Mammalian Target of Rapamycin Inhibitors and Wound Healing Complications in Kidney Transplantation: Old Myths and New Realities

Table 4

Summaries of randomized control trial performed on EVL.

Reference	Journal/year/design	Induction	Arms compared	EVL dose	EVL level	Finding
Vitko et al. [13]	Am J Transplant/2004/2 open label RCT studies	Study 1: without basiliximab; Study 2: with basiliximab	EVL 1.5 mg-CsA-Pred vs.; EVL 3 mg-CsA-Pred without basiliximab; vs.; EVL 1.5 mg-CsA-Pred vs.; EVL 3 mg-CsA-P ped with basiliximab	Both arms, two doses of EVL 1.5 mg/day vs. 3 mg/day	>3 ng/m L	Study 1: 15.2% had lymphocele in 1.5 mg group as compared to 6.4% in 3 mg group; Study 2: lymphocele was found in 10.3% in 1.5 mg EVL group as compared to 7.2% in 3 mg group; No comment on value
Vítko et al. [128]	Am J Transplant/2005/double blind RCT study	----------------	1-EVL-CsA-Pred; 2- EVL-CsA-Pred; 3-MMF-CsA-Pred	1.5 mg/day; 3 mg/day	>3 ng/m L	Lymphocele occurred in 9% in EVL 1.5 mg-CsA-Pred as compared; 12% in EVL 3 mg-CsA-Pred group and 4% in MMF-CsA-Pred ( value not significant)
Lorber et al. [129]	Transplantation/2005/open label RCT study	Methyl prednisolone	1-EVL-CsA-Pred; 2- EVL-CsA-Pred; 3-MMF-CsA-Pred	1.5 mg/day; 3mg/day	>3 ng/m L	Lymphocele occurred in EVL 1.5 mg group in 16.1%, 18.6% in EVL 3 mg, and 12.2% in MMF-CsA-Pred group.; value was insignificant
Chan et al. [130]	Transplantation/2008/open label RCT study	Basiliximab	1-EVL-low-dose TAC-Pred; 2-evl-standard-dose TAC-Pred	1.5 mg/day	>3 ng/mL	Wound infection (4.1%), dehiscence (2.1%), and lymphocele (4.1%) occurred in low-dose TAC; Wound infection (2.3%), dehiscence (4.7%), and lymphocele (2.3%) occurred in standard-dose TAC. No P value given
Margreiter et al. [131]	Transplantation/2008/pool analysis of 4 RCT trial	-------------------	1-MMF-CsA-Pred; 2-EVL (1.5 mg/day or 3 mg/day-low-dose CsA-Pred	1.5 mg/day; or 3 mg/day	3–8 ng/mL	Wound infection, dehiscence, and lymphocele (4.1% occurred in 9.7%, 3.6%, and 8.4% of MMF group, respectively, in EVL group wound infections were 11.4%, dehiscence was in 6.1%, and lymphocele in 7.5 % similar complication rates. No P value given
Albano et al. [132]	Transplantation/2009/open label RCT study	Basiliximab/daclizumab	1-immediate EVL (Day 1)-CsA-Pred; 2-delayed EVL (from week 5); MMF was given till week 5 along with CsA-Pred	0.75 mg twice a day adjusted to achieve 3–8 ng/mL	C0 = 3–8 ng/mL	Wound healing complication at week 4 was 23.1% vs.29.7% in immediate vs. delayed EVL group (P0.444); Wound healing complication at 3 months was 36.9% vs. 37.8% in immediate vs. delayed EVL group (P = 1); Fluid collection at week 4 was 23.1% vs. 25.7% in immediate vs. delayed EVL group
Salvadori et al. [14]	Transplantation/2009/open label randomized control trial	Basiliximab	1-EVL-low-dose CsA-Pred; 2- EVL-very low-dose CsA-Pred	0.75 mg twice a day adjusted to achieve 3–8 ng/mL; 0.75 mg twice a day adjusted to achieve 3–8 ng/mL during first week and then adjusted to achieve 6–12 ng/mL	C0 = 3–8 ng/m L; C0 = 6–12 ng/mL	Lymphocele in 15.4%; Lymphocele in 21.1%; The findings were not significant
Silva et al. [133]	Am J Transplant/2010/open label RCT study	Basiliximab	1-EVL (1.5 mg/day)-low-dose CsA-Pred; 2-evl (3 mg/day)-low-dose CsA-Pred; 2-MMF-CsA-Pred	1.5 mg/day; 3 mg/day	3–8 ng/ml; 6–12 ng/mL	Lymphocele occurred in 6.6%, 11.2%, and 5.1% in low-dose EVL, high-dose EVL, and MMF, respectively.; Impaired wound healing occurred in 1.8%, 4%, and 1.1% in low-dose EVL, high-dose EVL, and MMF, respectively; Wound dehiscence occurred in 1.5%, 3.2%, and 1.5% in low-dose EVL, high-dose EVL, and MMF, respectively; No comment on value for either of the finding
Dantal et al. [10]	Transpl Int/2010/open label RCT study	Basiliximab/daclizumab	1-immediate EVL (Day 1)-CsA-Pred; 2-delayed EVL (from week 5); MMF was given till week 5 along with CsA-Pred	0.75 mg twice a day adjusted to achieve 3–8 ng/mL	C0 = 3–8 ng/mL; in both the groups	Wound healing complications were 40% immediate group and 37.8% delayed group at 12 months respectfully ( = 0.86 NS); Wound healing complications were 36.9% in immediate group and 33.8% in delayed group at 12 months respectfully (-NS)
Cooper et al. [134]	Clin Transplant/2013/pool analysis of three RCT studies	----------------	1-EVL (1.5 mg/day)-CsA-Pred; 2-evl (3 mg/day)-CsA-Pred; 3-MMF-CsA-; 1.5 or 3.0 mg or MPA, with CsA and steroids	1.5 mg/day; 3 mg/day	------------------	Wound healing complication was 16.6% in 1.5 mg/day in EVL as compared to 14.3% in MMF ( = 0.255); But, it was 21.8% in EVL 3 mg/day significantly higher in MMF group ( < 0.001)
Cibrik et al. [135]	Transplantation/2013/open label RCT study	Basiliximab	1-EVL (3–8 ng/ml) + reduced exposure CsA + Pred; 2- EVL (6–12 ng/ml) + reduced exposure CsA + Pred; 3-MMF-standard CsA + Pred	Dose was adjusted to get level 3–8 ng/mL; Dose was adjusted to get level 6–12 ng/mL	C0 = 3–8 ng/mlc0 = 6–12 ng/mL	Rare wound healing events of 0.4% in EVL (3–8 ng/mL), 0.7% in EVL (6–12 ng/mL), and 1% in MMF group
Chadban et al. [136]	Transpl Int/2014/open label RCT study	Basiliximab	1-CsA-MPS-Pred for 14 days, then EVL-Pred (CsA and MPS withdrawal); 2-CsA-mps-Pred for 14 days. then EVL-CsA (Pred and MPS withdrawal); 3-CsA-mps-Pred	Dose adjusted for first 15 to 60 days to achieve level 6–10 ng/mL; From 61–120 days in CsA-MPA withdrawal group dose adjusted to level of 8–12 ng/mL. In Pred-MPA withdrawal group, EVL C0 level was kept at 6–10 ng/mL	15–60 days: both groups EVL C0 level = 6–10 ng/mL; 61-120 days: CsA-MPA WD : EVL = CO = 8–12/ng/mL; Pred-CNI WD : EVL = C0 = 6–10 ng/mL	Nonsignificant wound healing complication occurred in CsA-MPA WD (33%), Pred-MPA WD withdrawal (30%), and 32% in CsA-MMF-Pred
Nashan et al. [137]	Am J Transplant/2016/open label RCT study		Randomization after 10–14 weeks: 1-evl-mps-Pred; 2-CsA/TAC-mps-Pred	EVL CO = 6–10 ng/mL	CO = 6–10 ng/mL	Wound healing events were similar in both the arms (EVR, 6.6 vs. CNI, 5.8%;  = 0.66; The incidence of patients with wound problem was similar in ≤25 percentile BMI category (EVR, 0.9 vs. CNI, 0.8%;  = 0.846). The incidence was higher in EVR arm in >25–≤50 (2.6 vs. 1.1%;  = 0.271) and significantly higher in >50–≤75 categories (2.0 vs. 0.6%;  = 0.049).
Qazi et al. [138]	Am J Transplant/2017/open label RCT study	Basiliximab or ATG	1-EVL-low-dose TAC-Pred; 2-MMF-standard-dose TAC-Pred	EVR 0.75 mg twice a day (1.5 mg/day)	C0 = 3–8 ng/mL	Fluid collection (lymphocele, seroma, urinoma, and hematoma) adjacent to transplant was 22.5% (EVL) vs.15% (MMF); Delayed wound healing was 16.7% (EVL) vs. (11.8%)
de Fijter et al. [9]	Am J Transplant/2017/open label RCT study	Basiliximab	TAC or CsA-MPA-Pred for 10–14 weeks, then randomized to1-evl-mps-Pred; 2-TAC or CsA-mps-Pred	Dose adjusted to CO level 6–10 ng/mL	C0 = 6–10 ng/mL	Wound healing events were similar between groups 5.8% (CNI) vs. 6.5% (EVL)
Ueno et al. [105],; ATG	Transplantation/2017/subanalysis of open label RCT study	ATG/basiliximab	1-ATG followed by EVL-TAC-Pred; 2-basiliximab followed by EVL-TAC-Pred; 3-basiliximab followed by MPS-TAC-Pred	Dose adjusted to get level C0 = 4–8 ng/mL; Dose adjusted to get level C0 = 4–8 ng/mL	C0 = 4–8 ng/mL; C0 = 4–8 ng/mL	Basiliximab-EVL group has 35.2% wound healing complication vs. 22% in basiliximab-MPS ( = 0.033)
Tedesco-Silva et al. [69]	J Am Soc Nephrol/2018/Open label RCT study	Basiliximab/ATG	1-EVL-TAC or CsA-Pred; 2-mmf or MPS –TAC or CsA-Pred	EVL dose was 1.5 mg or 0.75 mg twice a day in TAC or CsA	C0 = 3–8 ng/mL	Wound healing was 19.8% in EVL group as compared to 16.2% with relative risk 1.22 (1.01 to 1.47)
Sommerer et al. [139]	Kidney International/2019/open label RCT study	Basiliximab	1-EVL-TAC-Pred; 2-EVL-CsA-Pred; 3-MMF-TAC-Pred	EVL dose was adjusted to C0 = 3–8 ng/mL	C0 = 3–8 ng/mL	Wound healing was 30.5%, 28.3%, and 33.3% in the three groups, respectively, and did not differ in three groups.; Lymphocele occurred in 18.1%, 24%, and 20.1% of the three groups, respectively
Manzia et al. [18],; IR VS. DR	Transplantation/2020/open label RCT study	IL-2 receptor antibodies/ATG	1-immediate (IE) EVR-low CsA-Pred; 2-delayed group (DE):MPS-CsA-Pred for 28 days followed by EVR-low CsA-Pred	EVL 0.75 mg BID	C0 = 3–8 ng/mL	Wound healing complications included in IE were fluid collection (17%), lymphocele (10%), and wound dehiscence (6%), which were not different at 3 months as compared to DE group; At 12 months, wound healing complications between IE and DE groups were not significant except hematoma which was significant in IE group ( = 0.02380) as compared to DE and lymphocele was more in DE group as compared to IE group (P0.0368)