Hanyang Med Rev.  2014 Nov;34(4):211-216. 10.7599/hmr.2014.34.4.211.

Current Issues in the Treatment of Chronic Antibody-Mediated Rejection in Kidney Transplantation

• Chung BH
• Yang CW

• KMID: 2168354
• DOI: http://doi.org/10.7599/hmr.2014.34.4.211

Abstract

Circulating alloantibodies are found in a substantial number of renal allograft recipients, and can induce chronic allograft injury, which is represented microscopically as transplant glomerulopathy and diffuse C4d deposition in peritubular capillaries (PTCs). Development of these injuries is significantly correlated with late allograft loss, and in this regard, it was included as a new disease entity named chronic antibody-mediated rejection (cAMR) in the updated Banff 05 classification. Usually, the prognosis of cAMR is poor and conventional immunosuppressants mainly targeting T cell-mediated immunity cannot prevent or reverse it. Therefore, some researchers have suggested that therapies directed at the humoral response may be required for the treatment of cAMR. Recently, some reports have suggested that the combined use of rituximab and intravenous immunoglobulin (IVIg) therapy may be useful for the treatment of cAMR. Our previous study also showed that rituximab and IVIg combination therapy effectively delayed the progression of cAMR. We administered rituximab and IVIg combination therapy to 18 biopsy-proven cAMR patients and found that it significantly slowed the decline of the estimated glomerular filtration rate. However, this effect was limited in patients with heavy proteinuria, and dissipated in all patients by 1 year post-treatment. Recently, new drugs targeting the humoral immune system, such as bortezomib and eculizumab, have been tested for the treatment of cAMR. However, the studies still lack definitive data in terms of successful treatment of cAMR. We speculate that those therapies will compensate for the limitation of previous anti-humoral therapies for cAMR.

Keyword

Kidney Transplantation; Chronic Rejection; Donor-Specific Antibodies; Pathology; Therapeutics

MeSH Terms

Allografts
Capillaries
Classification
Glomerular Filtration Rate
Humans
Immune System
Immunity, Cellular
Immunoglobulins
Immunoglobulins, Intravenous
Immunosuppressive Agents
Isoantibodies
Kidney Transplantation*
Pathology
Prognosis
Proteinuria
Bortezomib
Rituximab
Immunoglobulins
Immunoglobulins, Intravenous
Immunosuppressive Agents
Isoantibodies

Figure

• 

  Fig. 1 Stages of chronic antibody mediated rejection. The first stage is accommodation, in which circulating alloantibodies do not attack allograft tissue. This is followed by subclinical AMR in which allograft tissue injury progresses but its function is not compromised. Finally, overt chronic antibody-mediated rejection with graft dysfunction develops and progresses to graft failure. AMR, antibody-mediated rejection.

• 

  Fig. 2 Effect of drugs used for antibody-mediated rejection. Plasmapheresis removes circulating alloantibodies. Rituximab depletes B cells of all stages, and bortezomib directly suppresses antibody-producing plasma cells. Intravenous immunoglobulin can modulate various immune reactions through multiple mechanisms. Eculizumab inhibits the terminal complement pathway.

• 

  Fig. 3 Rituximab/intravenous immunoglobulin combination therapy protocol for chronic antibody-mediated rejection. On the first day, rituximab (375 mg/m2) was administered followed by intravenous immunoglobulin (0.4 g/kg) for 4 days. Concomitantly, 250 mg of methylprednisolone was administered twice a day, intravenously, for a period of 3 days, followed by oral prednisolone.

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