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single-center	6-mo of deteriorating renal function, BP-CAN	CsA, Prednisolone	12	MMF added, target 2 g per day; CsA withdrawn over 4 wk	6 mo	SCr + 0.03 mg/dL vs baseline (P = NS)	NA	NA	NA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 4 mg/dL, BP-CAN, deteriorating renal function	CsA or TAC, Prednisolone	18	MMF added, target 2 g; CsA withdrawn over 6 wk	35 wk	Slope 1/SCr 0.00585 ± 0.01122; 67% responders; Proteinuria 0.5 ± 0.55 g/24 h	0%	100%	NA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post transplant, BP-CAN, deteriorating renal function	CsA, azathioprine, prednisolone	15	MMF added, target 2 g; CsA withdrawn by 14 wk	6 mo	SCr - 58 μmol/L vs baseline (P 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post transplant, CAN	CsA or TAC, azathioprine, prednisolone	30	MMF added, target 1.5-2 g; azathioprine stopped; CNI withdrawn over 4 wk	1 yr	eGFR + 2 mL/min vs baseline	3.30%	86.70%	96.70%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or CsA/azathioprine/ corticosteroids	73	MMF added, target 2 g; azathioprine discontinued, if applicable; CsA withdrawn over 6 wk, if needed corticosteroid added	1 yr	Response rate (6 mo): 58% stabilized or reduced SCr; Response rate (1 yr): 48%; Least squares mean SCr -24.9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.