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. 2023 Feb;11(1):92-102.
doi: 10.1002/ueg2.12337. Epub 2022 Nov 28.

Markers of cell death predict therapy response in patients with cirrhosis and hepatorenal syndrome

Sophia Heinrich  1   2 , Thomas Austgen  1 , Darko Castven  3 , Moritz Hess  4 , Christian Labenz  1 , Martha Kirstein  3 , Carolin Zimpel  3 , Lena Stockhoff  2 , Benjamin Maasoumy  2 , Bernd Heinrich  2 , Hans Heinrich Wedemeyer  2 , Peter Robert Galle  1 , Harald Binder  4 , Marc Nguyen-Tat  1 , Jens Uwe Marquardt  3
Affiliations

Markers of cell death predict therapy response in patients with cirrhosis and hepatorenal syndrome

Sophia Heinrich et al. United European Gastroenterol J. 2023 Feb.

Abstract

Background and aims: Hepatorenal syndrome is a major complication in patients with cirrhosis and associated with high mortality. Predictive biomarkers for therapy response are largely missing. Cytokeratin18-based cell death markers are significantly elevated in patients with complications of chronic liver disease, but the role of these markers in patients with HRS treated with vasoconstrictors and albumin is unknown.

Methods: We prospectively analyzed a total of 138 patients with HRS, liver cirrhosis without HRS and acute kidney injury treated at the University Medical Center Mainz between April 2013 and July 2018. Serum levels of M30 and M65 were analyzed by ELISA and clinical data were collected. Predictive ability was assessed by Kaplan-Meier curves, logistic regression and c-statistic. Primary endpoint was response to therapy.

Results: M30 and M65 were significantly increased in patients with HRS compared to non-HRS controls (M30: p < 0.0001; M65: p < 0.0001). Both serum markers showed predictive ability for dialysis- and LTX-free survival but not overall survival. Logistic regression confirmed M30 and M65 as independent prognostic factors for response to therapy. A novel predictive score comprising bilirubin and M65 showed highest predictive ability to predict therapy response.

Conclusions: Serum levels of M30 and M65 can robustly discriminate patients into responders and non-responders to terlipressin therapy with a good predictive ability for dialysis- and LTX-free survival in cirrhotic patients. Cell death parameters might possess clinical relevance in patients with liver cirrhosis and HRS.

Keywords: cytokeratin-18; hepatorenal syndrome; terlipressin; therapy response.

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Conflict of interest statement

There are no conflicts of interest for all authors.

Figures

FIGURE 1
FIGURE 1
Flow chart study design and exclusion criteria.
FIGURE 2
FIGURE 2
Serum M30 and M65 levels for each group. (a) Serum M30 levels are significantly different between Hepatorenal Syndrom (HRS) patients and patients with cirrhosis without HRS or patients with acute kidney injury (AKI) (Kruskall Wallis test: p < 0.0001****). (b) Serum M65 levels are significantly different between HRS patients and patients with cirrhosis without HRS or patients with AKI (Kruskall Wallis test: p < 0.0001****).
FIGURE 3
FIGURE 3
Kaplan Meier analysis according to both, M30 and M65 high or low, serum levels. Survival curves show (a) HD and LTX free survival times (p = 0.006**), (b) HD, LTX and trans‐jugular intrahepatic portosystemic shunts (TIPS) free survival times (p = 0.027*) and (c) overall survival (OS) times (p = 0.78). For TIPS free survival two patients had to be excluded. Differences in survival were assessed by Gehan‐Breslow‐Wilcoxon‐test.
FIGURE 4
FIGURE 4
(a) Patient distribution in terlipressin responders and non‐responders. (b) Survival analysis of patients according to terlipressin therapy response (p = 0.0345*). Difference in survival times was assessed by Gehan‐Breslow‐Wilcoxon‐test. (c) Serum M30 and M65 serum level in terlipressin responders and non‐responders. Serum M30 levels are significantly higher in non‐responders (Mann‐Whitney test: p = 0.002***, left). Serum M65 levels are also significantly higher in non‐responders (Mann‐Whitney test: p < 0.0001****, right). (d) Serum M30 and M65 serum level in terlipressin responders and non‐responders separated in hepatorenal syndrom (HRS) Type I (left) and Type II (right). M30 and M65 level are significantly higher in non‐responders in HRS Type I as well as in Type II.
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