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Sensitization to human leukocyte antigens (HLA) is a significant barrier to transplantation. Currently, no proven therapy exists to improve access to transplantation for highly sensitized patients. Here, we report a novel approach using intravenous immune globulin to modulate anti-HLA antibody and improve the chances for successful transplantation.Forty-five highly HLA-sensitized patients presented as candidates for living-donor kidney transplantation (n=28), cadaveric kidney transplantation (n=15), or heart transplantation (n=2). All patients had a positive CDC crossmatch (CMX) with their donors. In living-donor recipients, intravenous immune globulin (IVIG) was added to the CMX evaluation to determine whether blocking antibodies present in IVIG could inhibit cytotoxicity. For those who showed in vitro inhibition with IVIG (n=26), IVIG was administered (usually as a single dose, 2 g/kg) and the CDC CMX was repeated against the prospective donor immediately after IVIG infusion. If negative, the patient underwent transplantation with their living-donor kidney within 24 to 72 hr. A similar but modified protocol was performed for cadaver donor candidates, all of whom were highly sensitized and had had CMX positivity with multiple donors, negating transplantation. Reductions in CMX positivity, posttransplantation serum creatinine level, number and severity of rejection episodes, and patient and graft survival rates were determined.Forty-two patients underwent transplantation. IVIG treatment completely abrogated the donor-specific CMXs in 35 of 42 patients. In the remaining 7 patients, the CDC CMX was inhibited, but flow cytometry CMXs remained positive. A total of 13 (31%) of 42 recipients developed rejection episodes 3 to 49 days after transplantation. Three grafts (7%) were lost to rejection. Mean serum creatinine level at 24 months was 1.4±0.4 mg/dL. Patient and graft survival rates were 97.6% and 89.1%, respectively, at 24 months.The in vitro IVIG CMX technique predicts the ability of IVIG to reduce anti-HLA antibody levels in highly sensitized patients. Subsequent in vivo IVIG treatment of responders eliminates the positive CDC CMX and allows for successful transplantation. Thus a positive CMX result is not necessarily a contraindication for transplantation and allows access to transplantation for patients for whom it was previously contraindicated.