A randomized controlled pilot trial of anakinra for hemodialysis inflammation

Laura M. Dember, Renal, Electrolyte and Hypertension Division, Department of Medicine, Department of Biostatistics, Epidemiology and Informatics, and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Adriana Hung, Division of Nephrology and Hypertension, Department of Medicine, and Vanderbilt Center for Kidney Disease, Vanderbilt University Medical Center and VA Tennessee Valley Healthcare System, Nashville, TN.
Rajnish Mehrotra, Kidney Research Institute and Harborview Medical Center, Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA.
Jesse Y. Hsu, Department of Biostatistics, Epidemiology and Informatics, and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Dominic S. Raj, Division of Renal Diseases and Hypertension, George Washington University School of Medicine, Washington, DC.
David M. Charytan, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
Finnian R. Mc Causland, Renal Division, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA.
Renu Regunathan-Shenk, Division of Renal Diseases and Hypertension, George Washington University School of Medicine, Washington, DC.
J Richard Landis, Department of Biostatistics, Epidemiology and Informatics, and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, Philadelphia, PA.
Paul L. Kimmel, National Institute of Diabetes Digestive and Kidney Diseases Bethesda, MD.
Alan S. Kliger, Department of Medicine, Yale School of Medicine and Yale New Haven Health System, New Haven, CT.
Jonathan Himmelfarb, Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA. Electronic address: himmej@uw.edu.
T Alp Ikizler, Division of Nephrology and Hypertension, Department of Medicine, and Vanderbilt Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, TN. Electronic address: alp.ikizler@vumc.org.

Document Type

Journal Article

Publication Date

7-19-2022

Journal

Kidney international

DOI

10.1016/j.kint.2022.06.022

Keywords

C-reactive protein; IL-1; IL-6; IL-I receptor antagonist; end-stage kidney disease; inflammation

Abstract

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included change in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant; 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients.

Department

Medicine

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