OKT3 induction in pediatric renal transplantation

Twenty cadaveric renal transplant patients (mean age 12.5±4.8 years) received 14 days (mean 13.0±2.8 days) of OKT3 (mean dose 0.16±0.09 mg/kg) along with prednisone 0.5 mg/kg per day, azathioprine 2 mg/kg per day and cyclosporine 5 mg/kg per day which was increased to obtain therapeutic levels before the discontinuation of OKT3. Actuarial patient and graft survival were 100% and 50%, respectively, at both 1 and 5 years. Four children lost their grafts within the first 48 h. One loss was technical in origin, the remaining 3 had pathological evidence of vascular thrombosis. Of the remaining 16 children, 12 (75%) experienced rejection episodes within the first 2 months post transplant (mean 27±15 days). Successful reversal of early rejection episodes was achieved in 11 of 12 patients. Clinically significant cytomegalovirus infection occurred in 4 patients and resulted in graft loss in 2 patients. Circulating OKT3 levels ranging from 1,000 to 32,000 ng/ml were seen in all patients within the first 48 h. There was a rapid and total depletion of circulating CD3-positive lymphocytes in all patients. Antiisotypic and anti-idiotypic OKT3 antibodies were assessed by enzyme-linked immunosorbent assay (ELISA), and blocking anti-idiotypic antibodies were detected by immunofluorescence inhibition assay. Positive OKT3 antibody titers were detected in 11 children by ELISA and 10 children by immunofluorescence inhibition assay. In summary, we have found that in pediatric renal transplant patients receiving OKT3 induction therap: (1) there is a high occurrence of vascular thrombosis; (2) the incidence of early acute rejection is high; (3) the time to first rejection is not as long as that reported for adults; (4) there is a substantial rate of sensitization against OKT3; (5) despite successful reversal of early acute rejection, long-term-graft survival does not appear to have been beneficially altered.     

A randomized prospective trial of OKT3 induction in the current immunosuppression era

Recent improvements in immunosuppression and subsequent decreases in the incidence of acute rejection have brought into question the benefit of the use peri-transplant antibody therapy (i.e. induction therapy). In the current era of immunosuppression that includes mycophenolate mofetil (MMF) and cyclosporine emulsion (Neoral, Novartis, Basle, Switzerland), we designed and have completed a prospective, randomized trial to address this question. Cadaveric and living donor renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone or MMF/immediate Neoral/prednisone without OKT3. The incidence of rejection episodes was the primary end point. Patients with delayed graft function were excluded. All rejection episodes were biopsy proven and all patients have been followed for a minimum of 2 yr. Fifty-four patients received OKT3 induction, of which 6 patients suffered a rejection episode (11%), while 13 patients (27%) not receiving OKT3 (p=0.04) had a rejection episode. Four patients in the no OKT3 group suffered multiple rejections, while there were only 2 with more than one episode in the OKT3 group. There was no increased incidence of infectious complications in the group receiving OKT3. Hospital costs tended to be higher in the OKT3-treated group, but were not significantly different. The low incidence of rejection in the OKT3-treated group was intriguing and validates the use of antibody therapy in the early post-operative periods even in the era of improved baseline immunosuppression.     

Toxicity of OKT 3 increases with dosage: a controlled study in renal transplant recipients

In the present study we prospectively compared side effects occurring in 12 patients after the first administration of low-dose OKT3 (0.5 mg twice daily) induction therapy with those in 10 patients who were treated with a conventional dose of OKT3 (5 mg daily) for acute rejection. We also investigated cytokine release and activation of complement and neutrophils as all of these are held responsible for OKT3-induced side effects. Low-dose OKT3 resulted in a significantly decreased side effects score compared to that after a conventional dose of OKT3 (1.8 vs 5.1, p=0.0006). Following the first administration of low-dose OKT3, TNF peak levels were significantly lower than after a conventional dose of OKT3. In contrast to our data on conventional dose OKT3 treatment, the first administration of low-dose OKT3 did not induce complement activation as reflected by C3a and C4b/c levels in plasma. Finally, the increase in neutrophil degranulation products lactoferrin and elastase-₁- was much less following 0.5 mg OKT3 than following 5 mg. We conclude that OKT3-induced toxicity is dose-dependent and is mediated not only by cytokine release but also by activation of complement and neutrophils.     

Low-dose OKT3 induction therapy following renal transplantation: a controlled study

In a prospective clinical study we tested the immunosuppressiveproperties and toxicity of low-dose OKT3 induction therapy inrenal transplant recipients. 50 consecutive renal transplantrecipients were alternat ingly assigned to low-dose OKT3 inductionor prednisolone/cyclosporin. Low-dose OKT3 induction treatmentconsisted of 0.5 mg OKT3 twice daily for 10 days, initiallycombined with azathioprine and prednisolone maintenance immunosuppressionthat was converted to prednisolone/cyclosporin at the end ofthe course. During a 15–29-month follow-up period, low-doseOKT3 induction therapy was found to reduce significantly theincidence of acute rejections, as com-pared to the usual prednisolone/cyclosporinmainten ance immunosuppression (21 versus 52%, P=0.02). Therealso was a tendency towards an improved graft function afterlow-dose OKT3, although no signific ance was reached. Furthermore,compared to a histor ical control group of renal transplantpatients in whom acute rejection was treated with 5 mg OKT3daily, low-dose OKT3 appeared to cause fewer side-effects. Weconclude that low-dose OKT3 induction therapy is superior toprednisolone/cyclosporin in preventing acute rejection afterrenal transplantation and that it is better tolerated than conventionalOKT3 treatment.     

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

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. Received: 27 June 1997 Received after revision: 15 October 1997 Accepted: 19 November 1997     

Reduced dose OKT3 prophylaxis in sensitised kidney recipients

Prophylactic use of the monoclonal antibody OKT3 has been studied for the prevention of rejection in sensitised renal transplant recipients. Patients receiving a full dose (FD) regimen were compared to a subsequent consecutive group of patients receiving a reduced dose (RD) regimen. The characteristics of the two groups were not significantly different with regard to age, HLA mismatch and panel-reactive antibody (PRA) status. The number of days that OKT3 was given was 12.9±1.8 for the FD regimen and 11.3±2.8 for the RD regimen. The total dose of OKT3 given was 64.4±9 mg (FD) and 38.3±8.5 mg (RD). Patient survival at 12 months was 8/8 for FD and 17/17 for RD. Graft survival at 12 months was 7/8 for FD and 17/17 for RD. Creatinine at 24 months was 185±68 and 201±81 mol/l for FD and RD, respectively. A reduced dose regimen of OKT3 produced excellent and comparable results to the standard recommended fulldose regimen. The cost per patient was reduced 40% from £5676 for FD to £3344 for RD.     

Triple therapy immunosuppression in cadaveric renal transplantation

One hundred and ninety-two patients received 200 consecutive cadaver renal transplants (158 first and 42 regrafts) and were treated with triple therapy immunosuppression consisting of low-dose cyclosporin, azathioprine and prednisolone. One-year patient and graft survival rates were 95% and 82%, respectively. Against this low rate of graft loss, the proportion of rejection-free patients in the first 3 months was strongly related to matching for HLA-DR (P<0.01), although HLA-DR matching was not associated with improved graft survival. More grafts were lost to nonimmunological causes than to rejection, and these losses fell into three main categories, namely, losses in elderly and diabetic patients and losses due to renal vascular thrombosis. Thus, triple therapy immunosuppression appears to offer effective immunosuppression, resulting in good graft and patient survival, especially in highly sensitised patients or patients receiving regrafts. There are relatively few serious adverse effects, although elderly and diabetic patients experienced significant morbidity and mortality after transplantation.     

The use of OKT3 in steroid-resistant rejections following cadaveric kidney transplantation

OKT3 has been proved to be effective in the treatment of steroid-resistant rejection after renal allograft transplantation [1]. We investigated the clinical course of OKT3 recipients to find out in which cases of steroid resistance OKT3 therapy might be ineffective.     

OKT3 serum levels as a guide for prophylactic therapy: a pilot study in kidney transplant recipients

The use of OKT3 as prophylaxis in renal transplantation results in a reduced incidence of graft rejection and appears to have beneficial effects on long-term kidney graft survival. However, we and others have observed that patients still experience rejection during the period of OKT3 prophylaxis given at the regular 5 mg/day dose. Many of these patients had no circulating CD3⁺ cells at the time of rejection, but their OKT3 serum levels were distinctly low (<500 ng/ml). This led us to adjust OKT3 doses (5 or 10 mg) daily, according to the patients' OKT3 levels, in order to maintain an OKT3 concentration of around 1000 ng/ml. In addition, patients were randomized to receive either 5 mg (group 1, n=15) or 10 mg (group 2, n=14) OKT3 as the initial three doses. Concomitant immunosuppression consisted of azathioprine and steroids, with the introduction of cyclosporin A on day 11. Patient survival was 100% after 3 months of follow-up. The intensity of OKT3 first-dose reactions was similar in both groups. Intragraft thrombosis, initially observed in a previous group of patients who received a fixed 10 mg/day OKT3 prophylaxis, occurred in three patients in group 1 and resulted in two graft losses. The cumulative OKT3 dose was similar in both groups (mean ± SEM 98±2 mg in group 1 vs 102±3 mg in group 2) and higher than the 70 mg usually administered. Group 2 patients had higher OKT3 serum levels during the first 4 days of therapy. No correlation could be found between patient weight and cumulative OKT3 dose (r=0.29). No patient in either group 1 or 2 experienced rejection during OKT3 therapy. This compared favorably with an historical group of kidney recipients treated with a fixed 5 mg/day OKT3 dose, as 6 out of 32 patients in this group developed rejection (P=0.045). The rejection rate up to 3 months post-transplantation in pooled group 1 and 2 patients was low (six episodes per 81 patientmonths of risk exposure). We conclude that adaptation of the OKT3 dose according to daily OKT3 levels is safe and allows for excellent prevention of early graft rejection.     

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.     

Basiliximab plus low-dose cyclosporin vs. OKT3 for induction immunosuppression following renal transplantation

BACKGROUND: Current immunosuppressive therapies are very effective in preventing acute rejection (AR) and graft loss following renal transplantation. Newer agents now make it possible to develop equally efficacious but better tolerated and less toxic strategies. This is especially relevant for our ageing recipients. We now compare the efficacy of basiliximab combined with early low-dose cyclosporin therapy to standard OKT3 induction therapy. METHODS: In this single-centre study, 100 consecutive recipients of cadaveric kidney transplants from November 1998 to August 2000 were treated with basiliximab combined with early low-dose cyclosporin, reduced steroids and mycophenolate mofetil (MMF). Clinical outcomes at 100 d and 1 yr were compared with a group of 26 patients transplanted from March 1995 to November 1998 who received OKT3, delayed full-dose cyclosporin, high-dose steroids and MMF. Amongst basiliximab treated patients, we compared clinical outcomes in those older and younger than 60 yr. RESULTS: Both groups were similar except for a shorter cold ischaemic time in the basiliximab group. Length of stay, number of readmissions, total hospitalization days and cytomegalovirus infections were lower in the basiliximab group. Despite a 40% reduction in steroids, basiliximab-treated patients had fewer biopsy-proven episodes of AR (basiliximab 14% vs. OKT3 35%) and required less antilymphocyte antibody therapy. Clinical outcomes including patient and graft survival were no different between groups. Long-term graft survival for patients over 60 yr was limited primarily by mortality. CONCLUSIONS: Compared with OKT3 induction therapy, the combination of early low-dose cyclosporin and basiliximab is steroid sparing, effective, well tolerated and relatively safe.     

Preventive OKT3 treatment with cyclosporine (Sandimmun) for second kidney transplantation

Abstract A total of 793 kidney transplantations (KTx) were performed from November 1073 to March 1993. Two hundred and forty-two patients were treated with conventional immunosuppression (azathioprine + prednisolone) and all the others with cyclosporine (Sandimmun) and prednisolone (SIM + PRED). The survival of the second graft was less good in both therapeutic groups than that of the first ones, so we have started to use preventive immunotherapy with OKT3 (CILAG) in combination with SIM (both before operation) and PRED. We compared 32 SIM-PRED patients with 20 OKT3 + SIM + PRED patients. All underwent a second KTx. The two groups were found to be comparable and homogeneous with regard to 14 of 18 parameters analysed statistically. Statistically significant differences were found between the two groups as regards the frequency of acute rejection within 30 days (46.69% vs 20%), the delta creatinine value on the 1st and 2nd postoperative days (- 4,3: -8 vs -8.6: -19.7%), patient survival after 4 years (78.2 vs 100%), and graft survival after 1 and 4 years (-58.9: -42.8 vs -83.5: -83.5%), with better results in the OKT3 group. We conclude that the preventive use of OKT3 simultaneously with SIM + PRED for the second KTx is the method of choice to prevent rejection and improve survival. This treatment results in patient and graft survival following the second KTx being as good as after the first KTx with SIM + PRED.     

High or low dose steroid therapy for acute renal transplant rejection after prophylactic OKT3 treatment: a prospective randomized study

In this prospective randomized study, acute renal transplant rejections occurring in patients who received prophylactic OKT3 therapy were treated with either 3 pulses of 8 mg/kg methylprednisolone (MPS) in an alternate-day regimen (total dose 25 mg/kg in 1 week, H group, n = 24) or 5 daily pulses of 3 mg/kg MPS (total dose 17 mg/kg, L group, n = 22). Acute rejection was proven by biopsy in more than 85% of cases in both groups. No difference was observed in rejection reversal (H 88%, L 91%), graft losses in the following 3 months (H 11%, L 4%) or the time evolution of the serum creatinine levels. The number (H 14, L 21) as well as the nature and severity of infections were similar in both groups. Only one death occurred in a patient who received OKT3 rescue therapy for corticoresistant rejections and developed Epstein-Barr virus (EBV)-related lymphoma. In conclusion, low dose MPS pulses appear as effective and safe as a higher dose to reverse acute rejection occurring after OKT3 prophylaxis. Thus, we favour the use of the low dose regimen in these patients.     

肾移植术后应用单克隆抗体OKT3的护理观察

目的总结使用OKT3出现并发症的处理方法,探讨有效的预防措施.方法回顾性分析2004年9月～2005年2月8例使用OKT3患者的临床资料,总结出现的并发症.结果本组8例患者均有效控制因OKT3使用出现的并发症.结论选择相应的处理方法和预防措施,可有效减少OKT3使用后的并发症.     

The role of OKT3 in clinical transplantation

OKT3 is a murine monoclonal anti-T cell antibody that is directed to CD3, a five-chain molecular complex found in association with the T cell receptor for antigen. OKT3 was the first monoclonal antibody to be used in organ transplantation and during the past 10 years there has been extensive experience of its use both for preventing and treating rejection in organ transplantation. OKT3 blocks T cell function by modulating CD3 and the T cell receptor from the T cell surface. A reaction to OKT3 results from cytokines released when OKT# first reacts with T cells. This reaction is generally mild but can be severe. First rejections following kidney transplantation are reversed in approximately 95% of cases. Steroid-resistant rejections are also susceptible to OKT3 but in only approximately 75% of cases. When used for prophylaxis, OKT3 completely blocks rejection in 95% of patients and significantly delays the onset of rejection in those who do reject. Antibodies to OKT3 are produced in approximately 75% of patients receiving it. However, seldom are the antibodies to OKT3 present in high titer and only in those cases is successful re-use of OKT3 prevented. As is the case with all potent immunosuppressive drugs, the use of OKT3 is associated with increased viral, specifically cytomegalovirus, infections. However, it appears that reduction of concomitant immunosuppression decreases the incidence of severe infections. Unquestionably, OKT3 has been a useful addition to the immunosuppression used for organ transplantation. In addition, its use has stimulated research on other monoclonal antibodies for use in organ transplantation.     

Reversal of acute glomerular renal allograft rejection: a possible effect of OKT3

A major cause of renal allograft loss is glomerulovascular rejection. This case report is about an episode of histologically proven acute glomerular rejection that was successfully reversed. Monoclonal antibody OKT3 may have been the effective agent.     

Historical controlled trial of OKT3 versus basiliximab induction therapy in simultaneous pancreas-renal transplantation

SUMMARY:   Simultaneous pancreas–kidney (SPK) transplant recipients are at high immunological risk of rejection. Antibody induction is beneficial but lymphocyte-depleting therapy is associated with a high incidence of side-effects. We performed a historical controlled trial to compare OKT3 versus anti-CD25 antibody (basiliximab) induction therapy with regard to patient, kidney and pancreas survival, as well as to examine for any differences in acute rejection, graft function, and infective complications. Twenty-eight consecutive SPK transplants were performed at the Monash Medical Centre between December 1997 and November 2001. Anti CD3 monoclonal antibody (OKT3) was used prior to March 2000 ( n  = 12) and basiliximab was used after ( n  = 16), both in combination with cyclosporin, mycophenolate, and prednisolone. A retrospective comparison of outcomes was performed. At 6 months, patient (100 vs 100%), kidney (91.7 vs 91.7%) and pancreas (75 vs 83.3%) survival were similar in the OKT3 and basiliximab groups, respectively. A minority of subjects in each group remained free from rejection (42% basiliximab vs 25% on OKT3, P  = NS). Renal function was superior in the basiliximab group (mean calculated creatinine clearance 79.4 ± 11.9 vs 54.5 ± 15.9 mL/min for  basiliximab vs OKT3, P  < 0.001). The incidence of major opportunistic infection was lower in basiliximab-treated patients (9 vs 50% in the OKT3 group, P  = 0.033). Basiliximab was associated with similar 6-month patient, kidney and pancreas survival, superior renal function and less opportunistic infection as compared with OKT3 induction therapy in SPK transplants. Basiliximab is at least as effective and is safer than OKT3 for induction therapy in SPK transplantation.     

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.     

Daclizumab induction/tacrolimus sparing: a randomized prospective trial in renal transplantation

Abstract: Tacrolimus inhibits lymphocyte responses by blocking calcium-dependent signalling pathways important in IL-2 generation. Daclizumab, a humanized monoclonal antibody, binds with high affinity to the Tac subunit of the IL-2 receptor complex. We reasoned therefore that the absence of IL-2R should permit lower doses of tacrolimus and thereby less toxicity. Twenty-eight patients were randomized and followed for 6 months: Group 1, high dose (HD) tacrolimus (trough 12–17 ng/mL; n  = 13); Group 2, low dose (LD) tacrolimus (trough 5–10 ng/mL; n  = 15). All patients received daclizumab induction (2 mg/kg) on days 0 and 14, mycophenolate mofetil (2 g/d except for one patient who received 1 g) and rapid prednisone taper. Serious infections were minimal in both groups. Hospitalizations, for various reasons, were HD ( n  = 12) and LD ( n  = 6). All patients and grafts survived for the 6-month study period. There was one rejection episode in a non-compliant patient at 101 d. LD tacrolimus appears equally effective as HD tacrolimus in preventing rejection episodes and may be associated with fewer adverse events.