Preliminary results of a prospectively randomized trial of ALG vs OKT3 for steroid-resistant rejection after renal transplantation in the early postoperative period. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. Ortho Multicenter Transplant Study Group. A controlled clinical trial of treatment with ALG in established rejection of renal allografts. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. A prospective randomized study comparing poly-ATG to mono-OKT3 clonal antibodies for the first rejection therapy after kidney transplantation: long-term results. Preliminary results from a randomized and prospective study of high-dose immunoglobulin versus monoclonal antibody in the rescue of steroid-resistant rejections. Treatment of acute rejection of cadaveric renal allografts with rabbit antithymocyte globulin. Use of antithymocyte globulin for reversal of acute allograft rejection. Therapy of acute cadaveric renal allograft rejection with adjunctive antithymocyte globulin. Multicenter comparison of rejection reversal: rabbit anti-human lymphocyte serum (ATS) versus horse anti-human lymphocyte globulin (ATGAM). Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection. Low-dose maintenance prednisone and antilymphoblast globulin for the treatment of acute rejection. A steroid-sparing approach to immunosuppressive therapy. Half dose of OKT3 is efficient in treatment of steroid-resistant renal allograft rejection. The use of antilymphoblast globulin in the treatment of renal allograft rejection: a double-blind, randomized study. Aggressive treatment of the first acute rejection episode using first-line anti-lymphocytic preparation reduces further acute rejection episodes after human kidney transplantation. Treatment of acute cellular rejection with T10B9.1A-31 or OKT3 in renal allograft recipients. A randomized prospective study comparing low-dose OKT3 to low-dose ATG for the treatment of acute steroid-resistant rejection episodes in kidney transplant recipients.
nan Since the murine monoclonal antibody OKT3 reacts with human T cells and blocks their function, we explored its effectiveness in treating T-cell-mediated rejection of renal allografts. In a prospective randomized multicenter trial, 123 patients undergoing acute rejection of cadaveric renal transplants were treated either with OKT3 daily for a mean of 14 days, with concomitant lowering of the dosage of other immunosuppressive drugs (63 patients), or with conventional high-dose steroids (60 patients). OKT3 reversed 94 per cent of the rejections--a figure that was significantly better (P = 0.009) than the 75 per cent reversal rate obtained with conventional steroid treatment. This superior reversal rate with OKT3 was reflected in an improved one-year graft survival of 62 per cent for the OKT3-treated group, as compared with 45 per cent for the steroid-treated group (P = 0.029), in patients who were all selected by virtue of having had acute rejection. We conclude that treatment with OKT3 (with concomitant lowering of the dosage of other immunosuppressive drugs) is an effective approach for acute renal-allograft rejection. A controlled clinical investigation of the effect of equine anti-human-lymphocyte globulin (ALG) on established rejection after transplantation has been carried out in a group of 31 patients. Compared with a control group, the treated group showed a significantly positive effect of ALG in the form of a faster reversal of rejection episodes (p less than 0.05). Leucocytes, lymphocytes, erythrocytes, thrombocytes and immunoglobulins were unaffected by the treatment, but there were signs of a complement-consuming process and an influence on blast transformation tests. No rise in antibody titre against equine globulin was seen. Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation.
                A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value).
                A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments.
                Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients. nan nan In a prospective randomized single-blind trial, we compared the effectiveness of rabbit antithymocyte globulin (RATG) in the treatment of acute renal graft rejection with the results of treatment by high oral doses of prednisone. Twenty recipients of cadaveric kidneys were included in each group. In the RATG group, the prednisone dose was not increased and a dose-by-rosette protocol was used to keep T cell levels between 50 and 150/mm3. In this group 15 of the 20 patients responded to the treatment. One of these patients lost her kidney afterward because of a technical failure. In five patients rejection was irreversible despite a subsequent course of high-dose prednisone orally. In the prednisone group, 13 patients showed a good response, but 3 of them only after a subsequent course of RATG. The remaining seven patients underwent nephrectomy before a course of RATG could be given. One patient in this group died of septicemia. In either group there were six second rejection episodes, but they developed 2.2 months later in the RATG group. All second rejection episodes were treated with the alternative regimen and all patients responded to this treatment. Renal function after 6 months was similar in both groups. Less infections occurred in the RATG group. Prior to rejection, there were no differences in concentrations of peripheral T cells between both groups. Treatment of acute rejections with RATG is an effective and safe procedure which is steroid sparing. nan A randomized and controlled study was conducted to evaluate the efficacy of adjunctive antithymocyte globulin (ATG) therapy for the treatment of the initial rejection episode in first cadaveric transplants. When compared to the control group (29), which received only standard antirejection treatment (SAT) of steroid pulsing and local irradiation, the adjunctive ATG treatment group (23) demonstrated significantly faster recovery rates (8.9 +/- 4.1 versus 6.9 +/- 3.7 days, P = 0.05, respectively) and better graft survival rates (62 +/- 9% versus 91 +/- 7%, respectively) after the first rejection. ATG treatment did not result in fewer subsequent rejection episodes than SAT but long-term allograft survival rates remained superior to controls for the entire 3-year study period. By avoiding ATG treatment in those patients who never experienced clinical rejection on maintenance immunosuppressive therapy, i.e., nonresponders (23 of 90), complications associated with excessive immunosuppression were minimized. The combined results of the non-responder group of patients and ATG-treated patients resulted in a 1-year patient survival of 97% and graft survival of 86%. These results suggest that the most efficacious use of ATG is therapeutic and not prophylactic in renal transplant patients. nan Acute steroid-resistant rejection episodes are recommended to be treated with set doses of anti-thymocyte globulin (ATG) or anti-CD3 monoclonal antibody (OKT3). Individualized T cell monitoring has been proposed as a tool for dose finding. A randomized study comparing the efficacy and safety of ATG (n = 27) with OKT3 (n = 28) in the treatment of biopsy verified acute steroid-resistant rejection (ASRR) when both drugs were administered on the basis of daily individualized T cell measurements. A drop to below 50 cells/mm3 CD2+ T cells was considered adequate and used to guide the dose of ATG/OKT3. Demographic, clinical and histopathological severities of rejections were equal in the two groups. During the 10 days of T cell monitoring and antibody treatment, 13 patients were in need of dialysis (ATG = 7/OKT3 = 6). Two grafts did not respond to antibody treatment and were lost due to rejection (ATG = 1/OKT3 = 1). There were 26 biopsy verified re-rejections (ATG = 12/OKT3 = 14) within the first 3 months following antibody treatment. Mean serum creatinine (micromol/L) was similar in the two groups (ATG/OKT3: before rejection 157 +/- 72/151 +/- 88, at start of antibody treatment 308 +/- 125/330 +/- 94, end of antibody treatment 254 +/- 122/246 +/- 144 and at follow-up after a mean of 32 months 166 +/- 55 (n = 24)/164 +/- 57(n = 23)). To keep the T cell count below 50 cells/mm3, average dose ATG given was 354 +/- 151 mg (2.3 administrations, range 1-4) and average OKT3 was 32.5 +/- 6.8 mg in 10 doses. In conclusion, individualized T cell monitored administration of ATG and OKT3 is safe and seems as effective as a standard set dose in treatment of ASRR. Tailoring the dose for each individual patient lowers the cost. The purpose of this prospective randomized trial was to evaluate an immunosuppressive protocol involving reduced maintenance and antirejection steroid dosages in cadaver renal transplantation. The study comprises 23 first cadaver graft recipients who experienced an acute rejection episode. All patients received an initial 14-day course of antilymphocyte globulin (ALG) and azathioprine 1.5 to 2.0 mg/kg/day. In 11 patients (group 1), a low maintenance dose of prednisone (30 mg/day) was administered and first rejection episodes were treated with a second 10-day course of ALG. The remaining 12 patients (group 2) received high maintenance doses of prednisone (2 mg/kg/day with tapering) and intravenous methylprednisolone (IVMP) for first rejection episodes. Subsequent rejections in both groups were treated with high doses of steroids. In group 1, all first rejection episodes were reversed with ALG alone, 6 patients experienced no subsequent rejection, and 10 patients currently have a functioning graft. In Group 2, the first rejection episode was reversed with IMVP alone in 10 patients; in two patients in whom IVMP therapy was unsuccessful, ALG was then administered, and subsequent rejection reversal was effected. In group 2, 4 patients experienced no subsequent rejection, and 9 patients currently have a functioning graft. Patients in group 1 received significantly lower (P less than .01) cumulative steroid doses in the first six months following transplantation, which resulted in a reduced number of major infections, as compared with patients in group 2. We conclude that the steroid-sparing regimen of low maintenance prednisone and ALG for first rejection is as effective immunologically as the established high steroid protocol. Rejection episodes in renal allograft recipients are usually efficiently treated with high doses of intravenous methylprednisolone. Rejection therapy with OKT3 is often reserved for steroid-resistant episodes. However, the optimal dose of OKT3 in the treatment of steroid-resistant rejection is not known. Therefore, we randomized renal transplant recipients with steroid-resistant rejection to treatment with a standard daily intravenous dose of either 5 mg of OKT3 (n=15) or 2.5 mg of OKT3 (n=15) for 10 days. Circulating T cells (measured as CD2+ cells) were adequately and equally depleted in the two groups. Three grafts were lost due to rejection within the first 3 months following OKT3 administration, one in the 2.5 mg OKT3 group and two in the 5 mg OKT3 group. Two nonimmunologic graft losses occurred in the 2.5 mg OKT3 group. Median serum creatinine values were not different between the two groups, neither at the start (median values: 200 micormol/L in the 5 mg OKT3 group vs. 188 micromol/L in the 2.5 mg group) nor immediately after OKT3 rescue therapy (202 micromol/L vs. 185 micromol/L, respectively). Eight cytomegalovirus infections occurred in each group. Two re-rejection episodes occurred in the 5 mg OKT3 group and one occurred in the 2.5 mg OKT3 group. All responded to treatment. Function of the remaining grafts estimated by serum creatinine after a mean long-term follow-up of 18 months (range, 6-36 months) revealed no differences (185 micromol/L in the 5 mg OKT3 group vs. 170 micromol/L in the 2.5 mg OKT3 group). We conclude that OKT3 treatment of steroid-resistant rejections in renal transplant recipients is equally effective in daily doses of 2.5 mg and 5 mg with respect to reversal rate and long-term outcome. A randomized, double-blind study comparing horse antilymphoblast globulin (ALG) (25 patients) with human IgG (20 patients) in addition to standard antirejection therapy was performed in recipients of first kidney transplants having their first rejection episodes. Patients received ALG (20 mg/kg/day) for 10 days, and a control group was given human IgG (20 mg/kg/day) for 10 days in addition to standard therapy. The groups were comparable with respect to HLA matching, age, time to onset of first rejection episode, and number of diabetics. The number of patients requiring transplant nephrectomy and/or dialysis, having a second rejection episode, having good late function, or dying did not differ in recipients of related kidneys receiving either ALG or human IgG. Recipients of cadaver kidney grafts had fewer (0.05 less than P less than 0.06) second rejection episodes if they received ALG during their first rejection episode. However, the number of patients requiring transplant nephrectomy and/or dialysis, having late good function, and dying did not differ significantly for recipients of cadaver kidneys. We conclude that ALG does not add significantly to standard antirejection therapy for the treatment of first rejection episodes. The detrimental effect of acute rejection episodes on long-term outcome of renal allografts in cyclosporin-treated patients is well established, although has not been seen by all investigators. To analyse the possibility that aggressive treatment of the first episode may ameliorate this detrimental effect, we performed an open label, randomised prospective trial in cyclosporin-based, immunosuppressed recipients of postmortem renal allografts in order to compare two different treatment protocols during primary acute rejection episodes: (1) group 1 of 25 patients received 3 x 250 mg methylprednisolone (MP) i.v.; (2) group 2 of 25 patients received 7 x anti-thymocyte globulin (ATG)-Fresenius i.v. (4 mg/kg body weight). During a period of 4 years, the following clinical observations were made: (1) The incidence of an acute re-rejection episode was significantly reduced in the ATG-treated study group (16%) compared to the MP-treated study group (72%); (2) The severity of the first acute rejection episode (intensity of renal dysfunction measured in terms of 10-day creatinine area under curve) showed no significant difference between the groups (37 mg x 10-d/dl to 58 mg x 10-d/dl); and (3) The half-lives of allografts in both groups have not shown any significant differences so far. In conclusion, aggressive treatment of the first rejection episode of renal allografts with the use of ATG reduced the incidence of re-rejection episodes which, however, are not reflected so far by improvement of the 4-year survival rate of these allografts. Since it could be observed that re-rejection is an even worse predictor for chronic transplant failure, a better long-term outcome of renal allografts in ATG-treated patients may be expected during a longer observation period. The incidence of a third episode was also reduced in the ATG-treated group (0%) compared to the MP-treated group (12%). T10B9.1A-31, a nonmitogenic immunoglobulin Mk monoclonal antibody that detects an epitope on the alpha/beta chains of the T cell antigen receptor (TCR alpha/beta), or OKT3, an anti-CD3 mAb, was employed in a randomized double-blind phase II clinical trial to treat biopsy-proven acute cellular renal allograft rejection. Two of the 40 patients initially selected for the protocol were considered to be nonevaluable. Analysis of the remaining 38 patients receiving both living related and cadaveric donor allografts revealed a patient survival of 100% and a graft survival of 97%. Primary rejection reversal was achieved in 18/19 (95%) patients treated with T10B9.1A-31 and in 20/21 (95%) of patients receiving OKT3. The two patients who did not respond to the first mAb responded to the crossover mAb. Rerejection occurred in 3/18 (17%) of patients treated with T10B9.1A-31 and in 3/20 (15%) treated with OKT3. The mean day of rejection reversal was 1.9 +/- 0.7 with T10B9.1A-31 and 3.37 +/- 1.21 with OKT3 treatment. The rise in mean serum creatinine after mAb administration and the mean creatinine on days 1 through 6 were significantly less in patients treated with T10B9.1A-31. Biopsy specimens analyzed for rejection revealed no significant difference between the T10B9.1A-31 and OKT3 cohorts. The mean serum creatinines at 30, 60, 180, and 360 days posttransplantation were the same for both groups. Significantly fewer febrile, respiratory, and untoward effects followed the first dose (day 0) and fewer febrile, gastrointestinal, and neurological side effects occurred with subsequent doses (days 1-9) in patients treated with T10B9.1A-31. Infectious complications occurred in 3/13 patients treated only with T10B9.1A-31, in 9/17 OKT3-treated patients, and in 4/8 patients treated with both mAb. Analysis of human antimouse antibody (HAMA) revealed that the development of HAMA with T10B9.1A-31 was similar to that of OKT3. Acute steroid-resistant rejection episodes in kidney allograft recipients require treatment with antilymphocyte antibodies. Monoclonal anti-CD3 and polyclonal antilymphocyte antibodies have been widely used but seldom compared. Recent data have suggested that these antibodies could be used at reduced doses without jeopardizing their efficacy. In this study, we randomized renal transplant recipients who encountered a first acute steroid-resistant rejection episode to low-dose ATG or low-dose OKT3 treatment. Sixty patients were enrolled in the study. They received prophylactic immunosuppression with cyclosporin, azathioprine, and prednisolone. Treatment of biopsy-proven rejection consisted of a 10-day course of either ATG (n = 31) or OKT3 (n = 29). The total ATG dose was 484 +/- 110 mg, i.e., 0.75 mg/kg per day. The total OKT3 dose was 32 +/- 4 mg, i.e., 0.05 mg/kg per day. We compared reversion of rejection, side effects, immunodepression, and graft function. Reversion of rejection was similar in the two groups, although we noted a trend in favor of ATG. Results were 3% vs 10% early graft failures, 13% vs 23% overall graft failures, 28% vs 38% 3-month actuarial incidence of rebound rejection, and 89% vs 81% 1-year graft survival rate in the ATG and OKT3 groups, respectively. Tolerance was worse in the OKT3 group due to the first-dose syndrome. Infections and cancers occurred with the same frequency. ATG resulted in a deeper and longer decrease in peripheral lymphocyte subsets. Graft function was similar in the two groups. We conclude that low-dose ATG and low-dose OKT3 are equally effective in reversing steroid-resistant acute rejection. Tolerance was better with ATG, which also gave a more potent and longlasting immunodepression. The use of reduced doses of ATG and OKT3 did not appear to lessen their efficacy.
In reversing first rejection, any antibody is better than steroid and also prevents graft loss, but subsequent rejection and patient survival are not significantly different. In reversing steroid-resistant rejection the effects of different antibodies are also not significantly different. Given the clinical problem caused by acute rejection, data are very sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed.