Intravenous Gammaglobulin (IVIG): A Novel Approach to Improve Transplant Rates and Outcomes in Highly HLA-Sensitized Patients

S. C. Jordan; A. A. Vo; A. Peng; M. Toyoda; D. Tyan


American Journal of Transplantation. 2006;6(3):459-466. 

In This Article

Abstract and Introduction


Intravenous immunoglobulin (IVIG) products are derived from pooled human plasma and have been used for the treatment of primary immunodeficiency disorders for more than 24 years. Shortly after their introduction, IVIG products were also found to be effective in the treatment of autoimmune and inflammatory disorders. Over the past 2 decades, the list of diseases where IVIG has a demonstrable beneficial effect has grown rapidly. These include Kawasaki disease, Guillain-Barre syndrome, myasthenia gravis, dermatomyositis and demyelinating polyneuropathy. Recently, we have described a beneficial effect on the reduction of anti-HLA antibodies with subsequent improvement in transplantation of highly HLA-sensitized patients as well as a potent anti-inflammatory effect that is beneficial in the treatment of antibody-mediated rejection (AMR). These advancements have enabled transplantation of patients previously considered untransplantable. These studies and relevant mechanism(s) of action will be discussed here.


The benefits of kidney transplantation are evidenced by prolonged survival and improved quality of life for both children and adults. Despite these well-documented benefits, transplant frequency remains low due to limited organ availability.[1,2,3,4] In patients with high levels of pre-formed anti-HLA antibodies (high panel reactive antibodies (PRA); highly sensitized), transplant rates are extremely low because of the additional immunologic barrier with increased rejection risk. From 1994 to 2003, the number of highly sensitized patients on the transplant list has continued to increase (12 808 in 1994 vs. 17 814 in 2003).[1] In 2003, 32% of the transplant list was considered sensitized to HLA antigens with 13.7% having PRAs >80%.[1] These antibodies result from exposure to nonself HLA antigens; usually from previous transplants, blood transfusions and/or pregnancies.[5]

In 2003, only 6.5% of all kidney transplants performed in the United States were in-patients with PRAs >80%, despite representing ~14% of the waiting list.[1,2] If transplanted, these patients experience an increased number of rejection episodes and have poorer graft survival.[6,7,8] The highly sensitized patient is destined to remain waitlisted for extended periods of time on dialysis, an added risk factor for patient and graft survival.[1,2,3,4,14] The financial and emotional costs of maintaining highly sensitized transplant candidates on dialysis for years are enormous. Thus, early transplantation would result in considerable cost savings, reduced morbidity and mortality and improvement in quality of life; a goal that has been difficult to achieve until recently.

Patel and Terasaki demonstrated the poor outcomes for kidneys transplanted across a positive crossmatch (CMX) barrier, and established the basis for modern CMX testing as a means of allocating kidneys.[6] Sensitization is a significant barrier to both access and success in organ transplantation. The risks for transplantation can be assessed using standard assays currently available. Today, the technique(s) used to detect anti-HLA antibody include cytotoxicity (CDC) with/without anti-human globulin (AHG), ELISA and flow cytometry (using cells and antigen coated beads). The development of newer, more sensitive assays has led to an increased ability to define highly sensitized patients and identify donor-specific antibody in patients with antibody-mediated rejection (AMR). Sensitization can be defined further in terms of risk for allograft loss and AMR.

The presence of IgG complement fixing antibody specific for donor HLA antigen (class I or class II) without the addition of AHG represents an unequivocal contraindication to transplantation. Patients transplanted across this barrier are at a very high risk for AMR. The risk is considered moderate to high if antibody detection requires the use of an anti-globulin reagent in the cytotoxicity assay or the use of a binding assay (e.g. ELISA, flow beads). The patient's history of sensitizing events (pregnancies, transplants, transfusions), the duration and thoroughness of the antibody screening history of the patient, the sera used in the CMX (number, timing), antibody titer and potential repeat mismatches are also considered important.[7,8]

Until recently, no therapeutic approaches existed to deal with this problem. Currently, two protocols have emerged. These include the plasmapheresis/CMVIg protocol (Johns Hopkins Protocol)[9] and the high-dose IVIG protocol (Cedars-Sinai Protocol).[10,11,12,13,14] Our center has extensive experience with the high-dose IVIG protocol, which will be discussed here.


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