***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: AIMS To compare the pharmacokinetics of mycophenolic acid ( MPA ) and its metabolite ( MPAG ) when mycophenolate mofetil ( MMF ) is administered in combination with sirolimus or ciclosporin ( CsA ) in renal allograft recipients .  Safety and efficacy ( biopsy-proven acute rejection ( BPAR ) ) were also assessed . METHODS Patients ( n = 45 ) were r and omized 2 : 1 to receive treatment with sirolimus ( n = 30 ; dosed to maintain trough concentrations of 10 - 25 ng ml(-1 ) until week 8 , and then 8 - 15 ng ml(-1 ) thereafter ) or CsA ( n = 15 ; administered as per centre practice ) both in combination with daclizumab , oral MMF and corticosteroids .  Pharmacokinetic assessment s were performed at day 7 , week 4 , and months 3 and 6 post-transplant . The primary endpoint was the AUC(0,12 h ) for MPA and MPAG . The pharmacokinetics of sirolimus  were also assessed . RESULTS MPA exposure was 39 - 50 % lower ( month 6 mean AUC(0,12 h ) ( 95%CI ) : 40.4 ( 33.8 , 47.0 ) vs. 68.5 ( 54.9 , 82.0 ) microg ml(-1 ) h ) and MPAG exposure was 25 - 52 % higher ( 722 ( 607 , 838 ) vs. 485 ( 402 , 569 ) microg ml(-1 ) h at month 6 ) in the presence of CsA compared with sirolimus across visits . BPAR was 40.0 % with sirolimus and 13.3 % with CsA. The incidence of hypertension , tremors and hirsutism was higher with CsA than with sirolimus , while the incidence of diarrhoea , hyperlipidaemia and impaired wound closure was higher with sirolimus . No deaths , malignancies or graft losses were reported . CONCLUSIONS Co-administration of sirolimus with MMF led to greater MPA exposure , but lower MPAG exposure , than co-administration with CsA. As rejection rates were higher in the absence of CsA , further study of calcineurin inhibitor-free regimens is required before general recommendations can be made BACKGROUND Acute rejection episodes after renal transplantation are an important clinical challenge , despite use of multidrug immunosuppressive regimens . We did a prospect i ve , multicentre , r and omised , double-blind trial to investigate the impact of the addition of sirolimus , compared with azathioprine , to a cyclosporin and prednisone regimen . METHODS 719 recipients of primary HLA-mismatched cadaveric or living-donor renal allografts who displayed initial graft function were r and omly assigned , after transplantation , sirolimus  2 mg daily ( n=284 ) or 5 mg daily ( n=274 ) , or azathioprine ( n=161 ) . We assessed the primary composite endpoint of efficacy failure , occurrence of biopsy-confirmed acute rejection episodes , graft loss , or death , and various secondary endpoints that characterise these episodes at 6 months and 12 months . Analyses were done by intention to treat . FINDINGS The rate of efficacy failure at 6 months was lower in the two sirolimus groups ( 2 mg 18.7 % , p=0.002 ; 5 mg 16.8 % , p<0.001 ) than in the azathioprine group ( 32.3 % ) . The frequency of biopsy-confirmed acute rejection episodes was also lower ( 2 mg 16.9 % , p=0.002 ; 5 mg 12.0 % , p<0.001 ; azathioprine 29.8 % ) . At 12 months , survival was similar in all groups for grafts ( 97.2 % , 96.0 % , and 98.1 % ) and patients ( 94.7 % , 92.7 % , and 93.8 % ) . Patients on sirolimus  showed a delay in the time to first acute rejection episode and decreased frequency of moderate and severe histological grade s of rejection episodes and related antibody treatment , compared with the azathioprine group . Rates of infection and malignant disorders were similar in all groups . INTERPRETATION Use of sirolimus reduced occurrence and severity of biopsy-confirmed acute rejection episodes with no increase in complications . Further studies are needed to establish the optimum doses for the combined regimen We performed a prospect i ve r and omized trial comparing sirolimus/mycophenolate mofetil (MMF)/prednisone to cyclosporine/MMF/prednisone and selected induction therapy with basiliximab .  Twenty patients received sirolimus ( 10 mg loading dose followed by 3 mg/m body surface area/day , keeping 24-hr trough levels at 10 - 15 ng/mL for six months and 5 - 10 ng/mL thereafter . Twenty-one patients began cyclosporine ( 4 to 8 mg/kg/day , keeping 12-hour trough levels at 150 - 300 ng/mL for 6 months and 100 - 200 ng/mL afterwards ) . Mean follow up was 15.8 months . One-year patient and graft survival was similar in both groups ( > 90 % ) . Acute rejection rate was 16.6 % in the sirolimus group and 5.2 % in the cyclosporine group ( P = NS ) . There were no differences in mean serum creatinine between groups . No patients who received basiliximab and had sirolimus target levels suffered acute rejection at one year . The sirolimus group had significantly higher cholesterol and triglycerides . A calcineurin inhibitor-free regimen using sirolimus produces comparable one-year transplant outcomes in living related kidney transplants compared to a calcineurin inhibitor regimen Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival , but their use has been implicated in the development of chronic nephrotoxicity . We performed a prospect i ve , r and omized trial in kidney transplantation comparing sirolimus‐MMF‐prednisone to tacrolimus‐MMF‐prednisone .  Eighty‐one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled ( mean follow‐up = 33 months ; range 13–47 months ) . At 1 year , patient survival was similar in the groups ( 98 % with sirolimus , 96 % with tacrolimus ; p = 0.42 ) as was graft survival ( 94 % sirolimus vs. 92 % tacrolimus , p = 0.95 ) . The incidence of clinical acute rejection was 10 % in the tacrolimus group and 13 % in the sirolimus group ( p = 0.58 ) . There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year ( 61 ± 19 mL/min vs. 63 ± 18 mL/min , p = 0.57 ) or 2 years ( 61 ± 17 mL/min vs. 61 ± 19 mL/min , p = 0.84 ) . At 1 year , chronicity using the Banff schema showed no difference in interstitial , tubular or glomerular changes , but fewer chronic vascular changes in the sirolimus group . This study shows that a CNI‐free regimen using sirolimus‐MMF‐prednisone produces similar acute rejection rates , graft survival and renal function 1–2 years after transplantation compared to tacrolimus‐MMF‐prednisone Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors ( CNIs ) and corticosteroids , both of which have toxicities that can impair recipient and allograft health . This 1‐year , r and omized , controlled , open‐label , exploratory study assessed two belatacept‐based regimens compared to a tacrolimus (TAC)‐based , steroid‐avoiding regimen . Recipients of living and deceased donor renal allografts were r and omized 1:1:1 to receive belatacept‐mycophenolate mofetil ( MMF ) , belatacept‐sirolimus ( SRL ) , or TAC‐MMF .  All patients received induction with 4 doses of Thymoglobulin ( 6 mg/kg maximum ) and an associated short course of corticosteroids . Eighty‐nine patients were r and omized and transplanted . Acute rejection occurred in 4 , 1 and 1 patient in the belatacept‐MMF , belatacept‐SRL and TAC‐MMF groups , respectively , by Month 6 ; most acute rejection occurred in the first 3 months . More than two‐thirds of patients in the belatacept groups remained on CNI‐ and steroid‐free regimens at 12 months and the calculated glomerular filtration rate was 8–10 mL/min higher with either belatacept regimen than with TAC‐MMF  . Overall safety was comparable between groups . In conclusion , primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased st and ard criteria donor kidneys , with acceptable rates of acute rejection and improved renal function relative to a TAC‐based regimen BACKGROUND Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients . This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens . METHODS We r and omly assigned 1645 renal-transplant recipients to receive st and ard-dose cyclosporine , mycophenolate mofetil , and corticosteroids , or daclizumab induction , mycophenolate mofetil , and corticosteroids in combination with low-dose cyclosporine , low-dose tacrolimus , or low-dose sirolimus . The primary end point was the estimated glomerular filtration rate ( GFR ) , as calculated by the Cockcroft-Gault formula , 12 months after transplantation . Secondary end points included acute rejection and allograft survival . RESULTS The mean calculated GFR was higher in patients receiving low-dose tacrolimus ( 65.4 ml per minute ) than in the other three groups ( range , 56.7 to 59.4 ml per minute ) . The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus ( 12.3 % ) than in those receiving st and ard-dose cyclosporine ( 25.8 % ) , low-dose cyclosporine ( 24.0 % ) , or low-dose sirolimus ( 37.2 % ) . Allograft survival differed significantly among the four groups ( P=0.02 ) and was highest in the low-dose tacrolimus group ( 94.2 % ) , followed by the low-dose cyclosporine group ( 93.1 % ) , the st and ard-dose cyclosporine group ( 89.3 % ) , and the low-dose sirolimus group ( 89.3 % ) . Serious adverse events were more common in the low-dose sirolimus group than in the other groups ( 53.2 % vs. a range of 43.4 to 44.3 % ) , although a similar proportion of patients in each group had at least one adverse event during treatment ( 86.3 to 90.5 % ) . CONCLUSIONS A regimen of daclizumab , mycophenolate mofetil , and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function , allograft survival , and acute rejection rates , as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with st and ard-dose cyclosporine without induction . ( Clinical Trials.gov number , NCT00231764 [ Clinical Trials.gov ] . ) The preliminary observation of marked erythrocyte microcytosis in patients treated with sirolimus ( SRL ) and mycophenolate mofetil ( MMF )  has been evaluated as part of a prospect i ve study comparing SRL and cyclosporin A ( CsA ) as a primary immunosuppressant . Normal risk de novo kidney recipients were r and omized either to  SRL or to CsA. Additional immunosuppressants consisted of MMF and prednisone . In patients with erythrocyte microcytosis , iron deficiency was excluded by measuring serum ferritin and transferrin saturation rate .  Fifty-nine patients ( 30 in SRL and 29 in CsA ) were included .  Mean corpuscular volume ( MCV ) ( fl ) on day 7 was 91.7 + /- 4.8 in SRL group versus 91.4 + /- 4.2 in CsA group ( P = 0.77 ) , whereas mean MCV on day 183 post-transplant was 78.5 + /- 3.8 in 
    Output:
    
Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients .
The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus .
Given the risk of mortality , however , the use of this drug does not seem warranted for most patients with kidney transplant .