High levels of exfoliated fragments following glycocalyx destruction in hemorrhagic fever with the renal syndrome are associated with mortality risk

Abstract

Background: The glycocalyx is a gel-like structure that covers the luminal side of vascular endothelial cells. It plays an important role in maintaining the integrity of the vascular endothelial barrier structure. However, the presence or absence of glycocalyx destruction in hemorrhagic fever with renal syndrome (HFRS) and its specific mechanism and role is still unclear.

Methods: In this study, we detected the levels of exfoliated glycocalyx fragments, namely, heparan sulfate (HS), hyaluronic acid (HA), and chondroitin sulfate (CS), in HFRS patients and investigated their clinical application value on the evaluation of disease severity and prognosis prediction.

Results: The expression of exfoliated glycocalyx fragments in plasma was significantly increased during the acute stage of HFRS. The levels of HS, HA, and CS in HFRS patients during the acute stage were significantly higher than in healthy controls and convalescent stages of the same type. HS and CS during the acute stage gradually increased with the aggravation of HFRS, and both fragments showed a significant association with disease severity. In addition, exfoliated glycocalyx fragments (especially HS and CS) showed a significant correlation with conventional laboratory parameters and hospitalization days. High levels of HS and CS during the acute phase were significantly associated with patient mortality and demonstrated an obvious predictive value for the mortality risk of HFRS.

Conclusion: Glycocalyx destruction and shedding may be closely associated with endothelial hyperpermeability and microvascular leakage in HFRS. The dynamic detection of the exfoliated glycocalyx fragments may be beneficial for the evaluation of disease severity and prognosis prediction in HFRS.

Keywords: chondroitin sulfate; glycocalyx; hemorrhagic fever with renal syndrome; heparan sulfate; hyaluronic acid.

Figure 1

Plasma levels of exfoliated glycocalyx components [heparan sulfate (HS), hyaluronic acid (HA), and chondroitin sulfate (CS)] in patients with HFRS. The levels of plasma HS (A), HA (B), and CS (C) during the acute stage were compared using the Kruskal–Wallis H-test; pairwise comparisons among the five groups were performed using the Nemenyi rank test. The levels of plasma HS (D), HA (E), and CS (F) during the acute stage were compared between the survivors and non-survivors using the Mann–Whitney U-test. The differences in plasma HS (G), HA (H), and CS (I) between the acute and the convalescent stages were compared using the Wilcoxon matched-pairs signed-ranks test. *p < 0.05.

Figure 2

The correlations of heparan sulfate (HS), hyaluronic acid (HA), and chondroitin sulfate (CS) with conventional laboratory parameters. Correlations were calculated using Spearman rank correlation analysis. The correlation coefficients were represented by different shades of color in panel (A); the red and blue colors represent positive and negative correlations, respectively. The correlations of HS, HA, and CS with individual laboratory parameters [white blood cells (WBC), aspartate transaminase (AST), and Fib] are shown in panels (B) through (J).

Figure 3

The ROC curves and survival curves of heparan sulfate (HS) and chondroitin sulfate (CS) for the prognosis (death) of hemorrhagic fever with renal syndrome (HFRS). (A) shows the predictive efficacy of HS, CS, white blood cells (WBC), platelets (PLT), aspartate transaminase (AST), and Fib for the prognosis (death) in patients with HFRS. HS and CS showed significant predictive values, with an AUC of 0.871 and 0.822, respectively. (B) and (C) represent the association of HS and CS with mortality in HFRS, respectively. Higher levels of HS and CS showed a higher risk of mortality.