Time-Dependent and Immunosuppressive Drug-Associated Adverse Event Profiles in De Novo Kidney Transplant Recipients Converted from Tacrolimus to Sirolimus Regimens.

To evaluate the safety and tolerability of immunosuppressive drugs used in a planned randomized conversion from a calcineurin inhibitor, tacrolimus, to a mammalian target of rapamycin inhibitor, sirolimus, in de novo kidney transplant recipients. Prospective safety analysis of data from a prospective, randomized, open-label, controlled study. A total of 119 adult kidney transplant recipients who received tacrolimus (TAC), mycophenolate sodium (MPS), and prednisone between February 2008 and May 2010; after 3 months of this regimen, 60 of these patients were randomized to conversion from TAC to sirolimus (SRL/MPS group), and 59 patients continued with the TAC regimen (TAC/MPS group). Both groups were followed for 24 months after transplantation for immunosuppressive regimen-associated and time-dependent occurrences of adverse events (AEs) and serious adverse events (SAEs). Before conversion from TAC to SRL, the cumulative incidence of AEs was 98%; 25% were SAEs. Gastrointestinal AEs (66%) and infections (58%) were the most frequent AEs. The incidences of TAC and MPS dose reductions due to AEs were 1.7% and 12%, respectively. After conversion, no significant differences were noted in the SRL/MPS group versus the TAC/MPS group in the cumulative incidences of AEs (100% vs. 98%) and SAEs (27% vs. 30%). The most common AEs were gastrointestinal (70% vs. 54%, p=0.23) and infection (77% vs. 73%, p=0.79) in the SRL/MPS versus TAC/MPS groups. The incidence of aphthous ulcer (28% vs. 0%, p=< 0.01), sinusitis (10% vs. 0%, p=0.01), dermatitis (15% vs. 3%, p=0.03), and dyslipidemia (35% vs. 14%, p=0.02) were higher in the SRL/MPS group compared with the TAC/MPS group. Cox proportion regression analysis showed a higher relative risk for gastrointestinal (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.01, p<0.05) and skin and subcutaneous tissue (HR 2.5, 95% CI 1.1-4.1, p<0.05) AEs in the SRL/MPS group compared with the TAC/MPS group. AE-related dose reductions occurred in 18.3% of patients receiving SRL and 3.3% of patients receiving TAC. MPS dose reductions due to AEs occurred in 11.7% of patients receiving SRL and 13.6% of patients receiving TAC. SRL/MPS treatment was associated with a time-dependent higher incidence of gastrointestinal and skin and subcutaneous tissue AEs, which occurred mainly during the first 6 months after conversion from TAC/MPS. Although the treatments with SRL or TAC after 3 months of transplantation showed different safety profiles, both regimens demonstrated adequate tolerability, with low rates of early discontinuation related to AEs.

Felix MJ ，Felipe CR ，Tedesco-Silva H ，Osmar Medina-Pestana J ... -  《-》

Subclinical Lesions and Donor-Specific Antibodies in Kidney Transplant Recipients Receiving Tacrolimus-Based Immunosuppressive Regimen Followed by Early Conversion to Sirolimus.

de Sandes-Freitas TV ，Felipe CR ，Campos ÉF ，de Lima MG ，Soares MF ，de Franco MF ，Aguiar WF ，Tedesco-Silva H ，Medina-Pestana JO ... -  《-》

Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes.

Anil Kumar MS ，Irfan Saeed M ，Ranganna K ，Malat G ，Sustento-Reodica N ，Kumar AM ，Meyers WC ... -  《TRANSPLANT IMMUNOLOGY》

Tacrolimus with mycophenolate mofetil or sirolimus compared with calcineurin inhibitor-free immunosuppression (sirolimus/mycophenolate mofetil) after heart transplantation: 5-year results.

Despite improvements in immunosuppressive therapy, the most advantageous combination for cardiac transplant recipients has not been established. This randomized controlled trial was performed to evaluate the efficacy and safety of 3 immunosuppressive protocols. Between 2003 and 2005, 78 de novo cardiac transplant recipients were randomized 2:2:1 to receive steroids and tacrolimus plus mycophenolate mofetil (TAC/MMF; n = 34), TAC and sirolimus (TAC/SRL; n = 29), or SRL and MMF (SRL/MMF) plus anti-thymocyte globulin (ATG; n = 15). Steroids were withdrawn after 6 months. The 5-year survival was 85.3% for TAC/MMF, 93.1% for TAC/SRL, and 86.7% for SRL/MMF (p = 0.31 for TAC/MMF vs TAC/SIR; p = 0.47 for TAC/MMF vs SIR/MMF and p = 0.86 for TAC/SIR vs SIR/MMF). Despite the use of ATG, patients in the SRL/MMF group revealed numerically fewer freedom from acute rejection episodes: TAC/MMF, 82.4%; TAC/SRL, 85.2%; SRL/MMF, 73.3% (p = 0.33). Mean creatinine at 5 years revealed preservation of renal function in the SRL/MMF vs the TAC/MMF group (p = 0.045): TAC/MMF, 1.70±0.91 mg/dl; TAC/SRL, 1.44±0.65 mg/dl; and SRL/MMF, 1.25±0.46 mg/dl. Freedom from cardiac allograft vasculopathy was improved in the SRL/MMF group (93.3%) compared with TAC/MMF (73.5%) and TAC/SRL (80.8%) groups, reaching no statistical significance. Freedom from cytomegalovirus infection was TAC/MMF, 72.2%; TAC/SRL, 89.7%; and SRL/MMF, 86.7%. There was a trend toward improved freedom from cytomegalovirus infection with TAC/SRL vs TAC/MMF (p = 0.076). More frequent discontinuations of study medication occurred in SRL-based immunosuppression protocols (TAC/SRL vs TAC/MMF, p = 0.034; SRL/MMF vs TAC/MMF, p = 0.003). The 3 strategies yield no survival advantage at 5 years, with higher numeric rates of rejection and adverse effects in the calcineurin inhibitor-free arm. A trend was observed in favor of freedom from cardiac allograft vasculopathy and preservation of renal function in the calcineurin inhibitor-free arm. However, the clinical relevance on outcomes is unclear because only few patients were receiving the assigned treatment protocols.

Kaczmarek I ，Zaruba MM ，Beiras-Fernandez A ，Reimann R ，Nickel T ，Grinninger C ，Sadoni S ，Hagl C ，Meiser B ... -  《-》

Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study.

Ekberg H ，Bernasconi C ，Nöldeke J ，Yussim A ，Mjörnstedt L ，Erken U ，Ketteler M ，Navrátil P ... -  《-》