany.
¹⁸ Critical Care Unit, Bethune Hospital, Bethune, France.
¹⁹ US Data Sciences Department, US Data Sciences bioMerieux Inc, Hazelwood, MO.
²⁰ Global Medical Affairs, bioMérieux, Marcy l'Etoile, France.
²¹ Service d'Anesthésie et de Réanimation, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
²² Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
²³ Cardiothoracic and Vascular Intensive Care Medicine, Orlando Regional Medical Center, Orlando, FL.
²⁴ Department of Nephrology, Dialysis and Transplantation, International Renal Research Institute of Vicenza, San Bortolo Hospital, University of Padova, Vicenza, Italy.

Abstract

Objectives: To determine the feasibility, safety, and efficacy of a biomarker-guided implementation of a kidney-sparing sepsis bundle (KSSB) of care in comparison with standard of care (SOC) on clinical outcomes in patients with sepsis.

Design: Adaptive, multicenter, randomized clinical trial.

Setting: Five University Hospitals in Europe and North America.

Patients: Adult patients, admitted to the ICU with an indwelling urinary catheter and diagnosis of sepsis or septic shock, without acute kidney injury (acute kidney injury) stage 2 or 3 or chronic kidney disease.

Interventions: A three-level KSSB based on Kidney Disease: Improving Global Outcomes (KDIGOs) recommendations guided by serial measurements of urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 used as a combined biomarker [TIMP2]•[IGFBP7].

Measurements and main results: The trial was stopped for low enrollment related to the COVID-19 pandemic. Nineteen patients enrolled in five sites over 12 months were randomized to the SOC (n = 8, 42.0%) or intervention (n = 11, 58.0%). The primary outcome was feasibility, and key secondary outcomes were safety and efficacy. Adherence to protocol in patients assigned to the first two levels of KSSB was 15 of 19 (81.8%) and 19 of 19 (100%) but was 1 of 4 (25%) for level 3 KSSB. Serious adverse events were more frequent in the intervention arm (4/11, 36.4%) than in the control arm (1/8, 12.5%), but none were related to study interventions. The secondary efficacy outcome was a composite of death, dialysis, or progression of greater than or equal to 2 stages of acute kidney injury within 72 hours after enrollment and was reached by 3 of 8 (37.5%) patients in the control arm, and 0 of 11 (0%) patients in the intervention arm. In the control arm, two patients experienced progression of acute kidney injury, and one patient died.

Conclusions: Although the COVID-19 pandemic impeded recruitment, the actual implementation of a therapeutic strategy that deploys a KDIGO-based KSSB of care guided by risk stratification using urinary [TIMP2]•[IGFBP7] seems feasible and appears to be safe in patients with sepsis.

Keywords: acute kidney injury; biomarker; cell cycle arrest; sepsis.

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States