Table 2.
Characteristics of included studies
| Study Name | Study Design | Participants | Intervention | Control | Outcomes Assessed |
|---|---|---|---|---|---|
| Comparison 1: mTORi versus CNI | |||||
| Rostaing et al., 2015 (17) | Multicenter, open label, prospective, randomized trial | n=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/ml | CsA target trough level of 100–150 ng/ml | Primary 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 groups | Cointerventions | Cointerventions | |||
| CMV prophylaxis: data not available | EC-MPS, steroids | EC-MPS, steroids | |||
| All patients were maintained on CsA + EC-MPS + steroids at baseline | Timing of conversion: 3 mo post-transplant | ||||
| Budde et al., 2015 (18) | Multicenter, open label, prospective, randomized, parallel-group study | n=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: low | EVR target trough of 6–10 ng/ml | CsA trough target range 80–150 ng/ml or TAC target range of 5–10 ng/ml; cointerventions: EC-MPS, steroids | Primary efficacy outcome: eGFR (Nankivell formula) 12 mo after randomization, safety outcomes, including CMV infection |
| Induction therapy: data not available | Cointerventions: EC-MPS, steroids | ||||
| CMV prophylaxis: data not available | Timing 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 study | n=78; Country: Germany; mean age: 48 yr; men: 62%; race: all white; donor type: deceased donor: 70%; immunologic risk: low | EVR target trough of 6–10 ng/ml | CsA trough target of 80–150 ng/ml or TAC target of 5–10 ng/ml; cointerventions: EC-MPS, steroids | Primary efficacy outcome: eGFR (Nankivell formula) 5 yr after randomization, safety outcomes, including CMV and BKPyV infection |
| Induction therapy: data not available | Cointerventions: EC-MPS, steroids | ||||
| CMV prophylaxis: data not available | Timing 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 trial | n=232; Country: Germany, Switzerland; mean age: 47.3 yr; men: 62%; race: 97% white; immunologic risk: low | EVR target trough of 6–10 ng/ml; cointerventions: EC-MPS ± steroids | CsA trough target of 100–150 ng/ml; cointerventions: EC-MPS ± steroids | Primary efficacy outcome: eGFR (Nankivell formula) 5 yr after randomization, safety outcomes, including CMV infection |
| Induction therapy: basiliximab in both arms | Proportion of patients on steroids was balanced between the two groups | ||||
| CMV prophylaxis: data not available | Timing 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 trial | n=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/ml | TAC trough target trough level of 5–10 ng/ml; cointerventions: EC-MPS + steroids | Primary outcome: eGFR at 24 mo (MDRD formula); secondary outcomes: acute rejection, adverse events, including CMV infection |
| Induction therapy: basiliximab in both arms | Cointerventions: EC-MPS + steroids | ||||
| CMV prophylaxis: data not available | Timing 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 study | n=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/ml | TAC target trough 6–8 ng/ml; cointerventions: MMF | Primary 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 prophylaxis | Cointerventions: 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 trial | n=60; Country: India; mean age: 30 yr; men: 86%; donor type: living related: 75%; living unrelated: 25%; immunologic risk: low | SIR target trough level 8–15 ng/ml; cointerventions: MMF + steroids; timing of conversion: 2 mo post-transplantation | TAC target trough level 6–8 ng/ml or CsA target trough level 150–250 ng/ml; cointerventions: MMF + steroids | Primary 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 trial | n=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-transplantation | CsA target trough level 50–150 ng/ml; cointerventions EC-MPS + steroids | Primary 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 trial | n=132; country: Germany; immunologic risk: low to moderate | SIR trough levels of 5–10 ng/ml; cointerventions: MMF + steroids; timing of conversion: 10–24 d post-transplantation | CsA trough levels 100–150 ng/ml; cointerventions: MMF + steroids | Primary 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 trial | n=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/ml | CNI (dosed according to center protocol); cointerventions: MMF ± steroids | Primary 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 groups | Cointerventions: MMF ± steroids | ||||
| CMV prophylaxis: antiviral prophylaxis given to around 40% of patients in both groups | Timing of conversion: | ||||
| All patients maintained on CNI + MMF ± steroids at baseline | 30–180 d post-transplantation | ||||
| Heilman et al., 2011 (27) | Prospective, randomized, nonblinded trial | n=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 groups | SIR to target trough level of at least 8 ng/ml; cointerventions: MMF; timing of conversion: 1 mo post-transplantation | TAC to trough of 5–8 ng/ml; cointerventions: MMF | Primary 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 trial | n=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 transplantation | CsA trough levels 100–150 ng/ml; cointerventions: MMF + steroids | Primary 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 trial | n=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 + steroids | CsA to trough level of 200–250 ng/ml; cointerventions: MMF + steroids | Primary 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 trial | n=192; Country: France; mean age: 46.5 yr; men: 70%; immunologic risk: low; donor type: cadaveric, noncardiac death | SIR to target trough level of 5–10 ng/ml; cointerventions: MMF + steroids; timing of conversion: 3 mo post-transplantation | CsA to C2 levels 500–800 ng/ml; cointerventions: MMF + steroids | Primary 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 trial | n=69; Country: France; mean age: 52 yr; immunologic risk: low/moderate; donor type: cadaveric, expanded criteria donor | SIR to trough levels of 10–20 ng/ml; cointerventions: MMF + steroids | CsA to trough level of 75–200 ng/ml; cointerventions: MMF + steroids | Primary 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 trial | n=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 + steroids | CsA trough level of 50–100 ng/ml or TAC trough level of 3–7 ng/ml; cointerventions: MMF + steroids | Primary 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 trial | n=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 + steroids | Primary 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 study | n=150; Country: France; mean age: 38.7 yr; men: 62%; race: white, 95%; immunologic risk: low to moderate; donor type: all deceased donors | SIR to trough level of 10–15 ng/ml; cointerventions: MMF ± steroids | CsA trough of 75–150 ng/ml; cointerventions: MMF ± steroids | Primary 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 study | n=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 + steroids | Tacrolimus to trough levels of 6–8 ng/ml; cointerventions: MMF + steroids | Outcomes: 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 trial | n=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 + steroids | CsA to trough levels of 200–250 ng/ml; cointerventions: MMF + steroids | Primary 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 trial | n=78; Country: France, Germany, Spain, Belgium; mean age: 43 yr; men: 70%; race: 95% white; immunologic risk: low to moderate; donor type: all cadaveric | SIR to trough 15 ng/ml; cointerventions: MMF + steroids | CsA to trough of 100–200 ng/ml; cointerventions: MMF + steroids | Primary 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 study | n=83; Country: Sweden, United Kingdom, France, Spain; mean age: 47 yr; men: 71%; race: 90% white; immunologic risk: low to moderate; donor type: all cadaveric | SIR to trough level 15 ng/ml; cointerventions: azathioprine + steroids | CsA to trough of 100–200 ng/ml; cointerventions: azathioprine + steroids | Primary 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 trial | n=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-transplantation | TAC to trough 6–8 ng/ml (regular-dose TAC) + MMF; cointerventions: prednisone | Primary 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 trial | n=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: 27.8 | SIR for a trough level 8–12 μg/L + TAC to trough of 3–7 μg/L | CSA for a trough of 150–200 μg/L + MMF | Primary 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 trial | n=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-transplantation | CsA to trough 100–250 ng/ml + MMF; cointerventions: steroids | Primary 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 trial | n=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 transplantation | Standard-dose CsA (trough target 100–250 ng/ml) + MPA; cointerventions: ± steroids | Primary 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 trial | n=106; Country: Italy; mean age: 49 yr; immunologic risk: low/moderate; donor type: deceased | EVR target trough level of 8–12 ng/ml + CsA C2: 250–300 ng/ml; cointerventions: steroids | CsA target C2 of 500–700 ng/ml + EC-MPS; cointerventions steroids | Outcomes: 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 trial | n=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 transplantation | Standard-dose CsA (trough target 100–250 ng/ml) + MPA; cointerventions: ± steroids | Primary 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.