Frontier
Copyright ©2013 Baishideng Publishing Group Co.
World J Transplant. Jun 24, 2013; 3(2): 7-25
Published online Jun 24, 2013. doi: 10.5500/wjt.v3.i2.7
Table 1 Withdrawal/conversion study
Study (yr)Intervention armControl armCNI sparing strategyStudy length (mo)
RMR (2004)SRL, Steroids, CsA→Withdrawal by 3 mo (n = 215)SRL, Steroids, CsA (n = 215)Withdrawal by 3 mo48
Spare the Nephron (2011)MMF, S, CNI→SRL (30-180 d) (n = 148)MMF, S, CNI (n = 151)Conversion by 30-180 d24
CONCEPT (2009)MMF, S, CsA→SRL by 3 mo (n = 95)MMF, S, CsA (n = 97)Conversion by 3 mo12
SMART (2010)MMF, S, CsA→SRL 10-24 d (n = 70)MMF, S, CsA (n = 71)Conversion by 10-24 d12
ZEUS (2012)EC-MPS, S, CsA→EVR by 4.5 d (n = 154)EC-MPS, S, CsA (n = 146)Conversion by 4.5 mo36
HERAKLES (2012)EC-MPS, S, CsA→EVR by 3 mo (n = 171)EC-MPS, S, CsA (n = 166)Conversion by 3 mo12
CNI: Calcineurin inhibitor; CsA: Cyclosporine; EVR: Everolimus; MMF: Mycophenolate mofetil; EC-MPS: Enteric coated mycophenolate sodium; SRL: Sirolimus; S: Steroids.
Table 2 Withdrawal/conversion trials
Study (yr)DrugsF-up(mo)Patient survival
Graft survival
Biopsyproven acuterejection
Glomerular filtration rate (mL/min)
SRL/EVRCNISRL/ EVRCNISRL/EVRCNISRL/EVRCNI
RMR (2004)SRL (SRL+CsA)4895.3%92.1%91.5%84.2%10.26.558.343.8
Spare the Nephron (2011)SRL/CNI24100%97.5%100%98.7%9.511.359.558.8
CONCEPT (2009)SRL/CsA12100%100%100%99.0%16.88.269.664.8
SMART (2010)SRL/CsA1299.0%99%99.0%97.0%17.415.564.553.4
ZEUS (2012)EVR/CsA3698.1%97.9%98.7%98.6%13.04.867.960.6
HERAKLES (2012)EVR/CsA1299.4%98.8%99.4%99.4%10.08.468.663.0
CNI: Calcineurin inhibitor; CsA: Cyclosporine; EVR: Everolimus; SRL: Sirolimus.
Table 3 Selected randomized trials on calcineurin inhibitors minimization
Study (yr)Intervention armControl armCNI minimizationStudy lenght (mo)
Andres (2009)IL2Ri + lCsA + MMF + SIL2Ri + lowCsA + MMF + SMinimization6
US09 (2008)IL2Ri + EVR + lowTAC + SIL2Ri + EVR + TAC + SMinimization6
Ciancio (2005)Alem + lowTAC + lowMMFrATG + TAC + MMF + SMinimization12
De Sevaux (2001)lowCsA + MMF + SCsA + MMF + SMinimization6
CAESAR (2007)IL2Ri +lowCsA + MMF + SCsA + MMF + SMinimization12
ELITE SYMPHONY (2007)DAC+lTAC/lCsA/SRL+MMF+SDAC+sCsA+MMF+SMinimization36
OptiCept (2009Induction + lowCNI +MMF + SInduction + CNI + MMF + SMinimization24
Hernandez (2007)IL2Ri + lowCsA + MMF + SIL2Ri + CsA + MMF + SMimimization24
Kandaswamy (2005rATG + lowTAC + SrATG + TAC + SMinimization24
RADB156 (2004)IL2Ri + lowCsA + EVR + SIL2Ri + CsA+ EVR + SMinimization36
EVEREST (2009standEVR + lowCsA +SHighEVR + vlowCsa +SMinimization36
Vathsala (2005)Alem + lowCsACsA + AZA + SMinimization6
ASSET (2012 )EVR + lowTACEVR + vlowTACMinimization12
rATG: Rabbit Antithymocyte globuline; Alem: Alemtuzumab; CNI: Calcineurin inhibitor; CsA: Cyclosporine; EVR: Everolimus; TAC: Tacrolimus; DAC: Daclizumab; IL2Ri: Interleukin 2 receptor inhibitors; MMF : Mycophenolate mofetil; S: Steroids.
Table 4 Efficacy and effects on biopsy proven and glomerular filtration rate of the main minimization trials
Calcineurin inhibitorsF-up (mo)Acute rejectionGraft survivalBiopsy provenGlomerular filtration rate
OptiCeptCsA/TAC24SimilarSimilarSimilarSimilar
CAESARCsA12SimilarSimilarSimilarSimilar
ASSETTAC12SimilarSimilarSimilarSimilar
AndresCsA6SimilarSimilarSimilarSimilar
2309CsA12SimilarSimilarSimilarSimilar
EVERESTCsA36SimilarSimilarSimilarSimilar
REFERENCE StudyCsA24SimilarSimilarSimilarSimilar
De SevauxCsA6SimilarSimilarSimilarSimilar
CsA: Cyclosporine; TAC: Tacrolimus.
Table 5 Glomerular filtration rate gain in different minimization trials
StudyCalcineurin inhibitorsLengthGlomerular filtration rate gain (mL/min)
US09TAC6 mo+2.8
De SevauxCsA6 mo+4.0
CAESAR StudyCsA12 mo+2.3
SYMPHONY StudyTAC vs CsA3 yr+4.6
A2309CsA12 mo+1.9
ASSET StudyTAC12 mo+5.3
B156CsA3 yr+4.9
EVERESTCsA6 mo+2.1
CsA: Cyclosporine; TAC: Tacrolimus.
Table 6 Immunosuppression regimens in alemtuzumab minimization trials
Ref. Study group Control group
InductionMaintenanceInductionMaintenance
Chan et al[59]AlemTAC, Ster82DacTAC, MMF, Ster41
Hanaway et al[60]AlemTAC, MMF, Ster164 70Bas rATGTAC, MMF, Ster TAC, MMF, Ster171 69
Ciancio et al[61]AlemTAC, MMF13Dac rATGTAC, MMF, Ster TAC, MMF, Ster12 13
Ciancio et al[62]AlemTAC, MMF, Ster30Dac rATGTAC, MMF, Ster TAC, MMF, Ster30 30
Farney et al[63]AlemTAC/CsA, MMF, Ster85rATGTAC/CsA, MMF, Ster95
Vathsala et al[64]AlemCsA, Ster20NoneCsA, AZA, Ster10
Alem: Alemtuzumab; TAC: Tacrolimus; Ster: Steroids; MMF: Mycophenolate mofetil; CsA: Cyclosporine; Dac: Daclizumab; Bas: Basiliximab; rATG: Rabbit antithymocyte globulin.
Table 7 Selected randomized trials on calcineurin inhibitors avoidance
Study (yr)Intervention armControl armStudy length (mo)
Flechner (2004)IL2Ri+ SRLcc + MMF + S (n = 31)IL2Ri + CsA + MMF + S (n = 30)24
Flechner (2007)IL2Ri +SRLcc + MMF+S (n = 31)IL2Ri + CsA + MMF + S (n = 30)60
Larson (2006)rATG + SRL + MMF + S (n = 81)rATG + TAC + MMF + S (n = 84)12
SYMPHONY (2007)IL2Ri + low SRL + MMF + S (n = 399)IL2Ri+sCsA+MMF+S (n = 390)36
Hamdy (2008)IL2Ri + SRL+ MMF+S (n = 67)IL2Ri + lowTAC+ SRL+S (n = 65)60
Lo (2004)rATG+SRL+MMF+S (n = 41)rATG+TAC+MMF+S (n = 29)12
Ruggenenti (2007)Alem+SRL+MMF+ S (n = 11)Alem+ CsA+MMF+S (n = 10)24
Spiesser group (2007)rATG +SRL + MMF + S (n = 71)rATG + CsA +MMF+S (n = 74)12
Glotz (2010 )rATG + SRL+ MMF + S (n = 71)rATG+ TAC+ MMF+ S (n = 70)12
ORION (2011)IL-2Ri + SRL + MMF+S (n = 155)IL-2Ri + TAC + MMF + S (n = 140)24
IL2Ri: Interleukin 2 receptor inhibitor; SRLcc: Sirolimus concentration controlled; MMF: Mycophenolate mofetil; S: steroids; CsA: Cyclosporine; rATG: rabbit antithymocyte globulin; TAC: Tacrolimus; Alem: Alemtuzumab.
Table 8 Calcineurin inhibitors avoidance trials
Study (yr)DrugsF-Up(mo)Patient survival
Graft survival
Biopsy provenAcute rejection
Glomerular filtration rate (mL/min)
SRLCNISRLCNISRLCNISRLCNI
Flechner (2004)SRL/CsA2493.50%100%93.50%93.60%6.50%16.60%60.649.2
Flechner (2007)SRL/CsA6087.10%90%83.90%76.70%12.90%23.30%66.750.7
Larson (2006)SRL/TAC1298.00%96%94%92%13%10%6361
SYMPHONY (2007)SRL/CsA3695%94%85%87%39%27%71.167.1
Hamdy (2008 )SRL/TAC6098.50%93.80%88%83%NANA8993
Lo (2004)SRL/TAC12100%98%89%80%7%10%72.450.5
Ruggenenti (2007)SRL/CsA24NANANANANANA5249.8
Spiesser Group (2007)SRL/TAC1297%97%90%93%14.30%8.60%6960
Glotz (2010)SRL/TAC1295.80%97.10%85.90%95.70%16.90%12.90%56.158.4
ORION (2011)SRL/TAC2494.5%97%89.9%95.4%32.8%12.3%63.466.7
CNI : Calcineurin inhibitor; SRL: Sirolimus; CsA: Cyclosporine; TAC: Tacrolimus; NA: Not available.