Jane Fisher

Heparin-Binding Protein (HBP): A Causative Marker and Potential Target for Heparin Treatment of Human Sepsis-Induced Acute Kidney Injury

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.

Elevated Plasma Angiopoietin-2 Levels Are Associated With Fluid Overload, Organ Dysfunction, and Mortality in Human Septic Shock.

Objectives:Angiopoietins modulate endothelial permeability via endothelial cell junctions. Angiopoietin-2 blocks the angiopoietin-1/Tie-2 interaction that stabilizes these junctions, and elevated plasma angiopoietin-2 levels are associated with vascular leakage. We hypothesized that plasma angiopoietin-1 and angiopoietin-2 levels are associated with indirect markers of increased vascular permeability, organ dysfunction, mortality, and plasma proinflammatory cytokine levels in human septic shock. Design:Multicenter observational cohort study derived from a randomized controlled trial (Vasopressin and Septic Shock Trial of vasopressin versus norepinephrine in septic shock). Setting:ICUs of hospitals in Canada, Australia, and the United States. Patients:Three hundred forty-one patients in the randomized, controlled Vasopressin and Septic Shock Trial trial of vasopressin versus norepinephrine in septic shock. Interventions:None. Measurement and Main Results:We measured plasma levels of angiopoietin-1 and angiopoietin-2 at study baseline and determined their association with percent fluid overload and acute organ dysfunction and generated a receiver operating characteristic curve for plasma angiopoietin-2 levels versus acute kidney injury. We also determined the association of angiopoietin-1 and angiopoietin-2 levels with hemodynamics, mortality, and plasma cytokine levels. Plasma angiopoietin-2 levels were directly associated with percent fluid overload at baseline (rs = 0.18; p = 0.0008) and at 6 hours (rs = 0.13; p = 0.023), but not at 24 hours (rs = 0.041; p = 0.46). Plasma angiopoietin-2 levels were associated with the development of hepatic (p < 0.0001) and coagulation (p < 0.0001) dysfunction and acute kidney injury (p < 0.0001). Receiver operating characteristic curve had an area under the curve of 0.73 for acute kidney injury. angiopoietin-2 levels were also inversely associated with days alive (r = –0.24; p = 0.010) and positively associated with increased 7-day (log-rank trend chi-square = 5.9; p = 0.015) and 28-day (log-rank chi square = 4.9; p = 0.027) mortality. A threshold of angiopoietin-2 levels above the first quartile (> 5,807 pg/mL) was observed to be associated with increased mortality risk, which aligns with prior studies. Plasma angiopoietin-2 levels were positively associated with plasma cytokine levels, including tumor necrosis factor-&agr; and interleukin-6 at baseline (rs = 0.39; p < 0.0001 and rs = 0.51; p < 0.0001) and at 24 hours (rs = 0.29; p < 0.0001 and rs = 0.41; p < 0.0001). Conclusions:Increased plasma angiopoietin-2 levels are associated with increased fluid overload, hepatic and coagulation dysfunction, acute kidney injury, mortality, and plasma cytokines in human septic shock. angiopoietin-2 activation may increase vascular leakage leading to increased fluid requirements, organ dysfunction, and death from septic shock.

Heparin-binding protein: a key player in the pathophysiology of organ dysfunction in sepsis

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.

Short-term organ dysfunction is associated with long-term (10-Yr) mortality of septic shock

Objectives:As mortality of septic shock decreases, new therapies focus on improving short-term organ dysfunction. However, it is not known whether short-term organ dysfunction is associated with long-term mortality of septic shock. Design:Retrospective single-center. Setting:Mixed medical-surgical ICU. Patients:One thousand three hundred and thirty-one patients with septic shock were included from 2000-2004. To remove the bias of 28-day nonsurvivors’ obvious association with long-term mortality, we determined the associations of days alive and free of ventilation, vasopressors and renal replacement therapy in 28-day and 1-year survivors with 1-, 5- and 10-year mortality in unadjusted analyses and analyses adjusted for age, gender, Acute Physiology and Chronic Health Evaluation II and presence of chronic comorbidities. Interventions:None. Measurements and Main Results:Days alive and free of ventilation, vasopressors, and renal replacement therapy were highly significantly associated with 1-, 5-, and 10-year mortality (p < 0.0001). In 28-day survivors, using Bonferroni-corrected multiple logistic regression, days alive and free of ventilation (p < 0.0001, p = 0.0002, and p = 0.001), vasopressors (p < 0.0001, p < 0.0001, and p = 0.0004), and renal replacement therapy (p = 0.0008, p = 0.0008, and p = 0.0002) were associated with increased 1-, 5-, and 10-year mortality, respectively. In 1-year survivors, none of the acute organ support and dysfunction measures were associated with 5- and 10-year mortality. Conclusions:Days alive and free of ventilation, vasopressors, and renal replacement therapy in septic shock in 28-day survivors was associated with 1-, 5-, and 10-year mortality. These associations are nullified in 1-year survivors in whom none of the acute organ support measures were associated with 5- and 10-year mortality. This suggests that therapies that decrease short-term organ dysfunction could also improve long-term outcomes of 28-day survivors of septic shock.

Erratum to: Heparin-binding protein is important for vascular leak in sepsis

Background: Elevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP. The objective of the present study was to test the hypothesis that HBP is a key mediator of the increased endothelial permeability observed in sepsis and to test potential treatments that inhibit HBPinduced increases in permeability.

Sepsis 2016 Agra, India

Table of contentsP1 D-Dimer in adult patients with presumed sepsis and their clinical outcomesSurinder Kumar Sharma, Anurag Rohatgi, Mansi BajajP2 Diagnosis of infection utilizing Acellix CD64Charles L. Sprung, Ricardo Calderon Morales, Harvey Kasdan, Allon Reiter, Tobias Volker, Julien MeissonnierP3 High levels of phenylcarboxylic acids reflect the severity in ICU patients and affect phagocytic activity of neutrophilsNatalia Beloborodova, Viktor Moroz, Aleksandra Bedova, Yulia Sarshor, Artem Osipov, Katerina ChernevskayaP4 The role of bacterial phenolic metabolites in mitochondrial dysfunctionNadezhda Fedotcheva, Ekaterina Chernevskaya, Natalia BeloborodovaP5 The early diagnosis of severe sepsis and judgment of rapid transport to critical care center: better prognostic factorHisashi Imahase, Kosuke C Yamada, Yuichiro Sakamoto, Miho Ohta, Ryota Sakurai, Mayuko Yahata, Mitsuru Umeka, Toru Miike, Hiroyuki Koami, Futoshi Nagashima, Takashi Iwamura, Satoshi InoueP6 Translational neuromodulation of the immune systemZhifeng Li, Dennis Grech, Patrick Morcillo, Alex Bekker, Luis UlloaP7 Pathway-level meta-analysis reveals transcriptional signature of septic shockSamanwoy Mukhopadhyay, Abhay D Pandey, Samsiddhi Bhattacharjee, Saroj K MohapatraP8 Antibiotic dosing in septic patients on the critical care unit - a literature reviewJulie K WilsonP9 Pandemic of Escherichia coli clone O25: H4-ST131 producing CTX-M-15 extended spectrum- β- lactamase- as serious cause of multidrug resistance extraintestinal pathogenic E. coli infections in IndiaSavita Jadhav, Rabindra Nath Misra, Nageswari Gandham, Kalpana Angadi, Chanda Vywahare, Neetu Gupta, Deepali DesaiP10 Detection and characterization of meningitis using a DDA-based mass spectrometry approachAnahita Bakochi, Tirthankar Mohanty, Adam Linder, Johan MalmströmP11 Diagnostic usefulness of lipid profile and procalcitonin in sepsis and trauma patientsDimple Anand, Seema Bhargava, Lalit Mohan Srivastava, Sumit RayP12 Heparin – a novel therapeutic in sepsis?Jane Fisher, Peter Bentzer, Adam LinderP13 Hypothalamic impairment is associated with vasopressin deficiency during sepsisLuis Henrique Angenendt da Costa, Nilton Nascimentos dos Santos Júnior Carlos Henrique Rocha Catalão, Maria José Alves da RochaP14 Presepsin (soluble CD14 subtype) is a dependable prognostic marker in critical septic patientsAlfredo Focà, Cinzia Peronace, Giovanni Matera, Aida Giancotti, Giorgio Settimo Barreca, Angela Quirino, Maria Teresa Loria, Pio Settembre, Maria Carla Liberto, Bruno AmanteaP15 Safety and efficacy of gelatin-containing solutions versus crystalloids and albumin - a systematic review with quantitative and qualitative summariesChristiane Hartog, Christiane Hartog, Claudia Moeller, Carolin Fleischmann, Daniel Thomas-Rueddel, Vlasislav Vlasakov, Bram Rochwerg, Philip Theurer, Konrad ReinhartP16 Immunomodulatory properties of peripheral blood mesenchymal stem cells following endotoxin stimulation in an equine modelAnna E. Smith, Sandra D. TaylorP17 Frequency and outcome of early sepsis-associated coagulopathyChristopher Da Costa, Amanda Radford, Terry Lee, Joel Singer, John Boyd, David Fineberg, Mark Williams, James A Russell

Sepsis 2016 Agra, India: Agra, India. 5-6 February 2016

Table of contentsP1 D-Dimer in adult patients with presumed sepsis and their clinical outcomesSurinder Kumar Sharma, Anurag Rohatgi, Mansi BajajP2 Diagnosis of infection utilizing Acellix CD64Charles L. Sprung, Ricardo Calderon Morales, Harvey Kasdan, Allon Reiter, Tobias Volker, Julien MeissonnierP3 High levels of phenylcarboxylic acids reflect the severity in ICU patients and affect phagocytic activity of neutrophilsNatalia Beloborodova, Viktor Moroz, Aleksandra Bedova, Yulia Sarshor, Artem Osipov, Katerina ChernevskayaP4 The role of bacterial phenolic metabolites in mitochondrial dysfunctionNadezhda Fedotcheva, Ekaterina Chernevskaya, Natalia BeloborodovaP5 The early diagnosis of severe sepsis and judgment of rapid transport to critical care center: better prognostic factorHisashi Imahase, Kosuke C Yamada, Yuichiro Sakamoto, Miho Ohta, Ryota Sakurai, Mayuko Yahata, Mitsuru Umeka, Toru Miike, Hiroyuki Koami, Futoshi Nagashima, Takashi Iwamura, Satoshi InoueP6 Translational neuromodulation of the immune systemZhifeng Li, Dennis Grech, Patrick Morcillo, Alex Bekker, Luis UlloaP7 Pathway-level meta-analysis reveals transcriptional signature of septic shockSamanwoy Mukhopadhyay, Abhay D Pandey, Samsiddhi Bhattacharjee, Saroj K MohapatraP8 Antibiotic dosing in septic patients on the critical care unit - a literature reviewJulie K WilsonP9 Pandemic of Escherichia coli clone O25: H4-ST131 producing CTX-M-15 extended spectrum- β- lactamase- as serious cause of multidrug resistance extraintestinal pathogenic E. coli infections in IndiaSavita Jadhav, Rabindra Nath Misra, Nageswari Gandham, Kalpana Angadi, Chanda Vywahare, Neetu Gupta, Deepali DesaiP10 Detection and characterization of meningitis using a DDA-based mass spectrometry approachAnahita Bakochi, Tirthankar Mohanty, Adam Linder, Johan MalmströmP11 Diagnostic usefulness of lipid profile and procalcitonin in sepsis and trauma patientsDimple Anand, Seema Bhargava, Lalit Mohan Srivastava, Sumit RayP12 Heparin – a novel therapeutic in sepsis?Jane Fisher, Peter Bentzer, Adam LinderP13 Hypothalamic impairment is associated with vasopressin deficiency during sepsisLuis Henrique Angenendt da Costa, Nilton Nascimentos dos Santos Júnior Carlos Henrique Rocha Catalão, Maria José Alves da RochaP14 Presepsin (soluble CD14 subtype) is a dependable prognostic marker in critical septic patientsAlfredo Focà, Cinzia Peronace, Giovanni Matera, Aida Giancotti, Giorgio Settimo Barreca, Angela Quirino, Maria Teresa Loria, Pio Settembre, Maria Carla Liberto, Bruno AmanteaP15 Safety and efficacy of gelatin-containing solutions versus crystalloids and albumin - a systematic review with quantitative and qualitative summariesChristiane Hartog, Christiane Hartog, Claudia Moeller, Carolin Fleischmann, Daniel Thomas-Rueddel, Vlasislav Vlasakov, Bram Rochwerg, Philip Theurer, Konrad ReinhartP16 Immunomodulatory properties of peripheral blood mesenchymal stem cells following endotoxin stimulation in an equine modelAnna E. Smith, Sandra D. TaylorP17 Frequency and outcome of early sepsis-associated coagulopathyChristopher Da Costa, Amanda Radford, Terry Lee, Joel Singer, John Boyd, David Fineberg, Mark Williams, James A Russell