Division of Respiratory Therapy, Department of Chest Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, 11217, Taiwan, Republic of China.
Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
Crit Care. 2019 Jan 18;23(1):18. doi: 10.1186/s13054-019-2315-y.
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.
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.
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).
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.
血管内皮钙黏蛋白（VE-cadherin）是一种膜蛋白，是内皮细胞之间黏附连接的主要组成部分。它对于调节血管完整性、内皮通透性和血管生成至关重要。在炎症过程中，VE-cadherin 会脱落到循环中（sVE-cadherin）。败血症、恶性肿瘤、自身免疫性疾病和冠状动脉粥样硬化症患者的血浆 sVE-cadherin 水平升高。然而，特定器官衰竭之间的关系，特别是需要肾脏替代治疗（AKI-RRT）的严重急性肾损伤（AKI），与严重败血症患者的血浆 sVE-cadherin 水平之间的关系尚未得到很好的研究。
本研究是一项对患有败血症和急性呼吸衰竭（年龄≥18 岁）的危重病成年人的前瞻性研究，这些患者纳入了 Validating Acute Lung Injury markers for Diagnosis（VALID）研究。在研究入组时测量血浆 sVE-cadherin。主要分析重点是 sVE-cadherin 水平与 AKI 的发展、AKI-RRT、布鲁塞尔器官衰竭评分定义的其他器官功能障碍、肺性或非肺性败血症、急性呼吸窘迫综合征（ARDS）以及院内死亡率之间的关系。
在 228 例严重败血症患者中，80 例（35%）发生 AKI-RRT。与未发生 AKI-RRT 的患者相比，发生 AKI-RRT 的患者的 sVE-cadherin 水平在入组时显著升高（p=0.003）。根据肾脏病改善全球结局（KDIGO）标准，按 quartile 划分的 sVE-cadherin 水平在严重败血症患者中，急性肾损伤第 3 期（p=0.044）患者中明显升高。有 2 个以上器官衰竭的患者的 sVE-cadherin 水平高于有 2 个或更少器官衰竭的患者（p<0.001）。在多变量分析中，sVE-cadherin 与 AKI-RRT 独立相关（血浆 sVE-cadherin 每增加 1 个对数，优势比为 6.44，95%CI 为 1.126-36.847，p=0.036）。与肺性败血症患者相比，非肺性败血症患者的 sVE-cadherin 水平显著升高（p<0.001）。
sVE-cadherin 的脱落与败血症患者的严重急性肾损伤和更严重的器官功能障碍有关，这表明内皮黏附连接的破坏可能导致败血症患者器官功能障碍的发病机制。需要进一步研究 sVE-cadherin 作为临床败血症疾病严重程度的生物标志物，以更好地阐明 VE-cadherin 脱落在败血症引起的严重器官功能障碍中的作用。
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