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

Fisher, Jane LU ; Russell, James A.; Bentzer, Peter LU ; Parsons, Devyn; Secchia, Stefano; Mörgelin, Matthias LU ; Walley, Keith R.; Boyd, John H. and Linder, Adam LU (2017) In Shock 48(3). p.313-320
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Shock
volume
48
issue
3
pages
8 pages
publisher
BioMedical Press
external identifiers
  • scopus:85015703783
  • wos:000407581500007
ISSN
1540-0514
DOI
10.1097/SHK.0000000000000862
language
English
LU publication?
yes
id
09152aab-e760-4ea0-b373-689925b9899d
date added to LUP
2017-09-14 09:59:53
date last changed
2018-01-16 13:25:38
@article{09152aab-e760-4ea0-b373-689925b9899d,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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.</p>},
  author       = {Fisher, Jane and Russell, James A. and Bentzer, Peter and Parsons, Devyn and Secchia, Stefano and Mörgelin, Matthias and Walley, Keith R. and Boyd, John H. and Linder, Adam},
  issn         = {1540-0514},
  language     = {eng},
  number       = {3},
  pages        = {313--320},
  publisher    = {BioMedical Press},
  series       = {Shock},
  title        = {Heparin-Binding Protein (HBP) : A Causative Marker and Potential Target for Heparin Treatment of Human Sepsis-Induced Acute Kidney Injury},
  url          = {http://dx.doi.org/10.1097/SHK.0000000000000862},
  volume       = {48},
  year         = {2017},
}