Soluble Fms-Like Tyrosine Kinase-1 Is A Marker of Endothelial Dysfunction During Sepsis

Abstract

Background: Sepsis is currently defined as a life-threatening organ dysfunction caused by a deregulated host response to infection. There is increasing evidence that the endothelium plays a crucial and pathogenic role in sepsis. Profound alterations of the endothelium associated with sepsis include increased leucocytes adhesions, shift to a procoagulant state, vasodilatation, altered barrier function with more permeable capillaries and tissue edema. The vascular endothelial growth factor (VEGF) pathway is involved in the control of microvascular permeability and has been involved in the pathogenesis of conditions associated with endothelial barrier disruption such as sepsis. sFlt-1 is a soluble variant of the VEGF receptor (Fms-like tyrosine kinase-1, Flt-1 or VEGFR-1) able to down-regulate the effects of VEGF by decreasing its signaling. We investigated the possible involvement of sFlt-1 as biomarker of endothelial alteration during sepsis, organ dysfunction and death.

Methods: Serum levels of s-Flt1 were measured in 170 hospitalized patients (77 with sepsis, confirmed by positive blood culture), and in 18 healthy volunteers. The sequential organ failure assessment (SOFA) score was determined by using biochemical and clinical parameters. In a small number of patients (9 individuals), s-Flt1 concentration was evaluated after negativization of the blood culture.

Results: Serum level of s-Flt1 was significantly higher in septic patients than blood culture-negative patients (277.7 ± 52.7 and 133.4 ± 12.4 pg/mL, respectively, P = 0.0088), both groups of patients had significantly higher concentration of sFlt-1 than healthy individuals (78.9 ± 2.5 pg/mL). Among sepsis cases, 68% was caused by Gram-negative bacteria, 27% by Gram-positive bacteria and 8% by Candida species. Serum level of s-Flt1 showed a significant difference between Gram-negative (274.1 pg/mL) and Gram-positive (145.7 pg/mL) sepsis. SOFA score (evaluated in 20 patients with sFlt-1 >190 pg/mL) showed a positive trend of correlation with the increasing sFlt-1 level. After blood culture negativization, serum level of sFlt-1 decreased (37%).

Conclusion: Our findings confirm, in a larger population of patients with sepsis, recent evidences that sFlt-1 levels are higher in patients with complicated-sepsis that evolve to septic shock and suggest that sFlt-1 could be a useful biomarker for sepsis severity. An anti-VEGF effect mediated by sFlt-1 could be hypothesized as salvage compensatory mechanism activated in response to sepsis.

Keywords: Endothelium dysfunction; SOFA score; Sepsis; sFlt-1.

Figure 1

Serum levels of sFlt-1 in patients groups. Septic patients showed significantly higher levels of sFlt-1 compared to sepsis-negative patients and healthy controls (P values indicated in figure; where not indicated, difference was not statistically significant). Two subgroups of sepsis-negative patients who underwent surgery or new borns were separately analyzed due to a potential not baseline condition for sFlt-1 assay after surgery or after birth; they showed a statistically significant difference with healthy controls but not with sepsis-positive nor -negative patients. Results are showed in semilogarithmic plot.

Figure 2

Serum levels of sFlt-1 in Gram-negative, Gram-positive, Candida infections and in sepsis-negative individuals. Significant higher levels of sFlt-1 have been observed in Gram-negative infected patients compared to both Gram-positive and sepsis-negative patients (P values indicated in figure; where not indicated, difference was not statistically significant).

Figure 3

sFlt-1 and sequential organ failure assessment in selected septic patients with serum levels of sFlt-1 higher than 190 pg/mL (see text for details). (a) sFlt-1 and SOFA score correlation, P < 0.0001 by Chi-squared test for trend. (b) serum levels of sFlt-1 mean values in patients deceased after sepsis and in alive individuals; SOFA score mean values are reported in the second axis. Higher serum levels of sFlt-1 and SOFA score are observed in deceased patients compared to survived (P < 0.05 by Chi-squared test). sFlt-1 values are showed in semilogarithmic plot.

Figure 4

sFlt-1 after sepsis resolution. (a) Serum levels of sFlt-1 measured in nine patients during and after sepsis. (b) Percentage reduction of sFlt-1 after sepsis. AV: mean percentage reduction.