Vascular endothelial cadherin shedding is more severe in sepsis patients with severe acute kidney injury

Abstract

Background: Vascular endothelial cadherin (VE-cadherin) is a membrane protein that is the major component of adherens junctions between endothelial cells. It is crucial for regulating vascular integrity, endothelial permeability, and angiogenesis. During inflammatory processes, VE-cadherin is shed into circulation (sVE-cadherin). Plasma sVE-cadherin is elevated in sepsis, malignancy, autoimmune diseases, and coronary atherosclerosis. However, the relationship between specific organ failures, especially severe acute kidney injury (AKI) defined by requirement for renal replacement therapy (AKI-RRT), and plasma sVE-cadherin levels in severe sepsis has not been well studied.

Methods: The present study is a prospective study of critically ill adults with sepsis and acute respiratory failure (age ≥ 18 years) enrolled in the Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma sVE-cadherin was measured at study enrollment. Primary analysis focused on the association between sVE-cadherin levels and the development of AKI, AKI-RRT, other organ dysfunction as defined by Brussels organ failure scores, pulmonary versus non-pulmonary sepsis, acute respiratory distress syndrome (ARDS), and in-hospital mortality.

Results: Of 228 severe sepsis patients included, 80 (35%) developed AKI-RRT. Plasma sVE-cadherin levels at enrollment were significantly higher in patients with AKI-RRT compared with patients without AKI-RRT (p = 0.003). Plasma sVE-cadherin levels by quartile were significantly higher in severe sepsis patients with acute kidney injury stage 3 (p = 0.044) as defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Patients with greater than 2 organ failures had higher plasma sVE-cadherin levels than patients with 2 or fewer organ failures (p < 0.001). In a multivariable analysis, plasma sVE-cadherin was independently associated with AKI-RRT (odds ratio 6.44 per log increase in plasma sVE-cadherin, 95% CI 1.126-36.847, p = 0.036). Plasma sVE-cadherin levels were significantly higher in patients with non-pulmonary sepsis compared to pulmonary sepsis (p < 0.001).

Conclusion: Shedding of sVE-cadherin is associated with severe acute kidney injury and with more severe organ dysfunction in patients with sepsis, suggesting that breakdown of endothelial adherens junctions may contribute to the pathogenesis of organ dysfunction in sepsis. Further studies of sVE-cadherin as a biomarker of disease severity in clinical sepsis are needed to better elucidate the role of VE-cadherin shedding in sepsis-induced severe organ dysfunction.

Keywords: Acute kidney injury; Endothelial injury; Renal replacement therapy; Sepsis; Soluble vascular endothelial cadherin.

Fig. 1

Plasma sVE-cadherin levels were weakly associated with a urine output and b serum creatinine levels on enrolling day. Higher plasma sVE-cadherin levels by quartile were significantly associated with c AKI stage 3 and d the need for renal replacement therapy

Fig. 2

Higher plasma sVE-cadherin levels by quartile were associated with a hepatic failure on enrolling day, but not with b circulatory failure on enrolling day or c coagulation failure on enrolling day. Organ failures were defined by Brussels organ failure scores [30]. d Plasma sVE-cadherin levels were not associated with the development of ARDS defined by Berlin criteria during the study period [32]. Data in panels a–d were analyzed by linear-by-linear association test. e Plasma sVE-cadherin levels were associated with the number of organ failures on enrolling day. f Plasma sVE-cadherin levels were significantly higher in patients with greater than 2 organ failures compared with patients with 2 or fewer organ failures on enrolling day. Data in panel e and f were summarized as boxplots where box encompasses 25th–75th percentile, error bars encompass 10th–90th percentile, and horizontal line shows median. Data in panels e and f were analyzed by Kruskal-Wallis H test

Fig. 3

a There was no significant difference in plasma sVE-cadherin levels between patients who died or survived from severe sepsis. b Plasma sVE-cadherin levels were significantly higher in patients with non-pulmonary sepsis compared to those with pulmonary sepsis. Data were summarized as boxplots where box encompasses 25th–75th percentile, error bars encompass 10th–90th percentile, and horizontal line shows median, and groups were compared by Mann-Whitney U test