Therapy for acute rejection in pediatric organ transplant recipients

Despite the availability of potent immunosuppressive drugs, rejection after organ transplantation in children remains a serious concern, and may lead to significant morbidity, graft loss, and death of the patient. Acute graft rejection in pediatric recipients is first treated with methylprednisolone pulses, followed by progressive taper of corticosteroid doses. After control of the rejection episode, baseline immunosuppression has to be adjusted and closely monitored since rejection (especially late episodes, occurring more than 6 months after transplantation) may be due to a lack of compliance or sub-therapeutic drug concentrations. The management of corticosteroid resistant rejection is not standardized, and depends on the transplanted organ and previous immunosuppressive regimen. In patients experiencing corticosteroid resistant acute rejection while on a cyclosporine-based immunosuppressive regimen, cyclosporine is generally changed to tacrolimus. In case of tacrolimus-based immunosuppression, tacrolimus blood levels may be increased, and/or mycophenolate mofetil (which nowadays tends to replace azathioprine) or sirolimus may be added, although pharmacodynamic data and clinical studies with these agents are still scarce in pediatric recipients. The use of antithymocyte globulins or monoclonal anti-CD3 antibodies, muromonab CD3 (OKT3) is hampered by numerous adverse effects, including a significant risk of over-immunosuppression. These therapies are nowadays indicated in very selected cases. Other treatments such as plasmapheresis and high dose immunoglobulins may be useful in difficult cases. In patients with refractory rejection despite therapeutic escalation, the risks of over-immunosuppression, including opportunistic infections and malignancies (especially the Epstein-Barr virus related post-transplant lymphoproliferative disease) have to be balanced with the consequences of graft loss due to rejection. Detransplantation or retransplantation may, in some instances, be preferable to severe infectious or tumoral complications.     

Enteric-coated mycophenolate sodium: tolerability profile compared with mycophenolate mofetil

Mycophenolate mofetil is one of the most frequently used immunosuppressive drugs in solid organ transplantation. Although the adverse effect profile of mycophenolate mofetil is comparatively benign, gastrointestinal adverse effects are a major concern. The adverse effects may require a dose reduction or discontinuation, thus limiting its clinical efficacy. Enteric-coated (EC) mycophenolate sodium is a new formulation of mycophenolic acid (MPA) that delivers the active moiety MPA, the same active moiety delivered by mycophenolate mofetil. It has been developed to help protect the upper gastrointestinal tract. It is implied that a reduction of adverse drug effects as well as a reduction of dose may improve efficacy and compliance. Noncompliance is often underestimated in solid organ transplant recipients, and adverse drug effects increase medication nonadherence. Recent clinical trials comparing EC mycophenolate sodium and mycophenolate mofetil in kidney recipients reported similar rates of efficacy and adverse effects. It is noteworthy that systemic MPA exposure is higher with EC mycophenolate sodium than with mycophenolate mofetil, without increased gastrointestinal toxicity. This finding is quite surprising, because part of MPA-associated gastrointestinal toxicity is related to its antiproliferative effect on enterocytes. However, enteric coating of MPA did not markedly reduce the number of gastrointestinal adverse effects. Further studies focusing on dosage, therapeutic drug monitoring and immunosuppressive regimens may reveal benefits of EC mycophenolate sodium for optimal individualised immunosuppression and improved compliance. At present, EC mycophenolate sodium is an alternative immunosuppressant to mycophenolate mofetil in kidney transplant recipients with an almost identical efficacy and safety profile.     

Pharmacology of immunosuppressive drugs

Immunosuppressive therapy of solid organ transplantation has become more potent, effective and selective since the results of earlier use of prednisone and azathioprine post renal transplantation. Calcineurin inhibitors and mycophenolate mofetil have been important additions to the effective antirejection armamentarium. Today, cyclosporin, tacrolimus, azathioprine, mycophenolate and prednisone are all effective immunosuppressive agents and are the cornerstone of immunosuppressive protocols used posttransplant. However, the use of these agents is hindered by a 20% rate of rejection, lack of selectivity and a high rate of major adverse drug reactions which ultimately lead to a decrease in patient and graft survival. A number of clinical trials are underway to compare efficacy, safety and tolerability of different combination protocols to improve patient and allograft survival and decrease adverse drug reactions. Clinical knowledge of the pharmacology, pharmacokinetics, pharmacodynamics, adverse drug reactions and therapeutic drug monitoring of antirejection agents is essential for designing an effective immunosuppressive protocol for individual solid organ transplant recipients. The clinical application of pharmacotherapeutic principles into the clinical practice will improve both long-term patient and allograft survival while minimizing systemic toxicity of immunosuppressive drugs.     

Immunosuppression for lung transplantation: evidence to date

With the introduction of ciclosporin (cyclosporine) into routine clinical practice 20 years ago, lung transplantation has become an established treatment for patients with advanced lung disease. Most lung transplant recipients routinely continue to receive a triple-drug maintenance immunosuppressive regimen consisting of a calcineurin inhibitor, an antimetabolite and corticosteroids. The use of antibody-based induction therapy remains common, although there has been a shift away from T cell-depleting agents, such as antithymocyte globulin, towards anti-interleukin-2 receptor monoclonal antibodies. Recent years have seen the introduction of sirolimus and everolimus, immunosuppressive drugs that act by blocking growth factor-driven cell proliferation. While the newer immunosuppressive drugs have been rigorously evaluated in large randomised trials in kidney, liver and cardiac transplantation, such studies are lacking in lung transplantation. Despite a shift towards more potent immunosuppressive regimens that incorporate tacrolimus and mycophenolate mofetil, the development of chronic allograft rejection, as manifested by the bronchiolitis obliterans syndrome continues to negatively impact on the long-term survival of lung transplant recipients. This article reviews the evidence for the immunosuppressive regimens used during induction and maintenance of patients undergoing lung transplantation, and discusses current strategies in the management of chronic rejection.     

Mycophenolate mofetil: a pharmacoeconomic review of its use in solid organ transplantation

Most pharmacoeconomic studies of mycophenolate mofetil have focused on its use as part of maintenance immunosuppression for renal transplantation, involving short-term (3 to 12 months) time frames. In general, mycophenolate mofetil reduced the treatment costs for rejection episodes and graft failure which offset its higher drug acquisition cost compared with azathioprine. Several cost analyses have been modelled on the large multicentre trials of adult renal transplant recipients. The use of mycophenolate mofetil was associated with either cost savings or no additional costs after 6 or 12 months in French, US and Canadian analyses of triple or quadruple immunosuppressant therapy. A further cost analysis utilising a registry database of renal transplant recipients in the US found mycophenolate mofetil to be cost saving compared with azathioprine after 6.4 years when evaluating costs due to graft loss only. Of the limited cost-effectiveness analyses with the drug, one US study modelled the 1- and 10-year cost effectiveness of mycophenolate mofetil and various other immunosuppressants used in combined regimens. Long-term use of mycophenolate mofetil was less cost effective than other regimens, but the use of long-term mycophenolate mofetil in high-risk patients was shown to be a relatively cost-effective strategy. In another US analysis comparing mycophenolate mofetil with azathioprine as part of quadruple therapy, mycophenolate mofetil was associated with slightly lower costs during the first year after renal transplantation as well as improved clinical outcomes. Conclusion: Pharmacoeconomic studies support the use of mycophenolate mofetil as part of immunosuppressant therapy in renal transplantation, at least in the short term. Although the cost effectiveness of mycophenolate mofetil in the long term is less clear, limited pharmacoeconomic data available appear promising. Among issues to be examined in future economic analyses in renal transplantation are the calcineurin-sparing potential of mycophenolate mofetil and the feasibility of using more efficient mycophenolate mofetil dosage regimens when using the drug on a long-term basis. Additional pharmacoeconomic analyses of mycophenolate mofetil are also needed in other types of 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: 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.     

Lack of toxic effects following acute overdose of cellcept (mycophenolate mofetil)

Mycophenolate mofetil is an immunosuppressive drug used for prevention of graft rejection following solid organ transplant and for treatment of autoimmune disorders. We report a case of a 24-year-old female with lupus nephritis that presented following ingestion of 10 grams of mycophenolate in a suicide gesture. Serum levels confirmed ingestion. The patient was treated with decontamination and supportive care and recovered with no adverse effect.     

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.     

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.     

Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral)1 in organ transplantation.

Cyclosporin is a lipophilic cyclic polypeptide immunosuppressant that interferes with the activity of T cells chiefly via calcineurin inhibition. The original oil-based oral formulation of this drug (Sandimmun)l was characterised by high intra- and interpatient pharmacokinetic variability, with poor bioavailability in many patients; a novel microemulsion formulation (Neoral)1 was therefore developed to circumvent these problems. Studies show increases, attributable chiefly to improved absorption in patients who absorb the drug only poorly from the original formulation, in mean systemic exposure to cyclosporin with the microemulsion, with no clinically significant differences in tolerability or drug interaction profiles. Cyclosporin microemulsion is at least as effective as the oil-based formulation in renal, liver and heart transplant recipients, with trends towards decreased incidence of acute rejection with the microemulsion formulation in some (statistically significant in a few) trials. Cyclosporin microemulsion and tacrolimus appear to have similar efficacy in preventing acute rejection episodes in most renal, pancreas-kidney, liver and heart transplant recipients. However, there are indications of superior efficacy for tacrolimus in some trials, particularly in the prevention of severe acute rejection and in Black transplant recipients. Current 12-month data also indicate equivalent efficacy of sirolimus in renal transplantation. Conversion from the oil-based to microemulsion formulation in stable renal, liver and heart transplant recipients is achievable with no change in acute rejection rates. The addition of an anti-interleukin-2 receptor monoclonal antibody and/or mycophenolate mofetil to cyclosporin microemulsion plus corticosteroids decreases rates of acute rejection; corticosteroid withdrawal without increased acute rejection rates was also achieved on the addition of these agents in some trials. Pharmacoeconomic analyses have shown savings in direct healthcare costs in kidney or liver transplantation when cyclosporin microemulsion is used in preference to the oil-based formulation, although studies incorporating indirect costs or expressing costs in terms of therapeutic outcomes are currently unavailable. CONCLUSIONS: The introduction of cyclosporin microemulsion has consolidated the place of the drug as a mainstay of therapy in all types of solid organ transplantation; research into optimisation of outcomes through more effective therapeutic monitoring in patients receiving this formulation is ongoing. Several novel immunosuppressants have been introduced in recent years: further clinical and pharmacoeconomic research will be needed to clarify the relative positioning of these agents, particularly with respect to specific patient groups. Other new drugs (basiliximab/daclizumab and mycophenolate mofetil) offer particular advantages when used in combination with cyclosporin.     

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: a proliferation signal inhibitor targeting primary causes of allograft dysfunction

Allograft dysfunction remains a major problem for long-term graft survival after kidney and heart transplantation. Current immunosuppressive regimens do not completely address the causes of allograft dysfunction which include acute rejection episodes, complications of immunodeficiency (for example, cytomegalovirus infection), nephrotoxicity from calcineurin inhibitors (cyclosporine and tacrolimus) and vascular remodeling and vasculopathy. Everolimus is a potent immunosuppressor that inhibits growth factor-stimulated proliferation of hematopoietic and nonhematopoietic cells, including vascular smooth muscle. Everolimus is indicated for the prophylaxis of acute rejection in kidney and heart transplant patients in a combined regimen with cyclosporine microemulsion and corticosteroids. Everolimus is formulated as both a tablet and a tablet for oral solution. It is rapidly absorbed and displays dose-proportional, stable pharmacokinetics. Everolimus has equivalent efficacy to mycophenolate mofetil in reducing the incidence of acute rejection after renal transplantation and superior efficacy to azathioprine after heart transplantation. Combination of everolimus with cyclosporine allows dose-reduction of cyclosporine while maintaining efficacy due to the synergistic immunosuppressive effects of the combination. Everolimus reduces intimal thickening of blood vessels to the graft and the incidence of allograft vasculopathy in heart transplantation. In both kidney and heart transplantation, the incidence of cytomegalovirus infection was lower in everolimus-treated patients compared with patients receiving the control treatment. Everolimus-related adverse events include elevated cholesterol and triglycerides, which respond to treatment, and decreased platelet count, which is transient. Nephrotoxicity may result from the combination of everolimus with full-dose cyclosporine but is mitigated by reducing the dose of cyclosporine. Everolimus is initiated at 0.75 mg b.i.d. with dose adjustments guided by therapeutic drug monitoring of predose blood levels. In clinical development trials, everolimus has demonstrated the ability to reduce the incidence of acute rejection episodes, cytomegalovirus infection and cardiac vasculopathy, thus addressing the primary causes of allograft dysfunction.     

Daclizumab: a review of its use in the prevention of acute rejection in renal transplant recipients

The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in renal transplant recipients. It is specific for the alpha subunit (Tac/CD25) of the interleukin-2 (IL-2) receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2-induced T cell proliferation. Daclizumab has advantages over murine antibodies to the IL-2 receptor, including improved effector function, a low potential for immunogenicity and long elimination half-life. When added to standard cyclosporin-based immunosuppressive therapy with or without azathioprine, daclizumab (1 mg/kg prior to surgery and once every 2 weeks thereafter for a total of 5 doses) significantly reduced the 6-month rate of acute rejection compared with placebo in 2 phase III studies. The mean number of rejection episodes was significantly reduced and the time to first acute rejection significantly increased in daclizumab versus placebo recipients. Patient survival at 1 year after transplantation was significantly higher with daclizumab than placebo in 1 study and showed a trend in favour of the drug in the other study. The 1-year graft survival rate tended to be greater in daclizumab than in placebo recipients in both studies, In a phase II study, acute rejection rates in patients treated with both daclizumab and mycophenolate mofetil (plus standard cyclosporin-based immunosuppression) were lower than those achieved with mycophenolate mofetil alone. Preliminary results indicate that daclizumab is also a useful agent in paediatric renal transplant recipients. Further investigation of the efficacy and tolerability of the drug in this patient group is clearly warranted. Daclizumab does not increase the incidence of adverse events when added to standard cyclosporin-based therapy. The incidence of opportunistic infections, lymphoproliferative disorders and malignancies was not increased above that seen with placebo. CONCLUSIONS: Although the effects of daclizumab on long term graft and patient survival require further investigation, available data indicate that daclizumab is an important advance in renal transplant immunosuppression, reducing acute graft rejection without affecting the tolerability of standard cyclosporin-based immunosuppression.     

肺移植受者应用巴利昔单抗诱导治疗的回顾性分析

目的:探讨肺移植受者应用巴利昔单抗诱导治疗的免疫抑制方案疗效。方法:回顾性分析101例肺移植患者,依照入选/排除标准筛选出有效病例73例。其中30例为诱导组,即分别在术中、术后给予两剂巴利昔单抗诱导治疗;另43例为对照组,即不接受诱导治疗。所有患者术后均采用他克莫司、吗替麦考酚酯和泼尼松三联免疫抑制方案预防排斥反应。2组患者均随访12个月,观察排斥反应、代谢并发症的发生以及患者的存活情况。结果:术后1年内,诱导组的急性排斥反应发生率为10%,对照组为33%,两组间差异有统计学意义(P<0.05)。诱导组并发症的发生率为63%,对照组为47%,两组间差异有统计学意义(P<0.05)。生存分析提示2组患者的半数生存期无统计学差异(P>0.05)。结论:以他克莫司为基础的免疫抑制方案中应用巴利昔单抗诱导治疗可以明显降低肺移植术后急性排斥反应发生率,但对肺移植患者的长期存活率没有显著性影响。     

Therapeutic monitoring of mycophenolate mofetil in organ transplant recipients: is it necessary?

Adequate immunosuppression minimising the risk of organ rejection with acceptable tolerability of the used drugs is a crucial step in organ transplantation. The primary goal is to maintain a consistent time-dependent target concentration by tailoring individual dosage leading to the best efficacy and tolerability combination. The use of therapeutic drug monitoring (TDM) to optimise immunosuppressive therapy is routinely employed for maintenance drugs such as cyclosporin and tacrolimus. The question whether therapeutic monitoring of mycophenolic acid (MPA) in organ transplant recipients treated with mycophenolate mofetil is necessary is not definitely answered. The correlation of mycophenolic acid pharmacokinetic parameters with efficacy and toxicity makes the therapeutic monitoring of this drug promising. However, further studies are mandatory to draw the best guidelines in order to achieve higher levels of evidence that MPA-TDM may improve patient outcome.     

Altered cytochrome p450 metabolism of calcineurin inhibitors: case report and review of the literature

A 19-year-old woman was admitted to receive a kidney transplant from a nonliving donor. At the time of transplantation, she was taking oral phenytoin 300 mg every morning, 100 mg at noon, and 300 mg every evening (total of 700 mg/day) to treat seizures secondary to hemodialysis. Immediately after the transplantation, phenytoin treatment was resumed, and immunosuppressive therapy consisting of antithymocyte globulin, cyclosporine, mycophenolate mofetil, and corticosteroids was started. Her cyclosporine blood levels varied over the first 10 days after transplantation. Cyclosporine was discontinued, and tacrolimus was begun after acute rejection was discovered. The rejection was treated with antithymocyte globulin, plasmapheresis, and intravenous immunoglobulin, and subsequently resolved; however, the patient's blood concentrations of tacrolimus varied widely. Phenytoin is an antiepileptic drug that induces hepatic enzymes, affecting the cytochrome P450 3A family. These enzymes metabolize approximately 50% of all prescribed drugs, including cyclosporine and tacrolimus. According to the Naranjo adverse drug reaction probability scale, this patient's adverse drug reaction probably occurred from altered metabolism of cyclosporine and tacrolimus due to phenytoin therapy. Clinicians must identify drug interactions between metabolic enzyme inducers or inhibitors and drug substrates with narrow therapeutic ranges, closely monitor drug concentrations, and observe patients for clinical signs and symptoms of therapeutic failure or toxicity. In daily practice, clinicians should explore the metabolic characteristics of drugs and their biotransformation pathways to identify patients who require alternative therapy.     

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.     

New treatments for acute humoral rejection of kidney allografts

Acute antibody-mediated rejection (acute humoral rejection; AHR) of organ allografts usually presents as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition with renal dysfunction, associated with circulating donor-specific anti-human leukocyte antigen alloantibodies, is diagnostic of AHR in kidney allografts. Removal of alloantibodies with suppression of antibody production and rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), tacrolimus, mycophenolate mofetil and/or intravenous immunoglobulins, as well as rituximab or splenectomy, have been recently used to successfully treat AHR. However, the optimal protocol to treat AHR still remains to be defined. Anti-CD20⁺ monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as rescue therapy in some episodes of steroid- and antilymphocyte-resistant humoral rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully desensitize selected high-immunological risk patients in anticipation of a previously cross-match positive (or ABO incompatible) kidney transplantation. In the near future, the possible role of new specific anti-B-cell approaches or, possibly, of new anti-T-cell activation approaches using selective agents such as belatacept should be assessed to further refine the present treatment of humoral rejection.     

The use of mycophenolate mofetil in liver transplant recipients

Mycophenolate mofetil is an important drug in the modern immunosuppressive arsenal. Mycophenolate mofetil is the semisynthetic morpholinoethyl ester of mycophenolate acid. Mycophenolate acid prevents T and B cell proliferation by specifically inhibiting a purine pathway required for lymphocyte division. This paper extensively reviews the experience of mycophenolate mofetil use in liver transplant recipients. In randomised trials, mycophenolate mofetil decreased the rate of acute rejection after liver transplantation, without a significant increase of septic complications. However, so far, there are no data indicating that mycophenolate mofetil increases liver transplant patient or graft survivals. Mycophenolate mofetil is interesting because of its particular side effects profile, which is very different from the other immunosuppressants. The absence of mycophenolate mofetil nephrotoxicity is of specific interest in liver recipients with impairment of renal function. The monitoring of mycophenolate acid area under the concentration time curve might be interesting to limit side effects and provide better clinical efficacy but the exact role of mycophenolate acid monitoring in liver recipients has yet to be further evaluated in large series.