6.2 Antibody-Mediated Rejection (AMR)

Antibody-Mediated Rejection (AMR) in Liver Transplantation

Lecture Summary – Prof. Sanjaya Satapathy, MD, FAASLD

1. Main Clinical Topics Discussed

• Antibody-mediated rejection (AMR) as a distinct form of liver allograft rejection
• Differentiation of AMR from acute cellular rejection (ACR) and other causes of graft dysfunction
• Immunopathogenesis, clinical recognition, diagnostic criteria, and management of AMR

2. Key Learning Points, Guidelines, and Recommendations

Immunologic Basis

• AMR is a humoral immune process driven by donor-specific antibodies (DSA) targeting donor HLA antigens on graft endothelial cells
• DSA may be preformed (pre-transplant sensitization) or de novo (developing post-transplant)
• Antibody binding activates the complement cascade, leading to microvascular inflammation and graft injury
• The liver has relative immunologic tolerance compared to the kidney, making AMR less common but more severe when it occurs

High-Risk Populations

• Prior transplantation, blood transfusions, or pregnancies (sensitized recipients)
• ABO-incompatible liver transplants
• Retransplantation candidates
• Patients with preformed antibodies against donor antigens

Clinical Presentation

• Marked elevation in liver enzymes (often more severe than ACR)
• Rapid deterioration of graft function
• Poor or absent response to corticosteroid pulse therapy
• Possible coagulopathy reflecting severe hepatic dysfunction

Diagnostic Approach (Stepwise)

1. Clinical suspicion – early graft dysfunction, steroid-resistant rejection, sensitized recipient

2. Exclude alternative causes – Doppler ultrasound (rule out hepatic artery thrombosis or vascular complications), biliary imaging, medication review, tacrolimus trough levels

3. Immunologic testing – DSA detection (preformed vs. de novo)

4. Liver biopsy – histologic confirmation with C4D immunostaining

Histologic Features of AMR

• Microvascular injury – damage to small intrahepatic vessels
• Endothelial damage – injury to vascular lining
• Portal inflammation (may overlap with other etiologies)
• Hepatocyte necrosis and dropout – eosinophilic debris reflecting parenchymal injury
• Positive C4D immunostaining – particularly in portal microvasculature (portal veins, capillaries, inlet venules); hallmark of complement activation

ACR vs. AMR – Key Distinctions

3. Specific Clinical Data, Statistics, or Study Results Cited

• AMR is less common than ACR in liver transplantation (no specific incidence figures quoted)
• The liver's inherent immunologic tolerance accounts for lower AMR frequency compared to kidney transplantation
• No specific randomized trial data or named studies were cited; content is primarily consensus-based and pathophysiology-focused

4. Practical Takeaways for Clinicians

• Board/clinical pearl: Early post-transplant rejection that is unusually severe and fails to respond to steroid pulse should immediately trigger workup for AMR rather than escalation of steroid therapy
• Critical differential: Distinguish AMR from hepatic artery thrombosis (HAT) – both present early with severe graft dysfunction; Doppler ultrasound is essential in the initial evaluation
• Diagnostic pitfall: Canalicular bile plugging on biopsy may mimic biliary obstruction but can reflect AMR-associated microvascular injury; avoid premature attribution to biliary causes
• Treatment is multimodal and goes beyond steroids:

- Plasmapheresis – removes circulating DSA

- **In