Lorente Leonardo, Martín María M, González-Rivero Agustín F, Ferreres José, Solé-Violán Jordi, Labarta Lorenzo, Díaz César, Jiménez Alejandro, Borreguero-León Juan M
Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz Tenerife, Spain.
PLoS One. 2014 Oct 7;9(10):e109618. doi: 10.1371/journal.pone.0109618. eCollection 2014.
Apoptosis is increased in sepsis. Cytokeratin 18 (CK-18), a protein of the intermediate filament group present in most epithelial and parenchymal cells, is cleaved by the action of caspases and released into the blood as caspase-cleaved CK (CCCK)-18 during apoptosis. Circulating levels of CCCK-18 have scarcely been explored in septic patients. In one study with 101 severe septic patients, the authors reported higher serum CCCK-18 levels in non-survivors than in survivors; however, the sample size was too small to demonstrate an association between serum CCCK-18 levels and early mortality and whether they could be used as a biomarker to predict outcomes in septic patients. Thus, these were the objectives of this study with a large series of patients.
We performed a prospective, multicenter, observational study in six Spanish Intensive Care Units with 224 severe septic patients. Blood samples were collected at the time that severe sepsis was diagnosed to determine serum levels of CCCK-18, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10. The end point was 30-day mortality.
Non-surviving patients (n = 80) showed higher serum CCCK-18 levels (P<0.001) than survivors (n = 144). Multiple logistic regression analysis showed that serum CCCK-18 levels>391 u/L were associated with 30-day survival (Odds ratio = 2.687; 95% confidence interval = 1.449-4.983; P = 0.002), controlling for SOFA score, serum lactic acid levels and age. Kaplan-Meier survival analysis showed that the risk of death in septic patients with serum CCCK-18 levels >391 u/L was higher than in patients with lower values (Hazard Ratio = 3.1; 95% CI = 1.96-4.84; P<0.001). Serum CCCK-18 levels were positively associated with serum levels of IL-6 and lactic acid, and with SOFA and APACHE scores.
The major novel finding of our study, the largest cohort of septic patients providing data on circulating CCCK-18 levels, was that serum CCCK-18 levels are associated with mortality in severe septic patients.
脓毒症时细胞凋亡增加。细胞角蛋白18（CK-18）是一种存在于大多数上皮细胞和实质细胞中的中间丝蛋白，在细胞凋亡过程中被半胱天冬酶作用裂解，并作为半胱天冬酶裂解的CK（CCCK）-18释放到血液中。脓毒症患者循环中CCCK-18水平的研究很少。在一项对101例严重脓毒症患者的研究中，作者报告非存活者血清CCCK-18水平高于存活者；然而，样本量太小，无法证明血清CCCK-18水平与早期死亡率之间的关联，以及它们是否可作为预测脓毒症患者预后的生物标志物。因此，本研究纳入大量患者以探讨这些问题。
我们在西班牙6个重症监护病房对224例严重脓毒症患者进行了一项前瞻性、多中心观察性研究。在诊断为严重脓毒症时采集血样，以测定血清CCCK-18、肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和IL-10水平。终点为30天死亡率。
非存活患者（n = 80）血清CCCK-18水平高于存活患者（n = 144）（P<0.001）。多因素logistic回归分析显示，血清CCCK-18水平>391 u/L与30天生存率相关（比值比=2.687；95%置信区间=1.449-4.983；P = 0.002），校正序贯器官衰竭评估（SOFA）评分、血清乳酸水平和年龄后仍有相关性。Kaplan-Meier生存分析显示，血清CCCK-18水平>391 u/L的脓毒症患者死亡风险高于较低水平患者（风险比=3.1；95%可信区间=1.96-4.84；P<0.001）。血清CCCK-18水平与血清IL-6水平、乳酸水平、SOFA评分和急性生理与慢性健康状况评分系统（APACHE）评分呈正相关。
我们的研究是提供循环CCCK-18水平数据的最大规模脓毒症患者队列，其主要新发现是血清CCCK-18水平与严重脓毒症患者的死亡率相关。
