Treatment of Antibody-Mediated Rejection in Kidney Transplantation
Initiate combination therapy with plasmapheresis, intravenous immunoglobulin (IVIG), and high-dose corticosteroids as first-line treatment for acute ABMR in kidney transplant recipients, with rituximab added for refractory cases and bortezomib reserved for severe or treatment-resistant rejection. 1
First-Line Treatment Protocol
The cornerstone approach involves three simultaneous interventions:
Corticosteroid pulse therapy forms the foundation, administered as methylprednisolone 250-1000 mg IV for 3 days, targeting nuclear factor-κB and activator protein-1 pathways to suppress immune activation 1
Plasmapheresis should be initiated immediately to physically remove circulating donor-specific antibodies (DSAs), typically performed 1-7 sessions per week for 1-4 weekly cycles, exchanging 1-2 plasma volumes per session 1
IVIG administration at 1-2 g/kg divided over 2-4 doses works through multiple mechanisms: blockade of Fc-γ receptors, complement inhibition, neutralization of circulating antibodies, and downregulation of B-cell receptors 1, 2
Despite limited high-quality evidence, plasmapheresis and IVIG have become standard-of-care for acute ABMR treatment, though meta-analyses show no significant difference in graft survival compared to controls (HR 0.76; 95% CI 0.35-1.63) 3. This reflects the reality that current treatments are based on consensus rather than robust controlled trial data 4, 3.
Optimization of Baseline Immunosuppression
- Ensure adequate mycophenolate mofetil (MMF) is part of the maintenance regimen, as MMF reduces B-cell proliferation and antibody production, with demonstrated reduction in both anti-HLA and non-HLA antibodies 1
Second-Line Therapies for Refractory ABMR
When first-line therapy fails or ABMR is severe at presentation:
Bortezomib (proteasome inhibitor) is indicated for severe or refractory ABMR, administered at 1.3 mg/m² on days 1,4,8, and 11 1, 5
Bortezomib uniquely targets plasma cells—the actual antibody-producing cells that rituximab cannot reach—and has demonstrated effectiveness in reducing DSA levels and achieving stable renal function in patients with severe ABMR 1, 5
In a single-center series, 4 of 6 patients with severe ABMR responded to bortezomib-based treatment with stable kidney function during median 14-month follow-up 5
Rituximab (anti-CD20 antibody) is commonly added to first-line therapy for refractory cases, though recent studies show it adds little or no benefit to plasmapheresis and IVIG alone 1, 3. This represents an important caveat: rituximab has become widely used despite weak evidence for efficacy 3.
Emerging Therapies for Severe Cases
Eculizumab (C5 complement inhibitor) may be considered for severe, life-threatening ABMR refractory to standard therapies, though it is not FDA-approved for this indication and cost/insurance coverage is prohibitive 1, 6
Daratumumab (anti-CD38 monoclonal antibody) represents a newer option for refractory cases, targeting CD38-expressing plasma cells and NK cells that produce DSAs, with recent evidence suggesting late AMR may be effectively treated with anti-CD38 therapy 2, 4
Therapies to Avoid
Do not use total lymphoid irradiation (TLI) due to potential long-term complications including myelodysplasia and acute myelogenous leukemia, with unclear efficacy for ABMR 1
Splenectomy should not be performed except as an absolute last resort after all other therapies have failed, given conflicting reports of death and infectious complications 1
Cyclophosphamide has only modest data supporting its use and is generally reserved for combination therapy in highly refractory cases, not as monotherapy 1
Critical Monitoring Parameters
Monitor DSA levels serially to assess treatment response, as reduction in DSA titers correlates with treatment success 1, 7
Perform follow-up kidney biopsies to document histologic response and guide therapy duration 1
Common adverse effects of IVIG include headache, chills, fever, myalgia, and potential volume overload, which require monitoring 2
Bortezomib adverse effects include diarrhea, sensory neuropathy, fatigue, thrombocytopenia, and conjunctivitis, with careful infection monitoring essential 8
Important Clinical Caveats
The treatment landscape for ABMR remains challenging because currently there are no FDA-approved therapies, and treatment guidelines are based on low-quality evidence and consensus 4, 6. The heterogeneity in treatment protocols, AMR definitions, and study quality limits definitive recommendations 3. Despite this uncertainty, the combination of plasmapheresis and IVIG has emerged as standard-of-care, with newer agents like bortezomib and daratumumab showing promise for refractory cases 1, 4.