***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: Background Most of the previous studies reported that tacrolimus ( TAC ) with sirolimus ( SRL ) was associated with worse post-transplant outcomes in kidney transplantation , compared with TAC with mycophenolate mofetil ( MMF ) . These might be attributable to high-dose SRL . However , outcomes using low-dose SRL with TAC for kidney transplantation are uncertain . The aim of this study was to assess the efficacy and safety of low-dose SRL with extended-release tacrolimus ( ER-TAC ) versus MMF with ER-TAC . Methods We r and omly assigned 158 renal transplant patients to receive low-dose SRL or MMF in combination with ER-TAC and corticosteroid . The primary endpoint was the composite efficacy failure rate , including biopsy-proven acute rejection ( BPAR ) , graft loss , death or loss to follow-up , within 12 months post-transplantation . This trial is registered with Clinical Trial.gov ( number NCT01680952 ) . Results The efficacy failure rate was 6.6 % in the low-dose SRL group and 13.3 % in the MMF group in the intention-to-treat population ( absolute difference , 6.8 % ; 95 % confidence interval , -2.8 % to 16.3 % ) . The incidence of BPAR within 12 months post-transplantation was 5.3 % in the low-dose SRL group and 13.3 % in the MMF group ( P = 0.09 ) . The mean estimated glomerular filtration rate at 12 months post-transplantation was 53.2 mL/min/1.73 m2 in the low-dose SRL group and 52.4 mL/min/1.73 m2 in the MMF group ( P = 0.76 ) . The incidences of adverse events and serious adverse events were similar between groups . Conclusion Low-dose SRL with ER-TAC was not inferior to MMF with ER-TAC with respect to efficacy and safety . When used for immunosuppression in kidney transplantation , low-dose SRL with ER-TAC can effectively prevent acute rejection and preserve renal function Background : The P450 oxidoreductase (POR)*28 variant allele has been associated with altered cytochrome P450 3A enzyme activities . Both CYP3A5 and CYP3A4 are involved in the metabolism of calcineurin inhibitors and recent data show that POR*28 may explain part of the variability observed in tacrolimus ( Tac ) pharmacokinetics . The aim of this study was to investigate the impact of the POR*28 allele on Tac and cyclosporine A ( CsA ) immunosuppressive therapies . Methods : Kidney transplant recipients receiving either Tac ( n = 184 ) or CsA ( n = 174 ) , participating in a prospect i ve multicenter trial , were genotyped for POR*28 , CYP3A4 * 22 , and CYP3A5 * 3 . Results : CYP3A5 expressers that were carriers of at least 1 POR*28 allele had a 16.9 % decrease in dose-adjusted predose concentrations when compared CYP3A5 expressers that carried the POR*1/*1 genotype ( P = 0.03 ) , indicating an increased CYP3A5 activity for POR*28 carriers . In CYP3A5 , nonexpressers carrying 2 POR*28 alleles , a 24.1 % ( confidence interval95 % = −39.4 % to −4.9 % ; P = 0.02 ) decrease in dose-adjusted predose concentrations was observed for Tac , suggesting higher CYP3A4 activity . For CsA , POR*28/*28 patients not expressing CYP3A5 and not carrying the CYP3A4 * 22 decrease-of-function allele showed 15 % lower CsA dose-adjusted predose concentrations ( P = 0.01 ) , indicating also increased CYP3A4 activity . In both cohorts ( ie , Tac and CsA ) , the POR*28 allele was neither associated with the incidence of delayed graft function nor with biopsy-proven acute rejection . These results were further confirmed in 2 independent cohorts . Conclusions : Our results show that the POR*28 allele is associated with increased in vivo CYP3A5 activity for Tac in CYP3A5 expressers , whereas POR*28 homozygosity was associated with a significant higher CYP3A4 activity in CYP3A5 nonexpressers for both Tac and Aim In a cohort of 298 de-novo renal recipients treated with a st and ard tacrolimus loading dose of 0.2 mg/kg , the combined effects of the CYP3A5 * 1 , POR*28 , and CYP3A4 * 22 genotypes on early tacrolimus exposure ( C 0 ) , dose requirements , and achievement of the therapeutic target , C 0 , were examined . The incidence of clinical events ( e.g. acute rejection , diabetes mellitus ) was compared between genotypes . Results Fast metabolizers ( CYP3A5 * 1/POR*28 T carriers ) had two-fold to three-fold higher  tacrolimus dose requirements compared with slow metabolizers ( CYP3A5 * 3/*3/CYP3A4 * 22 carriers ) and needed significantly more time to achieve the target tacrolimus C 0 of a minimum 10 ng/ml ( 3.3±1.7 vs. 1.34±0.75 days ; P<0.0001 ) . No differences in acute rejection incidence and time to first rejection were observed . Slow metabolizers more frequently had tacrolimus C 0 above the target range early after transplantation ( 70 vs. 13 % on day 3 ) ; however , this did not translate into a higher incidence of post-transplantation diabetes mellitus or graft dysfunction . Multivariate analyses identified the CYP3A5 * 1/POR*28/CYP3A4 * 22 genotype combination as the single strongest determinant of tacrolimus dose requirements throughout the first year , explaining between 24–40 % of its variability , whereas recipient age , hematocrit , and delayed graft function were additional nongenetic determinants of tacrolimus dose . Conclusion Combining the CYP3A5 * 1 , POR*28 and CYP3A4 * 22 genotypes allows partial differentiation of early tacrolimus dose requirements and the time to reach therapeutic target concentrations after transplantation , but without obvious clinical implication s. Larger prospect i ve studies need to address the clinical relevance of early combined genotype-based tacrolimus dosing in de-novo renal recipients Left ventricular hypertrophy ( LVH ) regression after kidney transplantation may be influenced by immunosuppression . In a 24-month open-label , multicenter , phase-IV study , 71 kidney allograft recipients without previous acute rejection , showing eGFR > 40 ml/min and proteinuria < 500 mg/day and between 6 months and 3 years post-transplantation , were r and omized to receive everolimus ( EVR ) + mycophenolic acid ( MPA ) or were maintained on tacrolimus ( TAC ) + MPA . The aim was to assess whether the conversion to EVR could reduce left ventricular mass index ( LVMi ) at month-24 . LVMi at month-24 decreased without differences between groups ( TAC : 54.0 vs. 48.2 g/m2.7 ; EVR : 53.4 vs. 49.4 g/m2.7 ) . The LVH prevalence at baseline and month-24 was 59.4 % and 40.6 % in TAC group and 57.1 % and 50.0 % in EVR group . EVR conversion was associated with nearly disappearance of concentric LVH and concentric remodeling pattern . The procollagen type I N-terminal propeptide at month-24 showed greater reduction in EVR group ( 51.6 vs. 58.2 mg/l ; P = 0.004 ) . Conversion from TAC to EVR was associated with a significant improvement of eGFR ( P = 0.0315 , ancova ) . Adverse events were similar between groups without rejection episode or graft loss . Conversion from TAC to EVR did not further reduce LVMi after 24 months , although its effect on concentric LVH deserves further investigation ( NCT01169701 ) Background : POR*28 is a recently newly described allelic variant of the cytochrome P450 oxidoreductase ( POR ) , which might be associated with an increased metabolic activity of P450 cytochromes ( CYP ) 3A5 and 3A4 . Consequently , carriers of at least 1 allele of this polymorphism could require increased calcineurin inhibitors doses to reach the target residual concentrations ( C0 ) . The objective of this study was to test whether the allelic variant of POR , which is associated with an increased metabolic activity of CYP3A , impacts  tacrolimus ( Tac ) pharmacokinetics . Methods : We tested this hypothesis in a population of 229 kidney transplant recipients ( KTR ) from a large , multicenter , prospect i ve and r and omized study . We have analyzed the association between POR*28 genotype and the proportion of individuals reaching the target Tac residual concentration ( Tac C0 ) 10 days after transplantation . We have also measured the association between POR*28 and the Tac C0 , and adjusted Tac C0 ( Tac C0/Tac dose ) over time using generalized mixed linear models . Results : Ten days after transplantation , there was no difference of frequencies of KTR within the target range of Tac C0 ( C0 10–15 ng/mL ) according to the POR*28 genotype ( P = 0.8 ) . The mean Tac C0 at day 10 in the POR*1/*1 group was 15.3 ± 9.7 ng/mL compared with 15.7 ± 7.8 ng/mL in the POR*1/*28 group and 14.2 ± 6.8 ng/mL , in the POR*28/*28 group , P = 0.8 . The adjusted Tac C0 was not associated with POR*28 genotype over time ( r and om effects model , P = 0.9 ) . When restricted to KTR expressing CYP3A5 , POR*28 genotype did not impact the proportion of individuals within the Tac C0 target range neither the adjusted Tac C0 ( r and om effects model , P = 0.1 ) . Conclusions : POR*28 does not significantly influence Tac pharmacokinetic parameters in a large cohort of KTR . This study does not confirm recent findings indicating that POR*28 carriers require more Tac to reach target C0 
    Output:
    
No significant association was observed in the combined effect analysis of CYP3A4 * 1 G and CYP3A5 * 3 with three significant SNPs in the POR gene .
Age , post-transplant duration , and the use of sirolimus were identified as the most important factors that influenced the TAC concentrations .
A meta- analysis of four studies results and our cohort indicated that compared with recipients carrying the CT or TT genotypes , recipients carrying the CC genotypes of POR*28 showed significantly higher TAC concentrations .
Our study suggested the positive influence of mutations in the POR gene on TAC exposure at 3 months after kidney transplantation