***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: In a r and omized , comparative study of cardiac transplant patients with mild‐to‐moderate renal insufficiency , conversion from calcineurin inhibitors ( CNIs ) to sirolimus improved renal function at 1 year versus continuing CNIs , with an attendant risk of biopsy‐confirmed acute rejection ( BCAR ) . Post hoc analyses were conducted to identify predictors of BCAR and GFR improvement associated with conversion . Patients with proteinuria > 500 mg/day were excluded . Univariate and multivariate regression analyses tested 13 parameters for BCAR and six for GFR improvement . In 57 sirolimus‐treated patients  , mean daily mycophenolate mofetil ( MMF ) dose was lower in those with versus without BCAR ( 1000 vs. 1420 mg ; p = 0.014 ) . Receiver operating characteristic analysis identified MMF dose ≤1000 mg/day as the optimal cutoff to predict BCAR . Multivariate analysis confirmed low MMF dose ( odds ratio : 9.94 ; p = 0.007 ) and non‐white race ( odds ratio : 15.3 ; p = 0.06 ) were independently associated with BCAR . GFR improvement was evaluated in intent‐to‐treat patients ( n = 116 ) . Significant interaction was detected between treatment effect and preexisting diabetes status ( univariate p = 0.077 ; multivariate p = 0.022 ) , indicating greater beneficial effect of sirolimus in those without preexisting diabetes . These findings suggest that sirolimus is more effective in improving GFR in patients without preexisting diabetes , and adequate MMF doses are needed for sirolimus conversion R and omized trials showed that mTOR inhibitors prevent early development of cardiac allograft vasculopathy ( CAV ) . However , the action of these drugs on CAV late after transplant is controversial , and their effectiveness for CAV prevention in clinical practice is poorly explored . In this observational study we included 143 consecutive heart transplant recipients who underwent serial intravascular ultrasound ( IVUS ) , receiving either everolimus or mycophenolate as adjunctive therapy to cyclosporine . Ninety‐one recipients comprised the early cohort , receiving IVUS at weeks 3–6 and year 1 after transplant , and 52 the late cohort , receiving IVUS at years 1 and 5 after transplant . Everolimus independently reduced the odds for early CAV ( 0.14 [ 0.01–0.77 ] ; p = 0.02 ) but it did not appear to influence late CAV progression . High‐dose statins were found to be associated with reduced CAV progression both early and late after transplant ( p ≤ 0.05 ) . Metabolic abnormalities , such as high triglycerides , were associated with late , but not with early CAV progression . By highlighting a differential effect of everolimus and metabolic abnormalities on early and late changes of graft coronary morphology , this observational study supports the hypothesis that everolimus may be effective for CAV prevention but not for CAV treatment , and that risk factors intervene in a time‐dependent sequence during CAV development BACKGROUND The aim of this study was to demonstrate noninferiority of everolimus with reduced cyclosporine ( CsA ) vs mycophenolate mofetil ( MMF ) with reduced CsA in improving renal function . METHODS In this 1-year r and omized , open-label , noninferiority study in maintenance heart transplant recipients with impaired renal function 70 patients received everolimus ( n = 36 ) or MMF ( n = 34 ) in combination with reduced CsA.  The planned sample size was not reached as the study was prematurely discontinued due to slow recruitment . RESULTS Noninferiority of the everolimus regimen could not be shown : In the total population MMF seemed to be favorable on renal function assessed by serum creatinine and filtration rates , but not in the subset of patients who reached the intended reduced CsA level . Incidence rates of rejection episodes were significantly higher under MMF at month 6 ( P = .0332 ) . CONCLUSIONS Overall , the results of this trial using reduced CsA in combination with either everolimus or MMF show that there is evidence to reduce the CsA level when everolimus is given concomitantly and that the benefit of MMF with reduced CsA levels is limited due to insufficient immunosuppression BACKGROUND Cyclosporine ( CsA ) is widely used after heart transplantation . The purpose of this prospect i ve r and omized study was to evaluate the safety and efficacy of reduction of CsA blood level to one-half of the traditional blood concentration under a regimen of everolimus ( EVL ) , CsA , and steroid . MATERIAL S AND METHODS This prospect i ve , 6 month , r and omized , open-label study included adult ( aged 18 to 65 years ) recipients of a primary heart transplant with serum creatinine < or=2.8 mg/dL. Among 52 patients who underwent heart transplantation from December 2004 to March 2006 we excluded those who were hepatitis B or C carriers , who were recipients of organs from donors>60 years old , had cold ischemia time>6 hours , or had plasma renin activity > or=25 % . All patients received CsA ( C2 blood level 1000 - 1400 ng/mL ) , EVL ( C0 target 3 - 8 ng/mL ) , and corticosteroids to day 60 , before r and om entry into one of 2 groups : SE ( C2 blood level from days 60 - 149=800 - 1200 ng/mL , and days 150 - 180 C2=600 - 1000 ng/mL ) , or RE group with CsA reduced by one-half after 3 months ( days 90 - 149 C2=400 - 600 ng/mL , and from days 150 - 180 C2=300 - 500 ng/mL ) . RESULTS The 25 recipients eligible for this study included 13 patients in the SE and 12 in the RE group . There was no operative mortality in either group . No death or graft loss was noted within 6-months in either group . Mean serum creatinine at month 6 tended to be lower in the RE cohort ( 1.23+/-0.44 mg/dL versus 1.55+/-0.85 mg/dL ; P=.093 ) . Biopsy-proven acute rejection > or= grade 3A was observed in only 1 patient ( 7.7 % ) , who was in the SE group . There were no acute rejection episodes associated with hemodynamic compromise . The incidences of adverse events in each group were similar . CONCLUSIONS Concentration-controlled EVL ( C0 target 3 - 8 ng/mL ) in combination with reduced CsA exposure of one-half the usual concentration achieved good efficacy and safety over 6 months . The renal function at 6 months among the RE group showed a trend toward improvement , suggesting a benefit of halving the target CsA blood level after heart transplantation This r and omized , comparative , multinational phase 3b/4 study of patients 1–8 years postcardiac transplantation ( mean 3.9 years ) evaluated the effect of conversion from a calcineurin inhibitor ( CNI ) to sirolimus on renal function in patients with renal insufficiency . In total , 116 patients on CNI therapy with GFR 40–90 mL/min/1.73m2 were r and omized ( 1:1 ) to sirolimus ( n = 57 ) or CNI ( n = 59 ) . Intent‐to‐treat analysis showed the 1‐year adjusted mean change from baseline in creatinine clearance ( Cockcroft‐Gault ) was significantly higher with sirolimus versus CNI treatment ( + 3.0 vs. −1.4 mL/min/1.73 m2 , respectively ; p = 0.004 ) . By on‐therapy analysis , values were + 4.7 and –2.1 , respectively ( p < 0.001 ) . Acute rejection ( AR ) rates were numerically higher in the sirolimus group ; 1 AR with hemodynamic compromise occurred in each group . A significantly higher treatment discontinuation rate due to adverse events ( AEs ; 33.3 % vs. 0 % ; p < 0.001 ) occurred in the sirolimus group . Most common treatment‐emergent AEs significantly higher in the sirolimus group were diarrhea ( 28.1 % ) , rash ( 28.1 % ) and infection ( 47.4 % ) . Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment , but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs In this 12‐month multicenter Sc and inavian study , 78 maintenance heart transplant ( HTx ) recipients r and omized to everolimus with reduced calcineurin inhibitor ( CNI ) exposure or continued st and ard CNI‐therapy underwent matched virtual histology ( VH ) examination to evaluate morphological progression of cardiac allograft vasculopathy ( CAV ) . Parallel measurement of a range of inflammatory markers was also performed . A similar rate of quantitative CAV progression was observed in the everolimus ( n = 30 ) and st and ard CNI group ( n = 48 ) ( plaque index 1.9 ± 3.8 % and 1.6 ± 3.9 % , respectively ; p = 0.65 ) . However , VH analysis revealed a significant increase in calcified ( 2.4 ± 4.0 vs. 0.3 ± 3.1 % ; p = 0.02 ) and necrotic component ( 6.5 ± 8.5 vs. 1.1 ± 8.6 % ; p = 0.01 ) among everolimus patients compared to controls . The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx > 5.1 years and was accompanied by a significant increase in levels of von Willebr and ( vWF ) factor ( p = 0.04 ) and vascular cell adhesion molecule ( VCAM ) ( p = 0.03 ) . Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx . A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation Background . Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation ( HTx ) . In this prospect i ve , r and omized , multicenter trial , the impact of immunosuppressive conversion toward CNI-free ( mycophenolate mofetil [ MMF ] and sirolimus ) or a CNI-reduced immunosuppressive regimen on renal function , efficacy , and safety was evaluated . Methods . Since 2004 , 63 HTx- patients ( 0.5–18.4 years after HTx ) with CNI-based immunosuppression and reduced creatinine clearance less than 60 mL/min ( 39±15 mL/min ) were included in this trial . Patients in the CNI-free-Group ( group 1 ) were converted to sirolimus that was started with 2 mg/day until target trough levels ( 8–14 ng/mL ) were achieved . Subsequently , CNIs were withdrawn . In CNI-reduction-Group ( group 2 ) , CNI target trough levels were reduced by 40 % . In both groups MMF was continued and trough level adjusted ( 1.5–4 & mgr;g/mL ) . Results . Patients demographics and survival ( mean follow-up time : 16.7±9 months ) was equal ( 100 % ) . Renal function improved significantly after complete CNI withdrawal while remaining unchanged with CNI-reduction ( Creatinine clearance after 12 months : 53±24 mg/dL [ group 1 ] vs. 38±20 mg/dL [ group 2 ] , P=0.01 ) . End-stage renal failure ( hemodialysis ) was avoided by CNI-withdrawal and occurred only after CNI reduction ( n=6 ; P=0.01 ) . Acute rejection episodes were more common in group 2 ( 4 vs. 2 ) . Graft function remained stable ( echocardiography ) within both groups . Adverse events were more common in group 1 ( 65 % ) than in group 2 ( n=40 % ) and were responsible for discontinuation in 4 and 0 cases , respectively . Conclusions . Conversion toward a CNI-free immunosuppression ( Mycophenolate , sirolimus ) is superior to CNI-reduced immunosuppression in improving renal failure in late HTx-recipients . However , this benefit is relativized by the increased incidence and severity of sirolimus/MMF-associated side effects Background . Pharmacokinetic modeling supports trough monitoring of everolimus , but prospect i ve data comparing this approach versus mycophenolate mofetil ( MMF ) in de novo cardiac transplant recipients are currently unavailable . Methods . In a 12-month multicenter open-label study , cardiac transplant patients received everolimus ( trough level 3–8 ng/mL ) with reduced cyclosporine A ( CsA ) or MMF ( 3 g/day ) with st and ard CsA , both with corticosteroids 
    Output:
    
Conversion from CNI to mTORi therapy may improve the renal function in HTRs , but the patients may suffer from a high incidence of mTORi-associated adverse events .