Renal transplantation in high-risk patients

Renal transplantation in high-risk patients is a growing phenomenon. More patients are progressing to endstage renal failure, in the setting of an increased incidence of diabetes mellitus and cardiovascular disease. Current organ shortages and the use of more marginal donors have affected both patient and graft survival. Acute rejection has been minimised under modern immunosuppression; however, patient and long-term allograft outcomes have not improved concurrently. Specific understanding of donor, recipient and allograft variables associated with stratification of patients as 'high risk for renal transplantation' is necessary to facilitate appropriate peri- and post-transplant pharmacotherapy. Induction and maintenance immunosuppression choices are different for high-risk patients and must be made to ensure optimal immunosuppression, while limiting patient and allograft toxicity.     

Single-agent immunosuppression after liver transplantation: what is possible?

Orthotopic liver transplantation is a life saving and life enhancing procedure. The development of immunosuppressive drugs has contributed to the high rate of success in terms of both patient and graft survival. However, the considerable adverse effects of these therapies are affecting long-term outcomes of transplant recipients. Complications related to immunosuppression are responsible for the majority of deaths in patients surviving more than 1 year. Therefore, the search for an optimal immunosuppressive regimen has become of paramount importance. The liver has proved to be an 'immunologically privileged' organ, capable in several animal models to be accepted as an allograft without any intervention on the immune system of the recipient. In some human liver allografts acceptance of the new organ is recognised after withdrawal of immunosuppressants, but prior identification of such individuals is not yet possible, thus negating this management option. Graft-recipient interaction is peculiar in liver transplantation: acute cellular rejection does not always need to be treated, and if it is not severe, appears to be associated with a better survival of both patient and graft. In the last decade there has been an evolution of immunosuppressive protocols, driven by empirical observation and a deeper understanding of immunological events after transplant. However, most modifications have been made because of the necessity to reduce long-term drug related morbidity and mortality. Withdrawal of corticosteroids has proven to be safely achievable in most patients, with no deleterious effects on patient or graft survival but with a great benefit in terms of reduction of incidence of metabolic and cardiovascular complications. Long-term 'steroid-free' regimens are therefore now widely used. Patients with stable graft function can be easily maintained using a single drug usually after 6 or 12 months and usually with a calcineurin inhibitor. The more evolved step of using monotherapy ab initio has also proven to be effective in a few studies and needs to be explored further. In the future new strategies will be designed to help the development of tolerance of the allograft, selectively stimulating instead of suppressing the immune reaction of the recipient.     

Immunosuppressive preconditioning or induction regimens : evidence to date

The success of solid organ transplantation has been directly related to the development of immunosuppressive drug therapies. Preconditioning or induction therapy was developed to reduce early immunological and nonimmunological renal injury, with the goal of increasing long-term graft survival. However, the routine induction of immunological tolerance to solid organ allograft is currently not achievable because of the morbidity and mortality related to the immunosuppressive regimens themselves. The different therapeutic preconditioning or induction agents and their associated effects on cellular rejection, graft survival outcomes and the need for multiagent post-transplant maintenance therapy are reviewed.     

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.     

Transplantation: tolerance

The immunosuppressive regimens currently in use have been responsible for major improvements in transplanted organ acceptance, but long-term survival can be compromised by drug toxicity and/or chronic immune deficiency. The ultimate goal for transplantation is tolerance, defined as durable, donor-specific allograft acceptance in the absence of long-term immunosuppression. This review describes current experimental strategies for tolerance induction in primate models that are poised for clinical application.     

Factors associated with long-term renal allograft survival.

Major advances in immunosuppression and reductions in the rates of acute rejection have led to increasing graft and patient survival rates during the past two decades. Chronic dysfunction of the renal allograft, however, remains a major clinical problem and probably represents the end result of the complex interplay between donor and recipient factors, immunologic injury, nonimmunologic insults, and drug-induced nephrotoxicity. Optimal function of the renal allograft is obtained by maintaining a balance between underimmunosuppression and acute rejection and overimmunosuppression and drug-induced toxicities. To minimize side effects while maintaining efficacy, immunosuppressive drugs are commonly used as combination therapy. Pharmacokinetic and pharmacodynamic interactions between these agents can affect graft survival and function. The evidence supporting the role of therapeutic drug monitoring as applied to commonly used immunosuppressants in modern transplantation is presented here, and the increasing role of therapeutic drug monitoring in the optimization of graft and patient survival rates in the modern era of renal transplantation is discussed.     

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.     

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.     

Immunopharmacologic Therapy in Renal Transplantation

The long-term kidney allograft survival rate is still far from optimum. Conventional immunosuppressive drugs used to prevent allograft rejection are associated with significant side effects. Moreover, withdrawal of these agents is often associated with graft loss due to rejection. No treatment is available for chronic rejection. Graft tolerance is difficult to achieve in humans, and therefore a continued goal in organ transplantation is to develop immunosuppressive regimens that are associated with fewer side effects and decreased rates of rejection, and that promote graft tolerance. The advent of newer pharmacologic agents and bioreagents is expected to improve patient and graft survival rates.     

Intestinal transplantation in children: a review of immunotherapy regimens

This review summarizes the outcomes and known adverse effects of current immunosuppression strategies in use in pediatric intestinal transplantation. Intestinal transplantation has evolved from an experimental therapy to a highly successful treatment for children with intestinal failure who have complications with total parenteral nutrition. Because of continued success with intestinal transplantation over the past decade, the focus of clinicians and researchers is shifting from short-term patient survival to optimizing long-term outcomes. Current 5-year patient and graft survival rates after intestinal transplantation are 58% and 40%, respectively, in the US; single centers have reported nearly 80% patient and 60% graft survival rates at 5 years. The immunosuppression strategy in intestinal transplantation includes a tacrolimus-based regimen, usually in conjunction with an antibody induction therapy such as rabbit-antithymocyte globulin, interleukin-2 receptor antagonists, or alemtuzumab. The use of these immunosuppressive regimens, along with improved medical and surgical care, has contributed significantly toward improved outcomes. Optimization of post-transplant immunosuppression strategies to reduce adverse effects while minimizing acute and chronic graft rejection is a strong clinical and research focus.     

Considerations in sirolimus use in the early and late post-transplant periods

Sirolimus is an antiproliferative immunosuppressive agent that inhibits the mammalian target of rapamycin. It is highly effective in preventing acute renal allograft rejection and can be used with either calcineurin inhibitors, antimetabolites or corticosteroids. Early studies in renal transplantation have provided insight into optimal dosing strategies of sirolimus and of concomitant immunosuppressive agents. Familiarity with the adverse effect profile of sirolimus and pharmacokinetic and dynamic interactions with other immunosuppressive agents allows for earlier recognition and better management of sirolimus-related complications. The role of sirolimus in preserving long-term renal function, post-transplant malignancies and in prevention of atherosclerosis is currently being considered.     

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.     

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.     

Advances in personalized medicine and noninvasive diagnostics in solid organ transplantation

Personalized medicine has been a mainstay and in practice in transplant pharmacotherapy since the advent of the field. Decisions pertaining to the diagnosis, selection, and monitoring of transplant pharmacotherapy are aimed toward the individual, the allograft, and the overall immunologic needs of the patient. Recent advances in pharmacogenomics, noninvasive biomarkers, and artificial intelligence (AI) technologies have the promise of transforming the way we individualize treatment and monitor allograft function. Pharmacogenomic testing can provide clinicians with additional data that can minimize toxicity and maximize therapeutic dosing in high-risk patients, leading to more informed decisions that may decrease the risk of rejection and adverse outcomes related to immunosuppressive therapies. Development of noninvasive strategies to monitor allograft function may offer safer and more convenient methods to detect allograft injury. Cell free DNA and gene expression profiling offer the potential to serve as “liquid biopsies” minimizing the risk to patients and providing clinicians with useful molecular data that may help individualize immunosuppression and rejection treatment. Use of big data in transplant and novel AI platforms, such as the iBox, hold tremendous promise in providing clinicians a “glimpse into the future” thereby allowing for a more individualized approach to immunosuppressive therapy that may minimize future adverse outcomes. Advances in diagnostics, laboratory science, and AI have made the application of personalized medicine even more tailored for solid organ transplant recipients. In this perspective, we summarize the current and emerging tools available, literature supporting use, and the horizon for future personalization of transplantation.     

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.     

Immunosuppression trends in solid organ transplantation: The future of individualization,monitoring, and management

Immunosuppression regimens used in solid organ transplant have evolved significantly over the past 70 years in the United States. Early immunosuppression and targets for allograft success were measured by incidence and severity of allograft rejection and 1-year patient survival. The limited number of agents, infancy of human leukocyte antigen (HLA) matching techniques and lack of understanding of immunoreactivity limited the early development of effective regimens. The 1980s and 1990s saw incredible advancements in these areas, with acute rejection rates halving in a short span of time. However, the constant struggle to achieve the optimal balance between under- and overimmunosuppression is weaved throughout the history of transplant immunosuppression. The aim of this paper is to discuss the different eras of immunosuppression and highlight the important milestones that were achieved while also discussing this in the context of rational agent selection and regimen design. This discussion sets the stage for how we can achieve optimal long-term outcomes during the next era of immunosuppression, which will move from universal protocols to patient-specific optimization.     

Cyclosporin: a pharmacoeconomic evaluation of its use in renal transplantation

Cyclosporin is a powerful immunosuppressive agent which has markedly improved the outcome of renal transplantation, a technique now well established as the treatment of choice for patients with end-stage renal disease (ESRD). Comparison of cyclosporin-based regimens with a regimen of azathioprine and a glucocorticoid (conventional immunosuppression) indicates an improved clinical course and increased long term graft survival rate with cyclosporin which is most apparent in the recipients of a kidney from a living related donor (human leucocyte antigen mismatched) or cadaver donor source. Cyclosporin has also improved the clinical outcome in patient subgroups previously associated with a higher risk of graft failure with conventional immunosuppression, namely older patients and those with diabetes mellitus. Cost-of-treatment studies conducted over the first post-transplant year in the US have found that higher pharmacy charges with cyclosporin-based regimens are associated with lower hospitalisation charges and total billed charges compared with conventional immunosuppression. Lower hospitalisation charges reflect an improved post-transplant clinical course with cyclosporin and this has been associated with an improved quality of life in the recipients of a cadaver donor kidney. Longer term, the direct cost to society of using cyclosporin-based dual therapy (in combination with a glucocorticoid) may be higher than that with conventional immunosuppression, although the difference is likely to be small compared with the ongoing cost of dialysis. Clinical research continues to focus on modified regimens which maximise the clinical benefits of cyclosporin while minimising the associated adverse events, in particular the potential for nephrotoxicity. Sequential drug therapy (induction with globulin, azathioprine and a glucocorticoid followed by delayed administration of cyclosporin) has been associated with an improved clinical course compared with dual therapy, as well as cost containment to a level comparable to that for conventional immunosuppression. Compared with sequential therapy, triple drug therapy (cyclosporin, azathioprine plus a glucocorticoid) has been associated with a similar clinical course and lower acquisition cost during the first post-transplant year, although its overall impact on the longer term cost of transplantation has yet to be assessed. Elimination of cyclosporin from the immunosuppressive protocol of carefully selected patients can be safely achieved during the first post-transplant year. However, it remains to be established whether savings in the long term acquisition cost of immunosuppression are more than offset by the cost of treating a potentially less favourable clinical course.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

An update on chemical pharmacotherapy options for the prevention of kidney transplant rejection with a focus on costimulation blockade

Introduction: The introduction of calcineurin inhibitors (CNI) has greatly improved graft survival in the past three decades. However, long-term graft survival is still limited due to chronic allograft injury and side-effects of immunosuppressive medication.

Areas covered: The present overview gives an update on pharmacotherapeutic strategies after kidney transplantation. The main focus is on CNI-sparing regimens using co-stimulatory blockade and on new substances on the horizone.

Expert opinion: CNI sparing regimens are well-established. Complete CNI avoidance after kidney transplantation was often associated with impaired graft survival until the approval of the co-stimulation blocker belatacept for de novo immunosuppression after kidney transplantation. Concerns still exist with respect to severe T-cell-mediated rejection episodes in the early phase after transplantation. Thus, a triple drug regimen with CNI, mycophenolic acid and steroids still represents the gold-standard of immunosuppressive therapy. Alternative substances expand the possibilities of tailoring individual immunosuppression for different indications such as biopsy-proven CNI toxicity, polyoma virus BK nephropathy or CNI-triggered thrombotic microangiopathy. However, a change of the immunosuppressive therapy must always be balanced against each patient´s individual immunological risk in order to address the importance of chronic antibody-mediated rejection driven by donor specific antibodies (DSA).