Treatment of Antibody-Mediated Rejection (ABMR) in Kidney Transplantation
Initiate combination therapy with plasmapheresis, intravenous immunoglobulin (IVIG), and high-dose corticosteroids as first-line treatment for acute ABMR, with rituximab added for refractory cases and bortezomib reserved for severe or treatment-resistant rejection. 1
First-Line Treatment Protocol for Acute ABMR
Begin with the following combination therapy simultaneously:
High-dose corticosteroids: Administer methylprednisolone 250-1000 mg IV daily for 3 consecutive days to suppress immune activation through nuclear factor-κB and activator protein-1 pathway inhibition 1
Plasmapheresis: Initiate 1-7 sessions per week for 1-4 weekly cycles, exchanging 1-2 plasma volumes per session to physically remove circulating donor-specific antibodies (DSAs) 1
IVIG: Administer 1-2 g/kg divided over 2-4 doses, which works through multiple mechanisms including Fc-γ receptor blockade, complement inhibition, neutralization of circulating antibodies, and B-cell receptor downregulation 1
Optimize baseline immunosuppression: Ensure mycophenolate mofetil (MMF) is part of the maintenance regimen, as it reduces B-cell proliferation and antibody production, with demonstrated reduction in both anti-HLA and non-HLA antibodies 1
Despite plasmapheresis and IVIG becoming standard-of-care for acute AMR, evidence quality remains low, with no significant difference in graft survival demonstrated in pooled analysis of randomized controlled trials (HR 0.76; 95% CI 0.35-1.63; P = 0.475) 2. However, this combination has become consensus-based standard therapy given the lack of superior alternatives 3, 2.
Second-Line Therapy for Refractory ABMR
If first-line therapy fails or rejection persists:
Rituximab (anti-CD20 monoclonal antibody): Add 375 mg/m² weekly for 4 weeks to deplete CD20-positive B cells 4, 1. However, rituximab shows little or no benefit when added to plasmapheresis and IVIG in recent studies, with no significant difference in early graft survival 2. The major limitation is that rituximab does not target plasma cells (which lack CD20 antigen), the actual antibody-producing cells 4.
Bortezomib (proteasome inhibitor): For severe or refractory ABMR, administer 1.3-1.5 mg/m² on days 1,4,8, and 11 4, 1, 5. Bortezomib uniquely targets plasma cells—the major alloantibody-producing cells that rituximab cannot reach 4. In kidney transplant recipients with refractory mixed AMR, all patients demonstrated reduction in DSA levels and improvement in allograft function after bortezomib treatment 4, 5. Critical caveat: Bortezomib was typically given with combination immunomodulatory therapies (cytolytic antibodies, corticosteroids, rituximab, plasmapheresis, IVIG), preventing definitive attribution of success to bortezomib alone 4. One study found bortezomib monotherapy did not decrease DSA levels in sensitized kidney transplant patients, suggesting success may require adjunctive therapies 4.
Third-Line Therapy for Severe, Life-Threatening ABMR
For cases refractory to all standard therapies:
Eculizumab (C5 complement inhibitor): Consider for severe, life-threatening ABMR, though not FDA-approved for this indication 4, 1, 6. Eculizumab blocks terminal complement activity, which is the predominant effector pathway of AMR 4. In highly sensitized kidney transplant patients, prophylactic eculizumab reduced the incidence of AMR 4. One case report showed complete resolution of AMR on biopsy after eculizumab was used as rescue therapy with rituximab, IVIG, and plasmapheresis 4. Major limitations: Cost is prohibitive, insurance coverage is typically denied for transplant rejection, and efficacy cannot be definitively attributed to eculizumab alone given polytherapy use 4, 1.
Daratumumab (anti-CD38 monoclonal antibody): Represents a newer option targeting CD38-expressing plasma cells and NK cells that produce DSAs 1, 3. Recent evidence suggests late AMR may be effectively treated with anti-CD38 therapy, which targets long-lived plasma cells 3. Case reports describe successful use in treatment of AMR 7.
Therapies to Avoid
Do not use the following interventions:
Total lymphoid irradiation (TLI): Not recommended due to potential development of myelodysplasia or acute myelogenous leukemia, with unclear efficacy for AMR 4, 1
Splenectomy: Should not be performed except as absolute last resort after all other therapies have failed, given conflicting reports of death and infectious complications in kidney transplant recipients 4, 1
Treatment Approach for Chronic Active ABMR
No treatment has been shown to be effective against chronic active AMR 8. The pathogenetic mechanisms differ between early (0-6 months) and late (beyond 6 months) AMR, with variable activation of complement-dependent and -independent inflammatory pathways 3. IL-6/IL-6 receptor blockers appear promising in chronic AMR, showing reduction in HLA-antibodies, improved histologic inflammation, and increased T-regulatory cells 7.
Critical Monitoring Parameters
Monitor DSA levels serially to assess treatment response, as reduction in DSA titers correlates with treatment success 1
Perform follow-up kidney biopsies to document histologic response and guide therapy duration 1
Assess individual risk using biomarkers and prediction models to determine graft failure risk and response to rejection treatment 8
Common Pitfalls to Avoid
Do not delay treatment: Active AMR with DSAs requires immediate intervention with plasmapheresis, IVIG, and corticosteroids 8
Do not use rituximab as monotherapy: Recent studies show little or no benefit when rituximab is added to standard therapy, and it does not target plasma cells 4, 2
Do not assume all DSAs are pathogenic: Not all donor-specific antibodies cause AMR, and treatment decisions should be based on biopsy-proven rejection with clinical/histologic evidence 3, 8
Monitor for bortezomib adverse effects: Common side effects include diarrhea, sensory neuropathy, fatigue, thrombocytopenia, and conjunctivitis, with careful infection monitoring essential 9