Maike Rebecca Pollmanns

Background: Transjugular intrahepatic portosystemic shunt (TIPS) placement leads to a reduction in portal pressure and an improvement in survival in patients with recurrent and refractory ascites and variceal haemorrhage. Prediction of post‐TIPS survival is primarily determined by factors identified before the TIPS procedure, as data collected during or after TIPS implantation are limited. The aim of the study was to evaluate the influence of early hemodynamic changes after TIPS placement on survival, in order to refine post TIPS management.Methods: In this prospective bicentric study, consecutive patients (n = 105) undergoing TIPS placement for ascites or variceal haemorrhage underwent measurement of portal pressure gradient (PPG) immediately at TIPS insertion (PPG0) and 24 h later (PPG24h) and the ΔPPG was calculated from PPG24h and PPG0 (ΔPPG = PPG24h‐PPG0). Kaplan–Meier survival analysis and uni‐ and multivariable regression analyses were conducted to identify survival predictors.Results: Patients with lack of increased ΔPPG exhibited poorer 90‐day and 1‐year survival compared to patients with increased ΔPPG. This worse survival was independent of The Model for End‐Stage Liver Disease (MELD) score, Child‐Pugh score, bilirubin levels, creatinine and the Freiburg index of post‐TIPS survival (FIPS) > 0.92. Among these patients with poorer outcome, elevated bilirubin (> 25 μmol/L) further distinguished survivors from non‐survivors.Conclusion: Lack of increased ΔPPG post‐TIPS insertion identifies a high‐risk patient group with worse survival. We propose incorporating this second PPG measurement and determining ΔPPG into clinical practice to identify these patients early and tailor post‐TIPS patient care.

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.

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.

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.

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.