Is it time to give up with calcineurin inhibitors in kidney transplantation?

doi:10.5500/wjt.v3.i2.7

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World Journal of Transplantation

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2220-3230

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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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 arm	Control arm	CNI sparing strategy	Study length (mo)
RMR (2004)	SRL, Steroids, CsA→Withdrawal by 3 mo (n = 215)	SRL, Steroids, CsA (n = 215)	Withdrawal by 3 mo	48
Spare the Nephron (2011)	MMF, S, CNI→SRL (30-180 d) (n = 148)	MMF, S, CNI (n = 151)	Conversion by 30-180 d	24
CONCEPT (2009)	MMF, S, CsA→SRL by 3 mo (n = 95)	MMF, S, CsA (n = 97)	Conversion by 3 mo	12
SMART (2010)	MMF, S, CsA→SRL 10-24 d (n = 70)	MMF, S, CsA (n = 71)	Conversion by 10-24 d	12
ZEUS (2012)	EC-MPS, S, CsA→EVR by 4.5 d (n = 154)	EC-MPS, S, CsA (n = 146)	Conversion by 4.5 mo	36
HERAKLES (2012)	EC-MPS, S, CsA→EVR by 3 mo (n = 171)	EC-MPS, S, CsA (n = 166)	Conversion by 3 mo	12

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)	Drugs	F-up(mo)	Patient survival		Graft survival		Biopsyproven acuterejection		Glomerular filtration rate (mL/min)
Study (yr)	Drugs	F-up(mo)	SRL/EVR	CNI	SRL/ EVR	CNI	SRL/EVR	CNI	SRL/EVR	CNI
RMR (2004)	SRL (SRL+CsA)	48	95.3%	92.1%	91.5%	84.2%	10.2	6.5	58.3	43.8
Spare the Nephron (2011)	SRL/CNI	24	100%	97.5%	100%	98.7%	9.5	11.3	59.5	58.8
CONCEPT (2009)	SRL/CsA	12	100%	100%	100%	99.0%	16.8	8.2	69.6	64.8
SMART (2010)	SRL/CsA	12	99.0%	99%	99.0%	97.0%	17.4	15.5	64.5	53.4
ZEUS (2012)	EVR/CsA	36	98.1%	97.9%	98.7%	98.6%	13.0	4.8	67.9	60.6
HERAKLES (2012)	EVR/CsA	12	99.4%	98.8%	99.4%	99.4%	10.0	8.4	68.6	63.0

CNI: Calcineurin inhibitor; CsA: Cyclosporine; EVR: Everolimus; SRL: Sirolimus.

Table 3 Selected randomized trials on calcineurin inhibitors minimization

Study (yr)	Intervention arm	Control arm	CNI minimization	Study lenght (mo)
Andres (2009)	IL2Ri + lCsA + MMF + S	IL2Ri + lowCsA + MMF + S	Minimization	6
US09 (2008)	IL2Ri + EVR + lowTAC + S	IL2Ri + EVR + TAC + S	Minimization	6
Ciancio (2005)	Alem + lowTAC + lowMMF	rATG + TAC + MMF + S	Minimization	12
De Sevaux (2001)	lowCsA + MMF + S	CsA + MMF + S	Minimization	6
CAESAR (2007)	IL2Ri +lowCsA + MMF + S	CsA + MMF + S	Minimization	12
ELITE SYMPHONY (2007)	DAC+lTAC/lCsA/SRL+MMF+S	DAC+sCsA+MMF+S	Minimization	36
OptiCept (2009	Induction + lowCNI +MMF + S	Induction + CNI + MMF + S	Minimization	24
Hernandez (2007)	IL2Ri + lowCsA + MMF + S	IL2Ri + CsA + MMF + S	Mimimization	24
Kandaswamy (2005	rATG + lowTAC + S	rATG + TAC + S	Minimization	24
RADB156 (2004)	IL2Ri + lowCsA + EVR + S	IL2Ri + CsA+ EVR + S	Minimization	36
EVEREST (2009	standEVR + lowCsA +S	HighEVR + vlowCsa +S	Minimization	36
Vathsala (2005)	Alem + lowCsA	CsA + AZA + S	Minimization	6
ASSET (2012 )	EVR + lowTAC	EVR + vlowTAC	Minimization	12

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 inhibitors	F-up (mo)	Acute rejection	Graft survival	Biopsy proven	Glomerular filtration rate
OptiCept	CsA/TAC	24	Similar	Similar	Similar	Similar
CAESAR	CsA	12	Similar	Similar	Similar	Similar
ASSET	TAC	12	Similar	Similar	Similar	Similar
Andres	CsA	6	Similar	Similar	Similar	Similar
2309	CsA	12	Similar	Similar	Similar	Similar
EVEREST	CsA	36	Similar	Similar	Similar	Similar
REFERENCE Study	CsA	24	Similar	Similar	Similar	Similar
De Sevaux	CsA	6	Similar	Similar	Similar	Similar

CsA: Cyclosporine; TAC: Tacrolimus.

Table 5 Glomerular filtration rate gain in different minimization trials

Study	Calcineurin inhibitors	Length	Glomerular filtration rate gain (mL/min)
US09	TAC	6 mo	+2.8
De Sevaux	CsA	6 mo	+4.0
CAESAR Study	CsA	12 mo	+2.3
SYMPHONY Study	TAC vs CsA	3 yr	+4.6
A2309	CsA	12 mo	+1.9
ASSET Study	TAC	12 mo	+5.3
B156	CsA	3 yr	+4.9
EVEREST	CsA	6 mo	+2.1

CsA: Cyclosporine; TAC: Tacrolimus.

Table 6 Immunosuppression regimens in alemtuzumab minimization trials

Ref.	Study group			Control group
Ref.	Induction	Maintenance		Induction	Maintenance
Chan et al[59]	Alem	TAC, Ster	82	Dac	TAC, MMF, Ster	41
Hanaway et al[60]	Alem	TAC, MMF, Ster	164 70	Bas rATG	TAC, MMF, Ster TAC, MMF, Ster	171 69
Ciancio et al[61]	Alem	TAC, MMF	13	Dac rATG	TAC, MMF, Ster TAC, MMF, Ster	12 13
Ciancio et al[62]	Alem	TAC, MMF, Ster	30	Dac rATG	TAC, MMF, Ster TAC, MMF, Ster	30 30
Farney et al[63]	Alem	TAC/CsA, MMF, Ster	85	rATG	TAC/CsA, MMF, Ster	95
Vathsala et al[64]	Alem	CsA, Ster	20	None	CsA, AZA, Ster	10

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 arm	Control arm	Study 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)	Drugs	F-Up(mo)	Patient survival		Graft survival		Biopsy provenAcute rejection		Glomerular filtration rate (mL/min)
			SRL	CNI	SRL	CNI	SRL	CNI	SRL	CNI
Flechner (2004)	SRL/CsA	24	93.50%	100%	93.50%	93.60%	6.50%	16.60%	60.6	49.2
Flechner (2007)	SRL/CsA	60	87.10%	90%	83.90%	76.70%	12.90%	23.30%	66.7	50.7
Larson (2006)	SRL/TAC	12	98.00%	96%	94%	92%	13%	10%	63	61
SYMPHONY (2007)	SRL/CsA	36	95%	94%	85%	87%	39%	27%	71.1	67.1
Hamdy (2008 )	SRL/TAC	60	98.50%	93.80%	88%	83%	NA	NA	89	93
Lo (2004)	SRL/TAC	12	100%	98%	89%	80%	7%	10%	72.4	50.5
Ruggenenti (2007)	SRL/CsA	24	NA	NA	NA	NA	NA	NA	52	49.8
Spiesser Group (2007)	SRL/TAC	12	97%	97%	90%	93%	14.30%	8.60%	69	60
Glotz (2010)	SRL/TAC	12	95.80%	97.10%	85.90%	95.70%	16.90%	12.90%	56.1	58.4
ORION (2011)	SRL/TAC	24	94.5%	97%	89.9%	95.4%	32.8%	12.3%	63.4	66.7

CNI : Calcineurin inhibitor; SRL: Sirolimus; CsA: Cyclosporine; TAC: Tacrolimus; NA: Not available.

Citation: Salvadori M, Bertoni E. Is it time to give up with calcineurin inhibitors in kidney transplantation? World J Transplant 2013; 3(2): 7-25
URL: https://www.wjgnet.com/2220-3230/full/v3/i2/7.htm
DOI: https://dx.doi.org/10.5500/wjt.v3.i2.7