Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial

Abstract

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

The Effect of Immunosuppression on Coagulation After Liver Transplantation

“…Moreover, in the present study, we further studied our patient populations and identified triggering factors, such as infection, surgical procedures, or increased plasma levels of factor VIII, that may have induced these thromboembolic complications. The 24‐month randomized controlled Mycophenolate sodium vs. Everolimus or Cyclosporine with Allograft Nephropathy as Outcome (MECANO) trial of the administration of EVR to renal transplant recipients found more cardiovascular complications and more events of venous thrombosis and lung embolus among the patients treated with EVR in combination with prednisone; these results confirm those of our study . Even so, our study is a retrospective analysis with all of the common limitations of this study design, such as the various observational times of the groups, and these limitations may bias the results.…”

“…Currently, EVR is commonly used after LT because of its beneficial nephroprotective, antiviral, and antiproliferative effects . Sirolimus has received black‐box warnings related to death and graft loss in LT, and concerns have thus been raised about mTOR inhibitors regarding thromboembolic complications mainly on the basis of studies showing an increased thromboembolic risk for sirolimus . In lung transplant recipients, sirolimus caused an increased risk for venous thromboembolism, whereas in LT patients, sirolimus was responsible for a higher incidence of artery and portal vein thrombosis .…”

“…However, in kidney transplantation patients, there were more cardiovascular complications and venous thrombosis in those treated with EVR . Baas et al observed a procoagulant state in the presence of EVR .…”

“…Despite these beneficial effects, it has been suggested that mTOR inhibitors may affect coagulation, thereby resulting in an increased risk of venous thromboembolism (15) or cardiovascular complications. (16) A prospective, multicenter, randomized study involving LT recipients found a significantly higher incidence of venous thromboembolism among patients treated with the mTOR inhibitor sirolimus. (15) LT recipients treated with sirolimus exhibited a higher occurrence of both hepatic artery thrombosis and portal vein thrombosis.…”

Hyaluronic Acid-Decorated Chitosan Nanoparticles for CD44-Targeted Delivery of Everolimus

“…EVE is successfully used in combination with cyclosporine and corticosteroids both in adult and paediatric population of renal- and cardiac-transplant recipients, but far less often for lung-transplant recipients [4,5,6,7]. Particularly for these patients, survival continues to be challenged by chronic allograft dysfunctions, such as obliterative bronchiolitis or its clinical correlate bronchiolitis obliterans syndrome (BOS), a fibrous obliteration of small airways caused by mesenchymal cells (MSc) abnormal proliferation, and extracellular matrix deposition causing bronchiolar occlusion and organ rejection [8,9,10,11].…”