Donor Specific HLA Alloantibodies in Liver Transplantation

• Conditions: Complication of Transplanted Liver
• Interventions: Other: HLA-alloantibodies exposure

• Registration Number: NCT02784080
• Lead Sponsor: Rigshospitalet, Denmark

Brief Summary

The aim is to evaluate the impact of donor specific HLA alloantibodies (DSA) on all-cause mortality and re-transplantation, early allograft dysfunction, acute and chronic rejection, fibrosis, vascular, and biliary complications. Furthermore, all biopsies will be C4d stained. The hypothesizes is that donor specific HLA alloantibodies facilitate an immune mediated damage to the liver allograft that impairs function and lead to various complications.

The investigators will do a prospective blinded multicenter cohort study in the Scandiatransplant organ sharing organization region.

Both preformed, persistent, and de novo donor specific HLA alloantibodies will studied. Blood samples will be taken immediately prior to transplantation, and 14 days, 3 months, and 1 year after transplantation. All liver biopsies performed during the study period will be evaluated for a humoral component and blood samples will be obtained prior to liver biopsies to investigate the presence of DSA.

Investigations will be fully blinded for the treatment responsible doctors.

Detailed Description

The outcome after liver transplantation has improved drastically over time, but this development has stagnated in recent years to a graft failure rate of 9-15 % within the first year and approximately 20-30 % at 5 years \[1\]. The primary goal is to improve the outcome after liver transplantation.

The impact of donor specific antibodies (DSA) on all-cause mortality and re-transplantation, early allograft dysfunction, acute and chronic rejection, vascular and biliary complications and fibrosis will be investigated.

Objectives:

1. The primary objective is to investigate if DSA both pre-formed, persistent, and de novo affect survival and allograft loss. For patients diagnosed with HLA antibodies a standard Luminex single antigen IgG analysis, a Luminex C1q and an IgG3 single antigen assay will be performed.

2. The secondary objective is to investigate if donor specific antibodies, both pre-formed, persistent, and de novo increase the risk of early allograft dysfunction, acute and chronic rejection, fibrosis, de novo autoimmune hepatitis (pediatric patients only), vascular and biliary complications. All liver biopsies will be stained by C4d and a DSA analysis will be undertaken.

3. Continuous measurements will be used to establish the kinetics of both preformed og de novo DSA after liver transplantation.

Pediatric patients will be analyzed separately.

Study Timeline

• Study Start: 2015-08
• Study First Submitted: 2016-05-24
• Study First Submitted QC: 2016-05-24
• Study First Posted: 2016-05-26
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-24
• Last Update Posted: 2020-02-26
• Primary Completion: 2021-09
• Study Completion: 2021-09

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 1162

Inclusion Criteria

• Undergo a liver transplanted during the study period.
• Pre-transplant serum sample of minimum 4 ml (relevant for pediatric patients)
• Informed consent is given.

Exclusion Criteria

• Withdrawal of informed consent.
• Blinding broken in a non-protocoled manner the patient will be excluded.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
HLA-alloantibodies exposure	HLA-alloantibodies exposure	Preformed, persistent, and de novo HLA-alloantibody exposure in the whole cohort.

Primary Outcome Measures

Name	Time	Method
All-cause mortality or re-transplantation (graft loss)	Minimum 1 year, accrual to study end

Secondary Outcome Measures

Name	Time	Method
Fibrosis, defined by METAVIR score.	Minimum 1 year, accrual to study end
Early allograft dysfunction are defined as total bilirubin >10 mg/dl or INR >1.6 at day 7 after liver transplantation or ALT >2000 IU/L within the first 7 days after liver transplantation.	7 days after transplantation
Acute rejection, both cellular and humoral rejection, as defined by Banff classification.	Minimum 1 year, accrual to study end
Chronic rejection, as defined by Banff classification, and as proposed by O'leary et al "Proposed Diagnostic Criteria for Chronic Antibody-Mediated Rejection in Liver Allografts".	Minimum 1 year, accrual to study end
Vascular complications (hepatic arterial stenosis, hepatic arterial thrombosis, portal vein thrombosis).	Minimum 1 year, accrual to study end
Biliary complications (biliary leakage, anastomotic biliary stricture, non-anastomotic biliary stricture, liver abscess, cholangitis, other).	Minimum 1 year, accrual to study end	Anastomotic strictures and non-anastomotic strictures will be investigated as a combined and solitary outcome.

Trial Locations

Locations (5)

Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital; 🇩🇰 Copenhagen, Denmark

Transplantation and Liver Surgery Clinic, Helsinki University Hospital; 🇫🇮 Helsinki, Finland

Department of Transplantation Medicine, Oslo University Hospital; 🇳🇴 Oslo, Norway

Surgery Department, Transplantation and Liver Surgery Unit, Sahlgrenska University Hospital; 🇸🇪 Göteborg, Sweden

Division of Transplantation Surgery, Karolinska Institutet; 🇸🇪 Stockholm, Sweden