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,Frank Tacke,Albrecht Eisert,Philipp Hohlstein,Karim Hamesch,Samira Jhaisha,Jonathan Brozat,Beate Weber,Theresa Wirtz,Sven Loosen,Burcin Özdirik,Alexander Koch,Lukas Geisler,Eray Yagmur,Christian Trautwein,Lukas Buendgens

doi:10.3390/diagnostics12010062

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 correlated 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.

Highlights

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]
We demonstrate that sRANKL plasma concentrations were significantly reduced in critically ill patients at intensive care unit (ICU) admission
A potential explanation of this outcome prediction might be associated with the fact that sRANKL serum levels correlated with various growth factors and adipokines in our patient cohort

Summary

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]. Major intracellular downstream targets of RANK are nuclear factor κ B (NF-κB) and c-Jun N-terminal kinases (JNK), key regulators of inflammatory processes, antiviral responses and apoptosis [7]. Recent studies highlighted the relevance and described the potential roles of various growth factors and adipokines (e.g., Adiponectin, Leptin, Omentin and Resistin) in the course of critical illness and sepsis [14]. SRANKL and its downstream targets are key regulators of a great spectrum of inflammatory responses, immune reactions and metabolic-related disorders, and potentially linked to critical illness. The relevance of sRANKL in critically ill and septic patients has not been reported to date and the functional role remains uncertain. We investigated the clinical and diagnostic relevance of sRANKL serum concentrations as a potential biomarker in a large cohort of 303 critically ill patients

Study Design

Statistical Analysis

Findings

Discussion