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

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				13	SRL added, CNI withdrawn		Proteinuria = + 0.67 g/d vs baseline (P = 0.02)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				8	SRL added, CNI withdrawn		Proteinuria = +1.1 g/d vs baseline (P = 0.05)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				10	SRL added, CNI withdrawn		Proteinuria = +2.3 g/d vs baseline (P = 0.01)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 1-yr post transplant, CsA-induced biochemical toxicity	Not specified	6	SRL added, CNI withdrawn	25 mo	Proteinuria = +0.06 g/d vs baseline eGFR = +12.2 mL/min vs baseline	NA	NA	NA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and intimal hyperplasia	CsA or TAC or azathioprine with corticosteroid	19	SRL added to target trough 8-12 ng/mL, CNI withdrawn by 3 mo	6 mo	Response rate: 57% improved or lacked deterioration in renal function	0%	NA	100%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.