Everolimus: preventing organ rejection in adult kidney transplant recipients

Heterotopic ossification is a common complication following total hip arthroplasty and surgery following acetabular trauma. It is associated with pain and a decreased range of movement. Prophylaxis is achieved by either non-steroidal anti-inflammatory drug treatment or localised irradiation therapy. The objective of this study was to evaluate the evidence for pharmacological agents used for the prophylaxis of heterotopic ossification following hip and acetabular surgery. The study used a comprehensive literature search to identify all major clinical studies investigating the pharmacological agents used in the prophylaxis of heterotopic ossification following hip and acetabular surgery. It was concluded that indometacin remains the ‘gold standard’ for heterotopic ossification prophylaxis following total hip arthroplasty and is the only drug proven to be effective against heterotopic ossification following acetabular surgery. Following total hip arthroplasty, other non-steroidal anti-inflammatory drugs, including naproxen and diclofenac, are equally as effective as indometacin and can be considered as alternative first-line treatments. Celecoxib is also of equal efficacy to indometacin and is associated with significantly fewer gastrointestinal side effects. However, serious concerns were raised over the safety of selective cyclooxygenase-2 inhibitors for the cardiovascular system and these should be used cautiously.     

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).     

Recent developments in the pharmacological treatment and prevention of corneal graft rejection

At present, given the high initial success rate of corneal transplantation (although late survival is poor), immunosuppression is often reserved for ‘high-risk’ patients. Despite immune privilege, corneal graft rejection remains the leading cause of corneal allograft failure. Interpreting the limited and also restricted design of most trials, immunosuppressive therapy has not enjoyed the success seen in solid organ grafts. This review discusses the limited data available whilst proposing newer therapies that have developed as a result of our increased understanding of the immunobiology of corneal graft rejection.     

New developments in immunosuppressive therapy for heart transplantation

Background: Heart transplantation is a well-established therapeutic option for many patients with end-stage heart disease. A major challenge in heart transplantation today is providing effective immunosuppression to prevent graft rejection while minimizing the many adverse effects of currently available therapies. Objective: To systematically review current immunosuppressive treatment strategies after heart transplantation and to review emerging drugs in various stages of development. Methods: A comprehensive literature review was performed using the online PubMed and Pharmaprojects databases. Results/conclusions: This article gives an overview of the immunosuppressive agents in current use, with a detailed review of emerging drugs with novel therapeutic targets.     

An update on the treatment options for focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is not a disease but a lesion initially affecting the podocyte. Various factors may induce ‘secondary’ FSGS, including defects in molecules that contribute to the podocyte slit diaphragm permselectivity to albumin. They do not represent indications for immunosuppression and require symptomatic treatment only, comprising angiotensin 2 and endothelin antagonists. Primary (idiopathic) FSGS is possibly but not certainly of immunologic origin, owing to an elusive glomerular permeability factor (GPF), explaining relapse on a renal transplant and justifying an immunosuppressive treatment. The best prognostic feature of primary nephrotic FSGS is its response to corticosteroids. Alkylating agents are mostly ineffective in steroid-resistant forms. An association of corticosteroids and cyclosporine A (CsA) remains the mainstay of treatment, with a good tolerability when CsA dosage is low. A definite advantage of tacrolimus on CsA has not yet been established. Sirolimus appears ineffective and potentially harmful. Azathioprine is not indicated. A number of mostly uncontrolled trials indicate that mycophenolate mofetil might find an adjunctive place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the GPF has not led to practical treatment options. Anecdotal reports on rituximab are as yet too few to determine whether this monoclonal anti-CD20 antibody will find a place in the treatment of primary FSGS.     

硼替佐米对大鼠肾移植AMR的保护作用及机制研究

目的研究硼替佐米对肾移植抗体介导排斥反应(AMR)的保护作用及机制。方法采用输血致敏法构建大鼠肾移植AMR模型。在此模型基础上,静脉注射硼替佐米,研究其对移植肾功能和病理损害的保护作用。流式细胞仪检测供体特异性抗体(DSA)的水平,免疫组织化学检测移植肾C4d表达,免疫荧光法检测CD68表达以反映巨噬细胞的浸润。结果硼替佐米可以明显改善肾移植AMR大鼠移植肾功能(P<0.05),减轻移植肾病理损害。硼替佐米显著降低大鼠肾移植AMR模型血清中IgM、IgG 2b和IgG 2c等DSA亚型的水平(P<0.05),同时抑制移植肾组织中C4d的表达和巨噬细胞浸润。结论硼替佐米对肾移植AMR具有明显的保护作用,其机制可能与抑制受体DSA产生及减少移植肾组织中巨噬细胞浸润有关。     

Everolimus and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK-binding protein 12

The calcineurin inhibitors cyclosporin A and tacrolimus and the inhibitors of the mTOR, sirolimus and everolimus bind immunophilins that are required for their immunosuppressive action. In contrast to cyclosporin A, tacrolimus and the mTOR inhibitors (MTIs) share common immunophilins, the FK506-binding proteins (FKBPs). We investigated the immunosuppressive interactions of MTIs on tacrolimus based immune suppression, since insights in immunological drug-drug interactions can be very relevant for optimization of immunosuppressive regimens in allograft transplantation medicine.Isolated peripheral blood mononuclear cells from healthy volunteers were incubated with combinations of MTIs and calcineurin inhibitors and when monitored for calcineurin activity and IL-2 excretion after mitogen stimulation, tacrolimus IC₅₀ concentrations shifted to higher concentrations in the presence of MTIs. This antagonism was absent for cyclosporin A, reproducible for 10 healthy volunteers (p < 0.001) and stronger for sirolimus than for everolimus. When cell lysate was treated with and without MTI, tacrolimus and FKBP12, FKBP12 could increase calcineurin inhibition by tacrolimus and reverse the MTI antagonism for both MTIs. These results demonstrate that FKBP12 can be rate limiting for calcineurin inhibition at high tacrolimus concentrations and that the antagonism of sirolimus and everolimus on tacrolimus based immune suppression is mediated via saturation of FKBP12.     

Preincubation With Everolimus and Sirolimus Reduces Organic Anion-Transporting Polypeptide (OATP)1B1- and 1B3-Mediated Transport Independently of mTOR Kinase Inhibition: Implication in Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions

Organic anion transporting polypeptides (OATP)1B1 and OATP1B3 mediate hepatic uptake of many drugs including lipid-lowering statins. Current studies determined the OATP1B1/1B3-mediated drug-drug interaction (DDI) potential of mammalian target of rapamycin (mTOR) inhibitors, everolimus and sirolimus, using R-value and physiologically based pharmacokinetic models. Preincubation with everolimus and sirolimus significantly decreased OATP1B1/1B3-mediated transport even after washing and decreased inhibition constant values up to 8.3- and 2.9-fold for OATP1B1 and both 2.7-fold for OATP1B3, respectively. R-values of everolimus, but not sirolimus, were greater than the FDA-recommended cutoff value of 1.1. Physiologically based pharmacokinetic models predict that everolimus and sirolimus have low OATP1B1/1B3-mediated DDI potential against pravastatin. OATP1B1/1B3-mediated transport was not affected by preincubation with INK-128 (10 μM, 1 h), which does however abolish mTOR kinase activity. The preincubation effects of everolimus and sirolimus on OATP1B1/1B3-mediated transport were similar in cells before preincubation with vehicle control or INK-128, suggesting that inhibition of mTOR activity is not a prerequisite for the preincubation effects observed for everolimus and sirolimus. Nine potential phosphorylation sites of OATP1B1 were identified by phosphoproteomics; none of these are the predicted mTOR phosphorylation sites. We report the everolimus/sirolimus-preincubation-induced inhibitory effects on OATP1B1/1B3 and relatively low OATP1B1/1B3-mediated DDI potential of everolimus and sirolimus.