Antibody induction therapy in adult kidney transplantation: A controversy continues

Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to reduce the incidence of acute rejection(AR) and graft loss from rejection. However, the choice of antibody remains controversial as the clinical studies were carried out on patients of different immunologic risk and in the context of varying maintenance regimens. Antibody selection should be guided by a comprehensive assessment of immunologic risk, patient comorbidities, financial burden as well as the maintenance immunosuppressives. Lymphocyte-depleting antibody(thymoglobulin, ATGAM or alemtuzumab) is usually recommended for those with high risk of rejection, although it increases the risk of infection and malignancy. For low risk patients, interleukin-2 receptor antibody(basiliximab or daclizumab) reduces the incidence of AR without much adverse effects, making its balance favorable in mostpatients. It should also be used in the high risk patients with other medical comorbidities that preclude usage of lymphocyte-depleting antibody safely. There are many patients with very low risk, who may be induced with intravenous steroids without any antibody, as long as combined potent immunosuppressives are kept as maintenance. In these patients, benefits with antibody induction may be too small to outweigh its adverse effects and financial cost. Rituximab can be used in desensitization protocols for ABO and/or HLA incompatible transplants. There are emerging data suggesting that alemtuzumab induction be more successful than other antibody for promoting less intensive maintenance protocols, such as steroid withdrawal, tacrolimus monotherapy or lower doses of tacrolimus and mycophenolic acid. However, the long-term efficacy and safety of these unconventional strategies remains unknown.     

Erbium:YAG fractional laser ablation for the percutaneous delivery of intact functional therapeutic antibodies

The physicochemical properties and stability requirements of therapeutic proteins necessitate their parenteral administration even for local therapy; however, unnecessary systemic exposure increases the risk of avoidable side-effects. The objective of this study was to use fractional laser ablation to enable the delivery of intact, functional therapeutic antibodies into the skin in vitro and in vivo. The laser-assisted delivery of Antithymocyte globulin (ATG) and Basiliximab - FDA-approved therapeutics for the induction of immunosuppression - was investigated. In vitro delivery experiments were performed using dermatomed porcine ear and human abdominal skins; an in vitro/in vivo correlation was shown using C57 BL/10 SCSnJ mice. Antibody transport was quantified by using ELISA methods developed in-house. Results showed that increasing the pore number from 300 to 450 and 900, increased total antibody delivery (sum of amounts permeated and deposited); e.g., for ATG, from 1.18 ± 0.10 to 3.98 ± 0.64 and 4.97 ± 0.83 μg/cm², respectively — corresponding to 19.7-, 66.3- and 82.8-fold increases over the control (untreated skin). Increasing laser fluence from 22.65 to 45.3 and 135.9 J/cm² increased total ATG delivery from 1.70 ± 0.65 to 4.97 ± 0.83 and 8.70 ± 1.55 μg/cm², respectively. The Basiliximab results confirmed the findings with ATG. Western blot demonstrated antibody identity and integrity post-delivery; human lymphocyte cytotoxicity assays showed that ATG retained biological activity post-delivery. Immunohistochemical staining was used to visualize ATG distribution in the epidermis. Total ATG delivery across porcine ear and human abdominal skin was statistically equivalent and an excellent in vitro/in vivo correlation was observed in the murine model. Based on published data, the ATG concentrations achieved in the laser-porated human skins were in the therapeutic range for providing local immunosuppression. These results challenge the perceived limitations of transdermal delivery with respect to biopharmaceuticals and suggest that controlled laser microporation provides a less invasive, more patient-friendly “needle-less” alternative to parenteral administration for the local delivery of therapeutic antibodies.     

肾移植后采用巴利昔单抗诱导治疗时的感染及预防

目的 探讨肾移植后采用巴利昔单抗诱导治疗时的感染发生情况以及采取感染预防措施的效果.方法 回顾分析2001年1月至2010年12月间肾移植后接受巴利昔单抗诱导治疗者的资料,共有204例患者人选,其中118例采取感染预防措施(预防组),余下86例未行感染预防(对照组).同期440例未接受巴利昔单抗以及其他抗体类制剂的肾移植受者,其中234例未采取感染预防措施(无诱导对照组),206例采取了感染预防措施(无诱导预防组).诱导治疗方案为移植术前2 h和术后第4天各滴注巴利昔单抗20mg,感染预防方案为更昔洛韦+联磺甲氧苄啶.分析感染并发症与抗体治疗的关系以及预防感染的效果.结果 204例应用巴利昔单抗诱导治疗者中,预防组23例(19.5%,23/118)因感染需住院治疗,其中重症病例3例(13.0%,3/23),因感染死亡3例(13.0%,3/23);对照组为27例(31.4%,27/86)因感染需住院治疗,其中重症病例7例(25.9%,7/27),因感染死亡4例(14.8%,4/27);预防组和对照组感染发生率的差异有统计学意义(P＜0.05),两组间重症感染率的差异有统计学意义(P＜0.05),而死亡率的差异无统计学意义(P＞0.05).同期肾移植后未行抗体诱导治疗440例,无诱导预防组感染发生率为15.0%(31/206),无重症病例,因感染死亡7例(22.6%,7/31);无诱导对照组感染发生率为12.8%(30/234),其中重症病例3例(10.0%,3/30),因感染死亡5例(16.7%,5/30).在未采取感染预防措施的情况下,采用抗体诱导治疗者的感染发生率(31.4%)明显高于无诱导者(12.8%),差异有统计学意义(P＜0.01).结论 肾移植后应用巴利昔单抗诱导治疗存在感染风险,但不增加死亡率;联合采取感染预防措施可以降低感染发生率和重症感染率,能有效预防感染并发症.

Abstract：

Objective To investigate the incidence of infection and the effect of anti-infection prophylaxis in renal transplanted patients after Basiliximab induction therapy. Methods A total of 204patients who have received renal transplantation and Basiliximab induction therapy from January 1,2001 to December 31, 2010 in our hospital have been retrospective analysed in this study. These patients were divided into a prophylaxis group (118 cases) with Ganciclovir + Sulfadiazine +Trimethoprim therapy and a control group (86 cases) without any anti-infection prophylaxis.Furthermore, 440 transplanted patients in the same peroid without any induction therapy were also analysed. They were also devided into two groups: an anti-infection prophylaxis group (206 cases)and a control group (234 cases) without any anti-infection prophylaxis. Results In the prophylaxis group with Basiliximab induction therapy, there were 23 patients (19. 5 %, 23/118)experienced hospitalization due to infection, 3 cases (13. 0 %,3/23) among them were severe infection, and 3patients (13.0 %, 3/23) died from vital infection. In the non-prophylaxis control group with Basiliximab induction therapy, 27 patients (31.4 %, 27/86) had infection complication, 7 patients (25.9 % ,7/27) among them were severe infection, and 4 patients(14. 8 % ,4/27)died. The incidence of infection between the above two groups is significantly different (P＜0. 05). In the prophylaxis group without induction therapy, the incidence of infection was 15.0 % (31/206), there were no severe infection cases but 7 patients (22. 6 %, 7/31) died from infection. In the non-prophylaxis control group without induction therapy, the incidence of infection was 12. 8 % (30/234), 3 cases among them were severe infection(10. 0 %,3/30)and 5 patients died from infection (16. 7 %, 5/30).The incidence of infection in Basiliximab induced patients without anti-infection prophylaxis is significantly higher than that in patients without induction therapy and anti-infection prophylaxis (31.4 % vs. 12.8 %,P＜0.01). Conclusion Basiliximab induction therapy increased the risk of infection, but not the rate of mortality. It is necessary to give anti-infection prophylaxis in renal transplanted patients with Basiliximab induction therapy.     

巴利昔单抗联合三联免疫抑制方案预防心脏移植后急性排斥反应

目的 评价巴利昔单抗联合常规三联免疫抑制方案预防心脏移植后排斥反应的临床效果及安全性.方法 2004年6月至2011年1月接受心脏移植的受者共214例.所有受者均在术前1h和术后4d时各应用1次巴利昔单抗,剂量为20 mg/次,三联免疫抑制方案为环孢素A(CsA)+吗替麦考酚酯(MMF)+皮质激素.术后采用心内膜活检诊断排斥反应,并按照国际心肺移植协会(ISHLT)的分级标准评价急性排斥反应的严重程度.术后对受者随访1年,收集心内膜活检及发生排斥反应的资料,观察术后并发症的发生情况及死亡情况.结果 受者接受心内膜活检的时间为术后(20.1±7.3) d(1～60 d),结果显示,Ⅰa 级63例(29.4％),Ⅰb 级8例(3.7％),Ⅱ级12例(5.6％);术后1年,143例受者接受心内膜活检,结果显示,Ⅰa 级29例(20.3％),Ⅰb 级1例(0.7％)及Ⅱ级11例(7.7％).住院期间,共有5例受者死亡,死亡原因包括移植心脏功能衰竭3例,多器官功能衰竭1例及猝死1例;出院后至术后1年内,有2例受者死亡,死亡原因包括严重排斥反应1例和多器官功能衰竭1例.术后1个月内,发生感染7例(3.3％),发生急性肾功能不全11例(5.1％),无受者发生肝功能衰竭.结论 应用巴利昔单抗联合常规三联免疫抑制方案是预防心脏移植术后早期急性排斥反应安全、有效的方式.     

A Prospective, Randomized, Multicenter Trial of Tacrolimus-Based Therapy with or without Basiliximab in Pediatric Renal Transplantation

In a 6-month, multicenter, randomized, controlled, open-label, parallel-group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus-based regimen in pediatric renal transplant recipients. Patients < 18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10-20 ng/mL between days 0-21 and 5-15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients < 40 kg) or 20 mg (patients > or = 40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy-proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid-resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 micromol/L in the TAS and 91 micromol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus-based regimen is safe in pediatric patients, but does not improve clinical efficacy.     

Remission of refractory minimal change nephrotic syndrome after basiliximab therapy

Minimal change nephrotic syndrome has been proposed to be a disorder of T cell dysfunction. It is hypothesized that a circulating factor(s) from activated T cells might alter glomerular permeability to protein. Some studies have provided evidence that up-regulation of interleukin-2 may be involved, not only in the pathophysiology of minimal change nephrotic syndrome, but also in steroid resistance. Basiliximab, an anti-interleukin-2 receptor antibody, is indicated for the prophylaxis of acute organ rejection in adults and children with kidney transplants. Clinical trials have shown that basiliximab is effective and well tolerated. We describe here a pediatric patient who continuously had massive proteinuria and hypoalbuminemia for 5 years, despite pulse therapy with methylprednisolone and cyclophosphamide and prolonged oral treatment with cyclosporine and mizoribine. He had experienced several disease- and treatment-associated complications, such as bacterial infections, indirect inguinal hernias, and cataracts. After he had been given a single dose of basiliximab, he achieved complete remission of proteinuria and then discontinued all immunosuppressant treatment.     

Basiliximab en el tratamiento del rechazo celular agudo resistente a los corticoides postrasplante hepático

We present the case of a liver transplant recipient with alcoholic liver cirrhosis and early-stage hepatocellular carcinoma who developed biopsy-proven acute steroid-resistant rejection 3 months after liver transplantation. After the failure of immunosuppressive therapy with intravenous boluses of 6-methyl-prednisolone and switching of the immunosuppressive regimen to tacrolimus plus mycophenolate mofetil, two doses of intravenous basiliximab were administered four days apart. Clinical, analytical, and biopsy-proven histological response was complete. No basiliximab-related adverse events were detected. Basiliximab may represent an alternative in liver transplantation immunosuppression to treat acute steroid-resistant rejection, without increasing the incidence of infections, neoplasms, or other adverse events, as shown by this case.     

Interleukin-2 receptor antagonists and aggressive steroid minimization strategies for kidney transplant patients

Steroid withdrawal during the first week after transplantation surgery, or complete avoidance of steroids, offers potential benefits. The interleukin-2 (IL-2) receptor antibodies, basiliximab and daclizumab, can enable aggressive steroid minimization protocols that are efficacious while reducing toxicity. A multicenter, randomized trial of kidney transplant recipients has shown the incidence of biopsy-proven acute rejection with basiliximab, cyclosporine and mycophenolate mofetil with steroids withdrawn at day 5 to be similar to a conventional triple-therapy regimen. A single perioperative dose of corticosteroids with an IL-2 receptor antagonist also seems as efficacious as standard steroid therapy. Corticosteroid-minimization with IL-2 receptor antagonists has also been investigated with sirolimus-containing regimens and has shown excellent outcomes. Experience with complete steroid avoidance, using an IL-2 receptor antagonist, is limited, but initial results are promising, particularly in pediatric patients. Administration of an IL-2 receptor antagonist with aggressive steroid minimization in selected, well-monitored patients seems reasonable, but further trials are required to define optimal protocols.     

Basiliximab induction therapy for live donor kidney transplantation: a long-term follow-up of prospective randomized controlled study

Background/Aims  The effect of basiliximab induction therapy on long-term patient and graft survival is not yet clear. We aimed to evaluate if there is any advantage of routine basiliximab induction on the long-term outcome of living related donor kidney transplantation. Methods  One hundred adult recipients with their first kidney allograft were randomized into two treatment groups, one group received basiliximab and the second served as a control. All patients received a maintenance triple immunosuppressive therapy (steroids, cyclosporine (CsA) micro-emulsion and azathioprinep) and were followed up thoroughly for 7 years. Results  Basiliximab significantly reduced the proportion of patients who experienced acute rejection in the first year (18/50) when compared to the control group (31/50), and in 7 years (28/50) when compared to (37/50) in controls. The cumulative steroid dose used throughout the whole study period was significantly lower in the basiliximab group. The overall incidence of post-transplant complications was comparable among the two treatment groups. There was no significant difference in patient or graft survival; 7 years patient and graft survival were 92, 76% for basiliximab and 92, 80% for the control group, respectively. Conclusion  Routine basiliximab induction significantly reduced the incidence of acute rejection without any noticeble beneficial effect on the long-term renal transplantation outcome.     

Prospective controlled protocol for three months steroid withdrawal with tacrolimus, basiliximab, and mycophenolate mofetil in renal transplant recipients

During the past few years, new immunosuppressants, such as tacrolimus, mycophenolate mofetil (MMF) and basiliximab, have been shown to successfully decrease the incidence of acute rejection, possibly acting as potent substrates for safe steroid withdrawal. Therefore, clinical outcome of 3 months steroid withdrawal, while using the above immunosuppressants, was analyzed. Clinical trial registry No. was NCT 01550445. Thirty de novo renal transplant recipients were enrolled, and prednisolone was slowly withdrawn 3 months post-transplantation by 2.5 mg at every two weeks, until 8 weeks. During steroid withdrawal, 10 patients (30.0%) discontinued the protocol and they were maintained on steroid treatment. Among 20 steroid free patients, 8 patients (40.0%) re-started the steroid within 12 months post-transplantation. By the study endpoint, 12 (40%) recipients did not take steroid and survival of patients and grafts was 100%. In conclusion, in kidney transplant patients, 3 months steroid withdrawal while taking tacrolimus, basiliximab and mycophenolate mofetil was not associated with increased mortality or graft loss. Despite various causes of failure of steroid withdrawal during the follow-up period, it is a strategy well advised for kidney transplant recipients with regard to long-term steroid-related complications.