Clinical relevance and cellular source of elevated soluble urokinase plasminogen activator receptor (suPAR) in acute liver failure.

BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening condition with a high mortality rate. The expression of urokinase plasminogen activator receptor (uPAR, CD87) and release of its shedded receptor into serum as soluble uPAR (suPAR) have been closely related to immune activation and prognosis in systemic inflammation and cirrhosis. We now aimed at investigating the clinical relevance and cellular source of uPAR and circulating suPAR in ALF. METHODS: Serum suPAR concentrations were measured in 48 ALF patients and 62 healthy controls from a German liver transplantation centre. Hepatic immune cell subsets and uPAR expression were studied by FACS, qPCR and immunohistochemistry. RESULTS: Circulating suPAR levels were significantly increased in ALF patients, independent from the underlying aetiology, in comparison to controls. Serum suPAR concentrations were closely correlated with parameters reflecting liver cell injury, decreased liver function and the model of end-stage liver disease (MELD) score in ALF patients. By immunohistochemistry from explanted livers, ALF was associated with distinct immune cell accumulation and strong up-regulation of intrahepatic uPAR mRNA expression. CD87 (uPAR) expression was specifically detected on intrahepatic 'non-classical' monocytes (CD14(+) CD16(+) ), NKT and CD56(dim) NK cells isolated from human liver, but not on parenchymal or other non-parenchymal hepatic cell types. Membrane-bound uPAR was rapidly cleaved from monocytes upon inflammatory stimulation by lipopolysaccharide (LPS) and partially by co-cultured lymphocytes. CONCLUSIONS: Similar to its prognostic properties in patients with sepsis or cirrhosis, intrahepatic uPAR activation and serum suPAR concentrations might serve as an interesting biomarker in ALF.

Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea.

PURPOSE: Proton pump inhibitors (PPIs) effectively prevent gastrointestinal bleedings in critically ill patients at the intensive care unit (ICU). In non-ICU hospitalized patients, PPI administration increases the risk of infectious complications, especially Clostridium difficile-associated diarrhea (CDAD); but no such data are available for the ICU setting. MATERIALS AND METHODS: This is a retrospective, observational, single-center analysis (1999-2010) including 3286 critically ill patients. RESULTS: A total of 91.3% of patients received stress ulcer prophylaxis by PPI (55.6%), histamine 2 receptor antagonists (5.8%), sucralfate (10.1%), or combinations (19.8%). Only 29 (0.9%) of 3286 patients developed gastrointestinal bleedings during the course of ICU treatment, independent from the type of prophylaxis. The PPIs were not an independent risk factor for nosocomial pneumonia. One hundred and ten (3.3%) patients developed CDAD during the course of ICU treatment, which was associated with prolonged ICU stay and increased ICU mortality (odds ratio, 1.59). Similar to fluoroquinolones and cephalosporins, PPI was identified as an independent risk factor (odds ratio, 3.11) for developing CDAD at the ICU by multivariate analysis. CONCLUSIONS: Proton pump inhibitor therapy was an independent risk factor for CDAD in medical ICU patients. Instead of routine PPI use for bleeding prophylaxis, further trials should investigate risk-adjusted algorithms, balancing benefits, and threats of PPI medication.

Elevated asymmetric dimethylarginine levels predict short- and long-term mortality risk in critically ill patients.

OBJECTIVE: Serum concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may contribute to endothelial dysfunction and organ failure in sepsis. We aimed at investigating ADMA levels as a potential diagnostic or prognostic biomarker in critically ill patients. METHODS: Two hundred fifty-five patients (164 with sepsis, 91 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 78 healthy controls. ADMA serum concentrations were correlated with clinical data and extensive laboratory parameters. Patients' survival was followed up for up to 3 years. RESULTS: ADMA serum levels were significantly elevated in critically ill patients at admission compared to controls. ADMA levels did not differ between patients with or without sepsis, but were closely related to hepatic and renal dysfunction, metabolism and clinical scores of disease severity. ADMA levels further increased during the first week of ICU treatment. ADMA serum levels at admission were an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU, but also for unfavorable long-term survival. CONCLUSION: Serum ADMA concentrations are significantly elevated in critically ill patients, associated with organ failure and related to short- and long-term mortality risk.

Regulation and prognostic relevance of symmetric dimethylarginine serum concentrations in critical illness and sepsis.

In systemic inflammation and sepsis, endothelial activation and microvascular dysfunction are characteristic features that promote multiorgan failure. As symmetric dimethylarginine (SDMA) impacts vascular tension and integrity via modulating nitric oxide (NO) pathways, we investigated circulating SDMA in critical illness and sepsis. 247 critically ill patients (160 with sepsis, 87 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 84 healthy controls. SDMA serum levels were significantly elevated in critically ill patients at admission to ICU compared to controls and remained stably elevated during the first week of ICU treatment. The highest SDMA levels were found in patients with sepsis. SDMA levels closely correlated with disease severity scores, biomarkers of inflammation, and organ failure (renal, hepatic, and circulatory). We identified SDMA serum concentrations at admission as an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU but also for unfavourable long-term survival. Thus, the significant increase of circulating SDMA in critically ill patients indicates a potential pathogenic involvement in endothelial dysfunction during sepsis and may be useful for mortality risk stratification at the ICU.

Increased liver stiffness denotes hepatic dysfunction and mortality risk in critically ill non-cirrhotic patients at a medical ICU.

INTRODUCTION: Hepatic dysfunction is a common finding in critically ill patients on the ICU and directly influences survival. Liver stiffness can be measured by the novel method of transient elastography (fibroscan) and is closely associated with hepatic fibrosis in patients with chronic liver disease, but also is increased in patients with acute hepatitis, acute liver failure and cholestasis. We investigated liver stiffness as a potentially useful tool for early detection of patients with hepatic deterioration and risk stratification with respect to short- and long-term mortality. METHODS: We prospectively evaluated 108 consecutive critically ill patients at our medical intensive care unit (ICU) with subsequent longitudinal liver stiffness measurements (admission, Day 3, Day 7 and weekly thereafter) during the course of ICU treatment. Outcome was followed after discharge (median observation time 237 days). RESULTS: Liver stiffness could be reliably measured in 71% of ICU patients at admission (65% at Day 3, 63% at Day 7). Critically ill patients (n = 108) had significantly increased liver stiffness compared to sex- and age-matched standard care patients (n = 25). ICU patients with decompensated cirrhosis showed highest liver stiffness, whereas other critical diseases (for example, sepsis) and comorbidities (for example, diabetes, obesity) did not impact stiffness values. At admission to the ICU, liver stiffness is closely related to hepatic damage (liver synthesis, cholestasis, fibrosis markers). During the course of ICU treatment, fluid overload (renal failure, volume therapy) and increased central venous pressure (mechanical ventilation, heart failure) were major factors determining liver stiffness. Liver stiffness values > 18 kilopascal (kPa) at ICU admission were associated with increased ICU and long-term mortality, even in non-cirrhotic patients. CONCLUSIONS: Considering that liver stiffness cannot be validly measured in about 30% of ICU patients, transient elastography performed at ICU admission might be a useful tool to early identify liver dysfunction and predict mortality in critically ill patients at a medical ICU.

Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill patients.

INTRODUCTION: suPAR is the soluble form of the urokinase plasminogen activator receptor (uPAR), which is expressed in various immunologically active cells. High suPAR serum concentrations are suggested to reflect the activation of the immune system in circumstances of inflammation and infection, and have been associated with increased mortality in different populations of non-intensive care patients. In this study we sequentially analyzed suPAR serum concentrations within the first week of intensive care in a large cohort of well characterized intensive care unit (ICU) patients, in order to investigate potential regulatory mechanisms and evaluate the prognostic significance in critically ill patients. METHODS: A total of 273 patients (197 with sepsis, 76 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU), on Day 3 and Day 7, and compared to 43 healthy controls. Clinical data, various laboratory parameters as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately one year. RESULTS: Upon admission to the ICU suPAR serum concentrations were elevated in critically ill patients as compared with healthy controls. In sepsis patients suPAR levels were higher than in non-sepsis patients (with or without systemic inflammatory response syndrome (SIRS)). During the first week after admission to the ICU serum suPAR concentrations remained stably elevated. suPAR serum concentrations measured upon admission were closely and independently correlated to various laboratory parameters, specifically biomarkers of inflammation (tumor necrosis factor (TNF), C-reactive protein (CRP)), hepatic and renal dysfunction. High suPAR levels at admission and at Day 3 were a strong independent predictor for both ICU and long-term mortality in critically ill patients. CONCLUSIONS: In sepsis and non-sepsis patients suPAR serum concentrations are increased upon admission to the ICU, likely reflecting the activation state of the immune system, and remain stably elevated in the initial course of treatment. Low suPAR levels are a positive predictor of ICU- and overall survival in critically ill patients, including sepsis and non-sepsis patients. Aside from its value as a promising new prognostic biomarker, both experimental and clinical studies are required in order to understand the specific effects and regulatory mechanisms of suPAR in SIRS and sepsis, and may reveal new therapeutic options.

Prognostic value of circulating amino-terminal pro-C-type natriuretic peptide in critically ill patients.

INTRODUCTION: C-type natriuretic peptide (CNP) is a paracrine molecule which is mainly synthesized in the vasculature. High levels have been reported in sepsis, and CNP has been proposed as a biomarker predicting sepsis in traumatized patients. We aimed at evaluating the diagnostic and prognostic value of N-terminal pro-CNP (NT-proCNP) for predicting sepsis, disease severity and mortality in critically ill medical patients. METHODS: 273 critically ill patients (197 patients with sepsis or septic shock, 76 without evidence of sepsis) and 43 healthy controls were consecutively included in a prospective clinical single-center non-interventional study at the Medical Intensive Care Unit, RWTH-University Aachen, Germany. Patients' outcome was followed for about 1 year. NT-proCNP serum concentrations were determined upon ICU admission, as well as in the mornings of day 3 and day 7 after admission. Intensive care treatment measures as well as routine and experimental laboratory parameters were recorded and analyzed. RESULTS: NT-proCNP serum concentrations upon admission to the ICU were elevated in critically ill patients as compared with healthy controls. Patients with sepsis had significantly higher NT-proCNP levels than non-sepsis patients. NT-proCNP was strongly associated with inflammatory parameters (i.e. C-reactive protein, procalcitonin and TNF-α), biomarkers of organ dysfunction and clinical composite scores (APACHE-II, SOFA, SAPS2). NT-proCNP levels at admission and day 3 were found to be a strong predictive marker for ICU- and overall survival. Moreover, a decline of serum NT-proCNP after admission to the ICU was associated with reduced mortality. The predictive power of serum NT-proCNP was similar to 'conventional' prognostic tools such as clinical scores. CONCLUSIONS: NT-proCNP is significantly elevated in critically ill patients, with highest levels in sepsis. Inflammation as well as organ function are strongly associated with NT-proCNP serum concentrations. Low initial NT-proCNP levels and a decline during initial treatment indicate a favourable ICU- and long-term outcome.

Circulating retinol binding protein 4 in critically ill patients before specific treatment: prognostic impact and correlation with organ function, metabolism and inflammation.

INTRODUCTION: Hyperglycemia and insulin resistance are well-known features of critical illness and impact the mortality rate, especially in sepsis. Retinol binding protein 4 (RBP4) promotes insulin resistance in mice and is systemically elevated in patients with obesity and type 2 diabetes. We investigated the potential role of RBP4 in critically ill patients. METHODS: We conducted a prospective single-center study of serum RBP4 concentrations in critically ill patients. One hundred twenty-three patients (85 with sepsis, 38 without sepsis) were studied at admission to a medical intensive care unit (ICU) before initiation of specific intensive care treatment measures and compared to 42 healthy nondiabetic controls. Clinical data, various laboratory parameters and metabolic and endocrine functions were assessed. Patients were followed for approximately 3 years. RESULTS: Serum RBP4 was significantly reduced in ICU patients, independently of sepsis, as compared to healthy controls (P < 0.001). Patients with liver cirrhosis as the primary underlying diagnosis for ICU admission had significantly lower RBP4 levels as compared with other ICU patients. Accordingly, in all ICU patients, serum RBP4 closely correlated with liver function and increased with renal failure. No significant differences of serum RBP4 concentrations in septic patients with pulmonary or other origins of sepsis or nonseptic patients could be revealed. Acute phase proteins were inversely correlated with RBP4 in sepsis patients. RBP4 did not differ between patients with or without obesity or preexisting diabetes. However, serum RBP4 levels correlated with endogenous insulin secretion (C-peptide) and insulin resistance (HOMA index). Low serum RBP4 upon admission was an adverse predictor of short-term survival in the ICU, but was not associated with overall survival during long-term follow-up. CONCLUSIONS: Serum RBP4 concentrations are significantly reduced in critically ill patients. The strong associations with hepatic and renal function, insulin resistance and acute mortality collectively suggest a role of RBP4 in the pathogenesis of critical illness, possibly as a negative acute phase reactant, and allow a proposition as a potential novel biomarker for ICU patients.