Schuett Katharina, Savvaidis Anna, Maxeiner Sebastian, Lysaja Katharina, Jankowski Vera, Schirmer Stephan H, Dimkovic Nada, Boor Peter, Kaesler Nadine, Dekker Friedo W, Floege Jürgen, Marx Nikolaus, Schlieper Georg
Departments of Internal Medicine I,
Departments of Internal Medicine I.
J Am Soc Nephrol. 2017 May;28(5):1622-1630. doi: 10.1681/ASN.2016030336. Epub 2017 Jan 5.
Patients with CKD on hemodialysis exhibit increased cardiovascular risk. Fibrin clot structure and clot lysis are crucially involved in development of cardiovascular events, but little is known about the influence of clot density on outcome in patients on hemodialysis. We determined fibrin clot structure parameters and effect on mortality in a prospective cohort of 171 patients on chronic hemodialysis (mean±SD age =59±11 years old; 54% men) using a validated turbidimetric assay. Kaplan-Meier analysis revealed that patients on hemodialysis with a denser clot structure had increased all-cause and cardiovascular mortality risks (log rank =0.004 and =0.003, respectively). Multivariate Cox regression models (adjusted for age, diabetes, sex, and duration of dialysis or fibrinogen, C-reactive protein, and complement C3) confirmed that denser clots are independently related to mortality risk. We also purified fibrinogen from healthy controls and patients on hemodialysis using the calcium-dependent IF-1 mAb against fibrinogen for additional investigation using mass spectrometric analysis and electron microscopy. Whereas purified fibrinogen from healthy controls displayed no post-translational modifications, fibrinogen from patients on hemodialysis was glycosylated and guanidinylated. Clots made of purified fibrinogen from patients on hemodialysis exhibited significantly thinner fibers compared with clots from fibrinogen of control individuals (mean±SD =63±2 and 77±2 nm, respectively; <0.001). guanidinylation of fibrinogen from healthy subjects increased the formation of thinner fibers, suggesting that difference in fiber thickness might be at least partially due to post-translational modifications. Thus, in patients on hemodialysis, a denser clot structure may be a potent independent risk factor for mortality.
接受血液透析的慢性肾脏病患者心血管风险增加。纤维蛋白凝块结构和凝块溶解在心血管事件的发生中起关键作用，但关于凝块密度对血液透析患者预后的影响知之甚少。我们使用经过验证的比浊法，在一个由171例慢性血液透析患者（平均±标准差年龄=59±11岁；54%为男性）组成的前瞻性队列中，确定了纤维蛋白凝块结构参数及其对死亡率的影响。Kaplan-Meier分析显示，血液透析患者中凝块结构更致密者全因死亡率和心血管死亡率风险增加（对数秩分别为0.004和0.003）。多变量Cox回归模型（对年龄、糖尿病、性别、透析时间或纤维蛋白原、C反应蛋白和补体C3进行校正）证实，更致密的凝块与死亡风险独立相关。我们还使用针对纤维蛋白原的钙依赖性IF-1单克隆抗体，从健康对照者和血液透析患者中纯化纤维蛋白原，以便使用质谱分析和电子显微镜进行进一步研究。健康对照者纯化的纤维蛋白原未显示翻译后修饰，而血液透析患者的纤维蛋白原发生了糖基化和胍基化。与对照个体纤维蛋白原形成的凝块相比，血液透析患者纯化纤维蛋白原形成的凝块纤维明显更细（平均±标准差分别为63±2和77±2nm；P<0.001）。健康受试者纤维蛋白原的胍基化增加了更细纤维的形成，这表明纤维厚度的差异可能至少部分归因于翻译后修饰。因此，在血液透析患者中，更致密的凝块结构可能是死亡率的一个强有力的独立危险因素。
