title: Serum levels of caspase-cleaved cytokeratin-18 and mortality are associated in severe septic patients: pilot study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lorente
authors.affiliation: Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Santa Cruz Tenerife, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Martín
authors.affiliation: Laboratory Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
authors.forename: Agustín F
authors.initials: AF
authors.lastname: González-Rivero
authors.affiliation: Intensive Care Unit, Hospital Clínico Universitario de Valencia, Valencia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Ferreres
authors.affiliation: Intensive Care Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Solé-Violán
authors.affiliation: Intensive Care Unit, Hospital San Jorge, Huesca, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Labarta
authors.affiliation: Intensive Care Unit, Hospital Insular, Las Palmas de Gran Canaria, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Díaz
authors.affiliation: Research Unit, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Jiménez
authors.affiliation: Laboratory Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Borreguero-León
mesh_terms: D018806:APACHE; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D020169:Caspases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D053538:Keratin-18 / Q000097:blood* / Q000737:chemistry; D019344:Lactic Acid / Q000097:blood; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010865:Pilot Projects; D011379:Prognosis; D011446:Prospective Studies; D018805:Sepsis / Q000097:blood* / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D053538:Keratin-18; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019344:Lactic Acid; D020169:Caspases