  Citation: Puengel, T.; Weber, B.; Wirtz, T.H.; Buendgens, L.; Loosen, S.H.; Geisler, L.; Özdirik, B.; Hamesch, K.; Jhaisha, S.A.; Brozat, J.F.; et al. Low Serum Levels of Soluble Receptor Activator of Nuclear Factor κ B Ligand (sRANKL) Are Associated with Metabolic Dysregulation and Predict Long-Term Mortality in Critically Ill Patients. Diagnostics 2022, 12, 62. https://doi.org/10.3390/ diagnostics12010062 Academic Editor: Timothy E. Sweeney Received: 7 November 2021 Accepted: 23 December 2021 Published: 28 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). diagnostics Article Low Serum Levels of Soluble Receptor Activator of Nuclear Factor κ B Ligand (sRANKL) Are Associated with Metabolic Dysregulation and Predict Long-Term Mortality in Critically Ill Patients Tobias Puengel 1,2, * , Beate Weber 2 , Theresa H. Wirtz 2 , Lukas Buendgens 2 , Sven H. Loosen 3 , Lukas Geisler 1 , Burcin Özdirik 1 , Karim Hamesch 2 , Samira Abu Jhaisha 2 , Jonathan F. Brozat 2 , Philipp Hohlstein 2 , Albrecht Eisert 4,5 , Eray Yagmur 6 , Christian Trautwein 2 , Frank Tacke 1 and Alexander Koch 2 1 Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Lukas.geisler@charite.de (L.G.); burcin.oezdirik@charite.de (B.Ö.); frank.tacke@charite.de (F.T.) 2 Department of Medicine III, RWTH-University Hospital Aachen, 52074 Aachen, Germany; beate.weber@rwth-aachen.de (B.W.); thwirtz@ukaachen.de (T.H.W.); lbuendgens@ukaachen.de (L.B.); khamesch@ukaachen.de (K.H.); sabujhaisha@ukaachen.de (S.A.J.); jbrozat@ukaachen.de (J.F.B.); phohlstein@ukaachen.de (P.H.); ctrautwein@ukaachen.de (C.T.); akoch@ukaachen.de (A.K.) 3 Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; Sven.Loosen@med.uni-duesseldorf.de 4 Hospital Pharmacy, RWTH-University Hospital Aachen, 52074 Aachen, Germany; aeisert@ukaachen.de 5 Institute of Clinical Pharmacology, RWTH-University Hospital Aachen, 52074 Aachen, Germany 6 Institute of Laboratory Medicine, Western Palatinate Hospital, 67655 Kaiserslautern, Germany; eyagmur@westpfalz-klinikum.de * Correspondence: tobias.puengel@charite.de Abstract: Soluble receptor activator of nuclear factor κ B ligand (sRANKL) is a member of the tumor necrosis factor receptor superfamily, and therefore, involved in various inflammatory processes. The role of sRANKL in the course of bone remodeling via activation of osteoclasts as well as chronic disease progression has been described extensively. However, the potential functional importance of sRANKL in critically ill or septic patients remained unknown. Therefore, we measured sRANKL serum concentrations in 303 critically ill patients, including 203 patients with sepsis and 100 with non-sepsis critical illness. Results were compared to 99 healthy controls. Strikingly, in critically ill patients sRANKL serum levels were significantly decreased at intensive care unit (ICU) admission (p = 0.011) without differences between sepsis and non-sepsis patients. Inline, sRANKL was corre- lated with markers of metabolic dysregulation, such as pre-existing diabetes and various adipokines (e.g., adiponectin, leptin receptor). Importantly, overall mortality of critically ill patients in a three- year follow-up was significantly associated with decreased sRANKL serum concentrations at ICU admission (p = 0.038). Therefore, our study suggests sRANKL as a biomarker in critically ill patients which is associated with poor prognosis and overall survival beyond ICU stay. Keywords: soluble receptor activator of nuclear factor κ B ligand (sRANKL); intensive care unit (ICU); critical illness; diabetes; glucose metabolism; adipokine; sepsis; inflammation; prognosis 1. Introduction Among critically ill patients sepsis and septic shock still represent the most common cause of death, due to multiple organ failures as a result of dysregulated immune responses to an infection [1]. Despite great advances in therapy for critically ill patients early di- agnosis and risk evaluation remain difficult but tremendously crucial for stratification according to prognosis and adequate management [2,3]. Therefore, biomarkers may ease Diagnostics 2022, 12, 62. https://doi.org/10.3390/diagnostics12010062 https://www.mdpi.com/journal/diagnostics