Jonathan Frederik Brozat

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.

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.

Background & Aims: Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are potential risk factors for severe pneumonia and other infections. Available data on the role of NAFLD/NASH in worsening outcomes for COVID‐19 are controversial and might be confounded by comorbidities. Methods: We used the PINC AI™ Healthcare Data Special Release (PHD‐SR) to identify patients with COVID‐19 (ICD‐10) at approximately 900 hospitals in the United States. We performed exact matching (age, gender, and ethnicity) for patients with or without NAFLD/NASH, adjusting for demographics (admission type, region) and comorbidities (e.g., obesity, diabetes) through inverse probability of treatment weighting and then analysed hospitalisation‐related outcomes. Results: Among 513 623 patients with SARS‐CoV‐2 (COVID‐19), we identified 14 667 with NAFLD/NASH who could be matched to 14 667 controls. Mean age was 57.6 (±14.9) years, 50.8% were females and 43.7% were non‐Hispanic whites. After matching, baseline characteristics (e.g., age, ethnicity, and gender) and comorbidities (e.g., hypertension, obesity, diabetes, and cardiovascular disease) were well balanced (standard difference (SD) <.10), except for cirrhosis and malignancies. Patients with COVID‐19 and NAFLD/NASH had higher FIB‐4 scores, a significantly longer hospital length of stay (LOS) and intensive care LOS than controls (9.4 vs. 8.3 days, and 10.4 vs. 9.3, respectively), even after adjusting for cirrhosis and malignancies. Patients with COVID‐19 and NAFLD/NASH also had significantly higher risk of needing invasive mandatory ventilation (IMV) (odds ratio 1.0727; 95% CI 1.0095–1.1400). Other outcomes were similar in both groups. Conclusions: In this large real‐world cohort of patients hospitalised for COVID‐19 in the United States, NAFLD/NASH were obesity‐independent risk factors for complicated disease courses.

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.

Background: In acute pancreatitis (AP), microcirculatory dysfunction and leukocyte activation contribute to organ damage, inflammation, and mortality. Given the role of macrophage activation, monocyte recruitment, and microthrombus formation in the early pathogenesis of AP, we examined the macrophage activation marker soluble mannose receptor (sCD206) and the endothelial function marker von Willebrand factor (vWF) in patients admitted for AP. Methods: In an exploratory analysis, serum sCD206 and plasma vWF were prospectively analyzed on day 1 and day 3 in 81 patients with AP admitted to the hospital. In addition, blood samples from 59 patients with early AP admitted to the intensive care unit and symptom onset < 24 h were retrospectively analyzed. Patients were dichotomized as per study protocol into two groups: (i) “non-severe edematous AP” including patients with mild AP without organ failure and patients with transient organ failure that resolves within 48 h and (ii) “severe/necrotizing AP” including patients with severe AP and persistent organ failure > 48 h and/or patients with local complications. Results: In the prospective cohort, 17% developed severe/necrotizing pancreatitis compared with 56% in the ICU cohort. Serum concentrations of sCD206 on admission were higher in patients with severe/necrotizing AP than in patients with non-severe edematous AP (prospective: 1.57 vs. 0.66 mg/l, P = 0.005; ICU: 1.76 vs. 1.25 mg/l, P = 0.006), whereas other inflammatory markers (leukocytes, C-reactive protein, procalcitonin) and disease severity (SOFA, SAPS II, APACHE II) did not show significant differences. Patients with severe/necrotizing AP had a greater increase in sCD206 than patients with non-severe edematous AP at day 3 in the prospective cohort. In contrast to routine coagulation parameters, vWF antigen levels were elevated on admission (prospective cohort: 375 vs. 257%, P = 0.02; ICU cohort: 240 vs. 184%, P = 0.03). When used as continuous variables, sCD206 and VWF antigen remained predictors of severe/necrotizing AP after adjustment for etiology and age in both cohorts. Conclusions: sCD206 identifies patients at risk of severe AP at earlier timepoints than routine markers of inflammation and coagulation. Prospective studies are needed to investigate whether incorporating early or repeated measurements into the existing scoring system will better identify patients at increased risk for complications of AP.

Background and Objective: International registries have reported high mortality rates in patients with liver disease and COVID‐19. However, the extent to which comorbidities contribute to excess COVID‐19 mortality in cirrhosis is controversial.Methods: We used the multinational Lean European Open Survey on SARS‐CoV‐2‐infected patients (LEOSS) to identify patients with cirrhosis documented between March 2020 and March 2021, when the wild‐type and alpha variant were predominant. We compared symptoms, disease progression and mortality after propensity score matching (PSM) for age, sex, obesity, smoking status, and concomitant diseases. Mortality was also compared with that of patients with spontaneous bacterial peritonitis (SBP) without SARS‐CoV‐2 infection, a common bacterial infection and well‐described precipitator of acute‐on‐chronic liver failure.Results: Among 7096 patients with SARS‐CoV‐2 infection eligible for analysis, 70 (0.99%) had cirrhosis, and all were hospitalized. Risk factors for severe COVID‐19, such as diabetes, renal disease, and cardiovascular disease were more frequent in patients with cirrhosis. Case fatality rate in patients with cirrhosis was 31.4% with the highest odds of death in patients older than 65 years (43.6% mortality; odds ratio [OR] 4.02; p = 0.018), Child‐Pugh class C (57.1%; OR 4.00; p = 0.026), and failure of two or more organs (81.8%; OR 19.93; p = 0.001). After PSM for demographics and comorbidity, the COVID‐19 case fatality of patients with cirrhosis did not significantly differ from that of matched patients without cirrhosis (28.8% vs. 26.1%; p = 0.644) and was similar to the 28‐day mortality in a comparison group of patients with cirrhosis and SBP (33.3% vs. 31.5%; p = 1.000).Conclusions: In immunologically naïve patients with cirrhosis, mortality from wild‐type SARS‐CoV‐2 and the alpha variant is high and is largely determined by cirrhosis‐associated comorbidities and extrahepatic organ failure.

Background and Aims: Leukocyte infiltration is a hallmark of hepatic inflammation. The Junctional Adhesion Molecule A (JAM‐A) is a crucial regulator of leukocyte extravasation and is upregulated in human viral fibrosis. Reduced shear stress within hepatic sinusoids and the specific phenotype of liver sinusoidal endothelial cells (LSEC) cumulate in differing adhesion characteristics during liver fibrosis. The aim of this study was to define the functional role of cell‐specific adhesion molecule JAM‐A during hepatic fibrogenesis.Methods: Complete, conditional (intestinal epithelial; endothelial) and bone marrow chimeric Jam‐a knockout animals and corresponding C57Bl/6 wild‐type animals were treated with carbon tetrachloride (CCl₄, 6 weeks). For functional analyses of JAM‐A, comprehensive in vivo studies, co‐culture models and flow‐based adhesion assays were performed.Results: Complete and bone marrow‐derived Jam‐a^−/− animals showed aggravated fibrosis with increased non‐sinusoidal, perivascular accumulation of CD11b⁺F4/80⁺ monocyte‐derived macrophages in contrast to wild‐type mice. Despite being associated with disturbed epithelial barrier function, an intestinal epithelial Jam‐a knockout did not affect fibrogenesis. In endothelial‐specific Jam‐a^−/− animals, liver fibrosis was aggravated alongside sinusoid capillarization and hepatic stellate cell (HSC) activation. HSC activation is induced via Jam‐a^−/− LSEC‐derived secretion of soluble factors. Sinusoid CD31 expression and hedgehog gene signalling were increased, but leukocyte infiltration and adhesion to LSECs remained unaffected.Conclusions: Our models decipher cell‐specific JAM‐A to exert crucial functions during hepatic fibrogenesis. JAM‐A on bone marrow‐derived cells regulates non‐sinusoidal vascular immune cell recruitment, while endothelial JAM‐A controls liver sinusoid capillarization and HSC quiescence.