Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies

Table 1 renal transplant studies utilizing mycophenolic acid to withdraw calcineurin inhibitor beyond 6 mo post-transplant (“Late”)[83-93]

Ref.	Design	Population (n)	Baseline Regimen	n	Strategy	Follow-up	Renal function	Acute rejection	Graft survival	Patient survival
Kosch et al[83]	Prospective, randomized, single-center	6-mo of deteriorating renal function, BP-CAN	CsA, Prednisolone	12	MMF added, target 2 g per day; CsA withdrawn over 4 wk	6 mo	SCr + 0.03 mg/dL vs baseline (P = NS)	NA	NA	NA
				12	MMF added, target 2 g; CsA continued		SCr + 0.07 mg/dL vs baseline (P = NS)	NA	NA	NA
Suwelack et al[84]	Prospective, randomized, single-center	> 1-yr post transplant, SCr < 4 mg/dL, BP-CAN, deteriorating renal function	CsA or TAC, Prednisolone	18	MMF added, target 2 g; CsA withdrawn over 6 wk	35 wk	Slope 1/SCr 0.00585 ± 0.01122; 67% responders; Proteinuria 0.5 ± 0.55 g/24 h	0%	100%	NA
				20	MMF added, target 2 g; CsA continued		Slope 1/SCr -0.00728 ± 0.01105 (P = 0.0018); 25% responders (P = 0.021); Proteinuria 1.5 ± 0.48 g/24 h (P = 0.01)	0%	85%	NA
McGrath et al[85]	Prospective, randomized, single-center	> 1-yr post transplant, BP-CAN, deteriorating renal function	CsA, azathioprine, prednisolone	15	MMF added, target 2 g; CsA withdrawn by 14 wk	6 mo	SCr - 58 μmol/L vs baseline (P < 0.001); isotope GFR + 8.5 mL/min vs baseline (P < 0.01)	0%	NA	NA
				15	CsA switch to TAC		SCr + 15 μmol/L vs baseline (P = NS); isotope GFR -2.1 mL/min vs baseline (P = NS)	0%	NA	NA
Hanvesakul et al[86]	Retrospective, consecutive patients, single-center	> 1-yr post transplant, CAN	CsA or TAC, azathioprine, prednisolone	30	MMF added, target 1.5-2 g; azathioprine stopped; CNI withdrawn over 4 wk	1 yr	eGFR + 2 mL/min vs baseline	3.30%	86.70%	96.70%
Dudley et al[87]	Randomized, open, multicenter	> 6-mo post transplant, deteriorating renal function, no recent ACR	CsA monotherapy, or CsA/corticosteroid, or CsA/azathioprine/ corticosteroids	73	MMF added, target 2 g; azathioprine discontinued, if applicable; CsA withdrawn over 6 wk, if needed corticosteroid added	1 yr	Response rate (6 mo): 58% stabilized or reduced SCr; Response rate (1 yr): 48%; Least squares mean SCr -24.9 μmol/L; Least squares mean CrCL +5 mL/min	0%	93.20%	95.90%
			CsA monotherapy, or CsA/corticosteroid, or CsA/azathioprine/ corticosteroids	70	Continued regimen		Response rate (6 mo): 32% stabilized or reduced SCr (P = 0.006); Response rate (1 yr): 35% (P = 0.1885); Least squares mean SCr +22.2 μmol/L (P < 0.01); Least squares mean CrCL -0.7 mL/min (P < 0.01)	0%	94.3%	100%
Weir et al[88]	Prospective, non-randomized, single-center	Mean 853.3 d post transplant, BP-CAN, deteriorating renal function, no ACR	CsA or TAC, prednisone, azathioprine or MMF	18	Azathioprine stopped; MMF added, target 2 g; CNI withdrawn	Mean 651 d	Response rate: 91.7% improved or lack of deterioration in renal function using least squares method slope 1/SCr (P = 0.038)	NCR	100%	NA
			CsA, prednisone, azathioprine or MMF	67	CsA dose reduced approximately 50%; azathioprine withdrawn; MMF added, target 2 g		Response rate: 51.7% improved or lack of deterioration	NCR	100%	NA
			TAC, prednisone, azathioprine or MMF	33	TAC dose reduced approximately 50%; azathioprine withdrawn; MMF added, target 2 g		59.3% improved or lack of deterioration	NCR	100%	NA
Weir et al[89]	Continuation of above trial			13	CNI withdrawn	76 mo	2.7 ± 0.2 mg/dL	7.7%	92.3%	100%
				64	CsA dose reduced	54 mo	3 ± 0.1 mg/dL	4.7%	62.5%	92.2%
				28	TAC dose reduced	42 mo	3 ± 0.2 mg/dL	7.1%	67.8%	100%
Abramowicz et al[90]	Randomized, controlled, multicenter	No recent ACR, ≤ 1 ACR overall, 12 to 30 mo post-transplant, stable renal function	CsA, prednisone, ± azathioprine or MMF	85	MMF added over 3 mo, target 2 g; CsA withdrawn over 3 mo	12 mo	CrCL improved 10% in 46%; SCr -1 μmol/L; CrCL + 4.5 mL/min vs control group (P = 0.16), eGFR + 2.3 mL/min vs control group (P = 0.24)	10.6%	100%	NA
				85	MMF added over 3 mo, target 2 g; continued triple therapy		SCr + 4 μmol/L	2.4% (P = 0.03)	100%
Abramowicz et al[91]	Continuation of above trial			74	CsA withdrawn	60 mo	CrCL 67.4 mL/min	10%	88%	93%
				77	Triple therapy		CrCL 61.7 mL/min (P = 0.05)	1% (P = 0.028)	92%	95%
Heeg et al[92]	Retrospective	BP-CNI toxicity, deteriorating renal function, mean 11.2 mo post-transplant	CsA or TAC, Prednisolone, ± MMF or MPS	17	MPS added; CNI withdrawn; MMF withdrawn	48 mo	All vs Baseline. SCr at 6 mo -0.5 mg/dL (P < 0.05); eGFR at 6 mo + 11 mL/min; SCr at 36 mo -0.5 mg/dL (P = 0.063); eGFR at 36 mo +11 mL/min P = 0.022); SCr at 48 mo + 0.6 mg/dL (P = 0.27); eGFR at 48 mo +1 mL/min (P = 0.91)	NA	NA	NA
Mourer et al[93]	Prospective, randomized, single-center	No recent ACR, ≤ 2 ACR overall, at least 12 mo post-transplant, stable renal function	CsA or TAC, Prednisone, MMF	79	CNI withdrawn, MMF concentration controlled	36 mo	eGFR 59.5 ± 2.1 mL/min	5.1%	98.7%	94.9%
				79	MMF withdrawn, CNI concentration controlled		eGFR 51.1 ± 2.1 mL/min (P = 0.006)	2.5%	98.7%	92.4%

ACR: Acute cellular rejection; BP-CAN: Biopsy-proven chronic allograft nephropathy; CAN: Chronic allograft nephropathy; CNI: Calcineurin inhibitor; CsA: Cyclosporine; eGFR: Estimated glomerular filtration rate; GFR: Glomerular filtration rate; MMF: Mycophenolate mofetil; MPS: Mycophenolate sodium; NA: not assessed/applicable; NCR: Not clearly reported by group; NS: Not significant; SCr: Serum creatinine; TAC: Tacrolimus.

Table 2 Renal transplant studies utilizing sirolimus to withdraw calcineurin inhibitor beyond 6 mo post-transplant

Ref.	Design	Population (n)	Baseline regimen	n	Strategy	Follow-up	Renal function	Acute rejection	Graft survival	Patient survival
Gutierrez et al[102]	Cohort	> 1-yr post transplant, chronic allograft dysfunction, no proteinuria	Not specified	8	SRL added, CNI dose reduced 50%	24.6 mo	Proteinuria = +0.56 g/d vs baseline (P = NS)	NA	90.50%	85.70%
				13	SRL added, CNI withdrawn		Proteinuria = + 0.67 g/d vs baseline (P = 0.02)
		> 1-yr post transplant, chronic allograft dysfunction, proteinuria = 0.3-0.8 g/d		10	SRL added, CNI dose reduced 50%	23.2 mo	Proteinuria = +0.5 g/d vs baseline (P = NS)	NA	83.30%	94.40%
				8	SRL added, CNI withdrawn		Proteinuria = +1.1 g/d vs baseline (P = 0.05)
		> 1-yr post transplant, chronic allograft dysfunction, proteinuria > 0.8 g/d		14	SRL added, CNI dose reduced 50%	25.9 mo	Proteinuria = -0.1 g/d vs baseline (NS)	NA	79.20%	87.50%
				10	SRL added, CNI withdrawn		Proteinuria = +2.3 g/d vs baseline (P = 0.01)
Maharaj et al[103]	Retrospective cohort	> 1-yr post transplant, CsA-induced biochemical toxicity	Not specified	6	SRL added, CNI withdrawn	25 mo	Proteinuria = +0.06 g/d vs baseline eGFR = +12.2 mL/min vs baseline	NA	NA	NA
		> 1-yr post transplant, CAN		6			Proteinuria = +0.85 g/d vs baseline eGFR = -9.7 mL/min vs baseline	NA	NA	NA
		> 1-yr post transplant, Severe gum hypertrophy		9			Proteinuria = +0.99 g/d vs baseline eGFR = -1.0 mL/min vs baseline	NA	NA	NA
		4.5 mo post transplant, Posttransplant diabetes		4			Proteinuria = -0.22 g/d vs baseline eGFR = +13.3 mL/min vs baseline	NA	NA	NA
		5.5 mo post transplant, CNI induced histological nephrotoxicty		2			Proteinuria = +0.63 g/d vs baseline eGFR = -10.0 mL/min vs baseline	NA	NA	NA
		> 1-yr post transplant, CNI associated malignancy		3			Proteinuria = +0.09 g/d vs baseline eGFR = +7.0 mL/min vs baseline	NA	NA	NA
Citterlo et al[104]	Cohort	> 6-mo post transplant, deteriorating renal function, sCr 2-4.5 mg/dL, proteinuria > 500 mg/d, biopsy confirmed fibrosis, tubular atrophy and intimal hyperplasia	CsA or TAC or azathioprine with corticosteroid	19	SRL added to target trough 8-12 ng/mL, CNI withdrawn by 3 mo	6 mo	Response rate: 57% improved or lacked deterioration in renal function	0%	NA	100%
Wu et al[105]	Retrospective cohort	> 1-yr post transplant, CAN	CsA or TAC/corticosteroids orCsA or TAC/corticosteroids/ MMF	32	SRL added with CNI dose reduced	8.5 mo	Response rate: 50% improved or lacked deterioration in renal function	3.10%	87.50%	NA
Chhabra et al[106]	Randomized, prospective, open-label, single-center	> 1-yr post transplant	TAC, MMF	123	SRL added to target trough 5-8 ng/mL, TAC withdrawn by week 2	41.1 mo	eGFR = -3.3 mL/min per 1.73 m2vs baseline proteinuria > 1 g/d = + 4.7% vs baseline	5.70% (ACR) 4.1% (AHR)	97.60%	97%
				64	Continue TAC to target trough 6-8 ng/mL	40.7 mo	eGFR = -8.7 mL/min per 1.73 m2vs baseline, proteinuria > 1 g/d = + 7.4% vs baseline	6.40% (ACR) 3.1% (AHR)	97%	100%
Wali et al[107]	Cohort	Renal dysfunction and biopsy confirmed CAN	TAC/MMF or TAC/MMF/corticosteroids	159	SRL added, target trough 8-10 ng/mL, TAC withdrawn after second dose of SRL	24 mo	sCr = -1.1 mg/dL vs baseline (P < 0.0001) eGFR = +21 mg/dL vs baseline (P < 0.0001)	9.60%	65%	90%
Diekmann et al[108]	Cohort	> 1-yr post transplant, biopsy confirmed CNI toxicity	CsA or TAC/corticosteroids, or CsA or TAC/corticosteroids/ azathioprine, or CsA or TAC/corticosteroids/ MMF,or CsA or TAC/MMF, or TAC/MMF/corticosteroids CsA or TAC/azathioprine	22	SRL added, target trough 8-12 ng/mL, CsA or TAC reduced by 50% immediately then further reduced 10%-20% weekly	6 mo	sCr = -0.7 mg/dL vs baseline (%= NS), Response rate: 59.1% improved or lacked deterioration in renal function	NA	86%	100%
Bumbea et al[109]	Prospective, single-center cohort	>6-mo post transplant, chronic allograft dysfunction or recurrent cutaneous cancer	CsA or TAC/corticosteroids, or CsA or TAC/corticosteroids/ azathioprine or CsA or TAC/corticosteroids/ MMF	43	SRL added, target trough = 8-12 ng/mL, CNI withdrawn abruptly or by week 3	27 mo	sCr = -17.8 μmol/L vs baseline (P = NS) CrCL = +2.3 mL/min vs baseline (P = NS) Proteinuria (> 1g/d): 20.6% at 2 yr (P = 0.01)	0%	93%	95.30%
Boratynska et al[110]	Cohort	> 1-yr post transplant, biopsy confirmed CAN	CsA, prednisone, azathioprine	5	SRL added, target trough 10-18 ng/mL, CsA withdrawn immediately. After 5 mo, SRL withdrawn and CsA reinitiated	3 mo	sCr = +1.6 mg/dL and proteinuria = +461 mg/dL after 3 mo SRL vs baseline sCr = +1.1 mg/dL and proteinuria = +6 mg/dL 6 mo after reconversion to CsA vs baseline sCr = -0.5 mg/dL and proteinuria = -455 mg/dL after reconversion to CsA vs SRL	0%	40%	100%
Martínez-Mier et al[111]	Retrospective cohort	> 6-mo post transplant, > 20% sCr increase in 6 mo or sCr 2-4.5 mg/dL	CsA, prednisone, MMF	15	SRL added, target trough 8-12 ng/mL, CsA withdrawn immediately	6 mo	sCr = -0.78 mg/dL vs baseline (P = 0.003) BUN = - 9.84 mg/dL vs baseline (P = NS)	0%	100%	100%
Kamar et al[112]	Prospective, multicenter, noncomparative, open-label cohort	> 1-yr post transplant, moderate renal insufficiency, sCr 160-265 µmol/L	CsA or TAC, corticosteroids, MMF	44	SRL added to target trough 6-10 ng/mL, CNI withdrawn	6 mo	GFR = +7.09 mL/min vs baseline (P = 0.03) Proteinuria = +0.57 g/d	2.30%	100%	100%
Chen et al[113]	Cohort	> 6-mo post transplant, biopsy confirmed CAN	CsA or TAC, prednisone, MMF	16	SRL added, target trough 5-8 ng/mL, CNI withdrawn	12 mo	Response rate: 43.8% improved or lacked deterioration in renal function	0%	88%	100%
Stallone et al[114]	Prospective, open-label, single-center	> 1-yr post transplant, Scr 1-3 mg/dL	CsA or TAC, corticosteroids, MMF	50	40% CNI dose reduction	24 mo	sCr = -0.02 mg/dL vs baseline (P = NS) CrCL -3.0 mL/min vs baseline (P = NS) Proteinuria = +0.17 vs baseline (P = NS) Follow-up biopsy: worsened CAN score, increased α-SMA	0%	84%	100%
				34	SRL added, CNI immediately withdrawn		sCr = -0.14 mg/dL vs baseline (P = NS) CrCL = +3.0 mg/dL vs baseline (P = NS) Proteinuria = +0.37 g/d vs baseline (P = NS) Follow-up biopsy: stable CAN score, improved α-SMA	0%	97% (P = 0.04)	100%
Paoletti et al[115]	Cohort	> 6-mo post transplant, biopsy confirmed renal allograft dysfunction	CsA or TAC, corticosteroids, MMF	13	SRL added, target trough 4-8 ng/mL, CNI withdrawn	3 yr	sCr = -0.3 mg/dL vs baseline (P = 0.016) eGFR = +5.5 mg/dL vs baseline (P = 0.011) Proteinuria = +0.21 g/d vs baseline (P = 0.83)	8%	100%	100%
		> 6-mo post transplant with stable graft function		26	Continued regimen		sCr= +0.3 mg/dL vs baseline (P = 0.016) eGFR = -6.4 mg/dL vs baseline (P = 0.011) Proteinuria = +0.17 g/d vs baseline (P = 0.83)	4%	96%	96%
Alarrayed et al[116]	Retrospective, Observational, single-center	> 1-yr post transplant, sCr < 140 µmol/L	CsA or TAC, corticosteroids, azathioprine or MMF	45	SRL added to target trough 5-8 ng/mL, CNI withdrawn immediately	72.8 mo	sCr = -6 μmol/L vs baseline (P = 0.001) Proteinuria = +0.2 g/d vs baseline (P = NS)	0%	100%	NA
		> 1-yr post transplant, sCr ≥ 140 µmol/L		19			sCr = -13 µmol/L vs baseline (P = 0.01) Proteinuria = +0.6 g/d vs baseline (P = 0.001)	36.40%	72.70%	NA
Fischereder et al[117]	Prospective cohort	> 1-yr post transplant, deteriorating renal function, Scr 1.8-4 mg/dL	CsA or TAC, corticosteroids, azathioprine or MMF	12	SRL added, target trough = 10-20 ng/mL, CNI withheld by 4 wk	12 mo	sCr = -0.3 mg/dL vs baseline (P = 0.198) CrCL = +5.8 mL/min (P = 0.0368) Proteinuria = +735 mg/g creatinine vs baseline (P = 0.13)	0%	100%	100%
Schena et al[118]	Randomized, prospective, open-label, multicenter, blinded, comparative trial	> 6-mo post transplant, baseline GFR > 40 mL/min	CsA or TAC, corticosteroids, azathioprine or MMF	497	SRL added, target trough 8-20 ng/mL, CNI withdrawn in 1 d, MMF or azathioprine dose reduced or withdrawn	24 mo	GFR = + 1.3 mL/min in patients converted to SRL as compared with patients continued on CNI at 12 mo (P = NS) GFR = +1.3 mL/min vs baseline, UPr/Cr = -84 vs baseline	7.80%	92.40%	95.60%
		> 6-mo post transplant, baseline GFR 20-40 mL/min		58			GFR = + 3.8 mL/min in patients converted to SRL as compared with patients continued on CNI at 24 mo (P = NS)	8.60%	65.50%	82.80%
		> 6-mo post transplant, baseline GFR > 40 mL/min		246	Continue regimen		GFR = -1.8 mL/min vs baseline, UPr/Cr = -31 vs baseline	6.50%	93.90%	96.30%
		> 6-mo post transplant, baseline GFR 20-40 mL/min		29			GFR = + 2.6 mL/min in patients continued on CNI as compared with patients converted to SRL at 12 mo (P = NS)	10.30%	62.10%	89.70%

α-SMA: Α-smooth muscle actin; AHR: Acute humoral rejection; CAN: Chronic allograft nephropathy; CNI: Calcineurin inhibitor; CsA: Cyclosporine; GFR: Glomerular filtration rate; MMF: Mycophenolate mofetil; NS: Not significant; SCr: Serum creatinine; TAC: Tacrolimus.

Table 3 Renal transplant studies utilizing everolimus to withdraw calcineurin inhibitor beyond 6 mo post-transplant

Ref.	Design	Population (n)	Baseline regimen	n	Strategy	Follow-up	Renal function	Acute rejection	Graft survival	Patient survival
Giron et al[126]	Case series	Conversion due to unspecified reasons in Hispanic renal transplant patients (15 from cadaveric donors), mean conversion 8 mo post-transplant	CsA or TAC, and unspecified regimen	21	Everolimus added with MPS or MMF with complete suspension of CNI	10 mo (range, 2 to 22)	Mean SCr showed a trend to decline: preconversion 1.7 mg/dL; post-conversion 1.5 mg/dL	17%	100%	100%
Sánchez Fructuoso et al[127]	Case series, prospective, open	CAN or other reasons, stable renal function, mean 77 mo post-transplant	CNI and unspecified regimen	78	Switched to everolimus with complete and quick elimination of the CNI: An initial dose of 3 mg/d was adequate to obtain the recommended trough levels between 5 and 10 ng/mL	12 mo	Baseline CrCL = 51.9 ± 2.7 mL/min, and 3 mo = 55.7 ± 3.2 (P = 0.02). 12-mo CrCL not stated. Proteinuria = increased at 3 mo (P < 0.001), decreased between 3 to 6 mo (P = 0.001), but remained higher than basal levels (P = 0.002). Everolimus stopped in 13 patients (16.7%)	NA	NA	NA
Ruiz et al[128]	Case Series	CAN with deteriorating renal function	CsA or TAC, and unspecified regimen; tripe drug (41%), double-drug (52%), monotherapy (7%)	32	Everolimus added, to eliminate CNI	6 mo	Baseline SCr 1.93 ± 0.13 mg/dL vs 1.86 ± 0.14, P = 0.07. Proteinuria = 1.62 ± 0.62 g/d vs 2.11 ± 0.73 (P = 0.11)	NA	NA	NA
Fernández et al[129]	Case series	Cadaveric renal transplant patients with CAN, at a mean 123.8 ± 74.2 mo post-transplant	CsA or TAC, ± MMF or azathioprine, corticosteroid not specified	17	Converted to everolimus with complete suspension of CNI	24 mo	Baseline SCr of 1.8 ± 0.4; after a year, 1.62 ± 0.49; and after 2 yr, 1.56 ± 0.49 mg/dL (P < 0.05). Proteinuria was baseline 0.30 ± 0.13 mg/mg, 1 yr = 0.63 ± 0.68 (P < 0.05), and 2 yr = 0.48 ± 0.34. Protein/creatinine quotient was: baseline 0.30 ± 0.13; one year 0.63 ± 0.68; and 2 yr 0.48 ± 0.34. CrCL was baseline 37.1 ± 11.14 mL/min and 2 yr = 46.6 ± 14.6 (P < 0.05)	NA	NA	100%
		Cadaveric renal transplant patients treated with non-CAN diagnosis at a mean 123.8 ± 74.2 mo post-transplant	CsA or TAC, ± MMF or azathioprine, corticosteroid not specified	10	Converted to everolimus with complete suspension of CNI	24 mo	Baseline SCr of 1.1 ± 0.32 mg/dL; , 1 yr 0.97 ± 0.15, and 2 yr 0.97 ± 0.15. Proteinuria at baseline 0.12 ± 0.07 mg/mg, 1 yr = 0.46 ± 0.68 (P < 0.05), and 2 yr = 0.32 ± 0.17 (P < 0.05). Protein/creatinine quotient was: baseline 0.2 ± 0.07, 1 yr = 0.73 ± 0.7, and 2 yr = 0.32 ± 0.17. CrCL was baseline 68.81 ± 19 mL/min and 2 yr 74.56 ± 12.3	NA	NA	50%, due to tumors
Kamar et al[130]	Retrospective case-control	DSA-free kidney transplant patients with CNI toxicity, CAN or other diagnosis	CsA or TAC or belatacept, ± MPA or azathioprine, ± corticosteroids	61	Converted to everolimus-based regimen without CNIs	36 ± 25 mo	SCr (mmol/L) baseline 135 ± 37 to 141 ± 54 (P = NS). aMDRD GFR (mL/min) 54 ± 18 to 56 ± 22 (P = NS)	NA	NA	NA
			CsA or TAC, ± MPA or azathioprine, ± corticosteroids	61	Matched control patients on CNI		SCr (mmol/L) baseline 133 ± 51 to 131 ± 45 (P = NS). aMDRD GFR (mL/min) 65.7 ± 25 to 62 ± 24 (P = NS)
Morales et al[131]	Case series	1st or 2nd transplant, converted due to CAN, nephrotoxicty or malignancy, mean 5 yr post-transplant	CsA or TAC, ± MMF or azathioprine, ± corticosteroid	8	Everolimus added to replace (n = 6) or decrease (30% reduction) CNI dose (n = 2) Antiproliferative dose reduced.	1-16 mo	Mean baseline SCr was 1.96 ± 0.69 mg/dL vs 1.59 ± 0.52. Mean CrCL = 51 ± 34.6 mL/min vs 56.5 ± 25.5. Mean Proteinuria:creatinine ratio = 1.34 ± 2.17 vs 1.28 ± 1.19 mg/g.	NA	NA	NA
Holdaas et al[132]	Prospective, randomized, open-label, multi-center. ASCERTAIN study	> 6-mopost transplant, renal impairment, no recent ACR < 3 mo	CsA or TAC, ± MPA or azathioprine, ± corticosteroids	127	Everolimus added, target 8-12 ng/mL; to eliminate CNI	24 mo	Mean measured GFR at month 24, 48 ± 22 mL/min per 1.73 m2 Difference vs control was 1.12 mL/min per 1.73 m2, 95%CI : -3.51-5.76 (P = 0.63). Urine protein: creatinine (mg/mmol) median increased from baseline 16.6 (3.5-413.7) to 32.6 (4.1-665.9; P = 0.007 vs control)	5.50%	94.50%	97.60%
				144	Everolimus added, target 3-8 ng/mL; to decrease CNI dose		Mean measured GFR at month 24, 46.6 ± 21.1 mL/min per 1.73 m2. Difference vs control was 0.59 mL/min per 1.73 m2, 95%CI: -3.88-5.07 (P = 0.79). Urine protein: creatinine (mg/mmol) median increased from baseline 13.5 (2.4-319.4) to 22.4 (5.1-513.5; P = 0.54 vs control)	5.60%	92.40%	97.90%
				123	Controls maintained current CNI-based regimen		Mean measure GFR at month 24 46 ± 20.4 mL/min. Urine protein:creatinine (mg/mmol) median remained stable from baseline 14.3 (3.3-431.9) to 19.3 (3.3-431.9)	2.40%	95.10%	100%
Inza et al[133]	Case series	Cadaveric kidney allograft, SCr > 2 mg/dL, proteinuria < 1 g/ 24 h	CsA or TAC, ± MPA or sirolimus, corticosteroids	22	Switched CNI to Everolimus, mean starting dose 1.4 mg/d.	24 mo	Baseline CrCL 29.31 ± 10.15 mL/min to 3-mo 37.99 ± 14.44 (P = 0.0076). No results specified for 24 mo, but authors stated CrCL trended to decline (P = 0.6). Proteinuria (mg/24 h) increased from baseline 384 ± 26.13 to one month, 958 ± 1019.38 (P = 0.05), to month 12, 1295 ± 1200.83 (P = 0.0106)	4.50%	90.50%	100%
Cataneo- Dávila et al[134]	Prospective, randomized, open pilot	> 6-mo post transplant, stable renal function, Banff grade I or IICAN within 6 mo, without ACR or grade III CAN in last 3 mo	CsA or TAC, MMF or azathioprine, corticosteroids	10	MMF or azathioprine were withdrawn and Everolimus added to decrease CNI dose by 80%.	12 mo	Baseline and end-of-study data were as follows: SCr, 1.27 ± 0.35 mg/dL vs 1.24 ± 0.4 mg/dL; estimated GFR = 72.4 ± 19.86 mL/min vs 76.26 ± 22.69 mL/min (P = NS); microalbuminuria 0 mg/g (range 0-50) vs 0 (range 0-609; P = NS)	10%	NA	NA
			CsA or TAC, MMF or azathioprine, corticosteroids	10	Everolimus added to eliminate CNI gradually. MMF or azathioprine withdrawn, then re-introduced at CNI elimination		Baseline and end-of-study data were as follows: SCr 1.27 ± 0.36 mg/dL vs 1.25 ± 0.3 mg/dL; estimated GFR 66.2 ± 12.95 mL/min vs 66.2 ± 13.73 mL/min (P = NS); microalbuminuria 0 mg/g (range 0-60) vs 0 (range 0-34; P = NS)	0%	NA	NA
Albano et al[135]	Prospective, randomized, open-label, multi-center. FOREVER trial	Completion of CALLISTO study of patients at risk for DGF, from transplantation to month 12, with proteinuria < 1 g/24 h at month 12	Low-exposure CsA, everolimus, corticosteroids	15	Switch CsA to mycophenolate sodium 720 mg/d, increase everolimus, target trough goal 6-10 ng/mL	12 mo	Median (range) mGFR was 54 (21-87) mL/min at baseline (P = 0.053 vs CNI at baseline) vs 56 (18-126) mL/min at month 12 (P = 0.007 vs CNI continuation; P = 0.3 vs baseline). Difference in mGFR (SE) was +10.3 mL/min (4.8) vs baseline. SCr (SE) = 24 μmol/mL (27). Proteinuria least squares mean change from baseline (SE) = 0.16 g/24 h (0.2)	0%	100%	100%
				15	Continue CsA and everolimus unchanged, trough goal 3-8 ng/mL		Median (range) mGFR was 37 (range 18-69) mL/min at baseline (P = 0.053) vs 32 (12-63) mL/min at month 12 (P = 0.007). Difference in mGFR (SE) was -4.1 mL/min (5) vs baseline. Proteinuria least squares mean change from baseline (SE) = 0.08 g/24 h (0.23)	6.67%	100%	93.3%

ACR: Acute cellular rejection; aMDRD: Abbreviated modified diet in renal disease; BP-CAN: Biopsy-proven chronic allograft nephropathy; CAN: Chronic allograft nephropathy; CNI: Calcineurin inhibitor; CsA: Cyclosporine; DGF: Delayed graft function; DSA: Donor specific antibody; eGFR: Estimated glomerular filtration rate; GFR: Glomerular filtration rate; MMF: Mycophenolate mofetil; MPA: Mycophenolic acid (includes MMF and MPS); MPS: Mycophenolate sodium; NA: Not assessed/applicable; NCR: Not clearly reported by group; NS: Not significant; SCr: Serum creatinine; TAC: Tacrolimus.