A randomized prospective trial of low-dose OKT3 induction therapy to prevent rejection and minimize side effects in recipients of kidney transplants

Background. We attempted to minimize the undesired side effects and maximiz e the benefit of OKT3 induction therapy in renal transplantation. Methods. One hundred and one recipients of kidney-only transplants were ran domized to three groups, Each received low-dose 2,5-mg OKT3 induction for 7 -14 days, but different premedication on days 0, 1, and 2, Group I was give n 250 mg i.v. methylprednisolone at 1 and 6 hr, and group II received anoth er 500 mg at 1 hr before initial OKT3. Group III received Atgam 15 mg/kg on day 0 and began OKT3 on day 1, A CD3+ T cell cut-off of 50/mms was used to guide therapy. Maintenance therapy included cyclosporine and steroids for each patient. However, groups I and II were also given mycophenolate mofeti l, and group III received azathioprine as a third agent. All rejections wer e biopsy confirmed and Banff scored. Results. No differences in demographic or transplant characteristics were n oted between groups I, II, and III, and mean follow-up was 25.7 (1-38) mont hs. There was no significant difference in actuarial patient (90%, 91%, 94% ) or graft survival (83%, 88%, 84%) at 3 years between the respective group s. Mean creatinine values and infectious complications were similar for eac h group, No patient experienced acute rejection during induction, and eight patients required dose escalation to sustain suppression of CD3 counts, Th e incidence of acute rejection at 6 and 12 months was significantly (P=0.00 4) greater in group III (38.2, 44.1%) than in either group I (15.1, 18.1%) or group II (14.7, 17.6%); relative risk 1.988 (95% CI 1.012-3.906). Format ion of anti-OKT3 antibody was significantly (P=0.006) greater in group III (26.5%) than in group I (6%) or group II (2.9%). Group I recipients enjoyed significantly (P=0.001) fewer (2.17) OKT3 side effects on days 6, 1, and 2 than group II (3.03) or group III (2.49), and contained the largest number (61%) of recipients who experienced no side effects. Group I also exhibite d the most suppressed profile of OKT3-induced release of tumor necrosis fac tor-alpha (P=0.006), interferon-gamma (P=NS), and interleukin-6 (P=0.01) on days 6 and 1. Conclusions. Low-dose 2.5-mg OKT3 with pretreatment of split-dose steroids on days 0, 1, and 2 provides the most effective method for OKT3 induction, which minimizes side effects for most patients. Subsequent maintenance ther apy with cyclosporine, mycophenolate mofetil, and steroids provides effecti ve rejection prophylaxis without increased complications for up to 3 years. Predepletion of T cells before exposure to OKT3 does not prevent cytokine release.