Monitoring and outcome prediction of sepsis by neutrophil specific biomarkers
Main Article Content
Abstract
HNL (human Neutrophil Lipocalin) is a protein secreted from the activated neutrophil granulocytes but also from epithelial cells. HNL is measured by sensitive immunoassays in most bodily fluids and exists in several variants of which the monomer and the dimer variants are the most abundant. Depending on the antibody configuration of the immunoassays we may detect different molecular variants of HNL, and which may have different cellular origins. The dimeric form of HNL is entirely neutrophil specific and other assays may preferentially detect HNL originating from epithelial cells such as the tubular cells of the kidney. In this brief review we have focused on the utility of HNL as a biomarker for antibiotics stewardship in patients with sepsis and show that the dimeric form of HNL is reduced within 24 hours as the response to successful antibiotic treatment in sepsis in contrast to the reduction of blood levels of procalcitonin and heparin-binding protein which takes 3-4 days. Another variant of HNL showed to be the most powerful predictor of outcome of these patients. We conclude that the measurements of these HNL variants should be considered for implementation in intensive care units and other settings with seriously ill infected patients.
Article Details
How to Cite
VENGE, Per; XU, Shengyuan.
Monitoring and outcome prediction of sepsis by neutrophil specific biomarkers.
Medical Research Archives, [S.l.], v. 12, n. 12, dec. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6202>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.6202.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
(1) Singer M, Deutschman CS, Seymour CW et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8):801-810.
(2) Saxena J, Das S, Kumar A et al. Biomarkers in sepsis. Clin Chim Acta 2024;562:119891.
(3) Xie Y, Huang P, Zhang J et al. Biomarkers for the diagnosis of sepsis-associated acute kidney injury: systematic review and meta-analysis. Ann Palliat Med 2021.
(4) Venge P, Peterson C, Xu S, Larsson A, Johansson J, Tydén J. HNL Dimer in plasma is a unique and useful biomarker for the monitoring of antibiotic treatment in sepsis. PLOS ONE 2024;In Press.
(5) Venge P, Xu S, Mårtensson J. HNL Dimer-A specific biomarker of neutrophil activity - in sepsis and antibiotic monitoring. A mini-review. Arch Clin Biomed Res 2022;6 (1):145-152.
(6) Albert C, Haase M, Albert A, Zapf A, Braun-Dullaeus RC, Haase-Fielitz A. Biomarker-Guided Risk Assessment for Acute Kidney Injury: Time for Clinical Implementation? Ann Lab Med 2021;41(1):1-15.
(7) Bellos I, Fitrou G, Daskalakis G, Perrea DN, Pergialiotis V. Neutrophil gelatinase-associated lipocalin as predictor of acute kidney injury in neonates with perinatal asphyxia: a systematic review and meta-analysis. Eur J Pediatr 2018;177(10):1425-1434.
(8) Cai L, Borowiec J, Xu S, Han W, Venge P. Assays of urine levels of HNL/NGAL in patients undergoing cardiac surgery and the impact of antibody configuration on their clinical performances. Clin Chim Acta 2009;403(1-2):121-125.
(9) Cai L, Rubin J, Han W, Venge P, Xu S. The Origin of Multiple Molecular Forms in Urine of HNL/NGAL. Clin J Am Soc Nephrol 2010.
(10) Claudel SE, Waikar SS. Systematic Review of Kidney Injury Biomarkers for the Evaluation of CKD of Uncertain Etiology. Kidney Int Rep 2024;9(6): 1614-1632.
(11) Ferreira GS, Frota ML, Gonzaga MJD, Vattimo MFF, Lima C. The Role of Biomarkers in Diagnosis of Sepsis and Acute Kidney Injury. Biomedicines 2024;12(5).
(12) Jaberi SA, Cohen A, D'Souza C et al. Lipocalin-2: Structure, function, distribution and role in metabolic disorders. Biomed Pharmacother 2021;142:112002.
(13) Khawaja S, Jafri L, Siddiqui I, Hashmi M, Ghani F. The utility of neutrophil gelatinase-associated Lipocalin (NGAL) as a marker of acute kidney injury (AKI) in critically ill patients. Biomark Res 2019;7:4.
(14) Marakala V. Neutrophil gelatinase-associated lipocalin (NGAL) in kidney injury - A systematic review. Clin Chim Acta 2022;536:135-141.
(15) Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol 2008;23(12):2151-2157.
(16) Romejko K, Markowska M, Niemczyk S. The Review of Current Knowledge on Neutrophil Gelatinase-Associated Lipocalin (NGAL). Int J Mol Sci 2023;24(13).
(17) Shi K, Jiang W, Song L et al. Persistent acute kidney injury biomarkers: A systematic review and meta-analysis. Clin Chim Acta 2025;564:119907.
(18) Xu S, Venge P. Lipocalins as biochemical markers of disease. Biochim Biophys Acta 2000;1482(1-2): 298-307.
(19) Xu SY, Carlson M, Engstrom A, Garcia R, Peterson CG, Venge P. Purification and characterization of a human neutrophil lipocalin (HNL) from the secondary granules of human neutrophils. Scand J Clin Lab Invest 1994;54:365-376.
(20) Bartsch S, Tschesche H. Cloning and expression of human neutrophil lipocalin cDNA derived from bone marrow and ovarian cancer cells. FEBS Lett 1995;357:255-259.
(21) Kjeldsen L, Bainton DF, Sengelov H, Borregaard N. Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils. Blood 1994;83 No.3:799-807.
(22) Xu SY, Höglund M, Venge P. The effect of granulocyte colony-stimulating factor (G-CSF) on the degranulation of secondary granule proteins from human neutrophils in vivo may be indirect. Br J Haematol 1996;93(3):558-568.
(23) Schmekel B, Seveus L, Xu SY, Venge P. Human neutrophil lipocalin (HNL) and myeloperoxidase (MPO). Studies of lung lavage fluid and lung tissue. Respir Med 2000;94(6):564-568.
(24) Albert C, Zapf A, Haase M et al. Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis. Am J Kidney Dis 2020;76(6):826-841.
(25) Glassford NJ, Schneider AG, Xu S et al. The nature and discriminatory value of urinary neutrophil gelatinase-associated lipocalin in critically ill patients at risk of acute kidney injury. Intensive Care Med 2013;39(10):1714-1724.
(26) Venge P, Xu S, Peterson C et al. Plasma biomarkers associated to outcome in patients with Sars-Cov-2 infection. J Clin Lab Med 2022;7(1):1-8.
(27) Xu SY, Pauksen K, Venge P. Serum measurements of human neutrophil lipocalin (HNL) discriminate between acute bacterial and viral infections. Scand J Clin Lab Invest 1995;55(2):125-131.
(28) Yu Z, Jing H, Hongtao P et al. Distinction between bacterial and viral infections by serum measurement of human neutrophil lipocalin (HNL) and the impact of antibody selection. J Immunol Methods 2016;432:82-86.
(29) Fang C, Wang Z, Dai Y, Chang W, Sun L, Ma X. Serum human neutrophil lipocalin: An effective biomarker for diagnosing bacterial infections. Clin Biochem 2020;75:23-29.
(30) Venge P, Douhan-Hakansson L, Garwicz D, Peterson C, Xu S, Pauksen K. Human Neutrophil Lipocalin as a Superior Diagnostic Means To Distinguish between Acute Bacterial and Viral Infections. Clin Vaccine Immunol 2015;22(9):1025-1032.
(31) Venge P, Hakansson LD, Garwicz D, Peterson C, Xu S, Pauksen K. Human neutrophil lipocalin in fMLP-activated whole blood as a diagnostic means to distinguish between acute bacterial and viral infections. J Immunol Methods 2015;424:85-90.
(32) Assarsson J, Korner U, Lundholm K. Evaluation of procalcitonin as a marker to predict antibiotic response in adult patients with acute appendicitis: a prospective observational study. Surg Infect (Larchmt ) 2014;15(5):601-605.
(33) Prkno A, Wacker C, Brunkhorst FM, Schlattmann P. Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock--a systematic review and meta-analysis. Crit Care 2013;17(6):R291.
(34) Shehabi Y, Sterba M, Garrett PM et al. Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med 2014;190(10):1102-1110.
(35) Jonsson N, Gille-Johnson P, Martling CR, Xu S, Venge P, Martensson J. Performance of plasma measurement of neutrophil gelatinase-associated lipocalin as a biomarker of bacterial infections in the intensive care unit. J Crit Care 2019;53:264-270.
(2) Saxena J, Das S, Kumar A et al. Biomarkers in sepsis. Clin Chim Acta 2024;562:119891.
(3) Xie Y, Huang P, Zhang J et al. Biomarkers for the diagnosis of sepsis-associated acute kidney injury: systematic review and meta-analysis. Ann Palliat Med 2021.
(4) Venge P, Peterson C, Xu S, Larsson A, Johansson J, Tydén J. HNL Dimer in plasma is a unique and useful biomarker for the monitoring of antibiotic treatment in sepsis. PLOS ONE 2024;In Press.
(5) Venge P, Xu S, Mårtensson J. HNL Dimer-A specific biomarker of neutrophil activity - in sepsis and antibiotic monitoring. A mini-review. Arch Clin Biomed Res 2022;6 (1):145-152.
(6) Albert C, Haase M, Albert A, Zapf A, Braun-Dullaeus RC, Haase-Fielitz A. Biomarker-Guided Risk Assessment for Acute Kidney Injury: Time for Clinical Implementation? Ann Lab Med 2021;41(1):1-15.
(7) Bellos I, Fitrou G, Daskalakis G, Perrea DN, Pergialiotis V. Neutrophil gelatinase-associated lipocalin as predictor of acute kidney injury in neonates with perinatal asphyxia: a systematic review and meta-analysis. Eur J Pediatr 2018;177(10):1425-1434.
(8) Cai L, Borowiec J, Xu S, Han W, Venge P. Assays of urine levels of HNL/NGAL in patients undergoing cardiac surgery and the impact of antibody configuration on their clinical performances. Clin Chim Acta 2009;403(1-2):121-125.
(9) Cai L, Rubin J, Han W, Venge P, Xu S. The Origin of Multiple Molecular Forms in Urine of HNL/NGAL. Clin J Am Soc Nephrol 2010.
(10) Claudel SE, Waikar SS. Systematic Review of Kidney Injury Biomarkers for the Evaluation of CKD of Uncertain Etiology. Kidney Int Rep 2024;9(6): 1614-1632.
(11) Ferreira GS, Frota ML, Gonzaga MJD, Vattimo MFF, Lima C. The Role of Biomarkers in Diagnosis of Sepsis and Acute Kidney Injury. Biomedicines 2024;12(5).
(12) Jaberi SA, Cohen A, D'Souza C et al. Lipocalin-2: Structure, function, distribution and role in metabolic disorders. Biomed Pharmacother 2021;142:112002.
(13) Khawaja S, Jafri L, Siddiqui I, Hashmi M, Ghani F. The utility of neutrophil gelatinase-associated Lipocalin (NGAL) as a marker of acute kidney injury (AKI) in critically ill patients. Biomark Res 2019;7:4.
(14) Marakala V. Neutrophil gelatinase-associated lipocalin (NGAL) in kidney injury - A systematic review. Clin Chim Acta 2022;536:135-141.
(15) Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol 2008;23(12):2151-2157.
(16) Romejko K, Markowska M, Niemczyk S. The Review of Current Knowledge on Neutrophil Gelatinase-Associated Lipocalin (NGAL). Int J Mol Sci 2023;24(13).
(17) Shi K, Jiang W, Song L et al. Persistent acute kidney injury biomarkers: A systematic review and meta-analysis. Clin Chim Acta 2025;564:119907.
(18) Xu S, Venge P. Lipocalins as biochemical markers of disease. Biochim Biophys Acta 2000;1482(1-2): 298-307.
(19) Xu SY, Carlson M, Engstrom A, Garcia R, Peterson CG, Venge P. Purification and characterization of a human neutrophil lipocalin (HNL) from the secondary granules of human neutrophils. Scand J Clin Lab Invest 1994;54:365-376.
(20) Bartsch S, Tschesche H. Cloning and expression of human neutrophil lipocalin cDNA derived from bone marrow and ovarian cancer cells. FEBS Lett 1995;357:255-259.
(21) Kjeldsen L, Bainton DF, Sengelov H, Borregaard N. Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils. Blood 1994;83 No.3:799-807.
(22) Xu SY, Höglund M, Venge P. The effect of granulocyte colony-stimulating factor (G-CSF) on the degranulation of secondary granule proteins from human neutrophils in vivo may be indirect. Br J Haematol 1996;93(3):558-568.
(23) Schmekel B, Seveus L, Xu SY, Venge P. Human neutrophil lipocalin (HNL) and myeloperoxidase (MPO). Studies of lung lavage fluid and lung tissue. Respir Med 2000;94(6):564-568.
(24) Albert C, Zapf A, Haase M et al. Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis. Am J Kidney Dis 2020;76(6):826-841.
(25) Glassford NJ, Schneider AG, Xu S et al. The nature and discriminatory value of urinary neutrophil gelatinase-associated lipocalin in critically ill patients at risk of acute kidney injury. Intensive Care Med 2013;39(10):1714-1724.
(26) Venge P, Xu S, Peterson C et al. Plasma biomarkers associated to outcome in patients with Sars-Cov-2 infection. J Clin Lab Med 2022;7(1):1-8.
(27) Xu SY, Pauksen K, Venge P. Serum measurements of human neutrophil lipocalin (HNL) discriminate between acute bacterial and viral infections. Scand J Clin Lab Invest 1995;55(2):125-131.
(28) Yu Z, Jing H, Hongtao P et al. Distinction between bacterial and viral infections by serum measurement of human neutrophil lipocalin (HNL) and the impact of antibody selection. J Immunol Methods 2016;432:82-86.
(29) Fang C, Wang Z, Dai Y, Chang W, Sun L, Ma X. Serum human neutrophil lipocalin: An effective biomarker for diagnosing bacterial infections. Clin Biochem 2020;75:23-29.
(30) Venge P, Douhan-Hakansson L, Garwicz D, Peterson C, Xu S, Pauksen K. Human Neutrophil Lipocalin as a Superior Diagnostic Means To Distinguish between Acute Bacterial and Viral Infections. Clin Vaccine Immunol 2015;22(9):1025-1032.
(31) Venge P, Hakansson LD, Garwicz D, Peterson C, Xu S, Pauksen K. Human neutrophil lipocalin in fMLP-activated whole blood as a diagnostic means to distinguish between acute bacterial and viral infections. J Immunol Methods 2015;424:85-90.
(32) Assarsson J, Korner U, Lundholm K. Evaluation of procalcitonin as a marker to predict antibiotic response in adult patients with acute appendicitis: a prospective observational study. Surg Infect (Larchmt ) 2014;15(5):601-605.
(33) Prkno A, Wacker C, Brunkhorst FM, Schlattmann P. Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock--a systematic review and meta-analysis. Crit Care 2013;17(6):R291.
(34) Shehabi Y, Sterba M, Garrett PM et al. Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med 2014;190(10):1102-1110.
(35) Jonsson N, Gille-Johnson P, Martling CR, Xu S, Venge P, Martensson J. Performance of plasma measurement of neutrophil gelatinase-associated lipocalin as a biomarker of bacterial infections in the intensive care unit. J Crit Care 2019;53:264-270.