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

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.