Table 2.

Characteristics of included studies

Study NameStudy DesignParticipantsInterventionControlOutcomes Assessed
Comparison 1: mTORi versus CNI
 Rostaing et al., 2015 (17)Multicenter, open label, prospective, randomized trialn=194; Country: France; mean age: 48 yr; men: 65%; immunologic risk: low/moderate; donor type: donor with brain stem death: 90%; living donor: 10%EVR target trough level of 6–10 ng/mlCsA target trough level of 100–150 ng/mlPrimary outcome: progression of IF/TA between 3 and 12 mo post-transplant; secondary outcomes included BPAR, eGFR (MDRD formula), adverse events, including CMV and BKPyV infections
Induction therapy: basiliximab in both groupsCointerventionsCointerventions
CMV prophylaxis: data not availableEC-MPS, steroidsEC-MPS, steroids
All patients were maintained on CsA + EC-MPS + steroids at baselineTiming of conversion: 3 mo post-transplant
 Budde et al., 2015 (18)Multicenter, open label, prospective, randomized, parallel-group studyn=93; Country: Germany; mean age: 51 yr; men: 63%; race: all white; donor type: deceased, noncardiac death: 54.3%; deceased, cardiac death: 13%; living related: 21%; living unrelated: 11%; immunologic risk: lowEVR target trough of 6–10 ng/mlCsA trough target range 80–150 ng/ml or TAC target range of 5–10 ng/ml; cointerventions: EC-MPS, steroidsPrimary efficacy outcome: eGFR (Nankivell formula) 12 mo after randomization, safety outcomes, including CMV infection
Induction therapy: data not availableCointerventions: EC-MPS, steroids
CMV prophylaxis: data not availableTiming of conversion: mean of 7 yr after kidney transplantation
All patients maintained on CNI + EC-MPS ± steroids at baseline
 Budde et al., 2015 (5-yr follow-up) (19)Multicenter, open label, prospective, randomized, parallel-group studyn=78; Country: Germany; mean age: 48 yr; men: 62%; race: all white; donor type: deceased donor: 70%; immunologic risk: lowEVR target trough of 6–10 ng/mlCsA trough target of 80–150 ng/ml or TAC target of 5–10 ng/ml; cointerventions: EC-MPS, steroidsPrimary efficacy outcome: eGFR (Nankivell formula) 5 yr after randomization, safety outcomes, including CMV and BKPyV infection
Induction therapy: data not availableCointerventions: EC-MPS, steroids
CMV prophylaxis: data not availableTiming of conversion: mean of 7 yr after kidney transplantation
All patients maintained on CNI + EC-MPS ± steroids at baseline
 Budde et al., 2015 (20)Multicenter, randomized, prospective, open label, parallel-group trialn=232; Country: Germany, Switzerland; mean age: 47.3 yr; men: 62%; race: 97% white; immunologic risk: lowEVR target trough of 6–10 ng/ml; cointerventions: EC-MPS ± steroidsCsA trough target of 100–150 ng/ml; cointerventions: EC-MPS ± steroidsPrimary efficacy outcome: eGFR (Nankivell formula) 5 yr after randomization, safety outcomes, including CMV infection
Induction therapy: basiliximab in both armsProportion of patients on steroids was balanced between the two groups
CMV prophylaxis: data not availableTiming of conversion: 4.5 mo post-transplantation
All patients maintained on CsA + EC-MPS + steroids at baseline
 Silva et al., 2013 (21)Prospective, multicenter, randomized, controlled, parallel-group trialn=297; Country: Brazil; mean age: 44.6 yr; men: 69%; race: white, 57%; black, 11%; mixed, 26%; other, 6%; immunologic risk: low; donor type: living related: 16%; living unrelated: 9%; deceased: 75%SIR target trough level of 8–12 ng/mlTAC trough target trough level of 5–10 ng/ml; cointerventions: EC-MPS + steroidsPrimary outcome: eGFR at 24 mo (MDRD formula); secondary outcomes: acute rejection, adverse events, including CMV infection
Induction therapy: basiliximab in both armsCointerventions: EC-MPS + steroids
CMV prophylaxis: data not availableTiming of conversion: 3 mo post-transplantation
All patients maintained on TAC + EC-MPS + steroids at baseline
 Chhabra et al., 2013 (22)Prospective, open label, single-center, randomized studyn=200; Country: United States; mean age: 49 yr; men: 52.8%; race: 53% white, 23% black, 20% Hispanic; donor type: deceased: 31%; living related: 41%; living unrelated: 27%SIR target trough level 5–8 ng/mlTAC target trough 6–8 ng/ml; cointerventions: MMFPrimary outcome: acute rejection at 24 mo; secondary outcomes: patient and graft survival, eGFR (MDRD formula), DSAs, and safety outcomes, including CMV and BKPyV infection
Induction therapy: alemtuzumab and methylprednisolone with rapid steroid elimination in both groups
CMV prophylaxis: all patients receiving kidneys from CMV-positive donors were given valganciclovir 450 mg orally once daily for 6 mo; seronegative recipients receiving a kidney from a CMV-negative donor did not receive CMV prophylaxisCointerventions: MMF
Timing of conversion: 12 mo post-transplantation
All patients were maintained on a steroid-free regimen with TAC and MMF at baseline
 Bansal et al., 2013 (23)Prospective, open label, randomized trialn=60; Country: India; mean age: 30 yr; men: 86%; donor type: living related: 75%; living unrelated: 25%; immunologic risk: lowSIR target trough level 8–15 ng/ml; cointerventions: MMF + steroids; timing of conversion: 2 mo post-transplantationTAC target trough level 6–8 ng/ml or CsA target trough level 150–250 ng/ml; cointerventions: MMF + steroidsPrimary outcome: eGFR by MDRD at 6 mo; secondary outcomes: BPAR, side effects, including CMV infection
Induction therapy: 18% of population received induction therapy, balanced between the two groups
CMV prophylaxis: data not available
All patients maintained on CNI + MMF + steroids at baseline
 Mjörnstedt et al., 2012 (24)Prospective, multicenter, randomized, controlled, parallel-group trialn=202; Country: Sweden, Norway, and Denmark; mean age: 55.5 yr; women: 31.4%; race: 97% white; immunologic risk: low; donor type: deceased donor: 73%EVR target trough level of 6–10 ng/ml; cointerventions EC-MPS + steroids; timing of conversion: 7 wk post-transplantationCsA target trough level 50–150 ng/ml; cointerventions EC-MPS + steroidsPrimary outcome: change in renal function from week 7 to month 12 (iohexol or 51Cr-EDTA clearance); secondary outcomes: safety outcomes, including CMV and BKPyV infection
Induction therapy: basiliximab in both groups
CMV prophylaxis: prophylactic treatment for CMV was given according to local practice
All patients maintained on CsA + EC-MPS + steroids at baseline
 Guba et al., 2012 (25) (follow-up of Guba et al., 2010 [28])Prospective, multicenter, randomized, controlled, parallel-group trialn=132; country: Germany; immunologic risk: low to moderateSIR trough levels of 5–10 ng/ml; cointerventions: MMF + steroids; timing of conversion: 10–24 d post-transplantationCsA trough levels 100–150 ng/ml; cointerventions: MMF + steroidsPrimary outcome: eGFR at 36 mo (Nankivell formula); secondary end points: acute rejection, recipient and allograft survival, adverse events, including CMV infection
Induction therapy: ATG in both groups
CMV prophylaxis: CMV-negative patients receiving kidneys from CMV-positive donors received prophylaxis according to local center practice
All patients maintained on CsA + MMF + steroids at baseline
 Weir et al., 2011 (26)Multicenter, randomized, prospective, open label trialn=299; Country: United States; mean age: 48.7 yr; men: 62.8%; race: 50% white; 32% black; immunologic risk: low/moderate; donor type: deceased: 60%; living related: 28%; living unrelated: 12%SIR to trough levels of 5–10 ng/mlCNI (dosed according to center protocol); cointerventions: MMF ± steroidsPrimary outcome: mean percentage change in renal function after 12 mo (clearance of cold iothalamate); secondary outcomes: acute rejection, graft loss, adverse events, including CMV and BKPyV infection
Induction therapy: induction therapy was used in 70% of patients in each group; use of ATG, basiliximab, daclizumab, and muromonab-CD3 was balanced between the two groupsCointerventions: MMF ± steroids
CMV prophylaxis: antiviral prophylaxis given to around 40% of patients in both groupsTiming of conversion:
All patients maintained on CNI + MMF ± steroids at baseline30–180 d post-transplantation
 Heilman et al., 2011 (27)Prospective, randomized, nonblinded trialn=122; Country: United States; mean age: 54 yr; men: 60%; race: 75% white, 15% Hispanic, 10% black; immunologic risk: low; donor type: deceased: 50%; living: 50%; induction therapy: ATG in both groupsSIR to target trough level of at least 8 ng/ml; cointerventions: MMF; timing of conversion: 1 mo post-transplantationTAC to trough of 5–8 ng/ml; cointerventions: MMFPrimary outcome: measured GFR by iothalamate at 1 yr; secondary outcomes: GFR at 2 yr, BPAR, adverse events, including CMV and BKPyV infection
CMV prophylaxis: valgancyclovir 450 mg daily for 3 mo if the recipient was CMV positive or the donor was positive and the recipient was negative
All patients maintained at baseline on CNI + MMF with rapid corticosteroid withdrawal
 Guba et al., 2010 (28)Prospective, multicenter, randomized, controlled, parallel-group trialn=141; Country: Germany; mean age: 47 yr; men: 65%; race: 98% white; immunologic risk: low to moderate; donor type: after brain death: 88.4%; living related: 11.6%SIR trough levels of 5–10 ng/ml; cointerventions: MMF + steroids; timing of conversion: 10–24 d after transplantationCsA trough levels 100–150 ng/ml; cointerventions: MMF + steroidsPrimary outcome: eGFR at 12 mo (Nankivell formula); secondary outcomes: acute rejection, recipient and allograft survival, adverse events, including CMV infection
Induction therapy: ATG in both groups
CMV prophylaxis: CMV-negative patients receiving kidneys from CMV-positive donors received prophylaxis according to local center practice
All patients were maintained on CsA + MMF + steroids at baseline
 Franz et al., 2010 (29)Prospective, single-center, randomized, open label trialn=127; Country: Switzerland; mean age: 48 yr; men: 70%; immunologic risk: low; donor type: cadaveric: 44%; living related: 31%; living unrelated: 25%SIR to trough of 8–15 ng/ml; cointerventions: MMF + steroidsCsA to trough level of 200–250 ng/ml; cointerventions: MMF + steroidsPrimary outcome: kidney function measured using serum creatinine level at 6 mo; secondary outcomes: patient and graft survival, no. of rejections, proteinuria, adverse events, including CMV infection
Induction therapy: not given
CMV prophylaxis: data not available
 Lebranchu et al., 2009 (30)Prospective, multicenter, randomized, open label trialn=192; Country: France; mean age: 46.5 yr; men: 70%; immunologic risk: low; donor type: cadaveric, noncardiac deathSIR to target trough level of 5–10 ng/ml; cointerventions: MMF + steroids; timing of conversion: 3 mo post-transplantationCsA to C2 levels 500–800 ng/ml; cointerventions: MMF + steroidsPrimary outcome: creatinine clearance by Cockcroft–Gault formula at 52 wk; secondary outcomes: graft and patient survival, BPAR, adverse events, including CMV and BKPyV infections
Induction therapy: daclizumab in both groups
CMV prophylaxis: all CMV-negative recipients who received a kidney from a CMV-positive donor received prophylaxis for CMV infection according to the center practice for a minimum of 12 wk
All patients were maintained on CsA + MMF + steroids at baseline
 Durrbach et al., 2008 (31)Prospective, multicenter, randomized, open label trialn=69; Country: France; mean age: 52 yr; immunologic risk: low/moderate; donor type: cadaveric, expanded criteria donorSIR to trough levels of 10–20 ng/ml; cointerventions: MMF + steroidsCsA to trough level of 75–200 ng/ml; cointerventions: MMF + steroidsPrimary outcome: creatinine clearance (Cockcroft–Gault formula) at 6 mo; secondary outcomes: patient and graft survival, BPAR, adverse events, including CMV infection
Induction therapy: ATG in both groups
CMV prophylaxis: valacyclovir or valganciclovir for 16 wk in CMV-negative recipients of a CMV-positive kidney
 Ekberg et al., 2007 (32)Prospective, multicenter, randomized, controlled, parallel-group trialn=1645; Country: international; mean age: 46 yr; men: 65%; race: 92% white; immunologic risk: low/moderate; donor type: deceased: 64%; living related: 29%; living unrelated: 6%; four arms: standard-dose CsA (excluded because different induction regimen), low-dose CsA, low-dose tacrolimus (control), low-dose SIR (intervention)SIR trough level of 4–8 ng/ml; cointerventions: MMF + steroidsCsA trough level of 50–100 ng/ml or TAC trough level of 3–7 ng/ml; cointerventions: MMF + steroidsPrimary outcome: eGFR (Cockcroft–Gault formula) at 12 mo; secondary end points: acute rejection, patient survival, graft survival, adverse events, including CMV infection
Induction therapy: daclizumab for 2 mo, except in standard-dose CsA group (this group was excluded from analysis)
CMV prophylaxis: data not available; however, proportion of CMV-negative patients receiving kidneys from CMV- positive donors was balanced between groups (around 14%)
 Flechner et al., 2007 (33) (5-yr follow-up of Flechner et al., 2002 [36]) Randomized, prospective trialn=61; Country: United States; mean age: 48 yr; men: 68%; race: 20% white, 8% black, 3% Asian; immunologic risk: low; donor type: deceased: 66%; living related: 23%; living unrelated: 11%CsA to trough levels of 200–250 ng/ml.; cointerventions: MMF + steroidsPrimary outcomes: renal function (eGFR, MDRD formula), acute rejection at 5 yr; secondary end points: patient and graft survival, medical and surgical complications, adverse event, including CMV infections
SIR trough level 5–10 ng/ml; cointerventions: MMF + steroids
 Büchler et al., 2007 (34)Prospective, multicenter, randomized studyn=150; Country: France; mean age: 38.7 yr; men: 62%; race: white, 95%; immunologic risk: low to moderate; donor type: all deceased donorsSIR to trough level of 10–15 ng/ml; cointerventions: MMF ± steroidsCsA trough of 75–150 ng/ml; cointerventions: MMF ± steroidsPrimary outcome: graft function–assessed eGFR at 12 mo (Nankivell formula); secondary end points: patient and graft survival at 12 mo, acute rejection, incidence of CMV infection, adverse events
Induction therapy: ATG in both groups
CMV prophylaxis: all CMV-negative patients who received a kidney from a CMV-positive donor received valacyclovir for 16 wk
 Larson et al., 2006 (35)Prospective, open label, randomized studyn=165; Country: United States; mean age: 49 yr; men: 54%; race: 96% white; immunologic risk: low; donor type: living: 83%; deceased: 17%SIR to trough of 10–15 ng/ml; cointerventions: MMF + steroidsTacrolimus to trough levels of 6–8 ng/ml; cointerventions: MMF + steroidsOutcomes: graft survival, patient survival, acute rejection at 12 mo, renal functions via iothalamate clearance, and adverse events, including CMV infections
Induction therapy: ATG in both groups
CMV prophylaxis: data not available
 Flechner et al., 2002 (36)Randomized, prospective trialn=61; Country: United States; mean age: 48 yr; men: 68%; race: 20% white, 8% black, 3% Asian; immunologic risk: low; donor type: deceased: 66%; living related: 23%; living unrelated: 11%SIR trough to 5–10 ng/ml; cointerventions: MMF + steroidsCsA to trough levels of 200–250 ng/ml; cointerventions: MMF + steroidsPrimary outcomes: renal function (eGFR; MDRD formula), acute rejection at 12 mo; secondary end points: patient and graft survival, medical and surgical complications, adverse events, including CMV infections
Induction therapy: basiliximab in both groups
CMV prophylaxis: 90 d of either oral acyclovir or ganciclovir was given according to donor-recipient serology
 Kreis et al., 2000 (37)Randomized, open label, parallel group, multicenter trialn=78; Country: France, Germany, Spain, Belgium; mean age: 43 yr; men: 70%; race: 95% white; immunologic risk: low to moderate; donor type: all cadavericSIR to trough 15 ng/ml; cointerventions: MMF + steroidsCsA to trough of 100–200 ng/ml; cointerventions: MMF + steroidsPrimary outcome: BPAR at 12 mo; secondary outcomes: patient and graft survival and graft function (eGFR with Nankivell formula); safety outcomes, including CMV infection
Induction therapy: none given
CMV prophylaxis: standard prophylactic
therapies for CMV were required
 Groth et al., 1999 (38)Randomized, open label, parallel-group, multicenter studyn=83; Country: Sweden, United Kingdom, France, Spain; mean age: 47 yr; men: 71%; race: 90% white; immunologic risk: low to moderate; donor type: all cadavericSIR to trough level 15 ng/ml; cointerventions: azathioprine + steroidsCsA to trough of 100–200 ng/ml; cointerventions: azathioprine + steroidsPrimary outcome: acute rejection, graft loss, and death at 12 mo; secondary outcomes: time to first rejection episode and graft function; safety outcomes, including CMV infection
Induction therapy: none given
CMV prophylaxis: standard prophylactic therapies per local practice were required and recommended for CMV for 6 mo
Comparison 2: mTORi + low-dose CNI versus regular-dose CNI + MPA
 Tedesco-Silva et al., 2015 (39)Single-center, prospective, randomized, open label, controlled trialn=300; Country: Brazil; mean age: 45 yr; men: 67%; race: 50% white; immunologic risk: low/moderate; donor type: deceased: 79%; living: 21%EVR to trough between 4 and 8 ng/ml + TAC to trough 3–5 ng/ml (low-dose TAC); cointerventions: prednisone; timing of interventions: day 1 post-transplantationTAC to trough 6–8 ng/ml (regular-dose TAC) + MMF; cointerventions: prednisonePrimary outcome: cumulative incidence of CMV infection after 12 mo; secondary outcomes: acute rejection, eGFR (MDRD formula), adverse events
Induction therapy: three arms: group 1: ATG (excluded from this analysis because of different induction regimen), basiliximab for group 2 (intervention), and group 3 (control)
CMV prophylaxis: not given in both groups, a preemptive strategy of weekly monitoring of CMV replication for 6 mo was used
 Suszynski et al., 2013 (40)Prospective, randomized, controlled trialn=440; Country: United States; mean age: 48 yr; men: 83%; race: 93% white; immunologic risk: low/moderate; donor type: deceased: 28.5%; living related: 43.7; living unrelated: 27.8SIR for a trough level 8–12 μg/L + TAC to trough of 3–7 μg/LCSA for a trough of 150–200 μg/L + MMFPrimary outcome: composite of a return to dialysis, death with function, chronic rejection at 10 yr; secondary outcomes: adverse events, including CMV and BKPyV infections
Induction therapy: ATG in all groups
CMV prophylaxis: CMV prophylaxis consisted of iv ganciclovir during hospitalization followed by oral ganciclovir or oral valganciclovir for 3 mo
Three arms: arm 1: CsA/MMF (control group); arm 2: high-dose TAC + low-dose sirolimus (excluded from analysis); arm 3: low-dose TAC/high-dose sirolimus (intervention group)
 Takahashi et al., 2013 (41)Prospective, multicenter, randomized, controlled trialn=122; Country: Japan; mean age: 42 yr; men: 75.4%; immunologic risk: low/moderate; donor type: deceased: 1.6%; living related: 59%; living unrelated: 39.3%EVR trough level 3–8 ng/ml + CsA to trough of 25–50 ng/ml (low-dose CNI); cointerventions: steroids; intervention started within 24–36 h post-transplantationCsA to trough 100–250 ng/ml + MMF; cointerventions: steroidsPrimary outcome: composite of BPAR, graft loss, death, or loss to follow-up at month 12; secondary end points: eGFR at 12 mo (MDRD formula), adverse events, including CMV infection
Induction therapy: basiliximab in both groups
CMV prophylaxis: was mandatory for CMV-negative patients receiving kidneys from CMV-positive donors; the duration of prophylaxis was not defined in the protocol; all other patients were treated according to local practice
 Cibrik et al., 2013 (42) (24-mo follow-up of Tedesco Silva et al., 2010 [44])Prospective, multicenter, randomized, controlled trialn=833; Country: international; mean age: 45 yr; men: 68%; immunologic risk: low/moderate; donor type: deceased heart beating: 46.2%; deceased after cardiac death: 0.4%; living related: 35.7%; living unrelated: 17.3%EVR to trough 3–8 or 6–12 ng/ml (two arms) + reduced-dose CsA (trough target 25–50 ng/ml); cointerventions: ± steroids; intervention initiated immediately after transplantationStandard-dose CsA (trough target 100–250 ng/ml) + MPA; cointerventions: ± steroidsPrimary outcome: treated acute rejection, death, graft loss, or loss to follow-up at 24 mo; secondary outcomes: eGFR (Nankivell and MDRD formulas); safety outcomes, adverse events, including CMV and BKPyV infection
Induction therapy: basiliximab in both groups
CMV prophylaxis: a minimum of 30 d of CMV prophylaxis was mandatory for CMV donor-positive/recipient-negative transplants; treatment with ganciclovir, CMV hyper-Ig, acyclovir, or valacyclovir was permitted and administered according to local practice
 Bertoni et al., 2011 (43) Prospective, single-center, randomized, open label trialn=106; Country: Italy; mean age: 49 yr; immunologic risk: low/moderate; donor type: deceasedEVR target trough level of 8–12 ng/ml + CsA C2: 250–300 ng/ml; cointerventions: steroidsCsA target C2 of 500–700 ng/ml + EC-MPS; cointerventions steroidsOutcomes: eGFR (Cockcroft–Gault) at 12 mo, BPAR, adverse events, including CMV infection
Induction therapy: basiliximab in both groups
CMV prophylaxis: not given; a preemptive strategy was used
 Tedesco Silva et al., 2010 (44)Prospective, multicenter, randomized, controlled trialn=833; Country: international; mean age: 45 yr; men: 68%; immunologic risk: low/moderate; donor type: deceased heart beating: 46.2%; deceased after cardiac death: 0.4%; living related: 35.7%; living unrelated: 17.3%EVR to trough 3–8 or 6–12 ng/ml (two arms) + reduced-dose CsA (trough target 25–50 ng/ml); cointerventions: ± steroids; intervention initiated immediately after transplantationStandard-dose CsA (trough target 100–250 ng/ml) + MPA; cointerventions: ± steroidsPrimary outcome: treated acute rejection, death, graft loss, or loss to follow-up at 24 mo; secondary outcomes: eGFR (Nankivell and MDRD formulas); safety outcomes, adverse events, including CMV and BKPyV infection
Induction therapy: basiliximab in both groups
CMV prophylaxis: a minimum of 30 d of CMV prophylaxis was mandatory for CMV donor-positive/recipient-negative transplants; treatment with ganciclovir, CMV hyper-Ig, acyclovir, or valacyclovir was permitted and administered according to local practice
  • mTORi, mammalian target of rapamycin inhibitor; CNI, calcineurin inhibitor; EVR, everolimus; CsA, cyclosporin A; IF/TA, interstitial fibrosis/tubular atrophy; BPAR, biopsy-proven acute rejection; MDRD, Modification of Diet in Renal Disease; CMV, cytomegalovirus; BKPyV, BK polyoma virus; EC-MPS, enteric-coated mycophenolate sodium; TAC, tacrolimus; SIR, sirolimus; MMF, mycophenolate mofetil; DSA, donor-specific antibody; ATG, antithymocyte globulin; MPA, mycophenolic acid.