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

Disclosures

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

In This Article

Clinical Use of IVIG in Kidney Transplantation

Intravenous immunoglobulin (IVIG) products are known to have powerful immunomodulatory effects on inflammatory and autoimmune diseases.[15] Data from our group and others suggest that IVIG therapy given to highly sensitized patients results in reduced allosensitization, reduced ischemia-reperfusion injuries, fewer acute rejection episodes and higher successful long-term allograft outcomes for cardiac and renal allograft recipients.[10,11,12,13,14,16,17,18,19] We and others have confirmed that pre-treatment with IVIG results in reductions of anti-HLA antibodies, and is effective in treatment of allograft rejection episodes.[12,18,19]

End stage renal disease (ESRD) patients awaiting a living-donor or deceased donor transplant who exhibit positive donor-specific CMXs or have high PRAs are candidates for desensitization with the IVIG protocol.

A summary of the Cedars-Sinai high-dose IVIG protocol was recently presented.[13] Briefly, we utilize the in vitro IVIG inhibition CMX test (Figure 1A, B) to determine if highly sensitized patients are candidates for the IVIG protocol. Patients first undergo a standard T-cell and B-cell cytotoxicity assay against a random panel of 50 donors to determine PRA. If positive, we then assess the utility of IVIG by incubating IVIG with the positive PRA sera. IVIG is added 1:1 and we then determine the extent of inhibition of T-cell and B-cell cytotoxicity. In our hands, this in vitro assay provides an idea of the expected efficacy of IVIG when given in vivo. Post-treatment, the patients can continue to be monitored using the CDC assay. Nonspecific binding of IgG (i.e. IVIG) can interfere with other assays for anti-HLA antibody, especially binding assays (flow cytometer, ELISA and flow beads). All assays used to measure anti-HLA antibody may be used after ~3 weeks (the half-life of IVIG) since the IVIG will have dissipated from the circulation and will no longer interfere with binding assays.

Figure 1A.

The panel reactive antibody status of a patient who is highly sensitized. The patient's sera contains antibodies that kill 34/50 (68% PRA) lymphocytes on the panel. The cytotoxicity is dependent upon complement as shown in the figure.

Figure 1B.

Shows that IVIG can inhibit the cytotoxicity completely in vitro and this is due to blocking antibodies present in the IVIG preparations. Other explanations (i.e. IVIG's complement inhibitory capacity) also exist for this observation. If IVIG shows inhibition of PRA or CMX tests in vitro, it is very predictive of in vivo responses.

It is important to mention that alternative explanations for the reduction of anti-HLA antibody-mediated cytotoxicity have emerged. These include inhibition of complement activation by the Fc fragment of IgG molecules in the IVIG preparations,[20,21] or possible contamination of IVIG products with soluble HLA molecules.[11] Wassmuth et al.[20] showed that significant inhibition of the in vitro CDC assay was accomplished with IgM/IgA containing products only and this was likely due to inhibition of complement. These authors also showed that much lower inhibitory effects were seen when ELISA techniques for measurement of anti-HLA antibodies were performed. Watanabe et al.[21] recently showed similar results, discounting the possibility that the IVIG-induced inhibition seen in the complement-dependent PRA system was due to anti-idiotypic antibody.

Our data[11,12,13] contrast greatly with these observations since no nonspecific inhibition (i.e. complement inhibition by IVIG (IgG)) was seen and no soluble HLA was detected in the products used. In addition, patterns of inhibition vary from patient to patient. Cytotoxicity can be completely inhibited against T and B cells, or inhibited partially. We also see inhibition of T-cell cytotoxicity with no inhibition of B-cell cytotoxicity. In addition, a role for blocking antibody can be postulated based on concomitant in vitro inhibition of flow cytometry CMXs, and our clinical observations that immediate post-IVIG infusion anti-HLA antibody titers are markedly decreased compared with pre-infusion.

Despite the limitations of the in vitro assay, we have also adapted it to determine the efficacy of IVIG in single donor/recipient pairs who have a positive CMX. If IVIG shows any reduction of T- or B-cell cytotoxicity, we then treat the recipient with 2 g/kg IVIG (maximum dose 140 g) monthly until the CMX is negative or acceptable. An acceptable CMX in our program is defined as a negative CDC, but a flow cytometry CMX (B, T or B and T cell) that remains positive at a flow channel shift of <200 CS (normal: <50 CS T cell and <100 CS B cell). This is based on our personal experience and that of others.[22] We usually give four doses of IVIG, and have adapted this for use in highly sensitized deceased donor transplant candidates who have been on the UNOS list for >5 years, have a PRA of >50% and who receive frequent offers for kidneys from donors with whom they have a positive CMX. These patients have an IVIG PRA assay, and if suppression or inhibition of the PRA is seen with IVIG, the patients are offered IVIG 2 g/kg monthly 4 times in hopes of achieving desensitization and receiving a CMX compatible kidney or other organ. These protocols are summarized in Figure 2A, B.

Figure 2.

(A) It is a summary of the IVIG desensitization protocol for patients with living donors. If IVIG shows in vitro inhibition or reduction of the donor-specific CMX, IVIG is given at 2 g/kg (maximum dose: 140 g) until a negative CMX is achieved (usually maximum of four doses given). When a negative or acceptable CMX is achieved, the patient is scheduled for transplant. The patient receives an additional 2 g/kg at 1 M post-transplant. (B) Shows the protocol for patients awaiting deceased donor transplantation. Briefly, a similar protocol for living donors is used. If IVIG shows in vitro reduction of PRA, patients receive 2 g/kg IVIG monthly 4 times. Sera are sent to the Organ Procurement Organization after each infusion and CMX with potential deceased donors.

Figure 2.

(A) It is a summary of the IVIG desensitization protocol for patients with living donors. If IVIG shows in vitro inhibition or reduction of the donor-specific CMX, IVIG is given at 2 g/kg (maximum dose: 140 g) until a negative CMX is achieved (usually maximum of four doses given). When a negative or acceptable CMX is achieved, the patient is scheduled for transplant. The patient receives an additional 2 g/kg at 1 M post-transplant. (B) Shows the protocol for patients awaiting deceased donor transplantation. Briefly, a similar protocol for living donors is used. If IVIG shows in vitro reduction of PRA, patients receive 2 g/kg IVIG monthly 4 times. Sera are sent to the Organ Procurement Organization after each infusion and CMX with potential deceased donors.

From July 2002 to July 2005, we evaluated 77 highly HLA-sensitized patients who had positive CMXs with potential donors in the IVIG-PRA test system. Eighty-one percent showed inhibition to some degree in the PRA or CMX system. Sixty-seven of seventy-seven (87%) were transplanted after IVIG desensitization therapy (42 LD, 25 CAD). Of the 10 patients who were not transplanted, six are awaiting a cadaver transplant offer and two did not respond to IVIG. Two others were successfully desensitized for living donors, but medical conditions prevented transplantation. Thus, only 2/77 (2.6%) failed to respond to IVIG sufficiently to allow transplantation to be considered. The mean PRAs for the cadaver recipients were 83% and nearly all patients had antibodies specific to their donors that were eliminated or reduced by IVIG therapy. The incidence of allograft rejection is 28% with a 3-year patient and graft survival of 97.5% and 87.1%, respectively. Five grafts were lost to rejection. The mean serum creatinines at 3 years were 1.4 mg/dL.

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