Basiliximab: a review of its use as induction therapy in renal transplantation

Basiliximab (Simulect), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents.Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual- (cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation.The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytomegalovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported.The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG.Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults. Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients.Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies.CONCLUSION: Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.     

Efficacy and safety of low-dose valganciclovir for prevention of cytomegalovirus disease in renal transplant recipients: a single-center, retrospective analysis

STUDY OBJECTIVE: To evaluate the safety and efficacy of valganciclovir 450 mg/day for 6 months for cytomegalovirus (CMV) prophylaxis in renal transplant recipients. DESIGN: Single-center, retrospective analysis. SETTING: Urban, academic medical center. PATIENTS: Fifty-eight patients who received de novo renal transplants from August 1, 2001-November 21, 2002. INTERVENTION: Valganciclovir 450 mg/day was administered to all renal transplant recipients at risk for CMV disease. Therapy was begun postoperatively and was dose adjusted to renal function. MEASUREMENTS AND MAIN RESULTS: Data collected from renal transplant recipients were demographics, immunosuppressive and antiviral drug therapy, and occurrence of CMV disease, acute rejection, allograft loss, and hematologic adverse events. Donor (D)/recipient (R) CMV serostatus was 37.9% D+/R+, 29.3% D-/R+, 17.3% D+/R-, and 15.5% D-/R-. Antithymocyte globulin (ATG) was administered to 62.1% of patients. Most of the transplant recipients received triple immunosuppression as maintenance therapy. Median follow-up was 20 months. The frequency of CMV disease was 1.7% within 6 months after transplantation and 5.2% at any point after transplantation. All patients who developed CMV disease were D+/R- and had received ATG. Leukopenia and thrombocytopenia associated with valganciclovir were seen in 28% and 24% of patients, respectively. One patient developed acute cellular rejection. No graft losses or deaths occurred. Early discontinuation of valganciclovir occurred in 20% of patients secondary to severe, persistent leukopenia, thrombocytopenia, and/or diarrhea. None of these patients developed CMV disease. CONCLUSION: A high rate of CMV disease was noted among the D+/R- population. Administration of ATG as an induction agent also increased the frequency of CMV disease. Despite the low dosage of valganciclovir, hematologic adverse events were common. However, valganciclovir, administered at 450 mg/day for 6 months, was effective and relatively safe for prophylaxis of CMV disease in renal transplant recipients.     

Muromonab CD3. A review of its pharmacology and therapeutic potential

Muromonab CD3 (Orthoclone OKT3, Orthoclone, OKT3) is the first monoclonal antibody to become available for therapy in humans. In effect it blocks all cytotoxic T cell function. Clinical trials show that muromonab CD3 is effective in reversing acute renal, hepatic, cardiac and combined kidney-pancreas transplant rejection episodes. It has also been shown to be effective in the treatment of rejections resistant to conventional treatment. As such it offers a significant alternative when no other therapeutic option remains open. Other clinical trials have shown that muromonab CD3 is more effective than high-dose corticosteroids in reversing first episodes of acute renal and hepatic rejection. Additionally, it appears effective as a prophylactic treatment against acute renal and cardiac rejection in the immediate post-transplantation period. Preliminary studies also indicate that it may be effective in preventing or reversing graft-versus-host disease in bone marrow transplant patients. The development of neutralising antibodies may limit the effectiveness of a second course of muromonab CD3 therapy in some patients. In conclusion, muromonab CD3 offers a significant new approach to immunosuppressive therapy and has provided a valuable therapeutic alternative for the treatment of acute solid organ transplant rejection.     

A cost analysis of alprostadil in liver transplantation

Alprostadil (prostaglandin E1) administration to liver transplant recipients has been shown to result in a significant reduction in the duration of hospital admission for transplantation, and in the need for re-operations (other than re-transplants) and renal support. To study the economic impact of this finding, we examined data from a controlled trial for all single-transplant surviving patients (42 alprostadil, 49 controls) for whom complete billing records were available for transplant days -2 to +150. All costs were measured in 1992 US dollars. Patients given alprostadil had lower total charges [mean +/- standard deviation (SD) $US175 297 +/- $US70 652] than patients given placebo (mean +/- SD $US225 672 +/- $US187 208) [p = 0.043]. The data suggest that the use of alprostadil may have a significant favourable impact on the cost of liver transplantation.     

Combination treatment of low dose Anti-Thymocyte Globulin (ATG), Rituximab and high dose Sirolimus as induction agents in immune-conditioned recipients

A prospective study was performed to evaluate low dose Anti-Thymocyte Globulin (ATG) and Rituximab along with high dose Sirolimus as induction agents for reducing the incidence of acute rejection in renal transplantation. 66 patients who were to undergo live renal transplantation were divided into the low risk Group I (GpI, n=41) and the high risk Group II (GpII, n=25) recipients. Induction therapy included single dose Rituximab (200 mg), ATG (2 mg/kg) and Sirolimus 12 mg/d administered minus 3 days pretransplant. All patients underwent splenic radiation and Double Filtration Plasmapheresis (DFPP). Post-operatively, all recipients received MMF, prednisolone 5-10 mg/d and Tacrolimus started when serum creatinine (Scr) fell below 2.5 mg/dl on the first Post Operative Day (POD). If creatinine still remained high second dose ATG and Sirolimus continued. Once serum creatinine fell below 1.5 mg/dl Tacrolimus initiated at 0.1 mg per kg per day dose stopping ATG. RESULTS: Acute rejection at 6 months for GpI was nil and for GpII it was 8%. Mean Scr on 1st POD was 1.8+/-0.6 mg/dl in GpI and 2.6+/-0.9 mg/dl in GpII. After 6 months the creatinine level in high risk was similar to that of low risk group (1.1+/-0.6 mg/dl in GpI and 1.2+/-0.8 mg/dl in GpII). No patient or graft loss was observed. Infections requiring hospitalization were observed in six patients and wound related complications requiring surgical intervention were observed in 4 of the 66 recipients. CONCLUSION: Low dose ATG with Rituximab and high dose Sirolimus can be used as induction agents in immune-conditioned recipients with better apparent results than using high dose induction ATG. This combinational regimen also helps in individualizing post-operative immunosuppressive drugs based upon the post-operative renal function.     

Induction immunosuppression in kidney transplant recipients older than 60 years of age : safety and efficacy of ATGAM, OKT3 and Simulect

BACKGROUND: The choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by the consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term adverse effects. OBJECTIVE: To compare the efficacy and safety of the antibody induction immunosuppression strategies in elderly recipients of kidney transplants. PATIENTS AND METHODS: We present retrospective data analysis on 183 kidney transplant recipients > or = 60 years of age at Hahnemann University Hospital (Philadelphia, PA, USA) over a 12-year period. We compared four consecutive cohorts of kidney transplant recipients receiving lymphocyte immune globulin, equine antithymocyte globulin (ATGAM) [n = 29]; muromonab CD3 (OKT3) [n = 45]; basiliximab (Simulect) with corticosteroid maintenance [n = 40]; and Simulect without corticosteroid maintenance (n = 69). RESULTS: Delayed graft function (DGF) was observed in 48% of patients receiving ATGAM, 35.6% in the OKT3 group and 35% in the Simulect group with corticosteroid maintenance and 36.2% in the Simulect group without corticosteroid maintenance. The rejection rate within the first 3 months was 31% in the ATGAM and OKT3 groups, 17.5% in the Simulect group with corticosteroid maintenance and 14.5% in the Simulect group without corticosteroid maintenance. These differences for DGF and acute rejection were statistically significant between patients receiving ATGAM and OKT3, ATGAM or OKT3 and both groups of Simulect (all p < 0.05). Patients receiving Simulect were free of adverse effects typically encountered by patients receiving polyclonal and monoclonal antibodies for induction. Patients receiving Simulect had much shorter hospital stays and benefited from significant reduction of costs compared with other groups. CONCLUSION: Our data indicate that kidney transplant recipients > or = 60 years of age benefit from induction therapy with Simulect followed by corticosteroid-free maintenance immunosuppression.     

Antibody-mediated rejection following renal transplantation

Antibody-mediated rejection (AMR) accounts for 20-30% of all acute rejection episodes following renal transplantation. AMR is generally less responsive to conventional anti-rejection therapy, resulting in poor allograft survival. Introduction of C4d immunostaining of renal allograft biopsies and the demonstration of donor-specific antibodies in the recipients have increased our ability to diagnose AMR. Therapeutic options are evolving and include plasmapheresis, intravenous immunoglobulin, immunoadsorption and rituximab, together with intensification of immunosuppression with a tacrolimus/mycophenolate mofetil combination. Future studies might further define optimal therapeutic approach in renal transplant recipients presenting with AMR.     

巴利昔单抗联合鼠抗人CD3单克隆抗体在高致敏受者肾移植中的临床应用

目的:探讨巴利昔单抗与鼠抗人CD3单克隆抗体(OKT3)联合诱导在高致敏受者肾移植临床应用中的有效性及安全性。方法:术前2个月内群体反应性抗体(PRA)检测值均>50%的尸体供肾肾移植受者20例,其中9例受者接受巴利昔单抗联合OKT3免疫诱导(联合诱导组),11例受者接受OKT3常规免疫诱导(OKT3诱导组),均以他克莫司(Tac)+吗替麦考酚酯(MMF)+泼尼松(Pred)为基础免疫抑制方案,评估术后移植肾功能恢复情况、3个月内急性排斥反应发生率、1年内肺部感染发生率、1年人/肾存活率及移植肾功能。结果:联合诱导组、OKT3诱导组肾移植术后3个月内急性排斥反应发生率及术后1年内肺部感染发生率分别为11.1%vs.36.4%(P=0.319),11.1%vs.63.6%(P=0.028);联合诱导组患者术后1周内移植肾功能恢复正常比例明显高于OKT3诱导组(88.9%vs.27.3%,P=0.010);联合诱导组术后1年人/肾存活率均为100%,与OKT3诱导组(分别为90.9%、81.8%)比较,差异不显著(P=1.00和P=0.100);术后1年联合诱导组、OKT3诱导组血肌酐值分别为(105±24)、(97±22)μmol·L-1(P=0.437)。结论:巴利昔单抗联合OKT3进行免疫诱导,在预防高致敏受者术后早期排斥反应的同时,缩短了移植肾功能的恢复时间,是一种安全、有效的防治策略。     

Rabbit antithymocyte globulin induction therapy in adult renal transplantation

Rabbit antithymocyte globulin (rATG) and horse antithymocyte globulin (horse ATG) are the polyclonal antithymocyte agents available for use in solid organ transplantation in the United States. Horse ATG is indicated for induction immunosuppression and for treatment of acute rejection episodes after kidney transplantation; rATG is indicated for treatment of acute rejection only. However, rATG is commonly used in clinical practice as an induction immunosuppressive agent, instigating many questions regarding appropriate dosing, tolerability, safety, and efficacy. Available evidence supports the use of rATG as an induction agent in adult renal transplant recipients. The use of this product for induction therapy has been studied in conjunction with a full-dose, triple-therapy maintenance regimen (sequential quadruple immunosuppression) consisting of a calcineurin inhibitor, an antimetabolite, and corticosteroids. Rabbit ATG has a proven safety and efficacy profile both as treatment of acute rejection and as induction therapy in patients undergoing kidney transplantation. The most common adverse events associated with rATG are cytokine release syndrome, thrombocytopenia, and lymphopenia. Results of early studies showed an increased rate of cytomegalovirus disease associated with rATG treatment, but recent studies indicate that routine administration of modern antiviral prophylaxis can reduce this risk. Current practice with rATG is evolving to minimize lifelong exposure to calcineurin inhibitors and corticosteroids.     

Anti-interleukin-2 receptor antibodies for the prevention of rejection in pediatric renal transplant patients: current status

The anti-interleukin-2 receptor (anti-IL-2R) antibody therapy is an exciting approach to the prevention of acute rejection after renal allograft transplantation whereby immunosuppression is exerted by a selective and competitive inhibition of IL-2-induced T cell proliferation, a critical pathway of allorecognition. The anti-IL-2R antibodies specifically block the alpha-subunit of the IL-2R on activated T cells, and prevent T cell proliferation and activation of the effector arms of the immune system. The anti-IL-2R antibodies are used as induction therapy, immediately after renal transplantation, for prevention of acute cellular rejection in children and adults. During acute rejection, the IL-2Ralpha chain is no longer expressed on T cells; thus, the antibodies cannot be used to treat an existing acute rejection. Two anti-IL-2R monoclonal antibodies are currently in clinical use: daclizumab and basiliximab. In placebo-controlled phase III clinical trials in adults, daclizumab and basiliximab in combination with calcineurin inhibitor-based immunosuppression, significantly reduced the incidence of acute rejection and corticosteroid-resistant acute rejection without increasing the risk of infectious or malignant complications, and neither antibody was associated with the cytokine-release syndrome. Children who receive calcineurin inhibitors and corticosteroids for maintenance immunosuppression, as well as children who receive augmented immunosuppression to treat acute rejection, are at increased risk of growth impairment, hypertension, hyperlipidemia, lymphoproliferative disorders, diabetes mellitus, and cosmetic changes. In older children, the cosmetic adverse effects frequently reduce compliance with the treatment, and subsequently increase the risk of allograft loss. Being effective and well tolerated in children, the anti-IL-2R antibodies reduce the need for calcineurin inhibitors while maintaining the overall efficacy of the regimen; thus, the anti-IL-2R antibodies increase the safety margin (less toxicity, fewer adverse effects) of the baseline immunosuppression. Secondly, the anti-IL-2R antibodies decrease the need for corticosteroids and muromonab CD3 (OKT3) in children as a result of decreased incidence of acute rejection. The recommended pediatric dose of daclizumab is 1 mg/kg intravenously every 14 days for five doses, with the first dose administered within 24 hours pre-transplantation. This administration regimen maintains daclizumab levels necessary to completely saturate the IL-2Ralpha (5-10 microg/mL) in children for at least 12 weeks.The recommended pediatric dose of basiliximab for recipients <35 kg is 10 mg, and 20 mg for recipients > or =35 kg, intravenously on days 0 and 4 post-transplantation. This administration regimen maintains basiliximab levels necessary to completely saturate the IL-2Ralpha (>0.2 microg/mL) in children for at least 3 weeks.     

Lack of economic benefit with basiliximab induction in living related donor adult renal transplant recipients

STUDY OBJECTIVE: To assess the effect of basiliximab (BAS) induction therapy on acute rejection rates and overall costs in adult living related donor (LRD) renal transplant recipients. Design. Retrospective chart review and cost-effectiveness analysis of the first 12 months after transplantation. SETTING: University hospital and outpatient renal transplant clinic. PATIENTS: Sixty consecutive adult LRD renal transplant recipients. INTERVENTION: The treatment group received BAS 20 mg intravenously on postoperative days 0 and 4. The control group received no induction agents. Both groups received cyclosporine microemulsion, azathioprine, and corticosteroids for maintenance immunosuppression. MEASUREMENTS AND MAIN RESULTS: Six patients (three in each group) were excluded; three had received muromonab-CD3 as an induction agent and three were lost to follow-up. At 12-months, the frequency of acute rejection episodes was 15% (4/27) in the control group and 22% (6/27) in the BAS group (NS). Renal function, as measured by average serum creatinine level, was similar at months 1, 2, 3, 6, and 12 for both groups. The frequency of infectious complications was similar in both groups. No adverse effects were associated with BAS. Mean initial hospitalization charges were dollar 51,970.01 and dollar 68,093.90 in the control and BAS groups, respectively (p < 0.05). The control group had more readmissions (18 vs 14 in the BAS group), but the average charge/readmission was lower (dollar 10,148.50 vs dollar 21,952.58 in the BAS group; NS). All costs were adjusted to 2000 dollars (US). CONCLUSION: Basiliximab induction therapy did not provide clear clinical efficacy benefit or prove to be cost-effective compared with no induction in LRD recipients.     

肾移植急性排斥受者外周血OX40 mRNA和Th1的变化及意义

目的 探讨外周血单个核细胞 OX40 mRNA和外周血 CD3+CD8- T辅助细胞（Th）1、Th2检测用于评估肾移植术后急性排斥的应用价值。方法 收集 2016年 1月—2017年 1月天津市第一中心医院器官移植中心行肾移植手术的 40例肾移植受者及 20名健康志愿者纳入研究,肾移植受者分为急性排斥组 20例和肾功能稳定组 20例。应用TaqMan实时荧光定量聚合酶链式反应（RT-PCR)定量检测 3组外周血单个核细胞（PBMCs）中 OX40 mRNA水平,应用流式细胞术检测外周血 CD3+CD8-T淋巴细胞中 IFN-γ（Th1）和 IL-4（Th2）表达率。ROC曲线评价 OX40和 Th1对预 测急性排斥的诊断价值。结果 肾移植术后急性排斥组 PBMCs 中 OX40 mRNA水平明显高于肾功能稳定组以及健康对照组（P＜0.01）,肾功能稳定组 PBMCs 中 OX40 mRNA水平与健康对照组差异无统计学意义（P＞0.05）。急性排斥组 Th1 表达率明显高于肾功能稳定组和正常对照组（P＜0.01）,3 组 Th2 表达率差异无统计学意义（P＞0.05）。OX40 mRNA 诊断急性排斥反应的 ROC 曲线下面积（AUC）为 0.903（95%CI：0.825~0.980）;Th1 的 AUC 为 0.731（95%CI：0.587~0.874）;两者联合诊断的 AUC 为 0.930（95%CI：0.859~1.001）。结论 监测肾移植受者外周血 OX40mRNA及 Th1细胞可以预测急性排斥反应。     

The use of mycophenolate mofetil in transplant recipients

With the development of new immunosuppressive agents, the focus of anti-rejection therapy has shifted from prevention of acute allograft rejection to an emphasis on sufficient immunosuppression with minimal toxicity. Mycophenolate mofetil (MMF) is a recently developed immunosuppressive drug, which acts to inhibit T and B cell proliferation by blocking the production of guanosine nucleotides required for DNA synthesis. It also prevents the glycosylation of adhesion molecules that are involved in attachment of lymphocytes to endothelium and potentially in leukocyte infiltration of an allograft during an immune response. High-quality randomized clinical trials have demonstrated that MMF, when used with cyclosporine (CsA) and steroids, reduces the frequency and severity of acute rejection episodes in kidney and heart transplants, improves patient and graft survival in heart allograft recipients and increases renal allograft survival at 3 years. It has also been effective in reversing acute and resistant rejection episodes in heart, kidney and liver recipients. The ability of MMF to facilitate sparing of other immunosuppressive agents, particularly in CsA-related nephrotoxicity, is also promising. By permitting reduction in CsA doses, MMF may stabilize or improve renal graft function in patients with CsA-related nephrotoxicity or chronic allograft nephropathy. Early results of phase I and II trials evaluating MMF therapy in liver and combined pancreas/kidney transplant recipients are encouraging. The main adverse effects associated with oral or intravenous MMF are gastrointestinal and hematologic in nature. Although the direct costs of using MMF vs. azathioprine (AZA) are higher, the decreased incidence and treatment of acute rejection in patients treated with MMF supports its use as a cost-effective option during the first year following transplantation.Thus, MMF has become an important therapeutic tool in the transplant clinician's armamentarium. Ongoing issues to be resolved in clinical trials include the role of MMF in the absence of other potent agents, e.g., as monotherapy or with a steroid but without calcineurin inhibitor; whether MMF will have an impact on chronic allograft dysfunction; and the cost-effectiveness of treatment following the first year of transplantation.     

高龄患者肾移植126例临床分析

目的 :探讨高龄患者肾移植的临床特点及四联免疫抑制疗法对临床治疗效果的影响。方法 :分析 1990年 1月至 2 0 0 0年 12月 12 5 1例肾移植中 12 6例高龄患者临床资料 ,将术后使用免疫抑制剂为三联疗法 (CsA +Aza +激素 )的 5 5例作组Ⅰ ;而使用四联疗法 (CsA +MMF +激素 +抗T细胞单抗 )的 71例作为组Ⅱ ,组Ⅱ中 4 7例患者术后使用 2周Wu -T3抗排斥治疗 ,另 2 4例应用抗IL- 2R抗体预防急性排斥反应。将两组的术后并发症、急性排斥率及 1年人 /肾存活率相比较 ,并与本院同期非高龄患者相同指标比较。结果 :高龄患者肾移植后心脑血管并发症以及感染发生率均明显高于非高龄患者。组Ⅰ和组Ⅱ患者的术后并发症发生率分别为 74 5 5 %和 38 0 3% ;急性排斥发生率分别为 12 73%和 4 2 3% ;1年人 /肾存活率分别为 81 82 % /78 18%和 97 18% /95 77%。结论 :高龄患者肾移植术后较容易发生心脑血管并发症及感染 ,使用新的四联免疫抑制疗法能有效地降低心脑血管并发症、感染和急性排斥反应的发生率 ,1年人 /肾存活率亦明显提高。     

A review of interleukin-2 receptor antagonists in solid organ transplantation.

Daclizumab and basiliximab, engineered human IgG monoclonal antibodies to the interleukin-2 (IL-2) receptor alpha-subunit, were approved to prevent acute rejection after renal transplantation. Daclizumab was studied in adult and pediatric renal allograft recipients, liver allograft recipients, and calcineurin-sparing protocols in renal transplant recipients. Basiliximab was studied in renal allograft recipients and subgroups of recipients of living-related and cadaveric transplants, and in patients with diabetes mellitus. Both agents reduced acute rejection and were associated with few adverse effects. However, information regarding their long-term effects on infection, malignancy, chronic rejection, and patient survival must be available before a final decision is made regarding their proper administration. We propose that a likely role the drugs will play in the field of solid organ transplantation is in new protocols that allow sparing of other more toxic immunosuppressive agents.     

Relationship between dose of mycophenolate mofetil and the occurrence of cytomegalovirus infection and diarrhea in renal transplant recipients

To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0+/-12.4 years, weight: 50.9+/-10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (-) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2+/-4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4+/-3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7+/-4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.     

Sirolimus use in recipients of expanded criteria donor kidneys

With changing donor characteristics and the growing shortage in organ supply, renal transplant practitioners have sought to optimize the use of expanded criteria donor (ECD) kidneys, which have poorer outcomes than standard criteria donor (SCD) kidneys. The outcomes may represent an acceptable trade-off if ECD transplants offer enhanced overall patient survival by reducing waiting times. ECD kidneys may be more susceptible to toxicity associated with calcineurin inhibitors (CNIs); therefore, a potential strategy to improve outcomes in this growing demographic is the use of CNI-free immunosuppressive protocols. To date, published clinical studies have demonstrated encouraging outcomes using sirolimus-based CNI-free regimens in SCD kidney transplant recipients. We conducted a pilot study to examine outcomes in ECD kidney transplant recipients receiving a CNI-free quadruple drug regimen, consisting of antithymocyte globulin (ATG), sirolimus, mycophenolate mofetil (MMF) and a corticosteroid, compared with outcomes in a retrospective CNI-control group of ECD recipients who had received standard CNI-based immunosuppressive treatment. Patient survival and allograft survival at 1 year were not significantly different between the CNI-free group (n = 13) and the CNI-control group (n = 13) [100% vs 92% and 92% vs 85%, respectively]; nor was the incidence of rejection (26% and 31%) or delayed graft function (38% of patients in both groups). Serum creatinine was significantly lower and the estimated glomerular filtration rate was significantly higher for the CNI-free group at 3-6 months but not at 1 year. Protocol biopsies in the CNI-free patients at 1 year revealed no significant progression of chronic vascular lesions. Banff chronic/sclerosing allograft nephropathy scores were 42% grade I, 25% grades II and III, and 33% grade 0. Thus, a sirolimus-based CNI-free regimen may improve outcomes in ECD kidney transplant recipients and merits further study.     

Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation

In the past decade, the availability of new immunosuppressive maintenance therapies for use in solid organ transplantation has remained limited. Patients and clinicians have relied on immunosuppressive drugs that require a significant amount of therapeutic monitoring and are associated with a variety of adverse effects that affect both quality of life and allograft function. Belatacept is an investigational intravenous biologic agent for long-term use in renal transplant recipients. The costimulatory pathway (signal 2) of T-cell activation and proliferation is produced by stimulation of the T-cell surface marker, CD28, and is essential to the immune system's cellular response and ability to recognize an allograft as foreign. Belatacept is a potent antagonist of B7-1 (CD80) and B7-2 (CD86) ligands present on antigen-presenting cells that are responsible for activation of CD28. Recent phase III trials describe various dosing strategies of belatacept versus a standard cyclosporine protocol in recipients of both living- and deceased-donor renal transplants, as well as in patients receiving kidneys transplanted from extended-criteria donors. Compared with cyclosporine, belatacept has been shown to be noninferior in both patient and allograft survival rates. However, the rate of biopsy-proven acute cellular rejection occurred more frequently in the belatacept groups. Also, compared with standard calcineurin-based regimens, the risk of posttransplant lymphoproliferative disorder is increased in patients receiving belatacept, with the greatest risk in transplant recipients who are Epstein-Barr virus seronegative before transplantation. However, this investigational immunosuppressive agent may avert common adverse effects experienced with standard immunosuppressive protocols including renal dysfunction, metabolic disorders, neurotoxicities, glucose abnormalities, and cosmetic effects. More data on the long-term risks of belatacept are needed to better define its role as immunosuppressive maintenance therapy. Aside from an increased risk of malignancy, belatacept's limited adverse-effect profile and convenient dosing strategy may make it an attractive option for immuno-suppressive maintenance for both the patient and clinician.     

Trough levels of mycophenolic acid and its glucuronidated metabolite in renal transplant recipients

OBJECTIVE: The prophylactic use of the immunosuppressant prodrug, mycophenolate mofetil (MMF) to prevent graft rejection in renal transplant patients is continuing to increase. We measured trough levels of the active metabolite, mycophenolic acid (MPA) and its inactive glucuronide (MPAG) in renal recipients with the aim of characterizing individual variability and of ascertaining factors influencing trough levels, in particular the effect of differences in renal function and the effect of drugs given concurrently. METHODS: Laboratory and clinical data obtained in 35 renal recipients treated with triple therapy (MMF, cyclosporin A (CsA), steroids) were included in this retrospective study. Trough levels of MPA and MPAG were obtained after transplantation and up to 16 months post transplantation where the mean observation period was 5.7 months. Plasma levels were measured using a validated HPLC assay. RESULTS: A total of 212 plasma concentrations of MPA and 209 of MPAG were measured. There was considerable intra- and interindividual variability in MPA and MPAG trough levels especially in the early post-transplantation phase. At a fixed dose of 2 g/d MMF, the mean MPA level during the first 30 days averaged 1.46 +/- 1.31 microg/ml vs. 1.87 +/- 0.89 microg/ml after 30 days and later (p = 0.130) and the mean MPAG concentration averaged 188.1 = 142.8 [microg/ml vs. 98.09 +/- 52.4 microlg/ml (p 0.003). The MPAG levels were positively correlated with the serum creatinine concentrations (r = 0.815, p < 0.001), and in the case of MPA there was a correlation with the serum protein concentrations (r = 0.258, p = 0.001). Concomitant drug treatment using CsA, steroids and furosemide were without effect of the measured plasma concentrations, but in the case of xipamide (+) and diltiazem (-) an effect on MPA and MPAG levels and a co-effect depending on the serum creatinine could not be excluded. Neither CsA trough levels nor hemoglobin levels were related to MPA and MPAG trough levels. CONCLUSIONS: The data of this study demonstrate that there is substantial individual variability in the trough levels of MPA and MPAG after renal transplantation which may be associated with the functional status of the graft and the serum protein level. Whether comedication with xipamide and diltiazem affects the plasma levels of MPA and MPAG remains to be clarified in further investigations.     

Adoptive transfer of CD4+CD25+ regulatory cells combined with low-dose sirolimus and anti-thymocyte globulin delays acute rejection of renal allografts in Cynomolgus monkeys

Although donor alloantigen specific Treg cells play an important role in transplant tolerance, therapeutic applications are limited by their low frequency. In this study, isolated Tregs from Cynomolgus monkeys were efficiently expanded by a co-culture system, and maintained suppressive function on the proliferation of CD4(+) effector cells in vitro. Adoptive transfer of expanded donor alloantigen specific Tregs without any immunosuppressants could prolong survival of MHC-mismatched allografts in Cynomolgus monkeys. To reach the feasibility of clinical transplantation, our objectives focused on whether exposure of monkey Tregs to immunosuppressants could preserve suppressive function in vitro and in vivo. The results showed that low-dose sirolimus selectively expanded Tregs, increased the expression of CD25(bright) and Foxp3 markers, and suppressed TCR- or allo-antigens induced CD4(+) T cell proliferation in vitro. In vivo, after pre-treated with anti-thymocyte globulin (ATG) for consecutive 3days, a 14-day therapy of adoptive infusion of donor alloantigen-specific Tregs combined with low-dose sirolimus delayed acute rejection of renal allografts in Cynomolgus monkeys, showing an MST of 48.5days as compared with those of untreated and sirolimus-treated monkeys (7days and 22days). The frequencies of CD4(+)CD25(bright) T cells were significantly elevated in mesenteric lymph nodes vs. those in inguino lymph nodes and peripheral blood. In summary, expanded donor alloantigen specific Tregs exposed to sirolimus can preserve inhibition in vitro and in vivo. Tregs are more resistant to sirolimus than other T cells. Expanded donor alloantigen specific Tregs combined with sirolimus and ATG prolongs renal allograft survival in monkeys, suggesting that sirolimus might be one of the best synergists for Tregs therapy.