The change of immunosuppressive regimen from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors and its effect on malignancy following heart transplantation

Malignancy is a significant cause of mortality after organ transplantation. There is an increased rate of malignancy following heart transplantation (HTx) compared to the general population and other organ transplant recipients. Post-HTx patients with a history of malignancy are also at a higher risk of developing new malignancies or exacerbation of their existing malignancies. Mammalian target of Rapamycin inhibitors (mTORIs) are newly introduced immunosuppressive drugs with a unique mechanism of action. By changing the immunosuppressive regimen from classic drugs, especially calcineurin inhibitors (CNIs) to mTORIs, the rate of developing de novo malignancies and the relapse of former malignancies is significantly reduced. However, issues like allograft function, total surveillance of patients, and post-transplantation complications should be considered during the conversion of drug regimens utilizing CNIs to drug regimens employing mTORIs. We reviewed different post-heart transplant maintenance immunosuppressive regimens and their effect on post-HTx malignancies with a focus on mTORIs, compared safety against effectiveness, and gathered conclusions based on our review of the literature, which may lead clinicians to make a better evidence-based decision regarding post-HTx maintenance immunosuppressive drug regimens. Overall, CNI to mTORI conversion in post-HTx maintenance immunosuppressive drug regimens was associated with a reduced rate of developing malignancy in post-HTx patients. Furthermore, nephrotoxicity decreased significantly while using mTORIs in combination with lower doses of CNIs and the rejection rate was equivalent to CNI-only regimens. In conclusion, mTORI-based maintenance immunosuppressive drug regimens seem to be safe and beneficial when considering efficacy vs. adverse effects, and all-cause mortality rates are significantly lower in patients switched to mTORIs when compared to CNI recipients.     

Emerging drugs in lung transplantation

The balance between immunosuppression to ensure graft tolerance while preventing emergence of infectious complications is key in lung transplantation. Although opportunistic infection may appear to be the most important of these complications, malignancies and severe drug toxicities significantly affect the short- and long-term outcomes of the patients. The present practice is combination therapy using drugs with complementary immunosuppressive action, to achieve synergistic immunosuppression with the lowest possible toxicity. Components of immunosuppression include induction and maintenance regimens. Primary graft failure remains an important cause of mortality and morbidity in the immediate post-transplant period. Acute rejection is a common complication after lung transplant, but responds well to augmented immunosuppression and immunomodulation. Chronic rejection still is the major cause of mortality in patients who survive the initial year post-transplantation. Several new drugs have shown promise in decreasing the rate of loss of graft function. This review discusses the current and emerging therapeutic regimens.     

Emerging drugs in lung transplantation

The balance between immunosuppression to ensure graft tolerance while preventing emergence of infectious complications is key in lung transplantation. Although opportunistic infection may appear to be the most important of these complications, malignancies and severe drug toxicities significantly affect the short- and long-term outcomes of the patients. The present practice is combination therapy using drugs with complementary immunosuppressive action, to achieve synergistic immunosuppression with the lowest possible toxicity. Components of immunosuppression include induction and maintenance regimens. Primary graft failure remains an important cause of mortality and morbidity in the immediate post-transplant period. Acute rejection is a common complication after lung transplant, but responds well to augmented immunosuppression and immunomodulation. Chronic rejection still is the major cause of mortality in patients who survive the initial year post-transplantation. Several new drugs have shown promise in decreasing the rate of loss of graft function. This review discusses the current and emerging therapeutic regimens.     

Options for induction immunosuppression in liver transplant recipients

Immunosuppression administered in the early postoperative period following liver transplantation plays a crucial role in the survival of the graft and the patient. The introduction of cyclosporin was an important landmark in transplantation, and to this day, calcineurin inhibitors form the basis of most induction immunosuppression regimens. New drugs are being developed which are more specifically targeted to prevention of rejection, and multiple drug combinations have been proposed as a means of reducing the adverse effects of individual drugs. Azathioprine and the newer antimetabolite mycophenolate mofetil have been added to calcineurin inhibitor-based regimens with varying amounts of success. Antibody induction has evolved as a potent form of immunosuppression as well as a means of avoiding certain adverse effects, particularly nephrotoxicity. The numerous adverse effects encountered with polyclonal preparations have been reduced with the development of more specific monoclonal antibodies such as muromonab CD3 (OKT3) or interleukin (IL)-2 receptor (IL-2R) antagonists. The anti-IL-2R antibody preparations basiliximab and daclizumab have shown excellent early results due to their potent yet highly targeted immunosuppressive effect and minimal adverse effects. Further study is needed to determine the most appropriate dosage, timing and patient population for these new drugs in the setting of liver transplantation. Although a number of different induction regimens have been described, no single protocol is suitable for all liver transplant recipients. Rather, certain regimens have advantages that could favour their use in a specific subgroup of patients. A number of clinical trials are underway to identify new, more specific drugs and combinations which could be useful in induction immunosuppression.     

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.     

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.     

Immunosuppressive drugs in paediatric liver transplantation

Orthotopic liver transplantation is established treatment for children with acute and chronic liver failure. Despite advances in pre- and postoperative management, innovative surgical techniques and new immunosuppressive drugs, acute and chronic rejection remains a problem. In addition, well established adverse effects of commonly used immunosuppressive drugs are no longer accept able. More potent, but less toxic, immunosuppressive agents have been developed and some novel compounds are now entering routine practice. Cyclosporin was the cornerstone of immunosuppressive therapy until the introduction of its novel pharmaceutical form (Neoral) with improved bioavailability, lower inter- and intraindividual pharmacokinetic variability and improved graft survival. Recently, tacrolimus, a macrolide drug with a similar mode of action, but much higher potency, was introduced and, at present, is the only agent which can successfully replace cyclosporin as a first-line immunosuppressive drug. Mycophenolate mofetil has recently been approved for use in adult and paediatric renal transplant recipients. It has a similar mode of action to cyclosporin and tacrolimus, but acts at a later stage of the T cell activation pathway. Administration with standard immunosuppressive drugs reduces the incidence of acute rejection and enables cyclosporin and tacrolimus dose reduction, thus reducing the risk of associated toxic effects. Phase I and II trials with sirolimus (rapamycin), a macrolide antibiotic, have shown comparable immunosuppressive action, when administered in conjunction with standard immunosuppressants. Further clinical trials need to be carried out to establish efficacy, tolerability and pharmacokinetics in paediatric transplant recipients. Monoclonal antibody therapy (daclizumab and basiliximab) is an exciting new development whereby T cell proliferation is inhibited by selective blockade of interleukin (IL)-2 receptors. Preliminary results, when used in combination with a standard immunosuppressive regimen, are good with respect to incidence of acute graft rejection, host immune response and adverse effects. FTY720 is a novel synthetic immunosuppressive compound which induces a reduction in peripheral blood lymphocyte count through apoptotic T cell death or accelerated trafficking of T cells into lymphatic tissues. Experimental animal studies demonstrated synergistic action in combination with low dose cyclosporin or tacrolimus, potentiating their immunosuppressive effects. Further studies are being carried out to determine its potential for application in organ transplantation. Despite this rapid development of novel compounds, it will take many years before they may become part of standard protocols in paediatric transplantation medicine. Further development and research of efficacy and tolerability of existing drugs is, therefore, vital.     

Induction therapy in pediatric renal transplant recipients: an overview

Induction therapy to prevent the acute rejection of mismatched allografts with the ultimate aim of prolonging the life of the allograft has been the cornerstone of immunosuppression since the introduction of renal transplantation. Agents used for induction therapy have changed over time. Their role in transplantation is expanding to include corticosteroid avoidance and immunosuppression minimization. This review provides an overview of induction therapies for renal transplantation including historic therapies such as total lymphoid irradiation and Minnesota antilymphocyte globulin, and current therapies with polyclonal and monoclonal antibodies and chemical agents, with special emphasis on children. Data from adult studies, and pediatric studies whenever available, are summarized. A brief summary of experimental therapies with fingolimod and belatacept is provided. Historically, induction therapies were targeted at T cells. The role of induction therapies targeted at B cells is emerging in select groups of patients that include highly sensitized recipients and those receiving transplants from blood group incompatible donors. With the advent of newer maintenance immunosuppressive medications and with very low rates of acute rejection, induction protocols for renal transplantation need to be targeted so that excessive immunosuppression and infections are avoided. Several single-center and registry data analyses in children suggest that the addition of an interleukin (IL)-2 receptor antagonist may improve graft survival compared with no induction. The safety profile of IL-2 receptor antagonists is indistinguishable from that of placebo, with no apparent difference in the incidence of infection or post-transplant lymphoproliferative disease. IL-2 receptor antagonists and polyclonal lymphocyte-depleting antibodies offer equivalent efficacy in standard-risk populations. However, in high-risk patients, acute rejection rates and graft outcomes may be improved with the use of lymphocyte-depleting agents such as Thymoglobulin. However, cytomegalovirus infection and other infections may be more common with this therapy. Therefore, in patients at high risk of graft loss, Thymoglobulin may be the preferred choice for induction therapy, while for all other patients, IL-2 receptor antagonists should be considered the first-line choice for induction therapy. Newer lymphocyte-depleting agents such as alemtuzumab may be better utilized in minimization regimens involving one or two oral maintenance immunosuppressive agents.     

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.     

Administration of Antithymocyte Globulin (Rabbit) to Treat a Severe,Mixed Rejection Episode in a Pregnant Renal Transplant Recipient

Pregnancy in solid organ transplant recipients carries numerous risks to the mother such as increased risk of rejection, gestational diabetes mellitus, and preeclampsia. The developing fetus is subjected to risks such as birth defects, preterm delivery, and low birth weight. Typically, these risks can be managed through intensive, multidisciplinary prenatal care and a proper immunosuppressive regimen. In the setting of rejection, however, little data are available to suggest safe and effective treatment of acute cellular rejection, antibody‐mediated rejection, or mixed rejection episodes in the pregnant solid organ transplant recipient. We describe the first case, to our knowledge, in which antithymocyte globulin (rabbit) was used to successfully treat a pregnant renal transplant recipient who experienced a mixed rejection episode. A 22‐year‐old, African American woman with stage 6 chronic kidney disease received a deceased donor renal transplant after undergoing hemodialysis for 3 years. Her maintenance immunosuppressive regimen at the time of transplantation consisted of tacrolimus, prednisone, and mycophenolate mofetil. Despite counseling efforts on the importance of having a planned pregnancy after kidney transplantation so that her immunosuppressive medications could be optimized, the patient became pregnant 12 months later; her mycophenolate mofetil was changed to azathioprine to reduce the risk of fetal deformities or death. Three months later, the patient was admitted for biopsy of her transplanted kidney and was evaluated for possible kidney rejection. After confirmation of a mixed 1B acute cellular rejection and antibody‐mediated rejection episode, the patient decided to pursue resolution of her rejection episode and continue the pregnancy despite the potential risks to the fetus. She was treated with high‐dose corticosteroids, intravenous immunoglobulin, plasmapheresis, and antithymocyte globulin (rabbit). Twenty‐nine months after transplantation, the patient was induced and gave birth to a healthy baby boy. Our patient's case offers unique insight into the potential management of a rejection episode requiring aggressive immunosuppressive therapy. Although potent immunosuppressive therapies were successfully used in our patient, further studies are needed to make definitive recommendations regarding the use of such therapies for treatment of rejection episodes in pregnant solid organ transplant recipients. The risks and uncertainties of treating rejection episodes should always be discussed with and understood by the patient before an informed decision is made.     

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.     

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.     

Immunosuppression in elderly renal transplant recipients: are current regimens too aggressive?

Renal transplantation is an accepted and successful treatment modality in elderly patients with end-stage renal disease. In comparison with maintenance dialysis, transplantation has been shown to confer a mortality benefit as well as improvements in quality of life in older individuals with end-stage renal disease. Despite this, overall outcomes of renal transplantation in elderly individuals have, in general, been less successful than those of younger renal transplant recipients. Largely, this has been due to the particular vulnerability of elderly patients to the immunosuppressive medications used in renal transplantation. This review article covers these issues in some detail and briefly discusses some of the pharmacokinetic, pharmacodynamic, physiological and immunological differences between younger and older transplant recipients. Elderly renal transplant recipients have both a higher rate of patient death and allograft loss censored for death. Upon multivariate analysis, age of the recipient is strongly associated with allograft loss independent of other known factors. Acute rejections are less frequent in older individuals; however the consequence of a rejection if it occurs is negative for long-term graft survival. On the other hand, death by infection is vastly increased in older versus younger renal transplant recipients. In general, the pharmacokinetics of the immunosuppressive agents are little affected by age, but the tolerance to these agents seems to decrease with increasing age. Elderly renal transplant recipients present a very difficult clinical challenge. As the elderly become an ever-increasing segment of the renal transplant population, new and innovative immunosuppressive strategies will have to be considered and applied.     

Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation

Tacrolimus (FK-506) is an immunosuppressant agent that acts by a variety of different mechanisms which include inhibition of calcineurin. It is used as a therapeutic alternative to cyclosporin, and therefore represents a cornerstone of immunosuppressive therapy in organ transplant recipients. Tacrolimus is now well established for primary immunosuppression in liver and kidney transplantation, and experience with its use in other types of solid organ transplantation, including heart, lung, pancreas and intestinal, as well as its use for the prevention of graft-versus-host disease in allogeneic bone marrow transplantation (BMT), is rapidly accumulating. Large randomised nonblind multicentre studies conducted in the US and Europe in both liver and kidney transplantation showed similar patient and graft survival rates between treatment groups (although rates were numerically higher with tacrolimus- versus cyclosporin-based immunosuppression in adults with liver transplants), and a consistent statistically significant advantage for tacrolimus with respect to acute rejection rate. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial, and a trend towards a lower rate of chronic rejection was noted with tacrolimus in a large multicentre renal transplantation study. In general, a similar trend in overall efficacy has been demonstrated in a number of additional clinical trials comparing tacrolimus- with cyclosporin-based immunosuppression in various types of transplantation. One notable exception is in BMT, where a large randomised trial showed significantly better 2-year patient survival with cyclosporin over tacrolimus, which was primarily attributed to patients with advanced haematological malignancies at the time of (matched sibling donor) BMT. These survival results in BMT require further elucidation. Tacrolimus has also demonstrated efficacy in various types of transplantation as rescue therapy in patients who experience persistent acute rejection (or significant adverse effect's) with cyclosporin-based therapy, whereas cyclosporin has not demonstrated a similar capacity to reverse refractory acute rejection. A corticosteroid-sparing effect has been demonstrated in several studies with tacrolimus, which may be a particularly useful consideration in children receiving transplants. The differences in the tolerability profiles of tacrolimus and cyclosporin may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, cyclosporin has a higher incidence of significant hypertension, hypercholesterolaemia, hirsutism and gingival hyperplasia, while tacrolimus has a higher incidence of diabetes mellitus, some types of neurotoxicity (e.g. tremor, paraesthesia), diarrhoea and alopecia. Conclusion: Tacrolimus is an important therapeutic option for the optimal individualisation of immunosuppressive therapy in transplant recipients.     

Towards graft-specific immune suppression: Gene therapy of the transplanted kidney

Kidney transplantation remains the best therapeutic option for patients with end-stage renal disease. Immunosuppressive therapy has largely resolved the issue of acute transplant rejection. However, because of its systemic nature, immunosuppressive therapy trades off efficacy against side-effects and its chronic use has been associated with severe infections and malignancy. Moreover, long-term survival of renal grafts did not change over the past twenty years. This situation may be improved by using gene therapy as an alternative or add-on strategy to the classic, systemic immune suppression. This review discusses gene therapy approaches in kidney transplantation by addressing the essentials of delivery vectors and by outlining strategies to achieve local immunosupression and allograft-specific tolerance, both in acute rejection and chronic transplant dysfunction. Employing such strategies, local suppression of the immune response and induction of transplantation-specific tolerance have been accomplished in experimental gene therapy. If successful in the clinical setting, gene therapy may (partially) substitute systemic, non-selective immunosuppressive medication, with a major impact on the quality of life and survival of the transplanted patients as well as on the waiting time for receiving a renal graft.     

Current pharmacotherapeutical options for the prevention of kidney transplant rejection

Introduction: Advances in immunosuppression and medical care over the past years resulted in better short- and long-term graft survival following kidney transplantation. Novel potent immunosuppressive agents, combinations of proven substances and the steadily expanding knowledge on the pathophysiology of kidney transplant rejection allows the extension of donor and recipient criteria, including the usage of organs from ABO-incompatible and crossmatch-positive donors, to overcome the increasing problem of organ shortage.

Areas covered: Immunosuppressive regimens for the prevention of kidney transplant rejections with a focus on regimens aiming at calcineurin inhibitor or steroid minimization, withdrawal or avoidance. Prevention of antibody-mediated rejections in standard-risk and sensitized recipients, as well as newly introduced immunosuppressive substances are covered.

Expert opinion: Currently applied immunosuppressive regimens are associated with excellent short-term graft survival. However, the long-term outcomes of different regimens substantially differ with regard to potential side effects, graft function, rejection and sensitization rates. The adverse effects of effective immunosuppression must carefully be balanced against the benefit, e.g., prevention of the development of donor-specific human leukocyte antigen antibodies and chronic (antibody-mediated) rejection. The choice of the appropriate immunosuppressive regimen requires clinical experience and careful consideration of recipient and transplant characteristics to achieve an optimal long-term graft survival.     

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.     

Induction therapy in renal transplantation : an overview of current developments

An overview of the past 10 years of clinical renal transplantation would include progress in the development of new induction protocols (non-depleting versus depleting monoclonal and polyclonal antibodies, plasmapheresis and intravenous immunoglobulins) designed to reduce the incidence and severity of rejection and adverse effects as well as improve long-term graft and patient survival. These modalities have been introduced primarily to reduce the incidence of acute rejection episodes leading to early graft loss, decrease the need for higher toxic doses of maintenance immunosuppressive drugs, such as calcineurin inhibitors, and possibly aid in the pursuit of the goal of achieving immunological tolerance and the avoidance of all long-term immunosuppressive therapy. What has resulted during the past 20 years as the use of induction agents has become more popular is the concurrent improvement in detection and treatment of acute and chronic infectious (primarily viral), and opportunistic and quasi-malignant disease accompanying the use of these agents and, therefore, their increase in popularity. However, the overall cost of therapy and the long-term results of protocols in which these agents have been used have not resulted in a definitive benefit thus far, because of the lack of sufficient numbers of defined randomised, long-term studies and the continuing introduction of newer protocols based on even more recent advances. The specific agents used for induction therapy to date, and the rationale for their introduction and mechanisms of action are discussed in this review.     

New developments in treatment after lung transplantation

Lung transplantation has evolved as an accepted therapy in selected adults and children with end-stage lung disease. Outcomes following lung transplantation have improved in the recent era with a 5-year survival of > 70% and an overall good functional status of surviving recipients. Many of the advances have been achieved by the use of modern immunosuppressive agents. To date, multiple strategies exist that may be employed when utilizing immunosuppression. These agents can be used in a variety of roles that may include induction, maintenance or rescue therapy, many of which are illustrated in this review including the current evidence to support their use. Infections in lung transplant recipients remain a significant cause of morbidity and mortality. Special considerations are required with the substantial burden of chronic infection in candidates with CF lung disease before transplantation, which are discussed. Furthermore, recent progress and advances in prevention and treatment of post-transplantation infectious complications are detailed. Chronic lung allograft dysfunction remains to be the burden of lung transplantation in the long-term. Unfortunately, there is no well-established therapy to address it. However, therapy attempts include change/augmentation of immunosupression, use of neomacrolides and extracorporeal photopheresis, all of which are reviewed in detail.