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Background: Adiponectin, an adipokine with anti-inflammatory properties, has been implicated in various liver diseases. This study aimed to elucidate the prognostic value of serum adiponectin levels in critically ill patients with liver disease. Methods: This observational study included 161 critically ill patients admitted to the medical ICU of RWTH Aachen University Hospital due to acute liver failure or decompensated advanced chronic liver disease. Serum adiponectin levels were measured at ICU admission and after 48 h. Clinical parameters and outcomes, including transplant-free survival, were analyzed. Results: Serum adiponectin concentrations were significantly elevated compared to healthy controls (p < 0.001). Levels were particularly high in patients with sepsis compared to those with gastrointestinal bleeding as the precipitating factor of acute decompensation (p = 0.045) and were higher in female patients (p = 0.023). Adiponectin concentrations correlated with the Model of End-Stage Liver Disease (MELD) score and Child–Pugh score. Multivariate analysis confirmed a significant correlation with total bilirubin (r = 0.292, p < 0.001) and serum sodium (r = −0.265, p = 0.028). Higher adiponectin concentrations were associated with a trend towards poorer 30- and 180-day survival. Cox regression analysis identified a significant association between increased adiponectin concentration and reduced transplant-free survival (p = 0.037), supported by a Kaplan–Meier analysis using a cutoff of 119 ng/mL (log-rank 5.145, p = 0.023). Conclusions: Elevated serum adiponectin concentrations are associated with liver dysfunction and poor outcomes in critically ill patients. Higher adiponectin levels at ICU admission may predict poorer transplant-free survival. Further research in larger, multicenter cohorts is warranted to validate these findings and explore the underlying mechanisms.

Differentiation between acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) can be challenging in patients with de novo liver disease but is important to indicate the referral to a transplant center and urgency of organ allocation. Leptin, an adipocyte-derived cytokine that regulates energy storage and satiety, has multiple regulatory functions in the liver. We enrolled 160 critically ill patients with liver disease and 20 healthy individuals to measure serum leptin concentrations as a potential biomarker for diagnostic and prognostic purposes. Notably, patients with ALF had higher concentrations of serum leptin compared to patients with decompensated advanced chronic liver disease (dACLD) or ACLF (110 vs. 50 vs. 29 pg/mL, p < 0.001). Levels of serum leptin below 56 pg/mL excluded ALF in patients with acute hepatic disease, with a negative predictive value (NPV) of 98.8% in our cohort. Lastly, serum leptin did not show any dynamic changes within the first 48 h of ICU treatment, especially not in comparison with patients with ALF vs. ACLF or survivors vs. non-survivors. In conclusion, serum leptin may represent a helpful biomarker to exclude ALF in critically ill patients who present with acute liver dysfunction.

The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and sepsis-associated AKI (SA-AKI). To characterise and compare KIM-1 in these settings, we analysed KIM-1 serum concentrations in 192 critically ill patients admitted to the intensive care unit. Irrespective of kidney dysfunction, KIM-1 serum levels were significantly higher in patients with sepsis compared with other critical illnesses (191.6 vs. 132.2 pg/mL, p = 0.019) and were highest in patients with urogenital sepsis, followed by liver failure. Furthermore, KIM-1 levels were significantly elevated in critically ill patients who developed AKI within 48 h (273.3 vs. 125.8 pg/mL, p = 0.026) or later received renal replacement therapy (RRT) (299.7 vs. 146.3 pg/mL, p < 0.001). KIM-1 correlated with markers of renal function, inflammatory parameters, hematopoietic function, and cholangiocellular injury. Among subcomponents of the SOFA score, KIM-1 was elevated in patients with hyperbilirubinaemia (>2 mg/dL, p < 0.001) and thrombocytopenia (p = 0.018). In univariate and multivariate regression analyses, KIM-1 predicted sepsis, the need for RRT, and multi-organ dysfunction (MOD, SOFA > 12 and APACHE II ≥ 20) on the day of admission, adjusting for relevant comorbidities, bilirubin, and platelet count. Additionally, KIM-1 in multivariate regression was able to predict sepsis in patients without prior (CKD) or present (AKI) kidney injury. Our study suggests that next to its established role as a biomarker in kidney dysfunction, KIM-1 is associated with sepsis, biliary injury, and critical illness severity. It thus may offer aid for risk stratification in these patients.

Critical illness and sepsis may cause organ failure and are recognized as mortality drivers in hospitalized patients. Neuropilin-1 (NRP-1) is a multifaceted transmembrane protein involved in the primary immune response and is expressed in immune cells such as T and dendritic cells. The soluble form of NRP-1 (sNRP-1) acts as an antagonist to NRP-1 by scavenging its ligands. The aim of this study was to determine the value of sNRP-1 as a biomarker in critical illness and sepsis. We enrolled 180 critically ill patients admitted to a medical intensive care unit and measured serum sNRP-1 concentrations at admission, comparing them to 48 healthy individuals. Critically ill and septic patients showed higher levels of sNRP-1 compared to healthy controls (median of 2.47 vs. 1.70 nmol/L, p < 0.001). Moreover, sNRP-1 was also elevated in patients with sepsis compared to other critical illness (2.60 vs. 2.13 nmol/L, p = 0.01), irrespective of disease severity or organ failure. In critically ill patients, sNRP-1 is positively correlated with markers of kidney and hepatic dysfunction. Most notably, critically ill patients not surviving in the long term (one year after admission) showed higher concentrations of sNRP-1 at the time of ICU admission (p = 0.036), with this association being dependent on the presence of organ failure. Critically ill and septic patients exhibit higher serum concentrations of circulating sNRP-1, which correlates to organ failure, particularly hepatic and kidney dysfunction.

Semaphorin 4D (Sema4D), also known as CD100, is a multifunctional transmembrane protein with immunoregulatory functions. Upon the activation of immune cells, soluble Semaphorin 4D (sSema4D) is proteolytically cleaved from the membrane by metalloproteinases. sSema4D levels are elevated in various (auto-)inflammatory diseases. Our aim was to investigate sSema4D levels in association with sepsis and critical illnesses and to evaluate sSema4D’s potential as a prognostic biomarker. We measured sSema4D levels in 192 patients upon admission to our medical intensive care unit. We found similar levels of sSema4D in 125 patients with sepsis compared to 67 non-septic patients. sSema4D levels correlated with leukocytes but not with other markers of systemic inflammation such as C-reactive protein or procalcitonin. Most interestingly, in a subgroup of patients suffering from pre-existing liver cirrhosis, we observed significantly higher levels of sSema4D. Consistently, sSema4D was also positively correlated with markers of hepatic and cholestatic injury. Our study suggests that sSema4D is not regulated in sepsis compared to other causes of critical illness. However, sSema4D seems to be associated with hepatic injury and inflammation.

Midkine (Mdk) is a multifunctional protein involved in inflammatory processes. Hence, circulating Mdk is increased in sepsis and has been previously suggested as a potential biomarker in these patients. The aim of this study was to elucidate the role of Mdk serum concentrations in critical illness and sepsis and to verify its value as a prognostic biomarker. Thus, we analyzed the Mdk serum concentrations of 192 critically ill patients on admission to the medical intensive care unit (ICU). While the serum levels of Mdk at admission were similar in septic and nonseptic critical illness (362 vs. 337 ng/L, p = 0.727), we found several interesting correlations of Mdk to laboratory and clinical markers associated with ischemia or hypoxia, e.g., to renal failure and hepatic injury. Mdk serum concentrations at admission did not differ between various causes of sepsis or other critical illness. Most noticeable, we observed upregulated Mdk serum concentrations at admission in patients surviving in the long-term, which was only seen in nonseptic critical illness but not in sepsis. Our study suggests a relevant role of Mdk in critically ill patients in general and highlights the possible protective features of Mdk in critical illness.

Sepsis is a major health burden with insufficiently understood mechanisms of inflammation and immune paralysis, leading to a life-threatening critical illness. The secreted frizzled related protein 5 (SFRP5) acts as an anti-inflammatory adipokine by antagonizing the Wnt5a pathway. The aim of this study was to elucidate the role of SFRP5 in critical illness and sepsis and to determine its value as a prognostic biomarker for mortality. We analyzed SFRP5 serum concentrations of 223 critically ill patients at admission to a medical intensive care unit (ICU) and compared those to 24 healthy individuals. SFRP5 serum concentrations were significantly decreased in critical illness as compared to healthy controls (24.66 vs. 100 ng/mL, p = 0.029). Even lower serum concentrations were found in septic as compared to nonseptic critically ill patients (19.21 vs. 32.83 ng/mL, p = 0.031). SFRP5 concentrations correlated with liver disease, age, anti-inflammation, and metabolic parameters. Furthermore, patients with sepsis recovered levels of SFRP5 in the first week of ICU treatment. SFRP5 levels at admission predicted short-term mortality in critically ill but not in septic patients. This study points to the role of the anti-inflammatory mediator SFRP5 not only in sepsis but also in nonseptic critically ill patients and associates high levels of SFRP5 to worse outcomes, predominantly in nonseptic critically ill patients.

Clusterin is a multifunctional protein that is recognized to mediate cellular stress response associated with organ failure, systemic inflammation, and metabolic alterations. The aim of this study was to determine the value of clusterin as a clinical biomarker in critical ill patients with or without sepsis. We analyzed clusterin plasma concentrations in 200 critically ill patients (133 with sepsis, 67 without sepsis) on admission to the medical intensive care unit (ICU). The results were compared with 66 healthy controls. Clusterin plasma concentration was significantly elevated in critically ill patients compared to healthy subjects. Clusterin levels were significantly higher in non-septic ICU patients than in patients with sepsis. Clusterin correlated inversely with routinely used biomarkers of inflammatory response. Furthermore, clusterin levels were higher in ICU patients with pre-existing obesity and type 2 diabetes. Clusterin was not associated with disease severity, organ failure, or mortality in the ICU. This study highlights significantly elevated clusterin levels in critically ill patients, predominantly in non-sepsis conditions, and associates circulating clusterin to inflammatory and metabolic dysfunctions.

ObjectiveObesity is a negative prognostic factor for various clinical conditions. In this observational cohort study, we evaluated a CT-based assessment of the adipose tissue distribution as a potential non-invasive prognostic parameter in critical illness.MethodsRoutine CT-scans upon admission to the intensive care unit (ICU) were used to analyze the visceral and subcutaneous adipose tissue areas at the 3rd lumbar vertebra in 155 patients. Results were correlated with various prognostic markers and both short-term- and overall survival. Multiple statistical tools were used for data analysis.ResultsWe observed a significantly larger visceral adipose tissue area in septic patients compared to non-sepsis patients. Interestingly, patients requiring mechanical ventilation had a significantly higher amount of visceral adipose tissue correlating with the duration of mechanical ventilation. Moreover, both visceral and subcutaneous adipose tissue area significantly correlated with several laboratory markers. While neither the visceral nor the subcutaneous adipose tissue area was predictive for short-term ICU survival, patients with a visceral adipose tissue area above the optimal cut-off (241.4 cm2) had a significantly impaired overall survival compared to patients with a lower visceral adipose tissue area.ConclusionsOur study supports a prognostic role of the individual adipose tissue distribution in critically ill patients. However, additional investigations need to confirm our suggestion that routine CT-based assessment of adipose tissue distribution can be used to yield further information on the patients' clinical course. Moreover, future studies should address functional and metabolic analysis of different adipose tissue compartments in critical illness.

Adrenomedullin (ADM) is a peptide with pleiotropic effects in systemic inflammation. Its more stable precursor protein midregional proadrenomedullin (MRproADM) can be measured more reliably compared to ADM. Our objective was to investigate the potential role of MRproADM as a diagnostic and prognostic biomarker in critically ill patients at the intensive care unit (ICU). We therefore measured MRproADM in 203 ICU patients and 66 healthy controls. We found that MRproADM levels are significantly increased in critically ill patients as compared to healthy controls. MRproADM levels are significantly increased in patients with sepsis, but its diagnostic value for identifying sepsis is numerically lower than that of established markers (e.g., interleukin-6, C-reactive protein, and procalcitonin). MRproADM levels are closely correlated to endothelial and organ dysfunction, inflammation, and established clinical scores (APACHE II, SOFA, and SAPS2). MRproADM concentrations correlate with vasopressor use but not fluid balance. Increased MRproADM levels (cut−off>1.4 nmol/L) in critically ill patients are independent predictors of ICU and overall mortality during a follow-up of up to 26 months (OR 3.15 for ICU mortality, 95% CI 1.08-9.20, p=0.036; OR for overall mortality 2.4, 95% CI 1.12-5.34, p=0.026). Our study demonstrates the potential of MRproADM serum levels as a prognostic biomarker in critical illness for ICU mortality and long-term survival during follow-up.

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.

Perilipin 2 (PLIN2) is a lipid droplet protein with various metabolic functions. However, studies investigating PLIN2 in the context of inflammation, especially in systemic and acute inflammation, are lacking. Hence, we assessed the relevance of serum PLIN2 in critically ill patients. We measured serum PLIN2 serum in 259 critically ill patients (166 with sepsis) upon admission to a medical intensive care unit (ICU) compared to 12 healthy controls. A subset of 36 patients underwent computed tomography to quantify body composition. Compared to controls, serum PLIN2 concentrations were elevated in critically ill patients at ICU admission. Interestingly, PLIN2 independently indicated multiple organ dysfunction (MOD), defined as a SOFA score > 9 points, at ICU admission, and was also able to independently predict MOD after 48 h. Moreover, serum PLIN2 levels were associated with severe respiratory failure potentially reflecting a moribund state. However, PLIN2 was neither a predictor of ICU mortality nor did it reflect metabolic dysregulation. Conclusively, the first study assessing serum PLIN2 in critical illness proved that it may assist in risk stratification because it is capable of independently indicating MOD at admission and predicting MOD 48 h after PLIN2 measurement. Further evaluation regarding the underlying mechanisms is warranted.

Abstract Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.

Background: Calprotectin is present in the cytosol of neutrophil granulocytes and released upon activation. Fecal calprotectin is applied in the clinical management of inflammatory bowel disease whereas serum calprotectin has been discussed as a biomarker in inflammatory disorders. However, its long-term prognostic relevance in critical illness remains unclear. Our aim was to investigate serum calprotectin concentrations as a prognostic biomarker in critically ill and septic patients. Methods: Serum calprotectin concentrations were analyzed in 165 critically ill patients (108 with sepsis, 57 without sepsis) included in our observational study. Patients were enrolled upon admission to the medical intensive care unit (ICU) of the RWTH Aachen University Hospital. Calprotectin concentrations were compared to 24 healthy controls and correlated with clinical parameters, therapeutic interventions, and survival. Results: Serum calprotectin concentrations were significantly increased in ICU patients as well as in septic patients compared to respective controls (p < 0.001 for ICU patients and p = 0.001 for septic patients). Lower calprotectin concentrations were measured in patients with comorbidities i.e., coronary artery disease. Calprotectin concentrations strongly correlated with the C-reactive protein (p < 0.001) and were closely associated to parameters of mechanical ventilation (i.a. inspiratory oxygen fraction, FiO2; p < 0.001). The overall survival was significantly impaired in septic patients with high baseline calprotectin concentrations (p = 0.036). However, patients with increasing calprotectin serum concentrations within the first week of ICU admission showed an improved overall survival (p = 0.009). Conclusions: In summary, serum calprotectin concentrations are significantly increased in critically ill patients with sepsis. High calprotectin concentrations at ICU admission predict long-term mortality risk, whereas increasing calprotectin concentrations are associated with a favorable long-term outcome.

Background: Growth differentiation factor 8, GDF-8 (Myostatin), is a protein released by myocytes inhibiting muscle growth and differentiation. Serum concentrations of Myostatin can predict poor survival in different chronic diseases, but its role in critical illness and sepsis is obscure. Our aim was to investigate Myostatin levels as a potential prognostic biomarker in critically ill patients with sepsis. Methods: We therefore measured Myostatin serum concentrations in 165 critically ill patients (106 with sepsis, 59 without sepsis) upon admission to the medical intensive care unit (ICU), in comparison to 14 healthy controls. Results: Myostatin levels were significantly decreased in ICU patients compared to controls but did not differ in patients with or without sepsis. However, Myostatin concentrations were significantly lower in patients requiring mechanical ventilation and indicated a trend towards dependency of intravenous vasopressors. Interestingly, we observed a negative correlation between Myostatin levels and markers of systemic inflammation. Strikingly, overall survival (OS) was significantly impaired in patients with low Myostatin levels in all critically ill patients. Low Myostatin levels at baseline turned out as an independent prognostic marker for OS in multivariate Cox-regression analysis (HR: 0.433, 95% CI: 0.211–0.889, p = 0.023). Conclusions: In summary, serum Myostatin concentrations are significantly decreased in critically ill patients and associated with disease severity. Low Myostatin levels also identify a subgroup of ICU patients that are more likely to face an unfavorable clinical outcome in terms of OS.