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Adam Linder - One of the best experts on this subject based on the ideXlab platform.

  • Is Heparin-Binding Protein Inhibition a Mechanism of Albumin's Efficacy in Human Septic Shock?
    Critical care medicine, 2020
    Co-Authors: Jane Fisher, Adam Linder, Peter Bentzer, John Boyd, Hyejin Julia Kong, Keith R Walley, James A Russell
    Abstract:

    Our objectives were to determine first whether albumin prevents Heparin-Binding Protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma Heparin-Binding Protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock. In vitro human endothelial and renal cell model and observation cohort of septic shock. Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial). Adult septic shock (norepinephrine dose > 5 μg/min for > 6 hr). In vitro: Heparin-Binding Protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation. Transendothelial electrical resistance-a marker of permeability-of human endothelial cells was measured using a voltohmmeter. We measured plasma Heparin-Binding Protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an Heparin-Binding Protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited Heparin-Binding Protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher Heparin-Binding Protein-to-albumin ratio (1.6 vs 0.89; p < 0.001) and Heparin-Binding Protein (38.2 vs 20.8 ng/mL; p < 0.001) than patients without acute kidney injury. The highest Heparin-Binding Protein-to-albumin ratio (> 3.05), Heparin-Binding Protein quartiles (> 69.8), and Heparin-Binding Protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-Binding Protein and Heparin-Binding Protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of Heparin-Binding Protein-to-albumin ratio and Heparin-Binding Protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality. Albumin inhibits Heparin-Binding Protein-induced increased human endothelial cell permeability and Heparin-Binding Protein greater than 30 ng/mL and Heparin-Binding Protein-to-albumin ratio greater than 3.01-but not serum albumin-identified patients at increased risk for acute kidney injury in septic shock.

  • is Heparin Binding Protein inhibition a mechanism of albumin s efficacy in human septic shock
    Critical Care Medicine, 2018
    Co-Authors: Jane Fisher, Adam Linder, Peter Bentzer, Hyejin Julia Kong, Keith R Walley, John H Boyd, James A Russell
    Abstract:

    Objectives: Our objectives were to determine first whether albumin prevents Heparin-Binding Protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma Heparin-Binding Protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock. Design: In vitro human endothelial and renal cell model and observation cohort of septic shock. Settings: Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial). Patients: Adult septic shock (norepinephrine dose > 5 μg/min for > 6 hr). Interventions: In vitro: Heparin-Binding Protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation. Measurements and Main Results: Transendothelial electrical resistance - a marker of permeability - of human endothelial cells was measured using a voltohmmeter. We measured plasma Heparin-Binding Protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an Heparin-Binding Protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited Heparin-Binding Protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher Heparin-Binding Protein-to-albumin ratio (1.6 vs 0.89; p 3.05), Heparin-Binding Protein quartiles (> 69.8), and Heparin-Binding Protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-Binding Protein and Heparin-Binding Protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of Heparin-Binding Protein-to-albumin ratio and Heparin-Binding Protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality. Conclusions: Albumin inhibits Heparin-Binding Protein-induced increased human endothelial cell permeability and Heparin-Binding Protein greater than 30 ng/mL and Heparin-Binding Protein-to-albumin ratio greater than 3.01 - but not serum albumin - identified patients at increased risk for acute kidney injury in septic shock. (Less)

  • Heparin Binding Protein hbp improves prediction of sepsis related acute kidney injury
    Annals of Intensive Care, 2017
    Co-Authors: Jonas Tverring, Jane Fisher, Ville Pettilä, Suvi T Vaara, Meri Poukkanen, Adam Linder
    Abstract:

    Sepsis-related acute kidney injury (AKI) accounts for major morbidity and mortality among the critically ill. Heparin-Binding Protein (HBP) is a promising biomarker in predicting development and prognosis of severe sepsis and septic shock that has recently been proposed to be involved in the pathophysiology of AKI. The objective of this study was to investigate the added predictive value of measuring plasma HBP on admission to the intensive care unit (ICU) regarding the development of septic AKI. We included 601 patients with severe sepsis or septic shock from the prospective, observational FINNAKI study conducted in seventeen Finnish ICUs during a 5-month period (1 September 2011–1 February 2012). The main outcome measure was the development of KDIGO AKI stages 2–3 from 12 h after admission up to 5 days. Statistical analysis for the primary endpoint included construction of a clinical risk model, area under the receiver operating curve (ROC area), category-free net reclassification index (cfNRI) and integrated discrimination improvement (IDI) with 95% confidence intervals (95% CI). Out of 511 eligible patients, 101 (20%) reached the primary endpoint. The addition of plasma HBP to a clinical risk model significantly increased ROC area (0.82 vs. 0.78, p = 0.03) and risk classification scores: cfNRI 62.0% (95% CI 40.5–82.4%) and IDI 0.053 (95% CI 0.029–0.075). Plasma HBP adds predictive value to known clinical risk factors in septic AKI. Further studies are warranted to compare the predictive performance of plasma HBP to other novel AKI biomarkers.

  • Heparin Binding Protein hbp a causative marker and potential target for Heparin treatment of human sepsis induced acute kidney injury
    Shock, 2017
    Co-Authors: Jane Fisher, Peter Bentzer, Keith R Walley, James A Russell, John H Boyd, Matthias Morgelin, Devyn Parsons, Stefano Secchia, Adam Linder
    Abstract:

    RATIONALE: Sepsis-induced acute kidney injury (AKI) is a common condition with high morbidity and mortality. Neutrophil-derived Heparin-Binding Protein (HBP) induces vascular leakage and is a promising biomarker of sepsis-induced organ dysfunction. It remains unknown if HBP is prognostic of AKI in septic shock and if HBP could play a role in the pathophysiology of sepsis-induced AKI.OBJECTIVES: To determine the association of plasma HBP levels with development of AKI, investigate the role of HBP in the pathophysiology of sepsis-induced AKI, and test the effect of blocking HBP using Heparin derivatives.METHODS: In 296 septic shock patients from the randomized multicenter Vasopressin and Septic Shock Trial (VASST) plasma HBP levels were associated with development of AKI and need for renal replacement therapy (RRT). Human renal tubular cells were exposed to recombinant HBP to evaluate inflammation and Heparin derivatives were used to abrogate these effects. Finally, mice were exposed to HBP with and without Heparin derivatives and the kidneys examined for signs of inflammation.FINDINGS: Plasma HBP levels were significantly higher in patients with AKI and those requiring RRT. HBP levels identified patients with moderate AKI with an area under curve (AUC) of 0.85. HBP increased IL-6 production in renal tubular epithelial cells. Different Heparin derivatives abrogated the HBP-induced increased inflammatory response in vitro and in vivo.CONCLUSION: Elevated plasma HBP is associated with development of sepsis-induced AKI and HBP is involved in its pathophysiology. Our studies suggest that Heparin(s) could be tested for efficacy and safety of prevention of sepsis-induced AKI. (Less)

  • Heparin Binding Protein a key player in the pathophysiology of organ dysfunction in sepsis
    Journal of Internal Medicine, 2017
    Co-Authors: Jane Fisher, Adam Linder
    Abstract:

    Infectious diseases remain a major health problem, and sepsis and other severe infectious diseases are common causes of morbidity and mortality. There is a need for clinical and laboratory tools to identify patients with severe infections early and to distinguish between bacterial and nonbacterial conditions. Heparin-Binding Protein (HBP), also known as azurocidin or cationic antimicrobial Protein of 37 KDa, is a promising biomarker to distinguish between patients with these conditions. It is biologically plausible that HBP is an early and predictive biomarker because it is prefabricated and rapidly mobilized from migrating neutrophils in response to bacterial infections. HBP induces vascular leakage and oedema formation and has a pro-inflammatory effect on a variety of white blood cells and epithelial cells. The dysregulation of vascular barrier function and cellular inflammatory responses can then lead to organ dysfunction. Indeed, it has been shown that patients with sepsis express elevated levels of HBP in plasma several hours before they develop hypotension or organ dysfunction. HBP has a major role in the pathophysiology of severe bacterial infections and thus represents a potential diagnostic marker and a target for the treatment of sepsis.

Heiko Herwald - One of the best experts on this subject based on the ideXlab platform.

  • renal clearance of Heparin Binding Protein and elimination during renal replacement therapy studies in icu patients and healthy volunteers
    PLOS ONE, 2019
    Co-Authors: Line Samuelsson, Heiko Herwald, Jonas Tyden, Magnus Hultin, Jakob Wallden, Folke Sjoberg, Ingrid Steinvall, Joakim Johansson
    Abstract:

    BACKGROUND: Heparin-Binding Protein (HBP) is released by neutrophils upon activation, and elevated plasma levels are seen in inflammatory states like sepsis, shock, cardiac arrest, and burns. However, little is known about the elimination of HBP. We wanted to study renal clearance of HBP in healthy individuals and in burn patients in intensive care units (ICUs). We also wished to examine the levels of HBP in the effluent of renal replacement circuits in ICU patients undergoing continuous renal replacement therapy (CRRT).METHODS: We measured plasma and urine levels of HBP and urine flow rate in 8 healthy individuals and 20 patients in a burn ICU. In 32 patients on CRRT, we measured levels of HBP in plasma and in the effluent of the CRRT circuit.RESULTS: Renal clearance of HBP (median (IQR) ml/min) was 0.19 (0.08-0.33) in healthy individuals and 0.30 (0.01-1.04) in burn ICU patients. In ICU patients with cystatin C levels exceeding 1.44 mg/l, clearance was 0.45 (0.15-2.81), and in patients with cystatin C below 1.44 mg/l clearance was lower 0.28 (0.14-0.55) (p = 0.04). Starting CRRT did not significantly alter plasma levels of HBP (p = 0.14), and the median HBP level in the effluent on CRRT was 9.1 ng/ml (IQR 7.8-14.4 ng/ml).CONCLUSION: In healthy individuals and critically ill burn patients, renal clearance of HBP is low. It is increased when renal function is impaired. Starting CRRT in critically ill patients does not alter plasma levels of HBP significantly, but HBP can be found in the effluent. It seems unlikely that impaired kidney function needs to be considered when interpreting concentrations of HBP in previous studies. Starting CRRT does not appear to be an effective way of reducing HBP concentrations. (Less)

  • Heparin Binding Protein release is strongly induced by leptospira species and is a candidate for an early diagnostic marker of human leptospirosis
    The Journal of Infectious Diseases, 2019
    Co-Authors: Monica L Vieira, Sandra T Persson, Monica Lopesferreira, Eliete Calo Romero, Karin Kirchgatter, Ana L T O Nascimento, Heiko Herwald
    Abstract:

    BACKGROUND: Leptospirosis, caused by spirochetes of the genus Leptospira, is one of the most widespread zoonoses worldwide. Efficient diagnostic methods for early diagnosis of leptospirosis are still lacking, and acute disease presents with nonspecific symptomatology and is often misdiagnosed. The leptospires pathogenic processes and virulence mechanisms remain virtually unknown. In severe infections, hemostatic impairment is frequently observed, and pathophysiological complications often develop when the host response is modulated by the pathogen. The neutrophil Heparin-Binding Protein (HBP) is an inflammatory mediator and potent inducer of vascular leakage. RESULTS: In this study, we found that leptospires and their secreted products induce the release of HBP from stimulated neutrophils through a controlled degranulation mechanism. We acknowledged 2 leptospiral Proteins as able to induce HBP degranulation. These findings have clinical implications, as high levels of HBP were detected in serum from patients with leptospirosis, especially at the early phase of the disease. CONCLUSION: In conclusion, we describe a new mechanism by which the leptospirosis pathophysiological complications may arise, such as vascular leakage and edema formation. We also propose HBP as a new early screening biomarker for human leptospirosis. (Less)

  • Heparin-Binding Protein as a biomarker of post-injury sepsis in trauma patients
    Acta Anaesthesiologica Scandinavica, 2018
    Co-Authors: H. D. Halldorsdottir, Heiko Herwald, J. Eriksson, Björn P. Persson, Lennart Lindbom, Eddie Weitzberg, Anders Oldner
    Abstract:

    Background: Heparin-Binding Protein (HBP) is a neutrophil-derived Protein advocated as a biomarker in sepsis. We evaluated plasma HBP as a predictor of post-injury sepsis in trauma patients. Methods: Ninety-seven trauma patients were studied during the first week of intensive care. Injury-related data were collected and clinical parameters registered daily. Plasma HBP was sampled on day 1, 3 and 5 after trauma and evaluated for associations with injury-related parameters and sepsis. The predictive properties of HBP were compared to C-reactive Protein (CRP) and white blood cell count (WBC). Results: Median Injury Severity Score was 33, one-third of the trauma patients received massive transfusion and a quarter was in shock on arrival. Overall 30-day mortality was 8%. Plasma HBP was significantly higher in severely injured patients and associated with shock on arrival, massive transfusions and organ failure. Septic patients had higher levels of HBP only on day 5. When evaluated for prediction of onset of sepsis during the two following days after plasma sampling by receiver operating characteristic (ROC) analyses, areas under the curves were non-significant for all time points. Similar patterns were seen for CRP and WBC. Conclusion: In trauma patients, HBP levels are related to severity of injury and organ dysfunction. Heparin-Binding Protein was weakly associated with sepsis and only at the later stage of the observation period of 1 week. Moreover, HBP showed poor discriminatory properties as an early biomarker of post-injury sepsis. Trauma-induced inflammation during the post-injury phase may blunt the sepsis-predictive performance of HBP. (Less)

  • Heparin Binding Protein as a biomarker of acute kidney injury in critical illness
    Acta Anaesthesiologica Scandinavica, 2017
    Co-Authors: Jonas Tyden, Heiko Herwald, Magnus Hultin, Jakob Wallden, Joakim Johansson
    Abstract:

    BACKGROUND: There is no biomarker with high sensitivity and specificity for the development of acute kidney injury (AKI) in a mixed intensive care unit (ICU) population. Heparin-Binding Protein (HB ...

  • increased plasma levels of Heparin Binding Protein on admission to intensive care are associated with respiratory and circulatory failure
    PLOS ONE, 2016
    Co-Authors: Jonas Tyden, Heiko Herwald, Folke Sjoberg, Joakim Johansson
    Abstract:

    Purpose Heparin-Binding Protein (HBP) is released by granulocytes and has been shown to increase vascular permeability in experimental investigations. Increased vascular permeability in the lungs c ...

Per Akesson - One of the best experts on this subject based on the ideXlab platform.

  • Heparin Binding Protein a diagnostic biomarker of urinary tract infection in adults
    Open Forum Infectious Diseases, 2014
    Co-Authors: Charlott Kjolvmark, Adam Linder, Per Akesson, Lisa I Pahlman
    Abstract:

    Background. Urinary tract infections (UTIs) are associated with significant morbidity and high frequency of antibiotic prescription. Diagnosing UTI is often difficult, particularly in the critically ill patient and in patients with unspecific and mild symptoms. The standard rapid tests have limited value, and there is a need for more reliable diagnostic tools. Heparin-Binding Protein (HBP) is released from neutrophils and has previously been studied as a diagnostic and predictive biomarker in different bacterial infections. Methods. This prospective survey enrolled adult patients at 2 primary care units and 2 hospital emergency departments, to investigate in urine HBP as a biomarker of UTI. In addition, urine levels of interleukin-6, white blood cells, and nitrite were analyzed and compared with HBP. Based on symptoms of UTI and microbiological findings, patients were classified into different groups, UTI (cystitis and pyelonephritis) and no UTI. Results. Three hundred ninety patients were evaluated. The prevalence of UTI in the study group was 45.4%. The sensitivity and specificity for HBP in urine as a marker for UTI were 89.2% and 89.8%, respectively. The positive and negative predictive values were 90.2% and 88.8%, respectively. Heparin-Binding Protein was the best diagnostic marker for UTI, with an area-under-curve value of 0.94 (95% confidence interval, 0.93–0.96). Heparin-Binding Protein was significantly better in distinguishing cystitis from pyelonephritis, compared with the other markers. Conclusions. An elevated level of HBP in the urine is associated with UTI and may be a useful diagnostic marker in adult patients with a suspected UTI.

  • elevated plasma levels of Heparin Binding Protein in intensive care unit patients with severe sepsis and septic shock
    Critical Care, 2012
    Co-Authors: Adam Linder, Per Akesson, Anna Linner, Malin Inghammar, Carljohan Treutiger, Jonas Sundencullberg
    Abstract:

    Introduction: Rapid detection of, and optimized treatment for, severe sepsis and septic shock is crucial for successful outcome. Heparin-Binding Protein (HBP), a potent inducer of increased vascular permeability, is a potentially useful biomarker for predicting outcome in patients with severe infections. Our aim was to study the systemic release and dynamics of HBP in the plasma of patients with severe sepsis and septic shock in the ICU. Methods: A prospective study was conducted of two patient cohorts treated in the ICU at Karolinska University Hospital Huddinge in Sweden. A total of 179 patients was included, of whom 151 had sepsis (126 with septic shock and 25 patients with severe sepsis) and 28 a non-septic critical condition. Blood samples were collected at five time points during six days after admission. Results: HBP levels were significantly higher in the sepsis group as compared to the control group. At admission to the ICU, a plasma HBP concentration of ≥15 ng/mL and/or a HBP (ng/mL)/white blood cell count (10 9 /L) ratio of >2 was found in 87.2% and 50.0% of critically ill patients with sepsis and non-septic illness, respectively. A lactate level of >2.5 mmol/L was detected in 64.9% and 56.0% of the same patient groups. Both in the sepsis group (n = 151) and in the whole group (n = 179), plasma HBP concentrations at admission and in the last measured sample within the 144 hour study period were significantly higher among 28-day non-survivors as compared to survivors and in the sepsis group, an elevated HBP-level at baseline was associated with an increased case-fatality rate at 28 days. Conclusions: Plasma HBP levels were significantly higher in patients with severe sepsis or septic shock compared to patients with a non-septic illness in the ICU. HBP was associated with severity of disease and an elevated HBP at admission was associated with an increased risk of death. HBP that rises over time may identify patients with a deteriorating prognosis. Thus, repeated HBP measurement in the ICU may help monitor treatment and predict outcome in patients with severe infections.

  • elevated urine levels of Heparin Binding Protein in children with urinary tract infection
    Pediatric Nephrology, 2012
    Co-Authors: Charlott Kjolvmark, Per Akesson, Adam Linder
    Abstract:

    Background Urinary tract infection (UTI) is a common infection diagnosis in children, and efficient diagnosis and treatment are important to avoid serious complications. In this study we investigated whether urinary levels of neutrophil-derived Heparin-Binding Protein (HBP) can be used as a marker of UTI in children. These results were compared to those of dipstick analysis, interleukin-6 (IL-6) analysis in urine, and bacterial culturing.

  • Heparin Binding Protein a diagnostic marker of acute bacterial meningitis
    Critical Care Medicine, 2011
    Co-Authors: Adam Linder, Per Akesson, Magnus Brink, Marie Studahl, Lars Bjorck, Bertil Christensson
    Abstract:

    BACKGROUND: The early detection of bacterial meningitis is crucial for successful outcome. Heparin-Binding Protein, a potent inducer of increased vascular permeability, is released from activated neutrophils in severe sepsis.OBJECTIVE: In this study we investigated whether Heparin-Binding Protein levels in cerebrospinal fluid could be used as a diagnostic marker for acute bacterial meningitis.DESIGN: One prospective and one retrospective patient cohort from two university hospitals in Sweden were analyzed.SETTING AND PATIENTS: Cerebrospinal fluid samples were collected from 174 patients with suspected central nervous system infection. Thirty-seven patients with acute community-acquired bacterial meningitis, four patients with neurosurgical bacterial meningitis, 29 patients with viral meningitis or encephalitis, seven patients with neuroborreliosis, and 97 control patients were included.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Cerebrospinal fluid samples were analyzed for the concentrations of Heparin-Binding Protein, lactate, Protein, glucose, neutrophils, and mononuclear cells. Heparin-Binding Protein levels were significantly higher (p < .01) in patients with acute bacterial meningitis (median 376 ng/mL, range 12-858 ng/mL) than in patients with viral central nervous system infection (median 4.7 ng/mL, range 3.0-41 ng/mL) or neuroborreliosis (median 3.6 ng/mL, range 3.2-10 ng/mL) or in control patients with a normal cerebrospinal fluid cell count (median 3.5 ng/mL, range 2.4-8.7 ng/mL). In the prospectively studied group, a Heparin-Binding Protein concentration exceeding 20 ng/mL gave a sensitivity of 100%, a specificity of 99.2%, and positive and negative predictive values of 96.2% and 100%, respectively, in diagnosing acute bacterial meningitis. The area under the receiver-operating characteristic curve for Heparin-Binding Protein was 0.994, which was higher than for the other investigated parameters.CONCLUSION: Elevated cerebrospinal fluid levels of Heparin-Binding Protein distinguish between patients with acute bacterial meningitis and patients with other central nervous system infections. (Less)

  • roles of Heparin Binding Protein in bacterial infections
    Journal of Innate Immunity, 2010
    Co-Authors: Adam Linder, Oliver Soehnlein, Per Akesson
    Abstract:

    Infectious diseases remain a major health problem, where sepsis and other severe infectious diseases are common causes of morbidity and mortality. The importance of early and appropriate treatment of

Jane Fisher - One of the best experts on this subject based on the ideXlab platform.

  • Is Heparin-Binding Protein Inhibition a Mechanism of Albumin's Efficacy in Human Septic Shock?
    Critical care medicine, 2020
    Co-Authors: Jane Fisher, Adam Linder, Peter Bentzer, John Boyd, Hyejin Julia Kong, Keith R Walley, James A Russell
    Abstract:

    Our objectives were to determine first whether albumin prevents Heparin-Binding Protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma Heparin-Binding Protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock. In vitro human endothelial and renal cell model and observation cohort of septic shock. Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial). Adult septic shock (norepinephrine dose > 5 μg/min for > 6 hr). In vitro: Heparin-Binding Protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation. Transendothelial electrical resistance-a marker of permeability-of human endothelial cells was measured using a voltohmmeter. We measured plasma Heparin-Binding Protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an Heparin-Binding Protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited Heparin-Binding Protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher Heparin-Binding Protein-to-albumin ratio (1.6 vs 0.89; p < 0.001) and Heparin-Binding Protein (38.2 vs 20.8 ng/mL; p < 0.001) than patients without acute kidney injury. The highest Heparin-Binding Protein-to-albumin ratio (> 3.05), Heparin-Binding Protein quartiles (> 69.8), and Heparin-Binding Protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-Binding Protein and Heparin-Binding Protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of Heparin-Binding Protein-to-albumin ratio and Heparin-Binding Protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality. Albumin inhibits Heparin-Binding Protein-induced increased human endothelial cell permeability and Heparin-Binding Protein greater than 30 ng/mL and Heparin-Binding Protein-to-albumin ratio greater than 3.01-but not serum albumin-identified patients at increased risk for acute kidney injury in septic shock.

  • is Heparin Binding Protein inhibition a mechanism of albumin s efficacy in human septic shock
    Critical Care Medicine, 2018
    Co-Authors: Jane Fisher, Adam Linder, Peter Bentzer, Hyejin Julia Kong, Keith R Walley, John H Boyd, James A Russell
    Abstract:

    Objectives: Our objectives were to determine first whether albumin prevents Heparin-Binding Protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma Heparin-Binding Protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock. Design: In vitro human endothelial and renal cell model and observation cohort of septic shock. Settings: Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial). Patients: Adult septic shock (norepinephrine dose > 5 μg/min for > 6 hr). Interventions: In vitro: Heparin-Binding Protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation. Measurements and Main Results: Transendothelial electrical resistance - a marker of permeability - of human endothelial cells was measured using a voltohmmeter. We measured plasma Heparin-Binding Protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an Heparin-Binding Protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited Heparin-Binding Protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher Heparin-Binding Protein-to-albumin ratio (1.6 vs 0.89; p 3.05), Heparin-Binding Protein quartiles (> 69.8), and Heparin-Binding Protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-Binding Protein and Heparin-Binding Protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of Heparin-Binding Protein-to-albumin ratio and Heparin-Binding Protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality. Conclusions: Albumin inhibits Heparin-Binding Protein-induced increased human endothelial cell permeability and Heparin-Binding Protein greater than 30 ng/mL and Heparin-Binding Protein-to-albumin ratio greater than 3.01 - but not serum albumin - identified patients at increased risk for acute kidney injury in septic shock. (Less)

  • Heparin Binding Protein hbp improves prediction of sepsis related acute kidney injury
    Annals of Intensive Care, 2017
    Co-Authors: Jonas Tverring, Jane Fisher, Ville Pettilä, Suvi T Vaara, Meri Poukkanen, Adam Linder
    Abstract:

    Sepsis-related acute kidney injury (AKI) accounts for major morbidity and mortality among the critically ill. Heparin-Binding Protein (HBP) is a promising biomarker in predicting development and prognosis of severe sepsis and septic shock that has recently been proposed to be involved in the pathophysiology of AKI. The objective of this study was to investigate the added predictive value of measuring plasma HBP on admission to the intensive care unit (ICU) regarding the development of septic AKI. We included 601 patients with severe sepsis or septic shock from the prospective, observational FINNAKI study conducted in seventeen Finnish ICUs during a 5-month period (1 September 2011–1 February 2012). The main outcome measure was the development of KDIGO AKI stages 2–3 from 12 h after admission up to 5 days. Statistical analysis for the primary endpoint included construction of a clinical risk model, area under the receiver operating curve (ROC area), category-free net reclassification index (cfNRI) and integrated discrimination improvement (IDI) with 95% confidence intervals (95% CI). Out of 511 eligible patients, 101 (20%) reached the primary endpoint. The addition of plasma HBP to a clinical risk model significantly increased ROC area (0.82 vs. 0.78, p = 0.03) and risk classification scores: cfNRI 62.0% (95% CI 40.5–82.4%) and IDI 0.053 (95% CI 0.029–0.075). Plasma HBP adds predictive value to known clinical risk factors in septic AKI. Further studies are warranted to compare the predictive performance of plasma HBP to other novel AKI biomarkers.

  • Heparin Binding Protein hbp a causative marker and potential target for Heparin treatment of human sepsis induced acute kidney injury
    Shock, 2017
    Co-Authors: Jane Fisher, Peter Bentzer, Keith R Walley, James A Russell, John H Boyd, Matthias Morgelin, Devyn Parsons, Stefano Secchia, Adam Linder
    Abstract:

    RATIONALE: Sepsis-induced acute kidney injury (AKI) is a common condition with high morbidity and mortality. Neutrophil-derived Heparin-Binding Protein (HBP) induces vascular leakage and is a promising biomarker of sepsis-induced organ dysfunction. It remains unknown if HBP is prognostic of AKI in septic shock and if HBP could play a role in the pathophysiology of sepsis-induced AKI.OBJECTIVES: To determine the association of plasma HBP levels with development of AKI, investigate the role of HBP in the pathophysiology of sepsis-induced AKI, and test the effect of blocking HBP using Heparin derivatives.METHODS: In 296 septic shock patients from the randomized multicenter Vasopressin and Septic Shock Trial (VASST) plasma HBP levels were associated with development of AKI and need for renal replacement therapy (RRT). Human renal tubular cells were exposed to recombinant HBP to evaluate inflammation and Heparin derivatives were used to abrogate these effects. Finally, mice were exposed to HBP with and without Heparin derivatives and the kidneys examined for signs of inflammation.FINDINGS: Plasma HBP levels were significantly higher in patients with AKI and those requiring RRT. HBP levels identified patients with moderate AKI with an area under curve (AUC) of 0.85. HBP increased IL-6 production in renal tubular epithelial cells. Different Heparin derivatives abrogated the HBP-induced increased inflammatory response in vitro and in vivo.CONCLUSION: Elevated plasma HBP is associated with development of sepsis-induced AKI and HBP is involved in its pathophysiology. Our studies suggest that Heparin(s) could be tested for efficacy and safety of prevention of sepsis-induced AKI. (Less)

  • Heparin Binding Protein a key player in the pathophysiology of organ dysfunction in sepsis
    Journal of Internal Medicine, 2017
    Co-Authors: Jane Fisher, Adam Linder
    Abstract:

    Infectious diseases remain a major health problem, and sepsis and other severe infectious diseases are common causes of morbidity and mortality. There is a need for clinical and laboratory tools to identify patients with severe infections early and to distinguish between bacterial and nonbacterial conditions. Heparin-Binding Protein (HBP), also known as azurocidin or cationic antimicrobial Protein of 37 KDa, is a promising biomarker to distinguish between patients with these conditions. It is biologically plausible that HBP is an early and predictive biomarker because it is prefabricated and rapidly mobilized from migrating neutrophils in response to bacterial infections. HBP induces vascular leakage and oedema formation and has a pro-inflammatory effect on a variety of white blood cells and epithelial cells. The dysregulation of vascular barrier function and cellular inflammatory responses can then lead to organ dysfunction. Indeed, it has been shown that patients with sepsis express elevated levels of HBP in plasma several hours before they develop hypotension or organ dysfunction. HBP has a major role in the pathophysiology of severe bacterial infections and thus represents a potential diagnostic marker and a target for the treatment of sepsis.

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