Introduction of everolimus in kidney transplant recipients at a late posttransplant stage

Table 1 Summary of late everolimus conversion clinical trials

Ref.	No. of subjects/follow-up	EVLtreatment	Groups	Outcomes
ASCERTAIN[17] (2011)	394/2 yr	Conversion to EVL with CNI elimination or minimization at mean of 5.6 yr	Gp 1: CNI elimination (EVL C0, 8-12 ng/mL), n = 127 Gp 2: CNI minimization (EVL C0, 3-8 ng/mL and CNI reduced to 80%-90% below baseline), n = 144 Gp 3: control (CsA C2, > 400 ng/mL; Tac C0, > 4 ng/mL), n = 123	Graft survival: 96.9%, 94.6%, 95.1% (P = NS) Patient survival: 97.6%, 97.1%, 100% (P = NS) Comparable eGFR in 3 groups; recipients with baseline CrCl > 50 mL/min had greater increase in measured GFR after CNI elimination Adverse events resulted in discontinuation: 28.3%, 16.7%, 4.1% (Gp 1 vs GP 3, P < 0.001; Gp 2 vs Gp 3, P = 0.020)
APOLLO[18] (2015)	93/1 yr	Conversion from CNI to EVL at mean of 7 yr	Gp 1: CNI elimination (EVL C0, 6-10 ng/mL), n = 46 Gp 2: control (CsA C0, 80-150 ng/mL; Tac C0, 5-10 ng/mL), n = 47	Graft survival: 100%, 100% Patient survival: 97.8%, 97.9% (P = NS) Adjusted eGFR was significantly higher in Gp 1 within on-treatment population Adverse events resulted in discontinuation: 32.6%, 10.6% (P < 0.01)

C0: Zero hour blood level; CNI: Calcineurin inhibitor; CrCl: Creatinine clearance; CsA: Cyclosporine; eGFR: Estimated glomerular filtration rate; EVL: Everolimus; Gp: Group; No.: Number; NS: Not significant; Tac: Tacrolimus.

Table 2 Summary of retrospective or nonrandomized studies for late everolimus conversion

Ref.	No. of subjects/follow-up	EVL treatment	Outcomes
Morales et al[20] (2007)/ retrospective	8/1-16 mo	Conversion to EVL with CNI elimination or reduction at mean of 5 yr	CrCl increased by 42% in recipients with CAN (grade 1 or 2) and CNI nephrotoxicity (P = 0.017)
Sanchez-Fructuoso et al[21] (2012)/ retrospective	220/1 yr	Conversion from CNI to EVL at mean of 69.4 mo	CrCl increased in recipients with baseline CrCl ≥ 40 mL/min and baseline proteinuria < 550 mg/d (P = 0.005) Median proteinuria increased from 304 mg/d to 458 mg/d (P < 0.001) EVL discontinuation rate was 24%
Chow et al[22] (2015)/ open-label, single arm	17/1 yr	Conversion to EVL with CNI minimization in recipients with CAN at mean of 4.2 yr	Mean slope of eGFR was - 4.31 mL/min/1.73 m2 per yr before conversion, as compared with 1.29 mL/min/1.73 m2 per yr at 12 mo after conversion (P = 0.036) Renal biopsy showed significant decrease of tubular atrophy (15.7% vs 7.1%, P = 0.005) and interstitial fibrosis (14.8% vs 7.2%, P = 0.013)
Miura et al[23] (2015)/ retrospective	13/1 yr	Conversion to EVL with Tac reduction in recipients with CNIA at mean of 43 mo	aah scores improved in 5 recipients (38%); No improvement was observed in recipients with aah3; No deterioration was observed. eGFR improved from 44.3 mL/min/1.73 m2 to 49.8 mL/min/1.73 m2 (P < 0.01).
Uchida et al[24] (2016)/ retrospective (our report)	26/1 yr	Conversion from antimetabolites (MMF or MZ) to EVL with CNI minimization at mean of 39.5 mo	eGFR significantly increased from 50.7 mL/min/1.73 m2 to 53.6 mL/min/1.73 m2 in the EVL continuation group EVL discontinuation rate was 42.3%
Nojima et al[25] (2017)/ retrospective	56/1 yr	Conversion to EVL with CNI reduction in recipients with CNI nephrotoxicity or IF/TA at mean of 7.4 yr	eGFR increased by 7% (P < 0.005) EVL discontinuation rate was 11%
Nanmoku et al[26] (2017)/ nonrandomized	86/ 1 yr	Conversion to EVL with Tac minimization, MMF reduction and steroid withdrawal in cases of complications such as diabetes, viral infection etc	Conventional group (n = 50); EVL group (n = 36) Biopsy-proven acute rejection rate exhibited no significant difference between these groups (12% vs 17%, P = 0.55) Serum creatinine significantly improved in the EVL group (P = 0.031) EVL discontinuation rate was 13.8%

CAN: Chronic allograft nephropathy; CNI: Calcineurin inhibitor; CNIA: Calcineurin inhibitor arteriolopathy; CrCl: Creatinine clearance; eGFR: Estimated glomerular filtration rate; EVL: Everolimus; IF/TA: Interstitial fibrosis/tubular atrophy; MMF: Mycophenolate mofetil; MZ: Mizoribine; No.: Number; Tac: Tacrolimus.

Table 3 Pros and cons of late conversion to everolimus with calcineurin inhibitor elimination or minimization in kidney transplant recipients

Advantage	Disadvantage
Due to EVL introduction Antitumoral effect (especially on nonmelanoma skin carcinoma) Antiviral effect (especially on CMV and BKV infection) Antiproliferative effect Antiatherosclerotic effect	Due to EVL introduction Adverse events (gastrointestinal disorders, hyperlipidemia, interstitial pneumonitis, edema, mouth ulcers, proteinuria, impaired wound healing, hematotoxicity and so on)
Due to CNI elimination or minimization Favorable graft function	Due to CNI elimination or minimization Risk of de novo DSA

BKV: BK virus; CMV: Cytomegalovirus; CNI: Calcineurin inhibitor; DSA: Donor-specific HLA antibodies; EVL: Everolimus.