Reperfusion-induced Self-antigen Excretion Following Major Liver Surgery (RISE)

Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow in order to prevent excessive blood loss. However, this predisposes the liver to a detrimental inflammatory response once the circulation is restored. Altogether, the effects that result from this temporary withdrawal of blood are known as ischemia and reperfusion (I/R) injury, and the extent to which this occurs determines the functional outcome of the liver after surgery.

Recently, it has become clear that (over)activation of the immune system forms the mainstay of I/R injury in the liver. More importantly, it has been shown in animal models that self-antigens, which are normal cellular constituents that become immunogenic mediators following their release from dying cells, are involved in the earliest stages of I/R injury of the liver. Clinical data on the release self-antigens in I/R injury are however scarce to date. Therefore, the aim of this study is to investigate the release of self-antigens in patients that undergo a major liver resection with or without withdrawal of the liver's blood flow. Also, the results will be correlated to genes involved in the inflammatory response as well as clinical parameters for liver damage and function.

Study Overview

• Status: Completed
• Conditions: Warm Hepatic Ischemia-reperfusion Injury

Detailed Description

Rationale

Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow in order to prevent excessive blood loss. Vascular inflow occlusion (VIO) however predisposes the liver to a detrimental inflammatory response once the circulation is restored. Altogether, the ramifications that result from this temporary withdrawal of oxygen supply are known as ischemia and reperfusion (I/R) injury, and the extent to which this occurs determines the functional outcome of the liver after surgery. Recently, it has become clear that (over)activation of the immune system forms the mainstay of hepatic I/R injury. More importantly, it has been shown in animal models that endogenous self-antigens, known as damage-associated molecular patterns (DAMPs), are released from stressed liver cells in the earliest stages of reperfusion and, as such, form the most proximal triggers of hepatic I/R injury. Clinical data on DAMP release following hepatic I/R are however scarce to date. Therefore, the aim of this study is to investigate DAMP release in patients that undergo a major liver resection with or without VIO and to correlate the results to the expression of acute- phase inflammatory response genes and routine clinical parameters for hepatocellular damage.

Objective

To investigate the release of damage-associated molecular patterns (DAMPs) following major hepatic resection with or without VIO and to correlate the outcomes to the acute inflammatory response and clinical parameters for hepatocellular damage.

Study design

The study is designed as an observational study. Because the decision to apply VIO is often made during surgery, patients will be allocated to a group postoperatively. Therefore, the inclusion of subjects in this study will continue until the calculated sample size of 15 patients has been reached in each group.

Study population

Eligible patients for participation in this study are those diagnosed with a malignant or benign hepatic tumor that are scheduled to undergo major hepatectomy (resection of ≥3 segments).

Main study parameters/endpoints

The primary endpoint of this study is defined as the effect of I/R on the release of DAMPs, measured in the systemic circulation. Secondary parameters constitute the expression of acute inflammatory response genes, AST, ALT, total bilirubin, and INR.

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• Netherlands
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1105 AZ
      • Academic Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients diagnosed with a malignant or benign hepatic tumor that are scheduled for a liver resection.

Description

Inclusion Criteria:

• Patients scheduled to undergo a major liver resection for a benign or malignant hepatic tumor
• Signed informed consent obtained prior to any study-specific procedure
• ASA classification I-III

Exclusion Criteria:

• VIO <20 min
• ASA classification IV/V
• Emergency operations
• Pregnancy or breast feeding

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
VIO; Patients operated under VIO.
Control; Patients operated without VIO.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DAMPs in systemic circulation	Plasma DAMP levels will be determined perioperatively.	8 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Up regulation of acute inflammatory response genes	Up regulation of acute inflammatory response genes will be determined in liver biopsy tissue (acquired intraoperatively) by means of qPCR.	1 hour
Parenchymal damage	Measured as plasma ALT and AST.	8 hours
Liver function	Assessed by means of total bilirubin levels and prothrombin time.	8 hours

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Study Director: Thomas M. van Gulik, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• van Golen RF, van Gulik TM, Heger M. The sterile immune response during hepatic ischemia/reperfusion. Cytokine Growth Factor Rev. 2012 Jun;23(3):69-84. doi: 10.1016/j.cytogfr.2012.04.006. Epub 2012 May 17.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: October 3, 2012
• First Submitted That Met QC Criteria: October 3, 2012
• First Posted (ESTIMATE): October 4, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): January 26, 2016
• Last Update Submitted That Met QC Criteria: January 25, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Ischemia; Reperfusion Injury
• Other Study ID Numbers: 2012_238; NL41737.018.12 (OTHER: Central Committee on Research involving Human Subjects, the Netherlands)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED