Treatment of Antibody-Mediated Rejection (ABMR) Post Kidney Transplant
For acute ABMR in kidney transplant recipients, initiate combination therapy with plasmapheresis, intravenous immunoglobulin (IVIG), and high-dose corticosteroids as first-line treatment, with rituximab added for refractory cases and bortezomib reserved for severe or treatment-resistant rejection. 1, 2
First-Line Treatment Protocol
Corticosteroid pulse therapy remains the foundation of ABMR treatment, typically 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 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. A critical caveat: plasmapheresis causes rebound antibody production, necessitating concurrent IVIG administration 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, 3. IVIG should be given after each plasmapheresis session to prevent antibody rebound and provide immediate immunomodulation 1, 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 in kidney transplant recipients 1. MMF reduces B-cell counts by nearly half at 1 year post-transplant 1.
Second-Line Therapies for Refractory ABMR
Rituximab (anti-CD20 monoclonal antibody) should be added for cases not responding to first-line therapy, typically as a single dose of 375 mg/m², targeting CD20-positive B lymphocytes 4, 5. However, recognize that rituximab does not target CD20-negative plasma cells, which are the primary antibody producers 6, 7.
Bortezomib (proteasome inhibitor) is indicated for severe or refractory ABMR, administered at 1.3 mg/m² on days 1,4,8, and 11 6, 4, 8. Bortezomib uniquely targets plasma cells—the actual antibody-producing cells that rituximab cannot reach 6, 7. In kidney transplant recipients with refractory ABMR, bortezomib achieved significant DSA reduction (P=0.028) and stabilized or improved renal function in 71% of patients 4, 8. Common adverse effects include diarrhea, sensory neuropathy, fatigue, and thrombocytopenia, requiring careful monitoring 6.
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. In kidney transplant recipients, eculizumab prophylaxis reduced ABMR incidence in highly sensitized patients, and case reports show resolution of refractory ABMR when combined with plasmapheresis, IVIG, and rituximab 1.
Daratumumab (anti-CD38 monoclonal antibody) represents a newer option for refractory cases, targeting CD38-expressing plasma cells and NK cells that produce DSAs 7, 2. The American Heart Association recognizes daratumumab as reasonable secondary therapy (Class IIa; Level of Evidence C), with protocols typically involving 8 weekly doses, followed by 8 doses every other week, then monthly maintenance 7. Recent evidence suggests late ABMR may be effectively treated with anti-CD38 therapy 2.
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 in kidney transplant recipients 1.
Cyclophosphamide has only modest data supporting its use and is generally reserved for combination therapy in highly refractory cases, not as monotherapy 1.
Treatment Algorithm by Severity
For early acute ABMR (0-6 months post-transplant):
- Corticosteroid pulse + plasmapheresis + IVIG 1, 2
- Add rituximab if no response after 1-2 weeks 4, 5
- Escalate to bortezomib for continued refractoriness 4, 8
For late ABMR (>6 months post-transplant):
- Same initial approach as early ABMR 2
- Consider daratumumab earlier in treatment course, as late ABMR may respond better to anti-CD38 therapy targeting long-lived plasma cells 7, 2
For chronic active ABMR:
- No treatment has proven effective 9
- Focus on optimizing maintenance immunosuppression with adequate MMF 1
- Consider enrollment in clinical trials 9
Critical Monitoring Parameters
Monitor DSA levels serially to assess treatment response, as reduction in DSA titers correlates with treatment success 4, 8, 9. Perform follow-up kidney biopsies to document histologic response and guide therapy duration 6, 3, 7. Track serum creatinine and estimated GFR as functional markers of graft response 4, 8.
Common Pitfalls
Avoid monotherapy approaches—combination therapy targeting multiple immune pathways is essential for ABMR treatment 1. Do not delay treatment escalation in refractory cases, as chronic active ABMR has no effective treatment and leads to graft loss 9. Remember that not all DSAs are pathogenic—correlate antibody findings with histologic evidence of rejection before initiating aggressive therapy 9.