***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: BACKGROUND Non-nephrotoxic immunosuppressive strategies that allow reduction of calcineurin-inhibitor exposure without compromising safety or efficacy remain a goal in kidney transplantation . Immunosuppression based on the mammalian-target-of-rapamycin inhibitor everolimus was assessed as a strategy for elimination of calcineurin-inhibitor exposure and optimisation of renal-graft function while maintaining efficacy . METHODS In the ZEUS multicentre , open-label study , 503 patients ( aged 18 - 65 years ) who had received de-novo kidney transplants were enrolled . After initial treatment with ciclosporin , based on trough concentrations , and enteric-coated mycophenolate sodium ( 1440 mg/day , orally ) , corticosteroids ( ≥5 mg/day prednisolone or equivalent , orally ) , and basiliximab induction ( 20 mg , intravenously , on day 0 [ 2 h before transplantation ] , and on day 4 ) , 300 ( 60 % ) patients were r and omly assigned at 4·5 months in a 1:1 ratio to undergo calcineurin-inhibitor elimination ( everolimus-based regimen that was based on trough concentrations [ 6 - 10 ng/mL ] and enteric-coated mycophenolate sodium [ 1440 mg/day ] with corticosteroids ) , or continue st and ard ciclosporin-based treatment . R and omisation was done by use of a central , vali date d system that automated the r and om assignment of treatment groups to r and omisation numbers . The primary objective was to show better renal function ( glomerular filtration rate [ GFR ] ; Nankivell formula ) with the calcineurin-inhibitor-free everolimus regimen at 12 months after transplantation . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00154310 . FINDINGS 118 ( 76 % ) of 155 everolimus-treated patients and 117 ( 81 % ) of 145 ciclosporin-treated patients completed treatment with study drug up to 12 months after transplantation . At this timepoint , the everolimus regimen was associated with a significant improvement in GFR versus the ciclosporin regimen ( 71·8 mL/min per 1·73 m(2 ) vs 61·9 mL/min per 1·73 m(2 ) , respectively ; mean difference 9·8 mL/min per 1·73 m(2 ) , 95 % CI -12·2 to -7·5 ) . Rates of biopsy-proven acute rejection were higher in the everolimus group than in the ciclosporin group after r and omisation ( 15 [ 10 % ] of 154 vs five [ 3 % ] of 146 ; p = 0·036 ) , but similar for the full study period ( 23 [ 15 % ] vs 22 [ 15 % ] ) . Compared with the ciclosporin regimen , higher mean lipid concentrations , slightly increased urinary protein excretion , and lower haemoglobin concentrations were noted with the everolimus regimen ; thrombocytopenia , aphthous stomatitis , and diarrhoea also occurred more often in the everolimus group . A higher incidence of hyperuricaemia was noted with ciclosporin . INTERPRETATION Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety , indicating that this strategy may facilitate improved long-term outcomes in selected patients . FUNDING Novartis Pharma New-onset diabetes ( NOD ) is associated with transplant failure . A few single-center studies have suggested that sirolimus is associated with NOD , but this is not well established . With the use of data from the United States Renal Data System , this study evaluated the association between sirolimus use at the time of transplantation and NOD among 20,124 adult recipients of a first kidney transplant without diabetes . Compared with patients treated with cyclosporine and either mycophenolate mofetil orazathioprine , sirolimus-treated patients were at increased risk for NOD , whether it was used in combination with cyclosporine ( adjusted hazard ratio [ HR ] 1.61 ; 95 % confidence interval [ CI ] 1.36 to 1.90),tacrolimus ( adjusted HR 1.66 ; 95 % CI 1.42 to 1.93 ) , or an antimetabolite ( mycophenolate mofetil orazathioprine ; adjusted HR 1.36 ; 95 % CI 1.09 to 1.69 ) . Similar results were obtained in a subgroup analysis that included the 16,861 patients who did not have their immunosuppressive regimen changed throughout the first posttransplantation year . In conclusion , sirolimus is independently associated with NOD . Given the negative impact of NOD on posttransplantation outcomes , these findings should be confirmed in prospect i ve studies or in meta-analyses of existing trials that involved sirolimus BACKGROUND Left ventricular hypertrophy ( LVH ) after renal transplantation may be affected by immunosuppressive therapy . STUDY DESIGN Nonr and omized controlled trial evaluating the effect of sirolimus ( SRL ) on LVH of renal transplant recipients ( RTRs ) . SETTING & PARTICIPANTS 13 RTRs without diabetes who had received a single-kidney transplant from a deceased donor with chronic allograft dysfunction and biopsy-proven allograft nephropathy who were converted from calcineurin-inhibitor ( CNI ) to SRL treatment ; 26 controls matched for age and year of transplantation who were not converted from CNI to SRL treatment .  INTERVENTION Conversion from CNI to SRL therapy . OUTCOMES & MEASUREMENTS Left ventricular mass determination by using echocardiography at baseline and again 1 year later . Blood pressure ( BP ) , hemoglobin level , serum creatinine level , uric acid level , lipid levels , trough levels of immunosuppressive drugs , and daily proteinuria were assessed at least twice monthly . Conventional antihypertensive therapy was used to achieve BP of 130/80 mm Hg or less . RESULTS The study population included 26 men and 13 women ( age , 25 to 66 years ) .  Changes in BP were similar in the 2 groups ( between-group difference , -4 + /- 5 mm Hg ; P = 0.5 for systolic BP ; -2 + /- 3 ; P = 0.6 for diastolic BP ) , whereas left ventricular mass significantly decreased in the SRL group alone ( between-group difference , 8.6 + /- 2.4 g/m(2.7 ) ; P < 0.001 ) because of a decrease in both the interventricular septum and left ventricular posterior wall . LVH regressed in 12 of 13 patients on SRL therapy and 10 of 26 controls ( P = 0.002 ) . LIMITATIONS Nonr and omized design . Single-center study with small sample size . CONCLUSIONS Conversion from CNI to SRL therapy may regress LVH in RTRs regardless of BP changes , mainly by decreasing left ventricular wall thickness , thus suggesting nonhemodynamic-effect mechanisms of SRL on left ventricular mass In this 12‐month , multicenter , r and omized , open‐label , noninferiority study , de novo renal transplant recipients ( RTxRs ) were r and omized ( 1:1 ) to receive everolimus plus low‐dose tacrolimus ( EVR+LTac ) or mycophenolate mofetil plus st and ard‐dose Tac ( MMF+STac ) with induction therapy ( basiliximab or rabbit anti‐thymocyte globulin ) . Noninferiority of composite efficacy failure rate ( treated biopsy‐proven acute rejection [tBPAR]/graft loss/death/loss to follow‐up ) in EVR+LTac versus MMF+STac was missed by 1.4 % , considering the noninferiority margin of 10 % ( 24.6 % vs. 20.4 % ; 4.2 % [ −3.0 , 11.4 ] ) . Incidence of tBPAR ( 19.1 % vs. 11.2 % ; p < 0.05 ) was significantly higher , while graft loss ( 1.3 % vs. 3.9 % ; p < 0.05 ) and composite of graft loss/death/lost to follow‐up ( 6.1 % vs. 10.5 % , p = 0.05 ) were significantly lower in EVR+LTac versus MMF+STac groups , respectively . Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups ( 63.1 [ 22.0 ] vs. 63.1 [ 19.5 ] mL/min/1.73 m2 ) and safety was comparable . In conclusion , EVR+LTac missed noninferiority versus MMF+STac based on the 10 % noninferiority margin . Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs In the Spare-the-Nephron ( STN ) Study , kidney transplant recipients r and omized about 115 days posttransplant to convert from CNI ( calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR ( mGFR ) at 12 months compared with those kept on CNI/MMF . The difference at 24 months was not statistically significant . From 14 top enrolling centers , 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational , noninterventional extension study to collect retrospectively and prospect ively annual follow-up data for the interval since baseline ( completion of the parent STN study at 24 months posttransplant ) . Overall , 11 patients died , including 5 ( 7.6 % ) in the SRL/MMF group and 6 ( 9.7 % ) in the CNI/MMF group . Twenty-two grafts have been lost including 10 ( 15.2 % ) in the SRL/MMF arm and 12 ( 19.4 % ) in the CNI/MMF arm . Death and chronic rejection were the most common causes of graft loss in both arms . There were modestly more cardiovascular events in the MMF/SRL  group . Estimated creatinine clearance ( Cockcroft-Gault ) from baseline out to 6 additional years ( 8 years posttransplant , ITT analysis , SRL/MMF , n = 34 ; CNI/MMF , n = 26 ) was 63.2 ± 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 ± 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant , but there is a clinical ly meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group . The long-term decision for immunosuppression needs to be carefully individualized Background . Everolimus is a proliferation inhibitor design ed to target chronic rejection , including prevention of acute rejection . Everolimus blocks growth factor-mediated transduction signals , preventing organ rejection by a mechanism different than that of calcineurin inhibitors and of mycophenolate mofetil ( MMF ) . Methods . Everolimus ( 1.5 mg or 3 mg daily ) was compared with MMF ( 2 g daily ) in a r and omized , multicenter , multinational , 12-month double-blind , double-dummy and 2-year open-label , phase 3 trial in de novo renal allograft recipients ( n=588 ) who also received cyclosporine and corticosteroids as part of a triple immunosuppressive regimen .  Results . At 12 months , there were no statistically significant differences between doses of 1.5 and 3 mg/day everolimus and MMF ( 2 g/day ) in incidence of biopsy-proven acute rejection ( 23.2 % , 19.7 % , and 24.0 % , respectively ) , graft loss ( 4.6 % , 10.6 % , and 9.2 % ) , or death ( 5.2 % , 4.0 % , and 2.6 % ) , respectively . Everolimus 1.5 mg/day and MMF were generally equally well tolerated . Both were better tolerated than everolimus 3 mg/day . The incidence of cytomegalovirus infection was significantly lower in patients receiving either 1.5 or 3 mg/day everolimus than in those receiving MMF ( 5.2 % and 7.6 % vs. 19.4 % , respectively ) ( P=.001 ) . Conclusions . Everolimus is effective in preventing acute rejection and graft loss in de novo renal allograft recipients receiving a triple immunosuppressive regimen . Prevention of acute rejection , along with reduction in cytomegalovirus infection , addresses two factors known to contribute to chronic rejection in such patients Background . This 36-month , r and omized , parallel-group study 
    Output:
    
Registry studies and systematic review s have shown higher risk for mortality and graft loss in patients in use of mTOR inhibitors ( mTORi ) compared to calcineurin-based ( CNI ) immunosuppressive regimens .
The new strategies using concentration controlled reduced exposure of mTORi and CNI or early conversion from CNI to mTORi use have shown comparable patient and graft survival .