A randomized clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection

A multiinstitutional randomized trial was undertaken comparing OKT3 with steroids for treatment of hepatic allograft rejection. All patients received baseline immunosuppression with Cyclosporine (CsA) and steroids. At the time of biopsy-confirmed rejection, up to 2 intravenous boluses (250-1000 mg) of methylprednisolone were initially administered. Twenty-eight patients who failed to respond were then randomly assigned to OKT3 or continued steroid therapy. Rescue therapy with the opposite treatment arm was added after 6 days if the primarily allocated protocol failed. Three of 13 patients assigned to the steroid group responded promptly, and continue with good function 7-12 months later. OKT3 rescue was required in 10 patients who failed to improve despite receiving up to 6 g of methylprednisolone (mean: 3.3 g/patient). One patient died of sepsis and hepatic failure. Rejection was reversed in 9 OKT3-rescue patients, 7 of whom are well 1-17 months later. In the OKT3 group, improved allograft function was observed within 72 hr in 11 of 15 patients. Two patients with inadequate response were successfully rescued with steroids; 1 patient underwent retransplantation; and 1 patient developed a biliary fistula that eventually resulted in sepsis and death. In summary, 23 of 28 hepatic recipients (82%) are alive with the original allograft 1-17 (mean 7.8) months after treatment for acute rejection. Another patient is alive 14 months following retransplantation. Eighteen (78%) of the survivors required OKT3 as initial (11) or rescue (7) therapy, whereas only 5 were successfully managed with steroids. OKT3 is superior to steroids for reversing liver allograft rejection and has greatly reduced the need for retransplantation even in recipients selected on the basis of having failed initial steroid therapy.     

Use of a brief steroid trial before initiating OKT3 therapy for renal allograft rejection

OKT3 (Ortho Pharmaceutical, Raritan, NJ) has been employed in a protocol where all patients received cyclosporine as part of their baseline immunosuppressive regimen and, after the diagnosis of rejection was established, were treated with up to three pulses of methylprednisolone before monoclonal antibody therapy was initiated. Use of this protocol has allowed 46% of rejection episodes encountered to be treated on an outpatient basis without resorting to inpatient use of OKT3, but has avoided delaying OKT3 therapy until after all other methods of rejection treatment were found to be ineffective. Of 83 rejection episodes treated with OKT3 between March 1985 and May 1987, 78 (94%) were reversed. Overall graft survival is 84% and patient survival is 96% in OKT3-treated patients. Of the 17 rejection episodes where OKT3 treatment was a second or third exposure to the drug, rejection was successfully reversed in 15 (88%). In cadaver donor allograft recipients transplanted between March 1985 and May 1986, actual 1-year graft survival is 80% for 30 patients requiring no rejection therapy, 80% for 20 patients with rejection episodes responding quickly to steroids, and 82% for 28 patients with OKT3-treated, steroid-insensitive rejections. Mean serum creatinine at 1 year posttransplant is 1.5 +/- 0.5; 1.9 +/- 0.7; and 2.1 +/- 0.8, respectively, for these groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improved results using OKT3 as induction immunosuppression in renal allograft recipients with delayed graft function

Delayed graft function remains a major problem in cadaveric renal allograft transplantation. We have used 2 different immunosuppressive induction regimens in patients with delayed graft function. The first regimen, used in 40 patients from January 1985 to December 1986, consisted of CsA (8 mg/kg/day, orally within 48 hr of cadaveric renal transplantation regardless of graft function), azathioprine (1.5-2.5 mg/kg/day), and steroids (methylprednisolone 375 mg on day 0, then prednisone tapered to 30 mg/day by day 10 with slow tapering to 7.5-10 mg/day over the first 6 months after transplantation). A second regimen, used from January 1987 to March 1989, employed the same doses of azathioprine and steroids; however, OKT3 (5 mg i.v./day for 7-21 days) was administered in the 34 patients who had delayed graft function. CsA was withheld until ATN resolved. The use of OKT3 as induction immunosuppression in patients with ATN led to a significant increase in 1-year graft survival (80% vs. 55%) while markedly decreasing the incidence of rejection episodes (44% vs. 82%) and the duration of nonfunction (9.4 vs. 14.9 days). There were 5 CMV infections in patients treated with OKT3. Antibodies to OKT3 developed in only 1 of 34 patients treated with OKT3. Five of 7 patients who received a second course of OKT3 successfully reversed the rejection episode. Patient survival (89%) was the same in the 2 groups. The benefit of OKT3 on long-term graft survival appears to stem from elimination of early rejection episodes that may be difficult to diagnose in a poorly functioning allograft. We conclude that OKT3 induction provides superior results over CsA induction at doses given in renal allograft recipients with delayed graft function without a significant increase in morbidity or mortality and permits the reuse of OKT3 for treatment of rejection in most cases.     

A prospective study on the use of monoclonal anti-T3-cell antibody (OKT3) to treat steroid-resistant liver transplant rejection

Conventional treatment of acute liver allograft rejection has included high doses of corticosteroids and antithymocyte globulin. Urgent retransplantation was the only option for patients who failed to respond. We report our initial experience with the use of monoclonal anti-T3-cell antibody (OKT3) in 25 patients with acute hepatic allograft rejection that was resistant to steroid and/or antithymocyte globulin therapy. Twenty-four of 25 patients had a response to OKT3, which was complete in 14 and partial in ten. With a mean follow-up of 8.2 months, allograft salvage has been 80% and patient survival 88%; two patients underwent successful retransplantation. Side effects have been mild and well tolerated. Repeated rejection has occurred in 40% of patients, but these episodes have responded to steroid therapy. We conclude that OKT3 is well tolerated and highly effective in reversing severe episodes of acute hepatic allograft rejection that is resistant to high-dose steroid therapy.     

Evaluation of OKT3 monoclonal antibody and anti-thymocyte globulin in the treatment of steroid-resistant acute allograft rejection in pediatric renal transplants

We reviewed the effectiveness of Muromonab-CD₃ (OKT3) and anti-thymocyte globulin (ATG) in the treatment of corticosteroid-resistant acute renal allograft rejection in 49 transplanted children. Reversal of rejection was successful in 22 of 23 patients (96%) treated with OKT3 and 21 of 26 (81%) treated with ATG (P=NS). Re-rejection episodes occurred within 1 month of cessation of therapy in 9 of 22 patients treated with OKT3 but only in 2 of 21 who received ATG (P<0.05). In the patients with re-rejection, 7 of the 9 patients originally given OKT3 and 1 of the 2 who received ATG responded to a repeat course of high-dose corticosteroids; thus, at 1 month post treatment, the incidence of graft loss due to initial rejection or re-rejection was 13% for the OKT3 and 23% for the ATG group (P=NS). Graft survival was similar at 6 months: 82% for OKT3- and 73% for ATG-treated patients (P=NS); 100% patient survival was noted in both groups. Mean calculated creatinine clearance prior to, during, and at 1 and 6 months post rejection was similar in the OKT3- and ATG-treated groups. Neutropenia and thrombocytopenia occurred more frequently in the ATG group, but there was no significant difference in infectious complications. Two patients developed high (1:1,000) OKT3 antibody titers. In our experience, children with corticosteroid-resistant acute renal allograft rejection treated with OKT3 and ATG had similar allograft survival and level of renal function at 1 and 6 months, and number of infectious complications post therapy.     

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 maximize the benefit of OKT3 induction therapy in renal transplantation. METHODS: One hundred and one recipients of kidney-only transplants were randomized 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 given 250 mg i.v. methylprednisolone at 1 and 6 hr, and group II received another 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/mm3 was used to guide therapy. Maintenance therapy included cyclosporine and steroids for each patient. However, groups I and II were also given mycophenolate mofetil, and group III received azathioprine as a third agent. All rejections were biopsy confirmed and Banff scored. RESULTS: No differences in demographic or transplant characteristics were noted between groups I, II, and III, and mean follow-up was 25.7 (1-38) months. There was no significant difference in actuarial patient (90%, 91%, 94%) or graft survival (83%, 88%, 84%) at 3 years between the respective groups. Mean creatinine values and infectious complications were similar for each group. No patient experienced acute rejection during induction, and eight patients required dose escalation to sustain suppression of CD3 counts. The incidence of acute rejection at 6 and 12 months was significantly (P=0.004) 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). Formation 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 0, 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 exhibited the most suppressed profile of OKT3-induced release of tumor necrosis factor-alpha (P=0.006), interferon-gamma (P=NS), and interleukin-6 (P=0.01) on days 0 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 therapy with cyclosporine, mycophenolate mofetil, and steroids provides effective rejection prophylaxis without increased complications for up to 3 years. Predepletion of T cells before exposure to OKT3 does not prevent cytokine release.     

Efficacy of tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients.

BACKGROUND: Refractory acute cellular rejection may occur despite triple-drug immunosuppression (cyclosporine A, steroids, azathioprine/mycophenolate mofetil). The purpose of this study was to determine the efficacy of tacrolimus rescue therapy in patients maintained on cyclosporine-based immunosuppression (CBI). METHODS: Between December 1993 and October 1996, 208 patients underwent thoracic organ transplantation at the Hospital of the University of Wisconsin at Madison. One hundred forty-nine patients underwent heart replacement; 59 underwent lung transplantation. One hundred thirty-nine of the heart transplant cohort received CBI preceded by induction therapy with OKT3. Forty-six of the lung transplant cohort received CBI without induction cytolytic therapy. Refractory rejection was defined as failure to respond to high-dose steroids (500 mg to 1 g IV methylprednisolone for 3 days) and/or monoclonal antibody therapy (OKT3, 5 to 10 mg IV/day for 7 to 14 days). In patients with refractory rejection, cyclosporine was replaced with tacrolimus. RESULTS: Overall, 16% (30/185) of patients receiving CBI experienced refractory rejection. Thirty-one episodes of grade IIIa or greater rejection occurred in 11% (15/139) of heart transplant recipients. Twenty episodes of grade II to IV rejection occurred in 33% (15/46) of lung transplant recipients. After tacrolimus rescue therapy, 93% (14/15) of patients in the heart transplant group converted to grade II or less rejection. Refractory rejection was reversed in 73% (11/15) of the lung transplant group. Reversal was documented at biopsy in all (8/8) lung recipients in whom it had been histologically identified. FEV1 values of 3 additional patients stabilized. CONCLUSIONS: The incidence of refractory rejection in thoracic organ transplant recipients on CBI is significant. Reversal of refractory rejection follows rescue immunotherapy with tacrolimus.     

Single-shot antithymocyte globulin (ATG) induction for pancreas/kidney transplantation: ATG-Fresenius versus Thymoglobulin

Single-shot antithymocyte globulin (ATG) prior to reperfusion followed by tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisolone (PRD) is an established induction therapy in simultaneous pancreas kidney transplant (SPK) recipients. We retrospectively analyzed 6-month data from 105 patients who received their first SPK. From January 1996 to December 2000, ATG-Fresenius was used. Since January 2001, Thymoglobulin has been administered. In the first group, 58 patients were treated with ATG-Fresenius (4-6 mg/kg body weight). In the second group, 47 patients received Thymoglobulin (1.5-2.5 mg/kg body weight). HLA-mismatch was comparable. After an observation period of 6 months, patients, kidney, and pancreas graft survival is 98.3%, 96.6%, and 93.1% in group I and 97.9%, 97.9%, and 85.1% in group II, respectively. In each group, one death with functioning graft (DWFG) was observed. Twenty (34.5%) acute rejection episodes (AR) were observed (18 patients) in group I. They were treated with steroids (n = 16) or steroids/OKT3 (n = 4). One kidney graft failure was observed due to rejection and one due to DWFG. Four pancreas grafts were lost (thrombosis, n = 2; AR, n = 1; DWFG, n = 1). In group II, 15 AR (31.9%) were seen in 12 patients and were treated with steroids (n = 12), steroids/ATG (n = 1), or steroids/OKT3 (n = 2). Seven pancreas (thrombosis, n = 5; rejection, n = 1; DWFG, n = 1) and one kidney (DWFG, n = 1) graft losses occurred. These data clearly establish that single-shot ATG prior to reperfusion, followed by TAC, MMF, and PRD results in a low incidence of AR (34.5% in group I and 31.9% in group II) after SPK. Only 6.9% (group I) and 6.4% (group II) of the patients received antibodies for rejection treatment.     

Anti-TNF-alpha therapy for acute rejection in intestinal transplantation

INTRODUCTION: We present our experience with infliximab rescue therapy for steroid- and OKT3-resistant rejection after intestinal transplantation (ITx). METHODS: Twelve ITx and one multivisceral transplant recipients were immunosuppressed with tacrolimus, rapamycin, daclizumab, steroids (n = 10) or tacrolimus, campath, and steroids (n = 3). RESULTS: In two patients, severe acute rejection did not resolve despite steroid bolus therapy plus 5 to 10 days of OKT3 treatment. Signs of moderate rejection persisted in the distal portions of the grafts. Treatment with infliximab, a chimeric anti-TNF-alpha antibody (four infusions of 3 mg/kg body weight), induced a complete remission of histological and clinical signs of rejection. Two further patients with steroid-resistant rejection received two courses of infliximab (3 mg/kg body weight) as antirejection therapy. All rejection episodes resolved completely. CONCLUSIONS: Infliximab effectively treats steroid and OKT3 resistant acute rejection episodes of intestinal transplantations.     

Sirolimus rescue therapy for refractory rejection in renal transplantation.

BACKGROUND: Acute renal allograft rejection episodes refractory to antilymphocyte preparations almost inevitably progress to transplantation loss. To reverse ongoing rejection processes, we administered sirolimus (RAPA) after failure of conventional immunosuppressive regimens including full courses of antilymphocyte sera. METHODS: All 36 renal transplantation recipients reported herein displayed either Grade IIB or Grade III biopsy-proven (Banff 1993 criteria) ongoing rejection episodes despite prior treatment with pulse and/or oral recycling of steroids and at least one 14- to 21-day course of murine (OKT3) or equine (ATGAM) antilymphocyte treatment. We compared the actual 12-month outcomes of two demographically similar cohorts of patients treated for refractory rejection with RAPA (Group I; n=24) or mycophenolate mofetil (MMF; Group II; n=12) added to a baseline regimen of cyclosporine (CsA)/prednisone (Pred). RESULTS: Rescue therapy reversed the renal dysfunction in 96% of patients in the RAPA group versus 67% in the MMF group (P=0.03) despite the fact that a greater fraction of patients in the RAPA (17 of 24) than the MMF group (6 of 12) had experienced two or more episodes of acute rejection before study entry and the fact that the recurrent bouts of acute rejection occurred within the first 6 months posttransplant in 94% of patients in the RAPA group compared with 50% (P=0.005) in the MMF group. Among the patients who were reversed successfully, the rates of rebound acute rejection were similar (4% vs. 8%). The mean serum creatinine values were slightly, although not significantly, lower among RAPA than MMF patients at 1, 3, 6, and 12 months: namely, 2.6 vs. 2.8, 2.8 vs. 3.2, 3.0 vs. 3.3, and 2.8 vs. 3.2 mg/dL, respectively. The 1-year patient and graft survival rates were similar: namely, 88% vs. 92% and 83% vs. 67% for the RAPA versus MMF groups. CONCLUSION: RAPA is a potent immunosuppressive agent for the treatment of refractory renal allograft rejection.     

Impact of renal graft nephrectomy on second kidney transplant survival

Purpose

To determine the impact of non-functional renal graft nephrectomy on second kidney transplantation survival.

Methods

We performed a retrospective study on patients managed in our department from April 1989 to April 2011. We compared the number of acute graft rejections and graft survival between patients undergoing second transplantation with (Group I) or without (Group II) prior graft nephrectomy.

Results

A total of ninety-one patients received a second renal graft: 43 underwent graft nephrectomy and 48 kept their non-functional renal graft. There were 5 episodes of acute graft rejection in Group I and 12 in Group II (p = 0.3). Six (13.9 %) grafts failed in Group I and eight (16.6 %) in Group II. Five and 10 years actuarial graft survival in Group I were, respectively, 91 and 85 %, while in Group II were 82.7 % and 69 % (p = 0.2). PRA level and number of acute rejection episodes did not have a statistically significant influence on graft survival, whether the patient had a nephrectomy or not (p = 0.2).

Conclusion

Nephrectomy of a failed allograft did not significantly improve the survival of a subsequent graft. Graft nephrectomy should be indicated in case of graft-related pain or a chronic inflammation syndrome.     

Late-onset acute rejection in orthotopic liver transplantation--associated risk factors and outcome.

A retrospective review of 375 consecutive orthotopic liver transplants was performed to determine the incidence and outcome of late rejection episodes ([LR] rejection occurring more than 6 months following transplant). A total of 31 episodes in 26 patients were identified. Eighteen of these episodes were associated with subtherapeutic levels of cyclosporine. Of these, 7 were due to noncompliance, 2 were due to biliary strictures, and 1 was due to malabsorption in a cystic fibrosis patient. All 31 episodes were treated initially with steroids, and 22 had a complete response, although one progressed to chronic rejection over a year later. Of the remaining 9, 1 received FK506 with a complete response, and 8 received OKT3. Of the 8 patients who received OKT3, 5 had a complete response, 1 received RS61443 following OKT3 and progressed to chronic rejection, and the remaining 2 received further steroids. Of these 2, 1 had a complete response following the steroids while the second was converted to FK506 with a complete response. Compared with 315 acute rejection episodes ([AR] occurring less than 6 months posttransplant), patients with late rejection episodes had an equivalent response to steroids (63.2% AR reversed vs. 71% LR reversed) but a lower response rate to OKT3 (91.5% AR reversed vs. 62.5% LR reversed). There was, therefore, a higher rate of persistent rejection (61% AR episodes vs. 15.4% LR episodes) but no increase in the incidence of chronic rejection (7% AR episodes vs. 7.7% LR episodes). We conclude that LR is a relatively common occurrence following liver transplant, which is most often associated with low cyclosporine levels. Many of these episodes are due to noncompliance, but biliary problems must also be investigated. The incidence of resistant rejection is higher in this group of patients but is not associated with a concurrent increase in chronic rejection.     

Tacrolimus-Basiliximab versus Cyclosporine-Basiliximab in renal transplantation "de novo": acute rejection and complications

BACKGROUND: Optimal immunosuppression is essential to maintain kidney allograft viability but minimizing toxicity is also fundamental. OBJECTIVE: This article compares immunosuppressants, corticosteroids, cyclosporine, tacrolimus, and basiliximab, which are used in the treatment regimens for renal transplantation. The analyses evaluated their effectiveness to prevent acute rejection episodes and to reduce the appearance of other complications, mainly infectious disease complications. METHODS: Ninety-five patients were analysed during the first year after primary renal transplantation. These patients were included in a random way in 3 different groups according to the immunosuppressant drug therapy: Group I (35 patients) received corticosteroids + CsA; Group II (35 patients) received corticosteroids + CsA + Basiliximab; Group III (25 patients) received corticosteroids + Tacrolimus + Basiliximab. RESULTS: Among the 95 patients, 9 presented with an acute rejection episode in Group I. None in Group II, and one in group III. With reference to the infectious disease complications, the incidence of oral herpes was one case in Group I, 4 cases in Group II, and 2 cases in group III. CONCLUSIONS: Treatment with Basiliximab produced a significantly lower incidence of acute rejection cases and an increase in infectious disease complications, such as lip herpes.     

Long-term outcome of the use of OKT3 to treat steroid-resistant acute renal allograft rejection

OKT3 was used to treat steroid-resistant acute renal allograft refection in 30 of 496 adult patients transplanted over a 6-year period. Rejection was reversed (defined as a fall in serum creatinine by 50% or more within 30 days of treatment with OKT3) in 40% of cases. Successful reversal was significantly more likely when rejection occurred shortly after transplantation (t ratio-2.53; P=0.019). The long-term outcome was disappointing; the actuarial graft survival at 1 year from the start of treatment with OKT3 was 42%, and no grafts have thus far survived longer than 3 years. Graft survival was horter in older patients (coefficient/standard error 2.226; P<0.05), and no other predictor of long-term outcome was identified. Patient survival at 3 years was 88%. Serious infection occurred in 33% of patients, with two deaths. Our experience suggests that treatment with OKT3 is unlikely to reverse acute renal allograft rejection in more than half of patients where rejection is resistant to steroids. Although long-term graft survival occurred in a few cases, the overall long-term outcome was disappointing, particularly in older patients. Finally, our analysis indicates the difficulty of predicting which patients will derive long-term benefit when OKT3 is used to treat steroidresistant rejection.     

An increased incidence of late acute rejection episodes in cadaver renal allograft recipients given azathioprine, cyclosporine, and prednisone

We studied the incidence of biopsy-proven, acute rejection episodes occurring after 1 year posttransplant in cadaver renal allograft recipients. The 328 patients evaluated were given three immunosuppressive drug protocols. Group I (transplanted 9/80-6/84) (n = 75) received azathioprine, prednisone (P), and antilymphoblast globulin; group II (transplanted 9/80-6/84) (n = 83) received cyclosporine and P; group III (transplanted 7/84-12/86) (n = 170) received ALG, AZA, CsA, and P (sequential therapy). The incidence of first acute rejection episodes occurring up to 1 year posttransplant was 55% in group I and 35% in groups II and III. The incidence of late (greater than 1 year) acute rejection episodes was 6.5% in group I, 2.5% in group II, and 9.5% in group III (group II vs. III, P = 0.02). In group III, 50% of the late rejections were first, 44% second, and 6% third. The primary etiologies of this increased incidence of late acute rejection may have included subtherapeutic CsA levels and lower P doses. Sequential immunosuppressive therapy has been shown to be advantageous in the first posttransplant year. However, unless adequate immunosuppression is maintained, this approach can be associated with a significantly increased incidence of late acute rejection.     

A multicenter, open-label, comparative trial of two daclizumab dosing strategies vs. no antibody induction in combination with tacrolimus, mycophenolate mofetil, and steroids for the prevention of acute rejection in simultaneous kidney-pancreas transplant recipients: interim analysis

INTRODUCTION: The safety and efficacy of daclizumab (1 mg/kg/dose every 14 d for five doses) has been established in kidney and heart transplant recipients. Alternative dosing regimens based on pharmacokinetic simulation and limited clinical trials are being investigated. The purpose of this ongoing multicenter study is to determine the safety and efficacy of two dosing regimens of daclizumab as an adjunctive immunosuppressive agent compared with no antibody induction in simultaneous kidney-pancreas transplant (SKPT) recipients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and steroids as primary immunosuppression. METHODS: This is an interim report of a multicenter, prospective, open-label, randomized study with a target enrolment of 290 patients. Eligible SKPT patients were randomized to one of three groups: daclizumab 1 mg/kg/dose every 14 d for five doses (Group I), daclizumab 2 mg/kg/dose every 14 d for two doses (Group II), and no antibody induction (Group III). The primary endpoint of the study is a composite of the incidence of presumed or biopsy-proven kidney or pancreas rejection, graft loss, or death within the first 6 months post-transplantation. RESULTS: A total of 166 patients were randomized into the three groups [Group I (n = 70), Group II (n = 74), Group III (n = 22)]. Demographic and transplant characteristics were similar among the groups. At a minimum follow-up of 3 months, patient, kidney and pancreas graft survival rates were similar among the three groups. However, the rates of acute renal allograft rejection were 18% (Group I), 8% (Group II), and 36% (Group III), p < 0.05. The probabilities of either kidney or pancreas allograft rejection were 22% (Group I), 8% (Group II), and 38% (Group III). At 3 months, the actuarial event-free survival (no acute rejection, allograft loss, or death) rates were 67, 81 and 50% in Groups I, II, and III, respectively. There were no differences in the incidence of infectious complications among the groups and no serious adverse events associated with daclizumab were observed. CONCLUSIONS: The two-dose regimen (Group II) appears to be as effective as the five-dose regimen (Group I) in preventing acute rejection after SKPT and is associated with the lowest acute rejection rates and the highest rate of event-free survival (no rejection or graft loss). However, the benefits of daclizumab compared with no antibody induction await larger sample size accrual.     

Reexposure to OKT3 in renal allograft recipients

Between 40% and 80% of patients treated with the monoclonal antibody OKT3 develop blocking antibody against its idiotypic region. Thus a major concern with the use of OKT3 as part of a baseline immunosuppressive regimen is that formation of blocking antibodies might preclude its subsequent use. Between 7/86 and 2/87, 32 patients received prophylactic OKT3 in addition to low-dose prednisone, azathioprine, and cyclosporine. Prophylactic OKT3 did not prevent rejection, as 21 of 32 patients studied developed rejection. Retreatment of 13 patients with OKT3 successfully reversed 12 rejections and lowered the number of T3-positive cells in spite of a low level of blocking antibody in two patients in this group. Of the patients analyzed, 38% developed blocking antibody on initial exposure to OKT3, but OKT3 reuse was denied only 4 patients due to the presence of these antibodies. Three of these had rejections reversed with steroids alone; the other patient lost the allograft. A high frequency of infectious complications occurred in the retreatment group, with viral infections predominating. Only one patient in the retreated group developed antibodies after the second use. Appearance of blocking antibodies after use of OKT3 as part of a base-line prophylactic immunosuppressive regimen did not significantly compromise access to OKT3 for treatment of subsequent rejection episodes, but multiple exposures to OKT3 did increase the frequency of infectious complications.     

OKT3 treatment of steroid-resistant renal allograft rejection

The monoclonal antibody, Orthoclone OKT3 (OKT3), has been used with great efficacy in a prospective multicenter trial as therapy for first rejection episodes in cadaveric donor (CD) renal allograft recipients treated with azathioprine (AZA) and prednisone (P). However, although almost all rejection episodes were reversed, recurrent rejection occurred in approximately two-thirds of OKT3-treated patients in this earlier trial; infections also occurred in about two-thirds of patients, often related to the additional immunosuppression necessary to reverse the rerejection episodes. In the current series of patients, OKT3 was used to treat rejection in CD renal graft recipients in a protocol differing from the multicenter trial in two respects: baseline immunosuppression was cyclosporine (CsA) and P or CsA, AZA, and P (probably more potent immunosuppressive combinations than the AZA and P in the multicenter trial); and OKT3 treatment was reserved for rejection episodes resistant to 3 bolus infusions of methylprednisolone (MP), 5-10 mg/kg, rather than as primary therapy for first rejection episodes. Using this protocol, 46 of 74 rejection episodes (62%) diagnosed between 3/85 and 3/86 in CD renal allograft recipients were treated successfully with MP. Of the remaining 28 steroid-resistant rejection episodes, 27 (96%) were reversed with a 7-14-day course of OKT3, 5 mg/day. Only 5 recurrent rejection episodes (19%) have been observed in the 2-14-month follow-up period after OKT3 treatment; infections have occurred in 10 patients (36%), and three grafts (11%) have been lost in OKT3 treated patients. These results suggest that recurrent rejection and subsequent infection after OKT3 is used to treat rejection may be reduced in a protocol where CD renal allograft recipients are treated with baseline immunosuppression regimens including CsA and where OKT3 is reserved for steroid-resistant rejection. This approach appears to be both more cost-effective than, and as effective therapeutically as, treating all first rejection episodes with the monoclonal antibody.     

ATG-F与OKT3在肾移植术后急性排斥反应中的应用研究

目的 探讨应用注射用兔抗人T淋巴细胞多克隆抗体(ATG-F)及注射用抗人T细胞CD3鼠单克隆抗体(OKT3)治疗肾移植术后急性排斥反应的效果、安全性和副反应等.方法 本中心施行同种异体肾移植术后对于激素冲击治疗不敏感的急性排斥患者51例,分为两组,分别给予多克隆抗体ATG-F和单克隆抗体OKT3治疗,并对治疗效果、安全性和药物的副反应等进行统计学分析.结果 ATG-F治疗28例,排斥逆转26例,治愈率89.3％;OKT3抗组23例,排斥逆转16例,治愈率69.6％.两组结果间有显著性差异(P＜0.05).结论 OKT3和ATG-F同为抗淋巴细胞的抗体,但其针对难治性急性排斥反应的治疗效果,存在明显差异.ATG-F临床效果肯定,并且用量灵活,副作用小.OKT3治疗效果一般,则具有术后感染发生率增加、白细胞减少等并发症.     

Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group

BACKGROUND: The novel agent sirolimus (SRL; Rapamune; rapamycin) inhibits the immune response by a mechanism distinct from those of calcineurin antagonists or antimetabolites. This randomized, controlled, multicenter, single blind, phase II trial examined the combination of SRL, steroids, and full versus reduced doses of cyclosporine (CsA) for prophylaxis of acute renal allograft rejection. METHODS: A total of 149 recipients of mismatched cadaveric- or living-donor primary renal allografts were randomized into six groups. Three groups received placebo or 1 or 3 mg/m2/day SRL, as well as steroids and full-dose CsA (Sandimmune). Three groups received steroids, reduced-dose CsA (target trough level 50% of full-dose range), and 1, 3, or 5 mg/m2/day SRL. RESULTS: The incidence of biopsy-proven acute rejection episodes within the first 6 months after transplant was reduced from 32.0% in the control group to 8.5% in patients receiving SRL (1 or 3 mg/m2/day) and full-dose Sandimmune CsA (P=0.018). Similar low rates of acute rejection episodes were observed among non-African-Americans, but not African-Americans, treated with SRL and reduced-dose Sandimmune CsA. Despite the augmented immunosuppression, 1-year patient and graft survival rates did not differ significantly across groups. Adverse effects attributable to CsA, including hypertension and new-onset diabetes mellitus, were not exacerbated by SRL. Except for an increased incidence of pneumonia among patients receiving full-dose CsA and 3 mg/m2/day SRL, the incidences of opportunistic infections were similar in all treatment groups. Although SRL produced more frequent, but reversible, hematological and lipid abnormalities, it had no apparent nephrotoxic effects to exacerbate CsA-induced renal dysfunction. CONCLUSIONS: SRL in combination with CsA and steroids not only lowers the incidence of biopsy-proven acute renal allograft rejection episodes, but also may permit CsA sparing, at least among Caucasian patients, without an increased risk of rejection.