Skip to main content

Impact of sepsis-associated cytokine storm on plasma NGAL during acute kidney injury in a model of polymicrobial sepsis

Acute kidney injury (AKI) is a common, early and severe organ dysfunction during sepsis [1]. One promising biomarker for its early detection is neutrophil gelatinase-associated lipocalin (NGAL) [2, 3]. During sepsis, cytokines, including TNFα, IL6 and IL10, initiate a broad variety of signalling that affect AKI development. Using a lipo polysaccharide-induced AKI animal model, correlation of NGAL expression to TNFα but not IL6 expression was previously described [4]. During polymicrobial sepsis, it remains unclear whether there is a correlation between protein levels and the role of plasma NGAL as an inflammatory protein rather than a marker of AKI.

After gaining permission (Thueringer Landesamt fuer Lebensmittelsicherheit und Verbraucherschutz; TVA02-10/10), sepsis in mice was induced by injection of human faeces. Mice were sacrificed at baseline, 6 h and 24 h post-sepsis insult. Plasma NGAL, cytokines, blood urea nitrogen (BUN), serum creatinine (Crea) and other laboratory markers were ascertained and ANOVA and Spearman correlation testing performed.

Sepsis symptoms developed within the first 6 h (Table 1). During sepsis, IL6, IL10, monocyte chemotactic protein-1 (MCP1), interferon-gamma (IFNγ) and TNFα significantly increased (Figure 1a). Concerning sepsis-associated AKI, plasma NGA L was already elevated at 6 h, whereas Crea and BUN remained stable (Figure 1b). After 24 h, these markers were increased as well. Although Crea was still normal at 6 h, there was a significant positive correlation with NGAL, which was maintained at 24 h (Table 2). A significant correlation between NGAL and TNFα was observed at 6 h and 24 h. In addition, significant correlations of NGAL with IL6, IL10 and MCP1 were found exclusively after 24 h but not after 6 h. No correlation was detected for IFNγ.

Table 1 Characteristics of healthy and polymicrobial infected mice
Figure 1
figure1

Laboratory findings during polymicrobial sepsis in mice. (a) Concentration of IL6, IL10, monocyte chemotactic protein-1 (MCP1), interferon-gamma (IFNγ) and TNFα in healthy untreated mice as well as 6 and 24 h after sepsis induction. (b) Concentration of creatinine (μg/dl), blood urea nitrogen (urea; mg/dl) and neutrophil gelatinase-associated lipocalin (NGAL; ng/ml) in healthy, untreated mice as well as 6 and 24 h after sepsis induction. *P < 0.05, **P < 0.01, ***P < 0.001, all compared to healthy untreated mice.

Table 2 Correlation of NGAL and creatinine with various cytokines

Data indicate that the early increase of plasma NGAL during sepsis is not solely a result of inflammation and its associated cytokine storm but rather results from early kidney damage. As described recently [4], the association of TNFα with NGAL could be confirmed during polymicrobial sepsis. Since cytokines stimulate the expression of each other, it might be assumed that the late association of NGAL with IL6, IL10 and MCP1 was triggered by TNFα. We hypothesize that septic AKI, as remote organ failure, is mainly initiated by TNFα. This might explain further why higher NGAL levels are found in septic versus non-septic AKI [5].

Abbreviations

AKI:

acute kidney injury

BUN:

blood urea nitrogen

Crea:

creatinine

IFN:

interferon

IL:

interleukin

MCP1:

monocyte chemotactic protein-1

NGAL:

neutrophil gelatinase-associated lipocalin

TNF:

tumour necrosis factor.

References

  1. 1.

    Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005, 16: 3365-3370. 10.1681/ASN.2004090740

    Article  PubMed  Google Scholar 

  2. 2.

    Clerico A, Galli C, Fortunato A, Ronco C: Neutrophil gelatinase-associated lipocalin (NGAL) as biomarker of acute kidney injury: a review of the laboratory characteristics and clinical evidences. Clin Chem Lab Med 2012, 50: 1505-1517.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Constantin JM, Futier E, Perbet S, Roszyk L, Lautrette A, Gillart T, Guerin R, Jabaudon M, Souweine B, Bazin JE, Sapin V: Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: a prospective study. J Crit Care 2010, 25: 176 e171-176.

    Article  Google Scholar 

  4. 4.

    Han M, Li Y, Liu M, Cong B: Renal neutrophil gelatinase associated lipocalin expression in lipopolysaccharide-induced acute kidney injury in the rat. BMC Nephrol 2012, 13: 25. 10.1186/1471-2369-13-25

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  5. 5.

    Bagshaw SM, Bennett M, Haase M, Haase-Fielitz A, Egi M, Morimatsu H, D'Amico G, Goldsmith D, Devarajan P, Bellomo R: Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med 2010, 36: 452-461. 10.1007/s00134-009-1724-9

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Edith Walter and Danny Himsel for their excellent technical support. This publication was supported by the BMBF to the Center of Sepsis Control and Care (BMBF; FKZ 01EO1002, CSCC; project number D1.21 and A1.2).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Gordon P Otto.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

GPO and MB designed the study and wrote the first draft of the manuscript. MS was involved in data analysis and interpretation. RAC was involved in supervision, and data analysis and its interpretation. All authors read and approved the final draft of the manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Otto, G.P., Busch, M., Sossdorf, M. et al. Impact of sepsis-associated cytokine storm on plasma NGAL during acute kidney injury in a model of polymicrobial sepsis. Crit Care 17, 419 (2013). https://doi.org/10.1186/cc12540

Download citation

Keywords

  • Blood Urea Nitrogen
  • Acute Kidney Injury
  • Spearman Correlation Testing
  • Cytokine Storm
  • NGAL Level