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More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high-dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high-dose IVIg+rituximab in non-randomized trials. Overall experience in multiple centers, however, has shown high antibody-mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low-dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low-dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell-targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non-deletional strategies with IVIg.