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.     

Differential influence of azathioprine and mycophenolate mofetil on the disposition of basiliximab in renal transplant patients

Pharmacokinetic sampling was performed in two multicenter trials in which basiliximab (anti-CD25 monoclonal antibody) was administered with triple immunosuppression consisting of cyclosporine microemulsion, corticosteroids, and either azathioprine or mycophenolate mofetil. Blood samples were collected over 12 wk post-transplant from 31 azathioprine-treated and 66 mycophenolate mofetil-treated patients. Empirical Bayes estimates of each patient's basiliximab disposition parameters were derived and the duration of CD25 saturation was estimated as the time over which serum concentrations exceeded 0.2 microg/mL as confirmed by flow cytometry measurements. Basiliximab clearance was 29+/-14 mL/h when coadministered with azathioprine and 18+/-8 mL/h with mycophenolate mofetil. Both were significantly lower compared with a clearance of 37+/-15 mL/h from a previous study of basiliximab with dual therapy (p<0.001). As a consequence of the lower clearance of basiliximab, the durations of CD25 saturation were prolonged in the presence of azathioprine (50+/-20 d; range, 13--84) and mycophenolate mofetil (59+/-17 d; range, 28--94) compared with dual therapy (36+/-14 d; range, 12--91). A total of 27 acute rejection episodes occurred during the first 6 months in the two studies. Durations of CD25 saturation were not different in these patients compared with those who remained rejection-free in each study. A single patient among 57 who were screened developed anti-idiotype antibodies to basiliximab. The average duration of CD25 saturation was prolonged by 39 and 64% in the presence of azathioprine and mycophenolate mofetil, respectively. This graded effect was also observed for basiliximab clearance and may be due in part to a differentially reduced humoral response to basiliximab. Nonetheless, the range of CD25 saturation durations and basiliximab clearances did not extend outside the range when basiliximab was used with dual therapy in the absence of these agents. Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil.     

Campath,calcineurin inhibitor reduction,and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial

Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short‐term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long‐term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation. The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus‐based and 197 to tacrolimus‐based therapy. Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline‐adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m² in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m² in the tacrolimus group (P = .50). Biopsy‐proven acute rejection (29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus‐based therapy, sirolimus‐based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection. ClinicalTrials.gov identifier NCT01120028 and ISRCTN88894088.     

Immunoprophylaxis with Basiliximab Compared with Antithymocyte Globulin in Renal Transplant Patients Receiving MMF-containing Triple Therapy

Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with Thymoglobulin or basiliximab has significantly reduced the incidence of acute rejection episodes and graft loss following kidney transplantation. This open, randomized, multicenter study investigated the efficacy and tolerability of basiliximab (20mg day 0-day 4) plus early cyclosporine from day 0 (n = 50) compared with Thymoglobulin plus delayed cyclosporine (n = 50) in adult kidney transplant patients. In addition, all patients received steroids and mycophenolate mofetil (MMF) at standard doses from day 0. Patient and graft survival rates at 12 months were 98 and 94% in the basiliximab group, respectively, compared with 100 and 96% in the Thymoglobulin' group. The incidences of biopsy-confirmed acute rejection (8.0% in each group) and treatment failure (14% in the basiliximab group vs. 8% in the Thymoglobulin group) were comparable in the two groups. There was a non-significant tendency to more dialysis (14 vs. 6%), and fewer cytomegalovirus (CMV) infections (p = 0.005) in the basiliximab group, but the percentage of clinical CMV was not different between the two groups (6 vs. 12%). Both strategies give excellent results, despite the differences in patterns, in nonhyperimmunized patients receiving their first cadaveric renal allograft.     

New developments in immunosuppressive therapy for heart transplantation

Background: Heart transplantation is a well-established therapeutic option for many patients with end-stage heart disease. A major challenge in heart transplantation today is providing effective immunosuppression to prevent graft rejection while minimizing the many adverse effects of currently available therapies. Objective: To systematically review current immunosuppressive treatment strategies after heart transplantation and to review emerging drugs in various stages of development. Methods: A comprehensive literature review was performed using the online PubMed and Pharmaprojects databases. Results/conclusions: This article gives an overview of the immunosuppressive agents in current use, with a detailed review of emerging drugs with novel therapeutic targets.     

Increased risk of rejection after basiliximab induction in sensitized kidney transplant recipients without pre‐existing donor‐specific antibodies – a retrospective study

Depleting induction therapy is recommended in sensitized kidney transplant recipients (KTRs), though the detrimental effect of nondonor‐specific anti‐HLA antibodies is not undeniable. We compared the efficacy and safety of basiliximab and rabbit anti‐thymocyte globulin (rATG) in sensitized KTRs without pre‐existing donor‐specific antibodies (DSAs). This monocentric retrospective study involved all sensitized KTR adults without pre‐existing DSAs (n = 218) who underwent transplantation after June 2007. Patients with basiliximab and rATG therapy were compared for risk of biopsy‐proven acute rejection (BPAR) and a composite endpoint (BPAR, graft loss and death) by univariate and multivariate analysis. Patients with basiliximab (n = 60) had lower mean calculated panel reactive antibody than those with rATG (n = 158; 23.7 ± 24.2 vs. 63.8 ± 32.3, P < 0.0001) and more often received a first graft (88% vs. 54%, P < 0.0001) and a transplant from a living donor (13% vs. 2%, P = 0.002). Risks of BPAR and of reaching the composite endpoint were greater with basiliximab than rATG [HR = 3.63 (1.70–7.77), P = 0.0009 and HR = 1.60 (0.99–2.59), P = 0.050, respectively]. Several adjustments did not change those risks [BPAR: 3.36 (1.23–9.16), P = 0.018; composite endpoint: 1.83 (0.99–3.39), P = 0.053]. Infections and malignancies were similar in both groups. rATG remains the first‐line treatment in sensitized KTR, even in the absence of pre‐existing DSAs.     

巴利昔单抗在预防肾移植后排斥反应中的应用

目的:探讨巴利昔单抗诱导治疗预防肾移植后急性排斥反应的有效性和安全性。方法:在使用环孢素、霉酚酸酯及激素三联抗排斥的基础上,将42例肾移植受者随机分2组,每组各21例,试验组术前30min及术后d4各给予巴利昔单抗20mg+氯化钠注射液100mL,静脉滴注,对照组只使用氯化钠注射液静脉滴注。评价急性排斥反应的发生率、严重程度以及巴利昔单抗治疗的安全性。结果:试验组急性排斥反应发生率10%(2/21),发生时间(2.8±s0.8)mo;对照组发生率29%(6/21),发生时间(1.1±0.7)mo,早于试验组(P<0.01)且严重程度高于试验组。血肌酐恢复正常的时间试验组(4.0±0.7)d,对照组(7.8±1.6)d,P<0.01。不良反应发生率2组间差异无显著意义,P<0.05。结论:巴利昔单抗联合环孢素、霉酚酸酯和激素预防肾移植后急性排斥反应安全有效。