***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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    ***EXAMPLES*** 
    Input: 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 ] . ) Recipients of extended criteria donor ( ECD ) kidneys are at increased risk for graft dysfunction/loss , and may benefit from immunosuppression that avoids calcineurin inhibitor ( CNI ) nephrotoxicity . Belatacept , a selective costimulation blocker , may preserve renal function and improve long‐term outcomes versus CNIs . BENEFIT‐EXT ( Belatacept Evaluation of Nephroprotection and Efficacy as First‐line Immunosuppression Trial — EXTended criteria donors ) is a 3‐year , Phase III study that assessed a more ( MI ) or less intensive ( LI ) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients . The co primary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint . Patient/graft survival with belatacept was similar to cyclosporine ( 86 % MI , 89 % LI , 85 % cyclosporine ) at 12 months . Fewer belatacept patients reached the composite renal impairment endpoint  versus cyclosporine ( 71 % MI , 77 % LI , 85 % cyclosporine ; p = 0.002 MI vs. cyclosporine ; p = 0.06 LI vs. cyclosporine ) . The mean measured glomerular filtration rate was 4–7 mL/min higher on belatacept versus cyclosporine ( p = 0.008 MI vs. cyclosporine ; p = 0.1039 LI vs. cyclosporine ) , and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine . The incidence of acute rejection was similar across groups ( 18 % MI ; 18 % LI ; 14 % cyclosporine  ) . Overall rates of infection and malignancy were similar between groups ; however , more cases of posttransplant lymphoproliferative disorder ( PTLD ) occurred in the CNS on belatacept . ECD kidney transplant recipients treated with belatacept‐based immunosuppression achieved similar patient/graft survival , better renal function , had an increased incidence of PTLD , and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine‐treated patients Background Patient-reported outcomes are increasingly incorporated in drug evaluation trials . Whether new immunosuppressive drugs result in an improved health-related quality of life ( HRQoL ) and a reduced side effect experiences remains unknown . Moreover , the relationship between HRQoL and kidney function has never been investigated in kidney transplant recipients . Methods Using the BENEFIT and BENEFIT-EXT trials , we investigated the following : ( a ) evolution of HRQoL , assessed by the Medical Outcomes Short Form Health Survey ( SF-36 ) in the first 3 years ( baseline , 12 , 24 , and 36 months ) after kidney transplantation ; ( b ) association among kidney function ( chronic kidney disease stage ) , HRQoL , and patient-reported side effects ( Modified Transplant Symptom Occurrence and Symptom Distress Scale-59R ; BENEFIT trial only ) ; and ( c ) impact of belatacept and cyclosporine on side effect experience and HRQoL. Results In the BENEFIT trial , all subjects reported clinical ly meaningful improvements compared with baseline and returned to general population scores , both for physical composite score ( PCS ) and mental composite score Short Form ( 36 ) Health Survey at 12 to 36 months after transplantation . In the BENEFIT-EXT trial , this was observed for PCS only .  Belatacept-treated patients reported better absolute PCSs compared with cyclosporine-treated patients . The differences were small but statistically significant at all times . Belatacept-treated patients tended to experience less side effects compared with cyclosporine-treated patients , except for dry skin . Worsening kidney function was associated with a significant decrease in HRQoL. Conclusion Worsening in kidney function was associated with lower HRQoL. Compared with cyclosporine , belatacept was associated with improved HRQoL , suggesting that use of non-nephrotoxic immunosuppressants may affect the patient ’s side effect experience and improve their The Symphony study showed that at 1 year posttransplant , a regimen based on daclizumab induction , 2 g mycophenolate mofetil ( MMF ) , low‐dose tacrolimus and steroids result ed in better renal function and lower acute rejection and graft loss rates compared with three other regimens : two with low‐doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and st and ard cyclosporine dosage . This is an observational follow‐up for 2 additional years with the same endpoints as the core study . Overall , 958 patients participated in the follow‐up . During the study , many patients changed their immunosuppressive regimen ( e.g. switched from sirolimus to tacrolimus ) , but the vast majority ( 95 % ) remained on MMF . During the follow‐up , renal function remained stable ( mean change : −0.6 ml/min ) , and rates of death , graft loss and acute rejection were low ( all about 1 % per year ) . The MMF and low‐dose tacrolimus arm continued to have the highest GFR ( 68.6 ± 23.8 ml/min vs. 65.9 ± 26.2 ml/min in the st and ard‐dose cyclosporine , 64.0 ± 23.1 ml/min in the low‐dose cyclosporine and 65.3 ± 26.2 ml/min in the low‐dose sirolimus arm ) , but the difference with the other arms was not significant ( p = 0.17 in an overall test and 0.077 , 0.039 and 0.11 , respectively , in pair‐wise tests ) . The MMF and low‐dose tacrolimus arm also had the highest graft survival rate , but with reduced differences between groups over time , and the least acute rejection rate . In the Symphony study , the largest ever prospect i ve study in de novo kidney transplantation , over 3 years , daclizumab induction , MMF , steroids and low‐dose tacrolimus proved highly efficacious , without the negative effects on renal function commonly reported for st and ard CNI regimens BACKGROUND AND OBJECTIVES Prolonged use of calcineurin inhibitors ( CNIs ) in kidney transplant recipients is associated with renal and nonrenal toxicity and an increase in cardiovascular risk factors . Belatacept-based regimens may provide a treatment option for patients who switch from CNI-based maintenance immunosuppression . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS This is a r and omized , open-label Phase II trial in renal transplant patients with stable graft function and receiving a CNI-based regimen . Patients who were ≥6 months but ≤36 months after transplantation were r and omized to either switch to belatacept or continue CNI treatment . All patients received background maintenance immunosuppression . The primary end point was the change in calculated GFR ( cGFR ) from baseline to month 12 . RESULTS Patients were r and omized either to switch to belatacept ( n=84 ) or to remain on a CNI-based regimen ( n=89 ) . At month 12 , the mean ( SD ) change from baseline in cGFR was higher in the belatacept group versus the CNI group . Six patients in the belatacept group had acute rejection episodes , all within the first 6 months ; all resolved with no allograft loss . By month 12 , one patient in the CNI group died with a functioning graft , whereas no patients in the belatacept group had graft loss . The overall safety profile was similar between groups . CONCLUSIONS The study identifies a potentially safe and feasible method for switching stable renal transplant patients from a cyclosporine- or tacrolimus-based regimen to a belatacept-based regimen , which may allow improved renal function in patients currently treated with CNIs Background Mycophenolic acid ( MPA ) is widely used as part of immunosuppressive regimens following allograft transplantation . The large pharmacokinetic ( PK ) and pharmacodynamic ( PD ) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring . The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept ( 2nd generation CTLA4-Ig ) or cyclosporine ( CsA ) . Methods Seven renal allograft recipients were r and omized to either belatacept ( n = 4 ) or cyclosporine ( n = 3 ) based immunosuppression . Sample s for MPA PK and PD evaluations were collected predose and at 1 , 2 and 13 weeks posttransplant . Plasma concentrations of MPA  were determined by HPLC-UV . Activity of inosine monophosphate dehydrogenase ( IMPDH ) and the expressions of two IMPDH isoforms were measured in CD4 + cells by HPLC-UV and real-time reverse-transcription PCR , respectively . Subsets of T cells were characterized by flow cytometry . Results The MPA exposure tended to be higher among belata 
    Output:
    
Risk of PTLD was similar in belatacept and CNI-treated recipients ( 4 studies , 1516 recipients : RR 2.79 , 95 % CI 0.61 to 12.66 ) and was no different among recipients who received different belatacept dosages ( high versus low dosage : ratio of risk ratios ( RRR ) 1.06 , 95 % CI 0.11 to 9.80 , test of difference = 0.96 ) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant ( seronegative versus seropositive ; RRR 1.49 , 95 % CI 0.15 to 14.76 , test for difference = 0.73).The belatacept dose used ( high versus low ) , type of donor kidney the recipient received ( extended versus st and ard criteria ) and whether the kidney transplant recipient received tacrolimus or cyclosporin made no difference to kidney transplant survival , incidence of acute rejection or estimated GFR .
There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection , graft loss and death , but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function .
Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI .
Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear .