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.     

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.     

Sequential use of Minnesota antilymphoblast globulin and cyclosporine in cadaveric renal transplantation

The use of Cyclosporine (CsA) immediately after renal transplantation may be associated with an increased incidence and duration of acute tubular necrosis (ATN) and permanent primary graft nonfunction. To avoid this potential interaction we treated recipients of primary cadaveric grafts initially with azathioprine (AZA), methylprednisolone (MP), and 5 daily doses of Minnesota antilymphoblast globulin (MAG) (postoperative days 3-7). AZA was discontinued and CsA started on day 6 if the graft was functioning by then. If ATN persisted beyond day 6, AZA and MAG (maximum 12 doses) were continued and CsA withheld until graft function was established (group 1-33 patients). This protocol is compared to our previous regimen of MAG (14 doses over the first 3 weeks), AZA and MP (group 2-68 primary cadaveric graft recipients). Improved one-year graft survival (81% vs. 60%, P less than 0.05) and patient survival (93% vs. 81%, P less than 0.05) were seen in group 1. The incidence and duration of ATN did not differ in the two groups. During the first year after transplantation more patients in group 1 were completely free of rejection episodes (40% vs. 20%, P less than 0.05) and the number of rejection episodes per patient was also lower in this group (1.0 +/- 15 vs. 1.6 +/- 49, P less than 0.05). The incidence of infections was not different in the two groups. No tumors have developed in either group. We conclude that in primary cadaveric renal transplantation the initial administration of a short course of MAG followed by CsA therapy results in excellent graft and patient survival while avoiding the potential adverse effect of CsA on an allograft already subjected to preservation injury.     

The long-term outcome of OKT3 compared with cyclosporine prophylaxis after liver transplantation

We report the long-term follow-up (greater than 1 year) of 46 patients (12 pediatric) randomized to receive OKT3 for the first 14 days after OLT with low-dose steroids compared with 39 patients (8 pediatric) who received cyclosporine, steroids, and azathioprine. The mean period of follow-up for survivors was 648 +/- 261 days for the OKT3 group and 682 +/- 216 days for the cyclosporine group. Of the OKT3 patients, 46% were rejection-free in the first month compared with 31% of CsA-treated patients (P = NS). Rejection occurred after 1 month in 21% of the OKT3 group patients compared with 19% of the CsA group patients. One patient in each group developed vanishing bile duct syndrome. Eight patients in the OKT3 group and 13 in the CsA group experienced steroid-resistant rejection and required OKT3 rescue. In the 8 patients in whom OKT3 was reused, 4 had a positive ELISA after prophylaxis, and in 6, CD3-positive cells were greater than 10% during OKT3 reuse. Five patients resolved the episode. Of patients receiving OKT3 prophylaxis, 39% developed anti-OKT3 antibodies. In the OKT3 group 83% of patients and in the CsA group 75% currently have normal liver function. There was no difference in serum creatinine for either adult or pediatric recipients at 12 months in the two groups. Eight episodes (2 CMV) of severe infection occurred after 1 month in the OKT3 group compared to 11 (4 CMV) in the CsA group. Graft survival, 63% for the OKT3 group and 73% for the CsA group, and patient survival, 67% for the OKT3 group and 84% for the CsA group, were not significantly different in the two groups. We recommend reserving the use of OKT3 for resistant rejection or when cyclosporine is contraindicated, as we can show no long-term benefit from its routine prophylactic use.     

Short-term combination of mycophenolate mofetil with cyclosporine as a therapeutic option for renal transplant recipients: A prospective,multicenter, randomized study

BACKGROUND: Mycophenolate mofetil (MMF), compared to azathioprine (AZA), reduces acute rejection and treatment failure in cyclosporine (CsA) and steroid regimens, but its effect on graft survival is unproven from prospective studies and prolonged use is costly. This study evaluated the efficacy and tolerability of replacing MMF by AZA after 3 months. METHODS: This 28 center, prospective, 12-month, parallel group, open-label study, randomized patients to three groups with microemulsion formulation of CsA (ME-CsA) and steroids as baseline therapy. Group 1 (n=158) received MMF for 3 months, replaced by AZA for 9 months; group 2 (n=162) received MMF for 12 months; and group 3 (n=157) received AZA for 12 months. RESULTS: Treatment failure and the cumulative rate of acute rejection were significantly lower in the MMF groups compared with the AZA group (P=0.007 and P=0.03, respectively). Graft loss, death, and safety profiles of all three treatments were similar over 12 months, as were mean serum creatinine levels. Switching from MMF to AZA did not affect treatment failure. No patient in group 1 experienced a recurrent rejection after month 3, one patient died, and nine patients experienced first rejection episodes. Most rejections (6/9) were steroid-sensitive and histologically mild. CONCLUSIONS: Replacement of MMF by AZA after 3 months of therapy with ME-CsA and steroids provides comparable efficacy and safety profiles to continuous MMF over 12 months. Although apparently a cost-effective option, long-term studies are required to assess the benefit/risk ratio of this therapy switch in different patient subpopulations.     

Antilymphocyte globulin versus OKT3 induction therapy in cadaveric kidney transplantation: a prospective randomized study.

Different induction therapies have been used in renal transplantation to avoid cyclosporine (CsA) nephrotoxicity and early acute graft rejection. This study compares the efficacy of a short course of prophylactic OKT3 to that of antilymphocyte globulin (ALG) in preventing acute renal allograft rejection when administered concomitantly with CsA and steroids. Between March 1988 and December 1990, 140 first-cadaver renal transplant recipients were randomly allocated to two immunosuppression groups--ALG group (n = 68): ALG 15 mg/kg just before transplant surgery, ALG 12 mg/kg the first day after transplant, followed by four doses of 10 mg/kg on alternate days; and OKT3 group (n = 72): OKT3 5 mg just before transplant, followed by four doses of 5 mg/d. Both groups included low-dose CsA and steroids. The incidence of rejection during the first 3 months after transplantation was 15% in the ALG group and 19% in the OKT3 group (NS). Kaplan-Meier estimates of patients free of rejection at 2 years was 85% in the ALG group and 77% in the OKT3 group (NS). The 3-year actuarial graft survival was 82% and 85% (NS), and 3-year patient survival was 97% and 98% (NS), in the ALG and OKT3 groups, respectively. These results indicate that the concomitant association of CsA and ALG or OKT3 constitutes a safe and effective therapeutic strategy that provides a low incidence of rejection and gives good results for patient and graft survival.     

Renal allograft biopsy and conversion of cyclosporine to azathioprine

A prospective nonrandomized study was conducted to evaluate the results of two conversion protocols on two similar groups of renal graft recipients totaling 54 patients who were converted from CsA to AZA at 6-12 months posttransplant. With protocol I, 24 patients (3 haploidentical, 21 cadaveric recipients) were converted with a graft biopsy followed by a 14-day overlap of CsA and AZA before the CsA dose was tapered and discontinued in 6 days. Of the 24 patients, 8 were found to have occult rejection in biopsy and received methylprednisolone 500 mg boluses for three days before overlap started. Thirty patients (2 haploidentical, 28 cadaveric recipients) were converted with protocol II, which had CsA and AZA overlap and tapering schedules identical to those of protocol I without a preconversion biopsy. Follow-up extended as far as 3 years posttransplant. There was a substantial incidence of chronic rejection and graft loss after conversion in protocol II patients. We also found that there was a possible link between postconversion acute rejection and late graft loss from chronic rejection. The incidence of acute rejection after conversion was significantly lower among protocol I patients as compared with that of protocol II (4% vs. 37%, P less than 0.001). However, if 8 patients with occult rejection in the preconversion biopsy were added to the total number of postconversion rejection in protocol I, the incidence of postconversion rejection in this group (38%) would be similar to that of protocol II. Using the time of conversion as the onset of the risk, protocol I patients had better graft survival than protocol II (100% vs. 80%, P less than 0.005) at 3 years posttransplant. If conversion becomes necessary, we recommend a preconversion graft biopsy to identify and treat patients with occult rejection before the beginning of CsA and AZA overlap, especially for those patients whose creatinine is higher than 2 mg/dl without obvious cause before conversion.     

Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation

A group of 52 liver transplant patients was prospectively randomized to receive prophylactic immunosuppressive therapy consisting of either Orthoclone OKT3 for 14 days, azathioprine, and steroids (25 patients); or cyclosporine, azathioprine, and steroids (27 patients). The groups were similarly matched for age, diagnosis, and Child's classification. The patients were studied to determine the effect of these two regimens on the incidence of rejection, infection, renal dysfunction, and mortality. Seven rejection episodes, as determined by clinical and histological criteria, occurred in seven of 25 patients (28%) receiving OKT3 compared with 18 episodes in 27 patients (67%) receiving cyclosporine during the first 14 days after transplantation (P less than 0.02). In 20% of the OKT3 patients, CD3+ levels of greater than 10% developed during therapy, and 16% of the patients developed anti-OKT3 antibodies during OKT3 treatment. Five patients were retreated with OKT3 for steroid-resistant acute rejection episodes; all had resolution of the rejection episode. Infectious complications were similar in each group. Renal function, as measured by serum creatinine, was significantly better with OKT3 than with cyclosporine (P less than 0.003) at 14 days. We conclude that prophylactic OKT3 is effective in reducing the number of early rejection episodes after liver transplantation; after 14 days the incidence of rejection is similar; reuse of OKT3 has been successful in liver transplant patients; infectious complications are similar between OKT3 and cyclosporine; and OKT3 preserves renal function better than cyclosporine and is thus indicated in patients with compromised preoperative renal function.     

Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients

In cyclosporine (CsA)-treated renal transplant recipients complete corticosteroid withdrawal followed by CsA monotherapy has been associated with severe rejection episodes in a significant proportion of patients. We report the results of replacement of steroids by azathioprine (AZA) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone (MP). MP taper was started 8.8 +/- 5.6 months posttransplant when the MP dose was either 10 mg/day or 20 mg every other day. MP was tapered off over a 5-month period. At the initiation of MP taper, AZA was added at 1 mg/kg/day and increased to 1.5 mg/kg/day after two months. The CsA dose was adjusted to maintain trough serum levels as measured by radioimmunoassay (RIA) of 50-75 ng/ml, during and after MP withdrawal. Seventeen patients have remained continuously off MP for 14.6 +/- 5.0 months with stable renal function. Reinstitution of MP at 10 mg/day was required in 8 patients, 6 for rejection (1.8 +/- 0.7 months after MP withdrawal), 1 for AZA-induced leukopenia, and 1 for de novo glomerulopathy. Renal function returned to baseline in all 6 patients with rejection after reinstitution of MP. Two of these patients have again been successfully retapered off MP. In the patients withdrawn from MP, body weight and mean arterial blood pressure had decreased by 2.1 +/- 1.3 kg (P less than .05) and 11 +/- 7 mmHg (P less than .05), respectively, at the time of the most recent follow-up compared with values at the initiation of steroid withdrawal. The number of blood pressure medications per patient decreased by 38% (P less than .05) and 6 patients were able to discontinue all antihypertensive drugs after cessation of steroids. Discontinuation of MP also resulted in a decrease in serum cholesterol concentration from 248 +/- 50 to 217 +/- 55 mg/dl (P less than .05). We conclude that steroids can be replaced by AZA in the majority of CsA-treated primary cadaveric renal transplant recipients by the end of the first posttransplant year without an adverse effect on graft survival. This protocol resulted in significant reductions in serum cholesterol, mean arterial blood pressure, and body weight, and may avoid the long-term side effects of steroid therapy.     

Anti-rejection therapy in renal transplantation: Use of the monoclonal antibody OKT3

The success of anti-rejection therapy was evaluated in 65 cadaveric renal allografts immunosuppressed with cyclosporin. All first rejection episodes were treated with 0.5 g methylprednisolone given daily for 3 days. Second rejection episodes were treated with either a further identical 3-day course of methylprednisolone or a 10-14-day course of the monoclonal antibody OKT3. The peak creatinine during second rejection episodes was higher in patients treated with OKT3 (481 +/- 54 mumol/l; mean +/-SEM) than in those treated with methylprednisolone (320 +/- 59 mumol/l) (P = 0.036), suggesting more severe rejection in the OKT3 group. Despite this the rejection reversal rate was higher in the OKT3-treated group (100%) when compared to the high-dose methylprednisolone group (64%) (P less than 0.05) and the creatinine at 6 months was less in the OKT3 group (162 +/- 17 mumol/l) than in the methylprednisolone group (230 +/- 22 mumol/l). These data suggest that OKT3 is a very effective treatment for second rejection episodes following renal transplantation and yields improved renal functions in comparison with high-dose steroids.     

Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients

BACKGROUND: Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. METHOD: In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. RESULTS: By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004). CONCLUSION: Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.     

New immunosuppressive treatment in kidney transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has been successfully introduced into clinical practice with evident benefits for renal transplant recipients. SUBJECTS AND METHODS: To evaluate some clinical results of MMF introduction, two groups of subjects underwent cadaveric renal transplants over the last 3 years and were retrospectively investigated. The first group (AZA group) contained 40 subjects (26 males and 14 females) on triple-drug therapy with steroids, cyclosporine and azathioprine (AZA). The second group (MMF group) contained 25 patients ( 19 males and 6 females) on the same regime with steroids and cyclosporine but MMF was administered as a third drug instead of AZA. The AZA group received renal transplant after a mean dialytic time of 32 +/- 19 months and the AZA group's dialytic time was 39.9 +/- 17 months. Clinical data, collected after a minimum 12 months observational period included a crude mortality rate and survival analysis recognized by Kaplan-Meyer curve, creatinine, creatinine clearance, rejection episodes and major clinical events such as infections and acute tubular necrosis. RESULTS: One subject died in each group. For kidney graft survival, Kaplan Meyer survival analysis showed a mean survival time of 1170.04 days in the AZA group vs 845 in the MMF group without statistical significance. Graft survival demonstrated 5:40 (12.5%) graft losses in the AZA group vs no kidney transplant loss in the MMF group (the only deceased patient had a well functioning kidney). The curve of graft cumulative proportion survival analysis demonstrated a more improved survival in the MMF group, but this difference did not reach a statistical significance (p = 0.07). Acute rejection episodes in the AZA group were 37.5% vs. 20% in the MMF group. In both groups, CMV infection was successfully treated with specific antiviral agents. CONCLUSIONS: MMF represents an important step towards induction and maintenance of immunosuppression. Our experience in a relatively small cohort investigated in a single center, demonstrates encouraging results regarding graft survival in comparison to those detected in conventional triple drug therapy. Surprisingly, in spite of stronger immunosuppressive treatment, the prevalence of CMV infections was not statistically different in the MMF versus the AZA group.     

Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols.

BACKGROUND: The need for better immunosuppressive protocols after lung transplantation led us to investigate tacrolimus (Tac) in combination with mycophenolate mofetil (MMF) and steroids or cyclosporine (CsA) in combination with MMF and steroids in a prospective, open, randomized trial after lung transplantation. METHODS: Between September 1997 and April 1999, 50 lung transplant recipients were randomized to receive either Tac (n = 26) or CsA (n = 24) in combination with MMF and steroids. All patients underwent induction therapy with rabbit antithymocyte globulin (ATG) for 3 days. Freedom from acute rejection (AR), patient survival, infection episodes, and side effects were monitored. RESULTS: There was no difference in patient demographics between the two groups. Six-month and 1-year survival was similar (84.6% and 73.1% in the Tac group vs 83.3% and 79.2% in the CsA group). Freedom from AR at 6 months and 1 year after lung transplantation was slightly higher in the Tac group (57.7% and 50% vs 45.8% and 33.3%, p = not significant [n.s.]), whereas the number of treated rejection episodes per 100 patient days in the Tac group was significantly lower (0.225 vs 0.426, p < .05). Four patients in the CsA group had to be switched to Tac. Two patients in the CsA group had to be retransplanted. Incidence of infections was similar in both groups with a trend toward more fungal infections in the Tac group (n = 7 vs n = 1, p = n.s.). CONCLUSIONS: The combination of Tac and MMF seems to have slightly higher immunosuppressive potential compared with CsA and MMF. The effectiveness of Tac as a rescue agent is not paralleled with undue signs of overimmunosuppression.     

Influence of immunosuppression regimen on heart transplantation survival

OBJECTIVE: To perform an analysis comparing long-term survival in heart transplant (HT) patients depending on the immunosuppressive regimen. MATERIALS AND METHODS: The study included 317 consecutive HT patients. We excluded pediatric cases, retransplants, combined transplants (lung and kidney), and immunosuppressive regimens with fewer than 10 cases. The six groups analyzed were: (1) OKT3 7 days + cyclosporine (CsA) + mycophenolate mofetil (MMF) + steroids (S); (2) OKT3 7 days + CsA + azathioprine (AZA) + S; (3) OKT3 10 days + CsA + MMF + S; (4) OKT3 10 days + CsA + AZA + S; (5) interleukin-2 (IL-2) antagonists + CsA + MMF + S; and (6) IL-2 antagonists + tacrolimus + MMF + S. Probability of survival was analyzed by Kaplan-Meier and log-rank methods. RESULTS: The groups were heterogeneous regarding the number of patients and follow-up. The baseline characteristics were similar, although there were differences in surgery times. The survivals by groups at the end of the follow-up period were: group 1: 75.8%; group 2: 51.2%; group 3: 63.6%; group 4: 25.3%; group 5: 91.2%; and group 6: 84.6%. A major reduction in survival was observed in the groups that were given induction with OKT3 monoclonal antibodies (groups 1, 2, 3, and 4), particularly when AZA was combined in the maintenance phase (groups 2 and 4) and when the induction dose was high (10-day therapy in groups 3 and 4). CONCLUSIONS: Our study suggested an association between the immunosuppressive regimen and the long-term survival of HT patients. The best results were obtained with an induction regimen based on IL-2 antagonists. On the basis of the survivals observed in this study, the maintenance combination we regard as "optimal" at this time is based on a combination of CsA, MMF, and steroids.     

A comparison of OKT3 monoclonal antibody and corticosteroids in the treatment of acute renal allograft rejection

The monoclonal antibody OKT3 (Ortho Pharmaceutical, Raritan, NJ) was utilized in two separate protocols for treatment of acute renal allograft rejection in patients receiving cyclosporine, azathioprine, and prednisone for maintenance immunosuppression. In Group I, 54 patients received steroids for primary treatment of acute rejection with OKT3 used for resistant rejections and second rejection episodes. In Group II, 34 patients received OKT3 as primary treatment of acute rejection while steroids were used for rescue and second rejection episodes. OKT3 successfully reversed 82% of initial acute rejection episodes in Group II as compared with a 63% reversal with steroids in Group I. Rescue treatment was required in only 15% of Group II patients compared with 33% of Group I patients. Overall patient survival was 96% and 94%, respectively, for steroid primary and OKT3 primary treatments. Allograft survival at 3 months was identical, 74% in both groups. Based on allograft survival data, OKT3 is equally effective either as primary treatment for allograft rejection, or for rescue therapy if initial corticosteroid treatment fails.     

A phase III prospective,randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients

BACKGROUND: This study evaluated the safety and efficacy of sirolimus plus steroids as a maintenance regimen with or without small-dose cyclosporine (CsA) adjunctive therapy in renal transplant recipients. METHODS: A total of 133 recipients of kidney allograft transplantations recruited in the United Kingdom and Ireland were enrolled into the study and are presented in this interim analysis. In the first 3 months, all patients received CsA plus sirolimus and small-dose steroids after transplantation. At 3 months, patients were randomized 1:1 to CsA elimination (e)CsA or CsA dose minimization (m)CsA. Dosing of agents was concentration-controlled and open label. RESULTS: Patient and graft survival were 97.7% and 95.5%, respectively (n = 133), whereas the biopsy-proven acute rejection rate in the first 6 months was 19.5% (26 episodes in 133 patients); incidents of acute rejection rates comprised 22 episodes (16.5%) during the first 3 months of the study and four episodes (3%) after randomization. Eighty-seven patients were randomized to receive eCsA or mCsA. At 6 months, creatinine clearance was significantly higher in the eCsA group versus mCsA group, respectively (65 mL/min vs. 57 mL/min; P = 0.027). There was no significant difference in serum cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein levels between the groups. CONCLUSION: These data demonstrate that withdrawal of CsA from a small-dose sirolimus maintenance regimen is safe and is associated with an improvement in renal function. The study also suggests that the addition of small-dose CsA to a sirolimus maintenance regimen does not increase immunosuppressive efficacy.     

A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation.

Patient entry is now complete in a prospective trial of anti-Tac, a murine IgG2a monoclonal antibody directed against the p55 chain of the human IL-2 receptor, for the prevention of renal allograft rejection. Recipients of primary cadaver allografts were randomized to receive either anti-Tac (20 mg q.d. x 10 days beginning POD 1) plus low-dose CsA (4 mg/kg/day), azathioprine (2 mg/kg/day), and prednisone (30 mg q.d.), or conventional triple therapy with CsA (8 mg/kg/day), azathioprine, and prednisone. Forty patients were entered in each group, with current followup from 6 to 26 months. The results show a significant reduction in early rejection episodes in the anti-Tac-treated patients. During the 10-day treatment, 5 of 40 anti-Tac patients had rejection episodes, compared with 21 of 40 control patients (P less than 0.001). Anti-Tac significantly delayed the time to the first rejection (12.5 +/- 6.3 vs. 7.6 +/- 6.7 days) (P less than 0.05). Despite these effects, there were no differences in either actual or actuarial graft or patient survival between the two groups. Pneumonia, primarily CMV, developed in 5 treated and 4 control patients. In patients with functioning grafts mean serum creatinine at 3 months was 1.8 +/- 0.7 in the anti-Tac group and 2.0 +/- 0.8 in the control group (P = NS); at 12 months the values were 2.3 +/- 1.5 and 1.8 +/- 0.5, respectively (P = NS). The peak expression of IL-2 receptors on circulating T-cells was significantly lower in anti-Tac patients (15.1 +/- 3.6%) than in controls (21.9 +/- 4.5%) (P less than 0.05). Seven of 10 patients tested to date developed antimouse immunoglobulin antibodies, with antiidiotype shown in 6. These antibodies do not preclude subsequent treatment with OKT3. Five patients in this and previous anti-Tac protocols have received OKT3 for acute rejection despite known pretreatment antimouse antibodies, with resolution of rejection in all cases.     

Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients

INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.     

Comparative study of clinical outcome in kidney transplantation between early steroid withdrawal protocol using basiliximab, calcineurin inhibitor, and mycophenolate mofetil and triple regimen consisting of calcineurin inhibitor, mycophenolate mofetil, and steroid

AIMS: Effect of early steroid withdrawal protocol using basiliximab in kidney transplantation (KTx) on the clinical outcomes was investigated as compared with triple regimen. METHODS: Kidney transplant patients in group 1 (n = 62) were treated with 8 mg/kg of cyclosporine (CsA), 2000 mg of MMF, two bolus IV injections of 20 mg of basiliximab and 500 mg of methylprednisolone (MP) rapidly tapered and withdrawn at 14 postoperative days (POD). Group 2 (n = 56) was treated with same dose of CsA and MMF, and 250 mg of MP tapered and continued. Acute rejection (AR) episodes were treated with MP pulse therapy followed by muromonab CD3 (OKT3) in case of steroid-resistant rejection. RESULTS: In 46 of 62 cases (74.2%) in group 1, steroid was successfully withdrawn at 13.7 +/- 1.7 POD. Graft survival at 3, 6, and 12 months in group 1 was 100%, 100%, and 98.4% (one death with functioning graft), and 100%, 98.2%, and 96.4% in group 2, respectively. The incidence of AR was 12.9% for group 1 and 42.9% for group 2, among which 21 cases in group 2 were treated with ALG or OKT3; no patient needed ALG or OKT3 in group 1. Fifteen cases in group 1 and 13 cases in group 2 developed CMV antigenemia, among which febrile episode was exhibited in 3 cases (4.8%) in group 1 and 5 cases (8.9%) in group 2. CONCLUSIONS: Early steroid withdrawal protocol using basiliximab is promising for reducing the incidence of AR (especially steroid-resistant rejection), CMV diseases, and steroid-related complications.     

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.