High Circulating Caspase-Cleaved Keratin 18 Fragments (M30) Indicate Short-Term Mortality in Critically Ill Patients.

Alexander Koch,Fabienne Schumacher,Ulf Herbers,Janine Linka,Ralf Weiskirchen,Christian Trautwein,Lukas Buendgens,Ger H Koek,Jan Bruensing,Eray Yagmur,Frank Tacke

doi:10.1155/2018/8583121

Alexander Koch, Fabienne Schumacher + Show 9 more

Open Access

https://doi.org/10.1155/2018/8583121

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Abstract

Caspase-cleaved fragments of the intermediate filament protein keratin 18 (cytokeratin-18 (CK18)) can be detected in serum as M30 levels and may serve as a circulating biomarker indicating apoptosis of epithelial and parenchymal cells. In order to evaluate M30 as a biomarker in critical illness, we analyzed circulating M30 levels in 243 critically ill patients (156 with sepsis, 87 without sepsis) at admission to the medical intensive care unit (ICU), in comparison to healthy controls (n = 32). M30 levels were significantly elevated in ICU patients compared with healthy controls. Circulating M30 was closely associated with disease severity but did not differ between patients with sepsis and ICU patients without sepsis. M30 serum levels were correlated with biomarkers of inflammation, cell injury, renal failure, and liver failure in critically ill patients. Patients that died at the ICU showed increased M30 levels at admission, compared with surviving patients. A similar trend was observed for the overall survival. Regression analyses confirmed that M30 levels are associated with mortality, and patients with M30 levels above 250.8 U/L displayed an excessive short-term mortality. Thus, our data support the utility of circulating levels of the apoptosis-related keratin fragment M30 as a prognostic biomarker at ICU admission.

Highlights

Excessive systemic inflammation as a consequence of massive innate immune cell activation is a key characteristic in critically ill patients
Circulating M30 levels were significantly increased in critically ill patients (n = 243, median 178.3 U/L, range 16.7–1001 U/L, Table 1) compared to the healthy control group (n = 32, median 107.1 U/L, range 48.3–217.1 U/L, p < 0 001, Figure 1(a))
M30 levels did not differ between patients with sepsis and critical illness without sepsis (median 193.6 U/L, range 16.7– 1001 U/L, Table 1, Figure 1(b))

Summary

Introduction

Excessive systemic inflammation as a consequence of massive innate immune cell activation is a key characteristic in critically ill patients. This is triggered by infection-related molecules, termed pathogen-associated molecular patterns (PAMPs), and by the release of endogenous immunogenic signals, termed danger-associated molecular patterns (DAMPs) [1]. Activated innate immune cells release abundant inflammatory cytokines (e.g., tumor necrosis factor and interleukins) that initiate inflammatory and cell death signaling cascades in immune cells and parenchymal cells [2]. The systemic release of caspase-cleaved fragments of keratin 18 (K18), a major type I intermediate filament protein of the cytoskeleton, has been identified as a specific biomarker reflecting apoptotic cell death.

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