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.

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 ( 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.

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.

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.

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.

Alterations in bone mineral density (BMD) have been suggested as independent predictors of survival for several diseases. However, little is known about the role of BMD in the context of critical illness and intensive care medicine. We therefore evaluated the prognostic role of BMD in critically ill patients upon admission to an intensive care unit (ICU). Routine computed tomography (CT) scans of 153 patients were used to assess BMD in the first lumbar vertebra. Results were correlated with clinical data and outcomes. While median BMD was comparable between patients with and without sepsis, BMD was lower in patients with pre-existing arterial hypertension or chronic obstructive pulmonary disease. A low BMD upon ICU admission was significantly associated with impaired short-term ICU survival. Moreover, patients with baseline BMD < 122 HU had significantly impaired overall survival. The prognostic relevance of low BMD was confirmed in uni- and multivariate Cox-regression analyses including several clinicopathological parameters. In the present study, we describe a previously unrecognised association of individual BMD with short- and long-term outcomes in critically ill patients. Due to its easy accessibility in routine CT, BMD provides a novel prognostic tool to guide decision making in critically ill patients.