Review of the proliferation inhibitor everolimus

Everolimus (Certican^?) is being developed for prevention of acute and chronic rejection of solid organ transplants. A novel proliferation inhibitor, everolimus synergies with cyclosporine to prevent and reverse acute rejection in preclinical models of kidney, heart or lung transplantation. The manifestations of chronic rejection that may contribute to graft loss are also inhibited by everolimus in preclinical models. Although everolimus is metabolised by the cytochrome P450 CYP3A isoenzyme, coadministration with cyclosporine does not alter the pharmacokinetics of cyclosporine, but cyclosporine coadministration increases exposure to everolimus. Everolimus interacts with inhibitors and inducers of this system; its clearance is reduced in patients with hepatic impairment. In an immunosuppressive regimen with cyclosporine microemulsion formulation and corticosteroids, transplant recipients treated with everolimus show low rates of acute rejection and, in one heart and one renal trial, lower rates of cytomegalovirus infection. Acute rejection rates are lower than those seen with azathioprine in cardiac transplant recipients and similar to those seen with mycophenolate mofetil in renal transplant recipients. Low rates of acute rejection are maintained when everolimus is given as part of a quadruple immunosuppressive regimen with low-dose cyclosporine in renal transplant recipients, with the added benefit of better renal function compared with full-dose cyclosporine. Use of C₂ monitoring to optimise cyclosporine exposure and enhance efficacy and safety of everolimus is planned in future studies. Hypertriglyceridaemia and hypercholesterolaemia have been associated with everolimus, but these effects are not dose-limiting. There is no clear upper therapeutic limit of everolimus. However, thrombocytopenia occurs at a rate of 17% at everolimus trough serum concentrations above 7.8 ng/ml in renal transplant recipients. There are limited safety data available in patients with trough concentrations > 12 ng/ml. Studies suggest everolimus targets primary causes of chronic rejection by reducing acute rejection, allowing for cyclosporine dose reduction (which may lead to improved renal function relative to full-dose cyclosporine) and by reducing cytomegalovirus infection and inhibiting vascular remodelling.     

Review of the proliferation inhibitor everolimus

Everolimus (Certican) is being developed for prevention of acute and chronic rejection of solid organ transplants. A novel proliferation inhibitor, everolimus synergies with cyclosporine to prevent and reverse acute rejection in preclinical models of kidney, heart or lung transplantation. The manifestations of chronic rejection that may contribute to graft loss are also inhibited by everolimus in preclinical models. Although everolimus is metabolised by the cytochrome P450 CYP3A isoenzyme, coadministration with cyclosporine does not alter the pharmacokinetics of cyclosporine, but cyclosporine coadministration increases exposure to everolimus. Everolimus interacts with inhibitors and inducers of this system; its clearance is reduced in patients with hepatic impairment. In an immunosuppressive regimen with cyclosporine microemulsion formulation and corticosteroids, transplant recipients treated with everolimus show low rates of acute rejection and, in one heart and one renal trial, lower rates of cytomegalovirus infection. Acute rejection rates are lower than those seen with azathioprine in cardiac transplant recipients and similar to those seen with mycophenolate mofetil in renal transplant recipients. Low rates of acute rejection are maintained when everolimus is given as part of a quadruple immunosuppressive regimen with low-dose cyclosporine in renal transplant recipients, with the added benefit of better renal function compared with full-dose cyclosporine. Use of C(2) monitoring to optimise cyclosporine exposure and enhance efficacy and safety of everolimus is planned in future studies. Hypertriglyceridaemia and hypercholesterolaemia have been associated with everolimus, but these effects are not dose-limiting. There is no clear upper therapeutic limit of everolimus. However, thrombocytopenia occurs at a rate of 17% at everolimus trough serum concentrations above 7.8 ng/ml in renal transplant recipients. There are limited safety data available in patients with trough concentrations > 12 ng/ml. Studies suggest everolimus targets primary causes of chronic rejection by reducing acute rejection, allowing for cyclosporine dose reduction (which may lead to improved renal function relative to full-dose cyclosporine) and by reducing cytomegalovirus infection and inhibiting vascular remodelling.     

Everolimus: a review of its use in renal and cardiac transplantation

Everolimus (Certican) is an orally administered mammalian target of rapamycin inhibitor (proliferation signal inhibitor) derived from sirolimus (rapamycin), which is used as part of immunosuppressant therapy in kidney and heart transplantation. When evaluated as part of triple therapy with ciclosporin and corticosteroids, everolimus showed equivalent efficacy to mycophenolate mofetil after renal transplantation, and superiority to azathioprine in cardiac transplant recipients, in terms of reducing efficacy failure after transplantation. Everolimus potentiates ciclosporin-associated nephrotoxicity, and it is recommended that concentration-controlled everolimus is used with reduced-dosage ciclosporin in order to limit renal toxicity while retaining immunosuppressive efficacy. Ongoing trials with everolimus, such as the evaluation of ciclosporin-withdrawal strategies, should help clarify its optimal usage. The use of everolimus may be associated with reduced rates of cytomegalovirus (CMV) infection and of cardiac allograft vasculopathy. Available data suggest that everolimus may be cost-neutral for healthcare providers.     

Everolimus: an immunosuppressive agent in transplantation

Everolimus is a novel immunosuppressive agent related to sirolimus. It is a proliferation signal inhibitor with an improved pharmacokinetic profile and bioavailability compared with sirolimus. Everolimus has been shown to be as effective as mycophenolate mofetil in reducing acute rejection in renal transplantation. In cardiac transplant recipients, it is superior to azathioprine in reducing acute rejection and cardiac allograft vasculopathy. Its use is also associated with a decrease in cytomegalovirus infection. However, coadministration with calcineurin inhibitors requires careful dose adjustment to prevent renal toxicity. Antiproliferative effects of everolimus may abrogate the increased risk of malignancy seen in solid organ transplantation.     

Everolimus: an immunosuppressive agent in transplantation

Everolimus is a novel immunosuppressive agent related to sirolimus. It is a proliferation signal inhibitor with an improved pharmacokinetic profile and bioavailability compared with sirolimus. Everolimus has been shown to be as effective as mycophenolate mofetil in reducing acute rejection in renal transplantation. In cardiac transplant recipients, it is superior to azathioprine in reducing acute rejection and cardiac allograft vasculopathy. Its use is also associated with a decrease in cytomegalovirus infection. However, coadministration with calcineurin inhibitors requires careful dose adjustment to prevent renal toxicity. Antiproliferative effects of everolimus may abrogate the increased risk of malignancy seen in solid organ transplantation.     

Everolimus

Everolimus is an immunosuppressant that blocks growth factor-mediated proliferation of haematopoietic and nonhaematopoietic cells. Oral everolimus 0.75 or 1.5mg twice daily significantly reduced the incidence of the primary composite endpoint, efficacy failure 6 months after transplantation, compared with azathioprine 1-3 mg/kg/day, in adult cardiac transplant recipients. All patients also received baseline immunosuppression with cyclosporin and corticosteroids. The incidence of efficacy failure remained significantly lower in everolimus recipients than in those receiving azathioprine 1 and 2 years after cardiac transplantation. However, graft and patient survival rates at 1 year were similar in patients receiving everolimus or azathioprine. The incidence of graft vasculopathy 2 years after transplantation was significantly lower in cardiac transplant recipients receiving everolimus 0.75 mg twice daily than in those receiving azathioprine. The combined incidence of biopsy-confirmed acute rejection, graft loss, death, or loss to follow-up was similar in adult patients receiving everolimus 1.5 or 3 mg/day or mycophenolate mofetil (MMF) 2 g/day 1 or 3 years after renal transplantation. Patients also received baseline immunosuppression with cyclosporin and corticosteroids. Compared with azathioprine and MMF, everolimus is associated with a lower incidence of cytomegalovirus infection in cardiac and renal transplant recipients. Everolimus has been associated with thrombocytopenia, leucopenia and elevated serum lipids and creatinine.     

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.     

Is everolimus useful in preventing allograft rejection and vasculopathy after heart transplant?

The main cause of illness and death after the first year of heart transplantation is vasculopathy of the cardiac allograft, probably initiated by early immunological and non-immunological endothelial damage. The incidence of multiple episodes of grade 3A rejection 6 months after primary heart transplantation was lower with everolimus (1.5 mg, 8.1% and 3 mg, 6.6%) than in the azathioprine group (14%). Allograft vasculopathy was less frequent with everolimus than azathioprine. A follow-up study is necessary to determine whether these effects translate into the important end points of reduced incidences of death, graft loss or a second transplantation.     

Early clinical experience with a novel rapamycin derivative.

SDZ RAD (everolimus, Certican is a novel macrolide immunosuppressant that blocks growth factor-driven transduction signals in the T-cell response to alloantigen. After stimulation of the IL-2 receptor on the activated T-cell, SDZ RAD inhibits p70S6 kinase, acting at a later stage in the T-cell mediated response than do cyclosporine and other calcineurin inhibitors (CNIs). Unlike the CNIs, SDZ RAD is a proliferation signal inhibitor, blocking growth factor-driven proliferation of both hematopoietic and nonhematopoietic cells. These activities are complementary to those of cyclosporine and provide a rationale for the addition of SDZ RAD to cyclosporine-based immunosuppression, with the potential for minimizing CNI nephrotoxicity, reducing the incidence of acute rejection, and favoring long-term graft survival. Potential also exists for beneficial effects on other factors that may influence the development of chronic rejection. These factors include comorbid diseases such as hypertension, which may affect transplant vasculopathy, and opportunistic infection with cytomegalovirus (CMV) and other viruses, which may increase the risk of chronic rejection. The synergistic effect of SDZ RAD and cyclosporine has been confirmed in preclinical models, with graft survival being significantly prolonged in rat models of kidney and heart allotransplantation. Clinical experience with SDZ RAD in cyclosporine-based immunosuppression, including low-dose cyclosporine regimens, has also resulted in predictable and favorable clinical outcomes. Low rates of acute rejection, excellent rates of patient and graft survival, lower incidence of CMV infections, better cholesterol, triglyceride and creatinine profiles, and better renal function have been demonstrated with SDZ RAD and lower doses of cyclosporine (Neoral; Novartis) in recipients of renal transplants. These findings, combined with good tolerability rates and an acceptable side-effect profile, indicate that the synergistic profile of SDZ RAD in combination with nontoxic dosages of CNI's and IL2 inhibitors will further improve longterm results in renal transplantation.     

免疫抑制剂在心脏移植中的应用现状

硫唑嘌呤＋环孢素A＋泼尼松是原位心脏移植术后免疫抑制治疗的经典方案。随着新抗增殖因子及新的免疫诱导因子的出现，新的治疗方法也为治疗提供了新的选择。目前在免疫抑制治疗中被广泛关注的问题包括：急性排斥反应、心脏移植物血管病变的预防以及血管排斥的治疗。如何保护肾功能、延缓心脏移植物血管病变的发展、降低机会性感染等并发症的发生仍然是免疫抑制治疗所面临的挑战。     

The role of therapeutic monitoring of everolimus in solid organ transplantation

Everolimus is a novel proliferation signal inhibitor used in immunosuppressive therapies for the prevention of acute and chronic rejection. A role for everolimus drug monitoring has been suggested because of the potential for improving efficacy and reducing adverse effects. Everolimus has proven efficacy for prevention of rejection in adult de novo renal and cardiac transplant recipients. Similar effects have been shown in pediatric renal transplant patients. Several analytic methods are available to quantify everolimus concentrations. A good relationship exists between everolimus concentration and pharmacological response. Mere clinical monitoring of efficacy is insufficient because clinical presentations of graft rejection vary for each patient and are nonspecific. Thus, the authors have used a previously published 9-step decision-making algorithm to evaluate the utility of therapeutic drug monitoring for everolimus. The recommended therapeutic range for everolimus is a trough concentration of 3 to 8 ng/mL, as concentrations over 3 ng/mL have been associated with a decreased incidence of rejection, and concentrations >8 ng/mL with increased toxicity. Everolimus exhibits interindividual pharmacokinetic variability. African American patients have higher apparent clearance, whereas patients with hepatic dysfunction or those on concomitant medications with potent cytochrome P450 (CYP) 3A4 inhibitor or inducer properties have lower or higher apparent clearance, respectively. Solid organ transplant recipients will likely be maintained on immunosuppressant therapy for the life of the graft and/or recipient and thus are likely to benefit from clinical pharmacokinetic monitoring. Based on the available evidence, therapeutic drug monitoring for everolimus may provide additional information on efficacy and safety than sound clinical judgment alone. Patients on everolimus who have problems with absorption, who take concurrent cytochrome P450 inhibitors or inducers, or are noncompliant will attain the greatest benefit from drug monitoring.     

5­year follow-up of a randomized clinical study comparing everolimus plus reduced-dose cyclosporine with mycophenolate mofetil plus standard-dose cyclosporine in de novo kidney transplantation: Retrospective single center assessment

The aim of this study is to evaluate the efficacy and safety of everolimus plus reduced­dose cyclosporine compared with mycophenolate mofetil plus standard­dose cyclosporine 5 years after living donor kidney transplantation.Between March 2008 and August 2009, 24 living donor kidney transplantations were enrolled in a 2-year, multicenter, randomized phase 3 study (RAD001A1202 study). 24 recipients were randomly classified into two groups and closely observed for 5 years. 13 recipients were administered steroid, reduced­dose cyclosporine, everolimus and basiliximab (EVR group). 11 recipients were administered steroid, standard-dose cyclosporine, mycophenolate mofetil and basiliximab (STD group). Two groups were compared not only in graft function including estimated glomerular filtration rate (eGFR), and proteinuria, but also in adverse events such as de novo donor-specific antibody (DSA) production, rejection, new­onset diabetes, hyperlipidemia, and cytomegalovirus (CMV) infection.No graft loss was identified in 5 years. The incidences of acute T cell rejection, de novo DSA production, hyperlipidemia, and new­onset diabetes were similar. eGFR levels throughout the observation periods were similar. Three cases of proteinuria were identified in STD group. One case of proteinuria observed in EVR group was well controlled with angiotensin receptor blocker. Incidence of CMV infection in CMV antibody­positive recipients was significantly lower in EVR group.The safety and efficacy of reduced­dose cyclosporine and everolimus protocol were similar to those of standard­dose cyclosporine and mycophenolate mofetil other than for superior prevention of CMV infection.     

Immunosuppression for long-term maintenance of renal allograft function

The incidence and severity of acute rejection episodes was markedly reduced by the introduction of new immunosuppressive drug regimens for renal transplantation, resulting in improved graft survival at 1 year. However, only modest improvement has been shown in long-term graft function rates.This overview evaluates the efficacy of currently used immunosuppressive drugs and drug combinations for long-term maintenance therapy. Prospective controlled trials rarely extend beyond 5 years; therefore, registry data and retrospective reports have also been employed. From currently available data it may be concluded that the initial beneficial effect of ciclosporin (cyclosporin) is lost 10 years after transplantation. Tacrolimus is an alternative to ciclosporin with a different profile of adverse effects and a higher efficacy in acute rejection treatment. For long-term maintenance, projected half-lives of kidney graft function are in favour of tacrolimus. Mycophenolate mofetil (MMF) has been shown to significantly reduce the incidence of early rejections. However, the improved long-term graft survival reported in retrospective studies has still to be confirmed in controlled trials. There is no convincing evidence for superiority of triple therapy including prednisone (or prednisolone), calcineurin inhibitors and azathioprine/MMF over dual therapy without azathioprine/MMF with respect to long-term outcome. Withdrawal of corticosteroids or calcineurin inhibitors clearly reduces adverse drug effects but carries the risk of acute rejection episodes. Avoidance of corticosteroids by using new immunosuppressive drug combinations may be an option to minimise toxic adverse effects in the future.At present, it seems unjustified to convert renal transplant recipients with stable graft function and tolerable adverse effects from one drug to another solely in expectation of future benefits. Acute early or late rejection episodes and intolerable adverse effects are good reasons for conversions between calcineurin inhibitors or cytotoxic agents. Chronic allograft nephropathy with slowly deteriorating graft function remains an unresolved problem.     

他克莫司和环孢素对无症状乙肝表面抗原阳性者肾移植预后的影响

目的：比较尿毒症病人中无症状乙肝表面抗原（HBsAg）阳性者肾移植术后应用环孢素和他克莫司的疗效及安全性。方法：84例无症状HbsAg阳性者肾移植术后分别应用环孢素＋麦考酚吗乙酯＋泼尼松（43例）和他克莫司＋麦考酚吗乙酯＋泼尼松（41例）,对比观察肾移植后一年内两组的排斥反应发生率及逆转率、药物的毒副作用及移植术后感染发生率。结果：他克莫司组和环孢素组的人/肾存活率分别为100%/100%和95.3%/100.0%;急性排斥反应发生率分别为4.9%和20.9%（P〈0.05）;抗排斥的逆转率均为100%。两组的毒副作用比较,他克莫司组肝功能损害、高血压和高脂血症的发生率（9.8%、12.8%和9.8%）显著低于环孢素组（27.9%、30.2%和27.9%,P〈0.05）,但术后糖尿病的发生率却高于环孢素组（19.5%vs4.6%,P〈0.05）。两组在术后感染的发生率方面未见显著性差异。结论：对尿毒症病人中HBsAg阳性者,肾移植术后应用他克莫司＋麦考酚吗乙酯＋泼尼松的疗效及安全性均优于环孢素＋麦考酚吗乙酯＋泼尼松。     

Cardiac allograft vasculopathy: the green lane hospital experience 1987-1998

AIMS: To determine the prevalence of cardiac allograft vasculopathy in heart transplant recipients at Green Lane Hospital and to examine potential risk factors for vasculopathy. METHODS: We retrospectively reviewed the coronary angiograms of all cardiac transplant recipients. Angiography was usually performed one, two and five years after operation. The diagnosis of allograft vasculopathy was made if there was any evidence of coronary artery disease. Patients' medical records were reviewed for potential risk factors. RESULTS: Ninety-one patients underwent cardiac transplantation between December 1987 and March 1998. One year survival was 87%. Angiographic evidence of coronary disease was present in 30 patients and in three patients coronary lesions were first identified at post mortem. Vasculopathy was present in 25%, 35% and 61% of patients at one two and five years following transplant. Donor-acquired lesions could not be excluded as few patients had immediate postoperative angiograms for comparison. Five late deaths have been due to vasculopathy. Recipient age, race, donor age and ischaemic time were similar for those with and without vasculopathy. Frequency or severity of acute rejection episodes, cytomegalovirus infection, lipid profiles, diabetes and hypertension were not significantly different in patients with vasculopathy. CONCLUSION: Cardiac allograft vasculopathy is a common finding after heart transplantation. No definite risk factors were identified in this patient group.     

Immunosuppressive therapy in older cardiac transplant patients

Cardiac transplantation has become an established intervention for end-stage heart disease. Clinical outcomes in older cardiac transplant patients have improved over the last decade and are almost similar to those in younger patients. Nevertheless, morbidity and mortality due to infections, cancer and chronic allograft vasculopathy remain problematic. On the other hand, older transplant patients seem to have lower incidences of acute rejection episodes than younger patients. Conventional immunosuppression with calcineurin-inhibiting drugs, azathioprine and corticosteroids is responsible for a number of adverse effects. Although these adverse effects can also be seen in younger patients, tolerance to these agents seems to decrease with increasing age. In particular, diabetes mellitus, osteoporosis and chronic renal insufficiency are associated with higher morbidity and mortality in older cardiac transplant patients. As the elderly become an ever-increasing segment of the cardiac transplant population, new and innovative immunosuppressive strategies will have to be developed and applied.Currently, the availability of new immunosuppressive drugs means more individualised immunosuppressive protocols can be used. New antibodies for induction therapy, a choice between ciclosporin and tacrolimus, and the advent of mycophenolate mofetil as well as proliferation signal inhibitors (everolimus, sirolimus) have changed immunosuppressive protocols dramatically. Therefore, a generalised protocol for all patients has been replaced by individualised immunosuppression depending on the patient group. Moreover, protocols can be modified during follow-up depending on the individual patient's requirements and problems. Hypertension and hyperlipidaemia could be influenced by the selection of tacrolimus over ciclosporin, and weaning of corticosteroids might have a positive impact on osteoporosis or diabetes. There is also no clear evidence that tacrolimus is associated with a higher risk for new onset of diabetes. Chronic renal insufficiency can be managed with calcineurin inhibitor-free immunosuppression consisting of mycophenolate mofetil and proliferation signal inhibitors. Both everolimus and sirolimus also seem to have a protective effect against the onset of graft vasculopathy and some sorts of cancer after cardiac transplantation. As a general rule, however, older cardiac transplant patients should be treated with lower doses and fewer immunosuppressive drugs to avoid over-immunosuppression.     

Tolerance-inducing immunosuppressive strategies in clinical transplantation: an overview

The significant development of immunosuppressive drug therapies within the past 20 years has had a major impact on the outcome of clinical solid organ transplantation, mainly by decreasing the incidence of acute rejection episodes and improving short-term patient and graft survival. However, long-term results remain relatively disappointing because of chronic allograft dysfunction and patient morbidity or mortality, which is often related to the adverse effects of immunosuppressive treatment. Thus, the induction of specific immunological tolerance of the recipient towards the allograft remains an important objective in transplantation. In this article, we first briefly describe the mechanisms of allograft rejection and immune tolerance. We then review in detail current tolerogenic strategies that could promote central or peripheral tolerance, highlighting the promises as well as the remaining challenges in clinical transplantation. The induction of haematopoietic mixed chimerism could be an approach to induce robust central tolerance, and we describe recent encouraging reports of end-stage kidney disease patients, without concomitant malignancy, who have undergone combined bone marrow and kidney transplantation. We discuss current studies suggesting that, while promoting peripheral transplantation tolerance in preclinical models, induction protocols based on lymphocyte depletion (polyclonal antithymocyte globulins, alemtuzumab) or co-stimulatory blockade (belatacept) should, at the current stage, be considered more as drug-minimization rather than tolerance-inducing strategies. Thus, a better understanding of the mechanisms that promote peripheral tolerance has led to newer approaches and the investigation of individualized donor-specific cellular therapies based on manipulated recipient regulatory T cells.     

Everolimus: efficacy and safety in cardiac transplantation

Importance of the field: Prognosis after cardiac transplantation continues to improve with long-term outcomes limited by malignancy and coronary allograft vasculopathy (CAV). Everolimus may potentially reduce these late term complications, while maintaining the low cellular rejection rates seen with standard therapy.

Areas covered in this review: Multiple studies have demonstrated the efficacy of everolimus in reducing acute rejection in heart transplant patients, progression and development of CAV, and the prevention and treatment of common malignancies, including skin cancer and Kaposi sarcoma. This review re-examines these studies with a focus on patient tolerability and safety.

What the reader will gain: Tolerability and safety of everolimus remain a concern with pneumonitis, effusions, mouth ulcers, edema and impaired wound healing associated with morbidity and mortality. Studies have repeatedly demonstrated renal function deterioration with concomitant everolimus and a standard dose calcineurin inhibitor (CNI). This impact can be partly reduced with CNI dose reduction without an increase in the rate of rejection.

Take home message: If future studies confirm reduced CAV and malignancy rates, everolimus will become an important agent in de novo and maintenance immunotherapy in cardiac transplantation. Patient centered immunotherapy is preferred to protocol-based immunotherapy as it allows tailoring of immune therapy to each individual patient's rejection risk and side profile.     

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。     

Calcineurin inhibitor-free immunosuppression in pediatric renal transplantation: a viable option?

The introduction, in the mid-1980s, of calcineurin inhibitors - namely ciclosporin (cyclosporine) and later tacrolimus - has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity. To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10-20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimus for calcineurin inhibitor-free immunosuppression in the pediatric kidney transplant patient population are lacking. At present, the safest therapeutic strategy for pediatric renal allograft recipients with chronic calcineurin inhibitor-induced nephrotoxicity appears to be a mycophenolate mofetil-based regimen with low-dose calcineurin inhibitor therapy and corticosteroids; available published data show that dual immunosuppression with mycophenolate mofetil and corticosteroids, as well as an mTOR inhibitor plus mycophenolate mofetil plus corticosteroid-based regimens, are associated with an increased risk of acute rejection episodes. In individual patients with evidenced chronic allograft dysfunction and over-immunosuppression leading to recurrent infections, dual maintenance immunosuppression with mycophenolate mofetil and corticosteroids may be appropriate. As stated in the annual report issued by the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, currently the most popular immunosuppressant protocol consists of a calcineurin inhibitor combined with mycophenolate mofetil and corticosteroids: 59.1% and 53.2% of patients with a functioning graft receive a calcineurin inhibitor plus mycophenolate mofetil plus corticosteroid-based immunosuppression at 1 and 5 years post-transplant, respectively. 91.4% and 87.8% of patients are administered a calcineurin inhibitor-containing regimen 1 and/or 5 years after transplantation, respectively. Undoubtedly, the use of calcineurin inhibitor-free immunosuppressant regimens with or without antibody induction, plus an mTOR inhibitor and mycophenolate mofetil, requires more comprehensive long-term investigations to determine whether acceptable rejection rates and conservation of renal function can be achieved.