Immune Tolerance After Pediatric Liver Transplantation

Recruiting

• Conditions: Immune Tolerance; Liver Transplant; Complications
• Interventions: Other: IS weaning off

• Registration Number: NCT05501301
• Lead Sponsor: RenJi Hospital

Brief Summary

Immunosuppressive (IS) agents are effective treatment to avoid acute or chronic rejection after pediatric liver transplantation. However, long-term side effect of IS intaking, like infection, kidney dysfunction, metabolic disorders and developmental retardation, should be aware, especially in pediatric recipients. Spontaneous immune tolerance is defined as recipients who cease to taking IS agents due to multiple reasons and the liver function maintained normal. However, the real ratio and safety of immune tolerance in pediatric liver transplantation recipients are rarely known. We would like to investigate the ratio and safety of spontaneous immune tolerance in pediatric liver transplantation recipients during long-term follow-up by constructing an immune tolerance cohort. In this cohort, long-term pediatric liver transplantation recipients with normal liver function and taking monotherapy of IS would be involved. The IS strategy would be monitored and adjusted according to the "Clinical guidelines for pediatric liver transplantation in China(2015)". For recipients suffering refractory virus infection, such as EBV or CMV infection, IS will be minimized to assist the clearance of virus until IS was weaned off. Since most of pediatric liver transplantation recipients may encounter chronic EBV or CMV infection within one year after transplantation, they may need IS minimization during follow-up. During the process of IS weaning off, liver function, immunological status and intrahepatic pathology will be closely monitored. If acute rejection or other complications were found, increase of IS dosage or other related treatments will be applied. Immune tolerance is defined as liver function and intrahepatic pathology maintain normal for more than one year after stop taking IS. At the end of study, the ratio of immune tolerance, acute rejection and all types of complications will be assessed.

Detailed Description

Background: Immune tolerance after liver transplantation is defined as the status that recipients no longer taking any immunosuppressive agents with normal liver function and intrahepatic pathology. For pediatric liver transplantation recipients, immune tolerance is easier to reach than adult liver transplantation recipients. It is reported that spontaneous immune tolerance ratio in pediatric liver transplantation recipients is between 15%-60%, varying among different centers. Some recipients could develop into spontaneous immune tolerance due to refractory infections or side effects of IS. Some recipients could also reach immune tolerance by gradually weaning off the IS if liver function maintained normal and stable in the long-term follow-up. What's more, immune tolerance could reduce the long-term side effects of IS in pediatric recipients. However, how the immune status was modulated, or which factors contribute to the development of immune tolerance is unknown. Besides, the long-term safety of immune tolerance also needs more research. This study is designed to figure out the ratio and safety of immune tolerance in pediatric liver transplantation recipients.

Assessment before enrollment: In this study, enrolled population should have received living donor liver transplantation (LDLT) in Ren Ji Hospital affiliated to Shanghai Jiao Tong University School of Medicine for more than one year and liver function maintains stable and normal for more than 3 months. No severe complication including vessel complications, biliary complications or renal dysfunction should occur before enrollment. Liver biopsy should indicate no signs of acute rejection or chronic rejection, and no obvious fibrosis (Ishak\<2).

Protocol after enrollment: After enrollment, the recipients will be evaluated for virus infection and side effects of IS. For patients with refractory EBV or CMV infections, or obvious side effects of IS, IS minimization should be applied. The dosage of IS will be weaned off as the 3/4 dosage of last dosage every 4 weeks. During the process of weaning off, liver function will be monitored every two weeks and liver biopsy should be conducted every six months. If liver dysfunction or acute rejection is detected during follow-up, steroid bolus and increased IS will be applied. For patients who have stop taking any IS, liver biopsy will be conducted to exclude potential liver injury in liver biopsy. For patients who have stop taking IS for more than one year with normal liver function and liver pathology, immune tolerance is considered as reached. At the endpoint of study, the ratio of immune tolerance, ratio of acute rejection and safety of immune tolerance will be assessed.

Study Timeline

• Study Start: 2022-08-01
• Study First Submitted: 2022-08-07
• Study First Submitted QC: 2022-08-11
• Study First Posted: 2022-08-15
• Status Verified: 2023-12
• Last Update Submitted: 2023-12-17
• Last Update Posted: 2023-12-19
• Primary Completion: 2025-07-31
• Study Completion: 2025-07-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Age at liver transplantation: 4 months to 18 years;
2. Original disease before liver transplantation: End-stage liver diseases including cholestatic diseases or metabolic diseases;
3. Type of liver transplantation: living donor liver transplantation, with donors of recipient's parents
4. Follow-up time after liver transplantation: more than one year
5. Liver function: liver function maintains normal and stable 3 months before enrollment
6. IS strategy: monotherapy of IS (FK or cyclosporine) or no longer taking any IS
7. Liver biopsy: No signs of acute rejection or chronic rejection, and no obvious fibrosis (Ishak<2)
8. Written consents are required

Exclusion Criteria

1. Original disease before liver transplantation: Tumor, hepatitis virus infection, autoimmune hepatitis, liver failure, secondary liver transplantation
2. Type of liver transplantation: ABO incompatible liver transplantation, donors are not recipient's parents or multiple organ transplantation
3. Hepatitis virus infection during follow-up
4. Severe compilations, including bleeding complication, biliary complication, vessel complication or renal dysfunction -

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Immune tolerance cohort	IS weaning off	Patients that are enrolled into this cohort will receive IS minimization if virus infection or side effects of IS was found. The strategy of IS minimization will follow the "Clinical guidelines for pediatric liver transplantation in China(2015)". Blood test and liver biopsy will be conducted to monitor liver function and intrahepatic pathological conditions. If IS is ceased for more than one year without liver dysfunction or signs of acute rejection in liver biopsy, immune tolerance was considered reached.

Primary Outcome Measures

Name	Time	Method
Ratio of immune tolerance	One year after withdraw of IS	The ratio of spontaneous immune tolerance in pediatric liver transplantation recipients, which is free of IS for more than one year with normal liver function

Secondary Outcome Measures

Name	Time	Method
Ratio of acute rejection	6 months, 1 year, 2 years and 3 years after enrolled into the study	The ratio of acute rejection that happens in recipients during the process of IS minimization

Trial Locations

Locations (1)

Ren Ji Hospital affiliated to Shanghai Jiao Tong University School of Medicine; 🇨🇳 Shanghai, Shanghai, China