Antibody-Mediated Rejection: Mechanisms, Diagnosis & Treatment in 2026

Antibody-mediated rejection (AMR) has emerged as the leading cause of late allograft loss in kidney transplantation and a significant barrier to long-term graft survival across all solid organ transplants. Unlike T-cell-mediated rejection (TCMR), which responds well to conventional immunosuppression, AMR remains difficult to treat and represents an area of intensive research focus.

Pathophysiology of Antibody-Mediated Rejection

AMR is driven by donor-specific antibodies (DSA) directed against HLA antigens or non-HLA endothelial antigens on the graft vasculature. The pathogenic cascade involves:

• DSA binding: Antibodies (predominantly IgG) bind to HLA class I (HLA-A, -B, -C) or class II (HLA-DR, -DQ, -DP) antigens on donor endothelial cells
• Complement activation: The classical complement pathway is activated (C1q binding, C4d deposition), leading to formation of the membrane attack complex (MAC, C5b-9) and endothelial injury
• Fc receptor-mediated effects: DSA engage Fc receptors on NK cells, macrophages, and neutrophils, triggering antibody-dependent cellular cytotoxicity (ADCC)
• Endothelial activation: Even without complement, DSA can directly activate endothelial signaling pathways, inducing proliferation, inflammation, and chronic vascular remodeling

Diagnostic Advances

The diagnosis of AMR has been transformed by molecular diagnostics. The Molecular Microscope Diagnostic System (MMDx) uses microarray-based gene expression profiling of biopsy tissue to classify rejection phenotypes with greater precision than conventional histology alone. Key molecular markers include endothelial-associated transcripts (ENDATs) and DSA-associated transcripts.

Donor-derived cell-free DNA (dd-cfDNA) has emerged as a promising non-invasive biomarker for AMR. Elevated dd-cfDNA (>1% of total cfDNA in kidney transplants) correlates with active rejection and may enable earlier detection than serum creatinine changes. Several commercial assays (AlloSure, Prospera) are now clinically available.

Treatment Approaches

Current treatment of acute AMR typically involves multimodal therapy:

• Plasmapheresis/plasma exchange: Removes circulating DSA
• Intravenous immunoglobulin (IVIG): Immunomodulatory effects including Fc receptor blockade, anti-idiotypic antibodies, and complement regulation (typically 2 g/kg)
• Anti-CD20 therapy (rituximab): Depletes B cells to reduce DSA production, though evidence is mixed (RITUX-ERAH trial was negative)
• Complement inhibitors: Eculizumab (anti-C5) has shown benefit in some severe/refractory cases. C1-esterase inhibitor is also being studied
• Proteasome inhibitors (bortezomib): Targets plasma cells producing DSA. Results have been variable (BORTEJECT trial was negative for chronic AMR)
• IL-6/IL-6R blockade (tocilizumab, clazakizumab): Emerging approach targeting the IL-6 pathway important for B cell and plasma cell differentiation. Phase 2 data are encouraging for chronic active AMR

Chronic Active AMR and Transplant Glomerulopathy

Chronic active AMR (caAMR) is characterized by ongoing antibody-mediated injury with features of chronicity including transplant glomerulopathy (double contours of glomerular basement membrane), peritubular capillary basement membrane multilayering, and arterial intimal fibrosis. It is the leading cause of kidney allograft loss beyond the first year.

No therapies have demonstrated convincing efficacy for established caAMR. The focus has shifted to prevention through improved HLA matching, virtual crossmatching, DSA monitoring, and optimized maintenance immunosuppression adherence. Non-adherence to immunosuppressive medications is the single most important modifiable risk factor for late AMR and graft loss.