Current Pharmaceutical Design - Volume 26, Issue 28, 2020

Heart transplantation is the standard of therapy for patients with end-stage heart disease. Since the first human-to-human heart transplantation, performed in 1967, advances in organ donation, surgical techniques, organ preservation, perioperative care, immunologic risk assessment, immunosuppression agents, monitoring of graft function and surveillance of long-term complications have drastically increased recipient survival. However, there are yet many challenges in the modern era of heart transplantation in which immunosuppression may play a key role in further advances in the field. A fine-tuning of immune modulation to prevent graft rejection while avoiding side effects from over immunosuppression has been the vital goal of basic and clinical research. Individualization of drug choices and strategies, taking into account the recipient's clinical characteristics, underlying heart failure diagnosis, immunologic risk and comorbidities seem to be the ideal approaches to improve post-transplant morbidity and survival while preventing both rejection and complications of immunosuppression. The aim of the present review is to provide a practical, comprehensive overview of contemporary immunosuppression in heart transplantation. Clinical evidence for immunosuppressive drugs is reviewed and practical approaches are provided. Cardiac allograft rejection classification and up-to-date management are summarized. Expanding therapies, such as photophoresis, are outlined. Drug-to-drug interactions of immunosuppressive agents focused on cardiovascular medications are summarized. Special situations involving heart transplantation such as sarcoidosis, Chagas diseases and pediatric immunosuppression are also reviewed. The evolution of phamacogenomics to individualize immunosuppressive therapy is described. Finally, future perspectives in the field of immunosuppression in heart transplantation are highlighted.

Long term survival and quality of life after lung transplantation are still affected by the development of chronic lung graft dysfunction (CLAD). CLAD is the number one cause of death one year after transplant; and there is no effective therapy available to date. Transplant centers’ approaches include perioperative immunosuppression, maintenance immunosuppression, and the treatment of eventual rejection. This review will focus on maintenance immunosuppression and the available data that support these strategies, as well as a brief description of our desensitization protocol and immunologic risk stratification. Optimization of immunosuppression is key to increase survival and graft function in transplant recipients, mostly through the combination of drugs. Since the therapeutic options to manage CLAD are still very limited, more studies are necessary to test new therapies and to clarify the potential role of new agents.

Background: Novel drugs and combinations for immunosuppression (IS) after liver transplantation is one main reason for improved graft and patient survival seen in the last decades. The backbone of IS is still steroids and calcineurin inhibitors, although novel drugs are being introduced, such as the mammalian target of rapamycin inhibitors (mTOR inhibitor). The challenge today, along with increased patient survival, is the adverse effects of long-term use of immunosuppressive drugs, mainly nephrotoxicity and other serious adverse effects. Concepts: The ultimate outcome after liver transplantation would be achieving tolerance, a state where all IS can be withdrawn. In the meantime, different approaches to reduce and withdraw IS have been tested out in different clinical trials with the aim to reduce the adverse effects of steroids and calcineurin inhibitors. This has formed the basis of today’s clinical practice. The different combinations of immunosuppressive drugs have included mTOR inhibitor such as everolimus and different induction drugs such as anti-interleukin 2 receptor antibodies. Regarding induction drugs, lymphocyte depleting (alemtuzumab and ATG) and non-depleting agents, such as basiliximab, have shown advantageous effects. Summary: Alongside steroid and calcineurin inhibitors reduction or elimination, current strategies for post-liver transplantation immunosuppression explore combinations of novel agents. The gauge (or yardstick) here is the fine balance between the adverse effects of IS drugs and the risk of rejection. Long-term maintenance IS regimens, development of tolerance and antibody-mediated rejection are also discussed in this review.

The last decades have witnessed a significant improvement in the field of pediatric liver transplantation (LT), resulting in longer patient and graft survival; adequate graft selection, surgical refinement, the use of live donors and optimal postoperative care are among the reasons why pediatric recipients are living longer. With this new condition, pediatric recipients are now more exposed to the deleterious effects of immunosuppression, including metabolic, infectious and neoplastic complications, nephrotoxicity and neurotoxicity. Due to all those particularities, the approach to avoid overimmunosuppression or underimmunosuppression may be more difficult in children than in adult recipients. Moreover, pediatric recipients are exposed to growth issues and specific problems during adolescence, like nonadherence to immunosuppressive therapy. This article highlights the current immunosuppressive strategies for pediatric liver transplant recipients.

ABO-incompatible (ABO-I) liver transplantation (LT) has been limited due to the increased rate of complications, including severe cellular and antibody-mediated rejection, hepatic necrosis, hepatic artery thrombosis, and biliary complications. However, several strategies for reducing preformed anti-donor ABO antibodies and B cell desensitization have improved the outcomes of ABO-I LT. As a result, ABO-I LT has become a routine procedure and is a feasible option in countries with a scarce deceased-organ donation or in cases without an available compatible organ donor. In this review, we describe past and present desensitizing protocols as well as emergent therapies for depleting B cell and anti-ABO antibodies with the objective of identifying approaches that could lead to new, refined strategies for maximizing the results of ABO-I LT.

Visceral transplant represents an immunologic challenge due to high intestinal graft immunogenicity. Over the last 20 years, significant advances in immunosuppression regimens have resulted in excellent short-term outcomes. Currently, visceral transplant is the standard of care for patients with gut failure having life-threatening complications and complex abdominal pathology. In this review, we describe immunosuppressive strategies in the visceral transplant field.

Background: Despite improved overall outcomes, rejection continues to occur frequently after pancreas transplantation. Objective: To review the literature and to provide a state-of-the-art assessment of current practice and developments of immunosuppressive regimens in pancreas transplantation. Methods: The literature was reviewed and relevant articles were retrieved and analyzed. Results: Induction therapy is used in approximately 90% of the transplants, with T-cell depleting antibodies being the prevalent therapy (>90%). Despite the initial enthusiasm on steroid-free regimens, maintenance protocols continue to be mostly based on a combination of steroids, tacrolimus, and mycophenolate mofetil. Tacrolimus is used in the majority of recipients. Sirolimus is rarely used at the time of transplant and is introduced later on in approximately 10% of the recipients, mostly in the context of a switching strategy to address the side effects of calcineurin inhibitors. The overall quality of published studies was quite low, because of the retrospective design, the heterogeneity of study groups with respect to PTx categories, the inclusion of mixed recipient categories with respect to immunologic risk profile, and the use of non-standardized concurrent immunosuppressive therapies. In addition, most reported studies were clearly underpowered, and treatment outcomes were not standardized. Conclusion: Since approximately two decades, immunosuppression in pancreas transplantation mostly consists of induction with depleting antibodies and maintenance therapy using a combination of steroids, tacrolimus, and mycophenolate mofetil. While true novelty would be very much needed, this review confirms the wide use and the clinical efficacy of this regimen.

Currently, kidney transplantation is the best treatment option for kidney failure for a majority of eligible patients. It is associated with a better quality of life and reduced mortality as compared to staying on dialysis. Many of the improvements in kidney transplant outcomes, observed in recent decades, are due to more efficient immunosuppression strategies. Therefore, developing expertise in the management of immunosuppressive drugs is key to the success of kidney transplantation. In this review, the historical aspects of organ transplant immunosuppression are briefly addressed and the basis of the allograft immune response to contextualize the main topic is provided, which is a deeper view of the immunosuppressive agents, including their known mechanisms of action, pharmacokinetics, interactions, toxicities, and clinical use. The most commonly used immunosuppressive protocols employed based on patients' and donors' characteristics are also presented here.

Kidney transplantation is a preferable treatment of children with end-stage kidney disease. All kidney transplant recipients, including pediatric need immunosuppressive medications to prevent rejection episodes and graft loss. Induction therapy is used temporarily only immediately following transplantation while maintenance immunosuppressive drugs are started and given long-term. There is currently no consensus regarding the use of induction therapy in children; its use should be decided based on the immunological risk of the child. The recent progress shows that the recommended strategy is to use as maintenance immunosuppressive therapy a combination of a calcineurin inhibitor (preferably tacrolimus) with an antiproliferative drug (preferably mycophenolate mofetil) with steroids that can be withdrawn early or late in low-risk children. The mTOR-inhibitors (sirolimus, everolimus) are used rarely in pediatrics because of common side effects and no evidence of a benefit over calcineurin inhibitors. The use of calcineurin inhibitors, mycophenolate, and mTOR-inhibitors should be followed by therapeutic drug monitoring. Immunosuppressive therapy of acute rejection consists of high-dose steroids and/or anti-lymphocyte antibodies (T-cell mediated rejection) or plasma exchange, intravenous immunoglobulines and/or rituximab (antibodymediated rejection). The future strategies for research are mainly precise characterisation of children needing induction therapy, more specific indications for mTOR-inhibitors and for the far future, the possibility to reach the immuno tolerance.

The organ shortage for kidney transplantation remains a challenging issue worldwide. Incompatibility between donor-recipient pairs, commonly occurring among transplant candidates who were sensitized from prior antigen exposure, serves as a significant barrier to kidney transplantation. In efforts to overcome this obstacle, living and deceased donor kidney transplantation across human leukocyte antigen barriers following desensitization has been pursued via positive crossmatch transplantation. The goal of desensitization therapy is to remove or denigrate donor-specific alloantibodies prior to transplantation in order to permit transplantation across the human leukocyte antigen barrier and prevent rejection. Various desensitization regimens have been utilized, including the use of plasmapheresis, intravenous immunoglobulin, and or immunoadsorption. Although long-term allograft outcomes for positive crossmatch kidney transplantation following desensitization therapy have been shown to be inferior to compatible transplantation, particularly with increasing strength of the crossmatch, there is an established survival benefit for positive crossmatch transplant recipients compared with remaining on the transplant waitlist. However, positive crossmatch transplantation may confer higher risks of infection and malignancy. Despite the fact that some of these heightened risks, positive crossmatch transplantation has also been demonstrated to have cost-savings compared with remaining on dialysis and may, therefore, be a cost-effective treatment option for sensitized patients who would face long waiting times and may never be able to achieve compatible transplantation. This review highlights both the risks and benefits of positive crossmatch transplantation and its role in the broader field of kidney transplantation.

Although acute renal graft rejection rate has declined in the last years, and because an adequate therapy can improve graft outcome, its therapy remains as one of the most significant challenges for pharmacists and physicians taking care of transplant patients. Due to the lack of evidence highlighted by the available metaanalyses, we performed a narrative review focused on the basic mechanisms and current and future therapies of acute rejection in kidney transplantation. According to Kidney Disease/Improving Global Outcomes (KDIGO) guidelines, both clinical and subclinical acute rejection episodes should be treated. Usually, high dose steroids and basal immunosuppression optimization are the first line of therapy in treating acute cellular rejection. Rabbit antithymocytic polyclonal globulins are used as rescue therapy for recurrent or steroid-resistant cellular rejection episodes. Current standard-of-care (SOC) therapy for acute antibody-mediated rejection (AbMR) is the combination of plasma exchange with intravenous immunoglobulin (IVIG). Since a significant rate of AbMR does not respond to SOC, different studies have analyzed the role of new drugs such as Rituximab, Bortezomib, Eculizumab and C1 inhibitors. Lack of randomized controlled trials and heterogenicity among performed studies limit obtaining definite conclusions. Data about new direct and indirect B cell and plasma cell depleting agents, proximal and terminal complement blockers, IL-6/IL-6R pathway inhibitors and antibody removal agents, among other promising drugs, are reviewed.

Cytomegalovirus is the classic opportunistic infection after solid organ transplantation. This review will discuss updates and future directions in the diagnosis, prevention and treatment of CMV infection in solid organ transplant recipients. Antiviral prophylaxis and pre-emptive therapy are the mainstays of CMV prevention, but they should not be mutually exclusive and each strategy should be considered depending on a specific situation. The lack of a widely applicable viral load threshold for diagnosis and preemptive therapy is emphasized as a major factor that should pave the way for an individualized approach to prevention. Valganciclovir and intravenous ganciclovir remain as drugs of choice for CMV management, and strategies for managing drug-resistant CMV infection are enumerated. There is increasing use of CMV-specific cell-mediated immune assays to stratify the risk of CMV infection after solid organ transplantation, and their potential role in optimizing CMV prevention and treatment efforts is discussed.