What is the treatment for Antibody-Mediated Rejection (ABMR) in kidney transplantation?

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 in kidney transplant recipients, adding rituximab for cases that don't respond adequately, and reserving bortezomib for severe or treatment-resistant rejection. 1

First-Line Treatment Protocol for Acute ABMR

Start with the triple combination immediately upon diagnosis:

• 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: Begin 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: Give 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

This triple combination has become standard-of-care despite limited high-quality evidence, with plasmapheresis and IVIG now serving as the foundation for acute AMR treatment 2

Optimization of Baseline Immunosuppression

• Ensure adequate 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

• Adjust tacrolimus levels to therapeutic range and consider intensifying maintenance immunosuppression as part of the overall treatment strategy 1

Second-Line Therapy: Rituximab

Add rituximab for refractory cases that don't respond to first-line therapy:

• Rituximab is a monoclonal antibody targeting CD20 on B cells, typically dosed at 375 mg/m² weekly for 4 weeks or as a single dose 3, 1

• Evidence from cardiac transplantation showed complete histological resolution of AMR with rituximab monotherapy, though kidney transplant data is more mixed 3

• Important caveat: Recent systematic reviews show rituximab may add little or no benefit to plasmapheresis and IVIG for early graft survival, but it remains widely used in clinical practice 2

Third-Line Therapy: Bortezomib for Severe/Refractory ABMR

Reserve bortezomib for severe or treatment-resistant ABMR:

• Bortezomib is a proteasome inhibitor that uniquely targets plasma cells—the actual antibody-producing cells that rituximab cannot reach because plasma cells don't express CD20 3, 1

• Dosing: 1.3-1.5 mg/m² administered on days 1,4,8, and 11 (one cycle over 11 days) 3, 1

• In kidney transplant recipients with refractory mixed AMR and cellular rejection, bortezomib demonstrated reduction in DSA levels and improvement in allograft function 3

• A single-center study of 6 kidney transplant patients with severe AMR treated with bortezomib-based regimen (including plasmapheresis, IVIG, steroids, and rituximab) showed 4 of 6 patients responded with stable kidney function at median 14-month follow-up 4

• Critical limitation: Most bortezomib studies used combination therapy, making it difficult to attribute success to bortezomib alone; one study showed bortezomib monotherapy did NOT decrease DSA levels in sensitized kidney transplant patients 3

Emerging Therapies for Severe, Life-Threatening Cases

Consider these agents only for severe, refractory ABMR after exhausting standard therapies:

• Eculizumab (C5 complement inhibitor): May be used for severe, life-threatening ABMR refractory to standard therapies, though it is NOT FDA-approved for this indication and cost/insurance coverage is prohibitive 3, 1

  • Dosing and administration follow protocols for paroxysmal nocturnal hemoglobinuria 3
  • Preclinical data is promising, but clinical evidence in kidney transplantation is limited to case reports 3

• Daratumumab (anti-CD38 monoclonal antibody): Represents a newer option for refractory cases, targeting CD38-expressing plasma cells and NK cells that produce DSAs 1, 5

  • Recent evidence suggests late AMR may be effectively treated with anti-CD38 therapy targeting long-lived plasma cells 5
  • This is an emerging therapy with limited but growing evidence 6

Therapies to AVOID

Do NOT use the following approaches:

• Total lymphoid irradiation (TLI): Not recommended due to potential long-term complications including myelodysplasia and acute myelogenous leukemia, with unclear efficacy for ABMR 3, 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 3, 1

Critical Monitoring Parameters

Track these markers to assess treatment response:

• Serial DSA monitoring: Reduction in DSA titers correlates with treatment success and should guide therapy duration 1

• Follow-up kidney biopsies: Perform to document histologic response, assess for resolution of C4d staining and peritubular capillaritis, and guide therapy duration 1, 4

• Serum creatinine and eGFR: Monitor renal function closely as a practical marker of graft response 4

Special Considerations for Chronic Active ABMR

No treatment has been shown to be effective against chronic active ABMR 7

• The focus should shift to preventing progression and optimizing maintenance immunosuppression rather than aggressive antibody removal 7

• Consider enrolling patients with chronic active AMR in clinical trials to assess novel therapeutic agents, as this represents a critical unmet need 7

Common Pitfalls to Avoid

• Don't delay treatment: ABMR requires immediate intervention; waiting for complete diagnostic workup can worsen outcomes 1

• Don't use rituximab or bortezomib as monotherapy: These agents work best in combination with plasmapheresis and IVIG, not alone 3, 2

• Don't assume all DSAs are pathogenic: Not all donor-specific antibodies cause rejection; correlate with biopsy findings and clinical context 7

• Don't forget infection monitoring: All these immunosuppressive therapies increase infection risk; maintain vigilance for opportunistic infections 8