Jamal Bamoulid

The need for minimization strategies: current problems of immunosuppression.

New immunosuppressants and the better use of immunosuppressant combination therapy have led to significant improvements in renal allograft outcomes over the last decades. Yet, despite dramatic reduction in rejection rates and improvement in 1‐year graft survival, long‐term graft attrition rates remained rather constant. Current immunosuppressant combinations are frequently leading to overimmunosuppression and are increasing cardiovascular risk. Importantly, calcineurin inhibitors are nephrotoxic, contribute to cardiovascular risk and chronic allograft dysfunction. Furthermore, immunosuppressant‐associated toxicities aggravate immune‐mediated nephron injury and side effects lead to nonadherence, an identified important reason for late acute and chronic antibody‐mediated rejections. The frequent development of a chronic humoral response indicates rather insufficient immunosuppression of current combinations than simple under‐immunosuppression. While there is no evidence that increasing immunosuppressive doses will improve outcomes or reduce de novo HLA‐antibody formation, there is clear evidence that adequate minimization strategies will reduce side effect burden. Because of low rejection risk, but frequent side effects, drug minimization is particularly relevant for the many maintenance patients. In summary, new therapeutic strategies need to be developed from adequately powered clinical trials for reduction of the many side effects of immunosuppressants. Such evidence‐based and time‐dependent immunosuppressive minimization strategies are needed to achieve better long‐term outcomes in the future.

The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts that develop de novo thrombotic microangiopathy.

Antibody‐mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co‐presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing.

Need for optimized immunosuppression in elderly kidney transplant recipients

UNLABELLED The proportion of elderly kidney transplant candidates is increasing worldwide due to higher number of patients with end-stage renal disease in aging societies. ALLOCATION Accordingly, organ allocation policies in this population were adjusted in several countries. The European Senior Program is the most prominent example, where elderly patients (≥65years) receive elderly (≥65years) donor organs with acceptable results. IMMUNOSENESCENCE Because of age-dependent changes in the immune response and higher susceptibility to immunosuppressant side effects, outcomes in elderly patients are different compared to younger kidney transplant recipients. However, elderly patients do reject, especially poorly matched elderly donor organs. This warrants tailored immunosuppressive regimes with regard to the age-related changes of the immune system. SIDE EFFECTS Rejection therapies may have detrimental side effects in the seniors and are frequently leading to over-immunosuppression (malignancy and infections) in long-term therapy. It is hypothesized that after initial graft adaptation elderly patients may benefit from less immunosuppression in order to lower cancer risk and reduce infection rates and cardiovascular comorbidities. LACK OF DATA Current evidence on recommended standard immunosuppressive therapy was mainly derived from trials, where elderly patients were excluded or only a minority. In order to improve immunosuppressive therapy in elderly transplant recipients, current immunosuppressive regimes have to be re-investigated in this growing population. Up to date, only a few well-designed prospective studies were performed in elderly populations and demonstrate the need for effective immunosuppression in the first months after transplantation. CONCLUSION It is evident that novel treatment strategies and adequately powered prospective clinical trials are needed to establish time-adapted immunosuppressive regimens according to the needs of this vulnerable group of kidney transplant recipients.

Advances in pharmacotherapy to treat kidney transplant rejection.

Introduction: Current immunosuppressive combination therapy provides excellent prevention of T-cell-mediated rejection following renal transplantation; however, antibody-mediated rejection remains of high concern and accounts for a large number of long-term allograft losses. The recent development of protocol biopsies resulted in the definition of subclinical rejection (SCR), showing histologic evidence for rejection but unremarkable clinical course. Areas covered: This review describes the current knowledge and evidence of pharmacotherapy to treat kidney allograft rejections and covers SCR treatment options. Each substance is analyzed with regard to its classical indication and further discussed for the treatment of other forms of rejection. Expert opinion: Despite a lack of randomized trials, early acute T-cell-mediated rejection can be treated effectively in most cases without graft loss. The necessity to treat SCR is currently unclear. Due to a lack of effective therapies, new treatment approaches for antibody-mediated rejection are an urgent medical need to improve long-term outcomes. Future research should aim to better define pathophysiology and histology, stratify risk, and develop rational treatment strategies from randomized controlled trials, in order to establish the value of novel therapies in the arsenal of rejection pharmacotherapy. However, the effective prevention of rejection with minimal side effects still remains the goal in immunosuppression.

Immunsuppression und Ergebnisse in der Nierentransplantation

BACKGROUND Current immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality. OBJECTIVES The purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival. METHODS Review of the current topic-related literature and discussion of our own experience. RESULTS The use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials. CONCLUSIONS Current immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.ZusammenfassungHintergrundModerne Immunsuppressiva ermöglichen eine effektive Prophylaxe von Abstoßungsreaktionen und erlauben bei der Mehrzahl der Patienten eine erfolgreiche Nierentransplantation. Negative Effekte der Langzeitimmunsuppression und die Toxizität der eingesetzten Präparate führen jedoch zu einer erheblichen Steigerung der Morbidität und Mortalität.FragestellungEs sollen Grundprinzipien der Immunsuppression mit den aktuell eingesetzten Medikamenten und Strategien zur Vermeidung von toxischen Effekten vorgestellt werden.Material und MethodeEine Auswertung der relevanten Primär- und Sekundärliteratur wird vorgestellt und eigene Erfahrungen diskutiert.ErgebnisseDurch Anwendung einer 4fach-Immunsuppression mit Antikörperinduktion, Calcineurininhibitoren, Mycophenolsäurepräparaten und Steroiden werden 1-Jahres-Überlebensraten von bis zu 95 % erreicht. Limitierende Effekte bestehen im vermehrten Auftreten von Infektionen, Malignomen und kardiovaskulären Erkrankungen. Das Transplantatüberleben wird durch die toxischen Effekte der Immunsuppressiva und die Bildung donorspezifischer Antikörper begrenzt. Eine Minimierung der unerwünschten Effekte kann durch Reduktion der kumulativen Gesamtexposition oder durch gezielte Reduktion von Calcineurininhibitoren und Steroiden erreicht werden. Mit den mTOR-Inhibitoren („mechanistic target of rapamycin“) und Belatacept stehen alternative Immunsuppressiva zur Verfügung deren Effektivität jedoch noch in Langzeitstudien überprüft werden muss.SchlussfolgerungAktuelle Immunsuppressionsschemata ermöglichen eine effektive Rejektionsprophylaxe, sind aber mit erheblichen negativen Auswirkungen verbunden. Neue Immunsuppressiva und optimierte Minimierungsstrategien können in Zukunft zu einer Verbesserung des Langzeitergebnisses nach Nierentransplantation beitragen.AbstractBackgroundCurrent immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality.ObjectivesThe purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival.MethodsReview of the current topic-related literature and discussion of our own experience.ResultsThe use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials.ConclusionsCurrent immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.

Immunosuppression and its use in kidney transplantation

BACKGROUND Current immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality. OBJECTIVES The purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival. METHODS Review of the current topic-related literature and discussion of our own experience. RESULTS The use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials. CONCLUSIONS Current immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.ZusammenfassungHintergrundModerne Immunsuppressiva ermöglichen eine effektive Prophylaxe von Abstoßungsreaktionen und erlauben bei der Mehrzahl der Patienten eine erfolgreiche Nierentransplantation. Negative Effekte der Langzeitimmunsuppression und die Toxizität der eingesetzten Präparate führen jedoch zu einer erheblichen Steigerung der Morbidität und Mortalität.FragestellungEs sollen Grundprinzipien der Immunsuppression mit den aktuell eingesetzten Medikamenten und Strategien zur Vermeidung von toxischen Effekten vorgestellt werden.Material und MethodeEine Auswertung der relevanten Primär- und Sekundärliteratur wird vorgestellt und eigene Erfahrungen diskutiert.ErgebnisseDurch Anwendung einer 4fach-Immunsuppression mit Antikörperinduktion, Calcineurininhibitoren, Mycophenolsäurepräparaten und Steroiden werden 1-Jahres-Überlebensraten von bis zu 95 % erreicht. Limitierende Effekte bestehen im vermehrten Auftreten von Infektionen, Malignomen und kardiovaskulären Erkrankungen. Das Transplantatüberleben wird durch die toxischen Effekte der Immunsuppressiva und die Bildung donorspezifischer Antikörper begrenzt. Eine Minimierung der unerwünschten Effekte kann durch Reduktion der kumulativen Gesamtexposition oder durch gezielte Reduktion von Calcineurininhibitoren und Steroiden erreicht werden. Mit den mTOR-Inhibitoren („mechanistic target of rapamycin“) und Belatacept stehen alternative Immunsuppressiva zur Verfügung deren Effektivität jedoch noch in Langzeitstudien überprüft werden muss.SchlussfolgerungAktuelle Immunsuppressionsschemata ermöglichen eine effektive Rejektionsprophylaxe, sind aber mit erheblichen negativen Auswirkungen verbunden. Neue Immunsuppressiva und optimierte Minimierungsstrategien können in Zukunft zu einer Verbesserung des Langzeitergebnisses nach Nierentransplantation beitragen.AbstractBackgroundCurrent immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality.ObjectivesThe purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival.MethodsReview of the current topic-related literature and discussion of our own experience.ResultsThe use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials.ConclusionsCurrent immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.

Immunsuppression und Ergebnisse in der Nierentransplantation@@@Immunosuppression and its use in kidney transplantation

BACKGROUND Current immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality. OBJECTIVES The purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival. METHODS Review of the current topic-related literature and discussion of our own experience. RESULTS The use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials. CONCLUSIONS Current immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.ZusammenfassungHintergrundModerne Immunsuppressiva ermöglichen eine effektive Prophylaxe von Abstoßungsreaktionen und erlauben bei der Mehrzahl der Patienten eine erfolgreiche Nierentransplantation. Negative Effekte der Langzeitimmunsuppression und die Toxizität der eingesetzten Präparate führen jedoch zu einer erheblichen Steigerung der Morbidität und Mortalität.FragestellungEs sollen Grundprinzipien der Immunsuppression mit den aktuell eingesetzten Medikamenten und Strategien zur Vermeidung von toxischen Effekten vorgestellt werden.Material und MethodeEine Auswertung der relevanten Primär- und Sekundärliteratur wird vorgestellt und eigene Erfahrungen diskutiert.ErgebnisseDurch Anwendung einer 4fach-Immunsuppression mit Antikörperinduktion, Calcineurininhibitoren, Mycophenolsäurepräparaten und Steroiden werden 1-Jahres-Überlebensraten von bis zu 95 % erreicht. Limitierende Effekte bestehen im vermehrten Auftreten von Infektionen, Malignomen und kardiovaskulären Erkrankungen. Das Transplantatüberleben wird durch die toxischen Effekte der Immunsuppressiva und die Bildung donorspezifischer Antikörper begrenzt. Eine Minimierung der unerwünschten Effekte kann durch Reduktion der kumulativen Gesamtexposition oder durch gezielte Reduktion von Calcineurininhibitoren und Steroiden erreicht werden. Mit den mTOR-Inhibitoren („mechanistic target of rapamycin“) und Belatacept stehen alternative Immunsuppressiva zur Verfügung deren Effektivität jedoch noch in Langzeitstudien überprüft werden muss.SchlussfolgerungAktuelle Immunsuppressionsschemata ermöglichen eine effektive Rejektionsprophylaxe, sind aber mit erheblichen negativen Auswirkungen verbunden. Neue Immunsuppressiva und optimierte Minimierungsstrategien können in Zukunft zu einer Verbesserung des Langzeitergebnisses nach Nierentransplantation beitragen.AbstractBackgroundCurrent immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality.ObjectivesThe purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival.MethodsReview of the current topic-related literature and discussion of our own experience.ResultsThe use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials.ConclusionsCurrent immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.