What is the treatment for rejection post liver transplantation?

Treatment of Rejection Post Liver Transplantation

Acute cellular rejection after liver transplantation should be treated with increased immunosuppression, primarily high-dose corticosteroids, while chronic rejection requires intensification of baseline immunosuppression regimens and may necessitate retransplantation in cases with significant allograft dysfunction. 1

Types of Rejection and Diagnosis

• Approximately 15-30% of liver transplant recipients develop one or more episodes of acute cellular rejection, which typically occurs within the first 3 months post-transplantation but can occur at any time 1
• Rejection is often suspected by hepatocellular abnormalities on liver function tests, but can also present with cholestatic patterns 1
• Advanced rejection may present with fever, jaundice, and abdominal pain 1
• Liver biopsy remains the gold standard for definitive diagnosis of rejection 1, 2
• Chronic (ductopenic) rejection can develop with fibrosis and disappearance of bile ducts, resulting in severe biliary obstruction and jaundice 1

Treatment of Acute Rejection

First-Line Treatment

• High-dose corticosteroids are the first-line treatment for acute cellular rejection 2, 3
• Approximately 75% of acute rejection episodes respond to initial steroid therapy 3
• Standard protocol involves intravenous methylprednisolone boluses followed by a steroid taper 1, 3
• Baseline immunosuppression should be optimized by ensuring adequate tacrolimus trough levels (typically 5-20 ng/mL in the first year post-transplant) 4, 5

Steroid-Resistant Rejection

• For steroid-resistant rejection, IL-2 receptor monoclonal antibodies (basiliximab) can be effective 3
• Anti-thymocyte globulin (ATG) may be used as rescue therapy for severe steroid-resistant rejection 3
• Adding mycophenolate mofetil (MMF) has shown efficacy as rescue therapy for steroid-resistant rejection 3

Treatment of Chronic Rejection

• Chronic rejection can be effectively treated only in early cases and may lead to graft loss if advanced 1
• Treatment options include:
  • Increasing calcineurin inhibitor (CNI) levels 1
  • Addition of mTOR inhibitors (sirolimus/everolimus) to baseline immunosuppression 1, 6
  • Approximately 52% of patients with chronic rejection respond to the addition of mTOR inhibitors 6
• Retransplantation should be considered if significant allograft synthetic dysfunction or portal hypertensive complications exist 1

Immunosuppression Management

• Calcineurin inhibitor (CNI)-based immunosuppression is the cornerstone of immunosuppressive regimens in liver transplantation 1
• Tacrolimus results in better long-term graft and patient survival than cyclosporine 1
• Recommended tacrolimus trough levels:
  • Month 1-3: 7-20 ng/mL
  • Month 4-12: 5-15 ng/mL 4
• Low tacrolimus levels are temporally related to rejection episodes, with levels often dropping in the weeks preceding rejection 5
• Complete withdrawal of immunosuppression should not be attempted as standard care, even after an extended rejection-free period 1

Risk Factors and Prevention

• Risk factors for chronic rejection include:
  • CMV viremia
  • Previous episodes of acute cellular rejection
  • History of anastomotic biliary strictures
  • Medication non-compliance 6
• Younger recipients, primary biliary cirrhosis, and previous graft loss are independent predictors of late acute rejection 5
• Monitoring for donor-specific antibodies (DSAs) may help identify patients at risk of antibody-mediated rejection 1

Prognosis and Outcomes

• The rate of graft loss due to ductopenic rejection has significantly decreased to less than 2% with modern immunosuppression regimens 1
• Poor response to treatment correlates with the development of ductopenic rejection 5
• Graft survival is worse in those with late acute rejection compared to those with early acute rejection or no rejection 5
• Approximately half of patients with early ductopenic rejection may eventually die without retransplantation 5

Special Considerations

• Antibody-mediated rejection (AMR) may require plasmapheresis and/or intravenous immunoglobulin in addition to standard rejection treatment 1
• For persistent AMR not responding to first-line therapy, rituximab (to deplete B cells) or eculizumab (to inhibit complement activation) can be considered 1
• Rejection can be confused with recurrence of primary liver disease, particularly viral hepatitis, so careful differential diagnosis is essential 2