Prevention, Diagnosis and Treatment of Acute Kidney Transplant Rejection

Kidney transplant rejection is complex clinical problem with long-lasting consequences for the patient. The focus of this thesis is optimization of the maintenance immunosuppressive therapy, diagnosis and treatment of kidney transplant rejection. The conclusions of this thesis are: __i)__ belatacept remains a promising immunosuppressive drug for subgroups of kidney transplant recipients, for instance in patients with post-transplantation diabetes mellitus, but a more tailored st

Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation

Alemtuzumab is a humanized monoclonal antibody against CD52 and causes depletion of T and B lymphocytes, monocytes, and NK cells. Alemtuzumab is registered for the treatment of multiple sclerosis (MS) and is also used in chronic lymphocytic leukemia (CLL). Alemtuzumab is used off-label in kidney transplantation as induction and anti-rejection therapy. The objective of this review is to present a review of the pharmacokinetics, pharmacodynamics, and use of alemtuzumab in kidney transplantation. A systematic literature search was conducted using Ovid Medline, Embase, and Cochrane Central Register of controlled trials. No pharmacokinetic or dose-finding studies of alemtuzumab have been performed in kidney transplantation. Although such studies were conducted in patients with CLL and MS, these findings cannot be directly extrapolated to transplant recipients, because CLL patients have a much higher load of CD52-positive cells and, therefore, target-mediated clearance will differ between these two indications. Alemtuzumab used as inductio

Costimulation Blockade in Kidney Transplant Recipients

Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications

Costimulation Blockade in Kidney Transplant Recipients

Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications

Clinical and Molecular Profiling to Develop a Potential Prediction Model for the Response to Alemtuzumab Therapy for Acute Kidney Transplant Rejection

Alemtuzumab, a monoclonal antibody that depletes CD52‐bearing immune cells, is an effective drug for the treatment of severe or glucocorticoid‐resistant acute kidney transplant rejection (AR). Patient‐specific predictions on treatment response are, however, urgently needed, given the severe side effects of alemtuzumab. This study developed a multidimensional prediction model with the aim of generating clinically useful prognostic scores for the response to alemtuzumab. Clinical and histological characteristics were collected retrospectively from patients who were treated with alemtuzumab for AR. In addition, targeted gene expression profiling of AR biopsy tissues was performed. Least absolute shrinkage and selection operator (LASSO) logistic regression modeling was used to construct the ALEMtuzumab for Acute Rejection (ALEMAR) prognostic score. Response to alemtuzumab was defined as patient and allograft survival and at least once an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m(2) during the first 6 months after treatment. One hundred fifteen patients were included, of which 84 (73%) had a response to alemtuzumab. The ALEMAR‐score accurately predicted the chance of response. Gene expression analysis identified 13 differentially expressed genes between responders and nonresponders. The combination of the ALEMAR‐score and selected genes resulted in improved predictions of treatment response. The present preliminary prediction model is potentially helpful for the development of stratified alemtuzumab treatment for acute kidney transplant rejection but requires validation

Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms

The introduction of immunosuppressant belatacept, an inhibitor of the CD28-80/86 pathway, has improved 1-year outcomes in kidney transplant recipients with preexistent diabetes mellitus and has also reduced the risk of posttransplant diabetes mellitus. So far, no studies have compared a tacrolimus-based with a belatacept-based immunosuppressive regimen with regard to improving glucose tolerance after kidney transplantation. Here, we present the case of a 54-year-old man with type 2 diabetes mellitus who was converted from belatacept to tacrolimus 1 year after a successful kidney transplantation. Thereafter, he quickly developed severe hyperglycemia, and administration of insulin was needed to improve metabolic control. Six months after this episode, he was converted back to belatacept because of nausea, diarrhea, and hyperglycemia. After switching back to belatacept and within 4 days aft

A Decade of Experience With Alemtuzumab Therapy for Severe or Glucocorticoid-Resistant Kidney Transplant Rejection

Alemtuzumab is used as lymphocyte-depleting therapy for severe or glucocorticoid-resistant kidney transplant rejection. However, the long-term efficacy and toxicity of alemtuzumab therapy are unclear. Therefore, all cases of alemtuzumab anti-rejection therapy between 2012 and 2022 in our institution were investigated. Graft survival, graft function, lymphocyte depletion, serious infections, malignancies, and patient survival were analyzed and compared with a reference cohort of transplanted patients who did not require alemtuzumab anti-rejection therapy. A total of 225 patients treated with alemtuzumab were identified and compared with a reference cohort of 1,668 patients. Over 60% of grafts was salvaged with alemtuzumab therapy, but graft survival was significantly poorer compared to the reference cohort. The median time of profound T- and B lymphocyte depletion was 272 and 344 days, respectively. Serious infection rate after alemtuzumab therapy was 54.1/100 person-years. The risk of death (hazard ratio 1.75, 95%-CI 1.28–2.39) and infection-related death (hazard ratio 2.36, 95%-CI 1.35–4.11) were higher in the alemtuzumab-treated cohort. In conclusion, alemtuzumab is an effective treatment for severe kidney transplant rejection, but causes long-lasting lymphocyte depletion and is associated with frequent infections and worse patient survival outcomes.</p