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Copyright ©The Author(s) 2023.
World J Transplant. Dec 18, 2023; 13(6): 299-308
Published online Dec 18, 2023. doi: 10.5500/wjt.v13.i6.299
Table 1 Summary of randomized clinical trial studies
No.Ref.Study designATG – dose & durationGraft outcomeDeathOther adverse events
1Shield et al[50], 1979Prospective, randomised, single centre, United States; First rejectioneATG 15 mg/kg daily for 14 d (n = 10) vs MP 1 g/d for 5 d (n = 10)Reversal – 8/10 (ATG) vs 6/10 (MP); Recurrent rejection 1/10 (ATG) vs 5/10 (MP); Graft loss at 12 mo – 1/10 (ATG) vs 1/10 (MP)At 12 mo – 0/10 (ATG) vs 1/10 (MP)Infection – 3/10 (ATG) vs 0/10 (MP); AVN – 1/10 (ATG) vs 0/10 (MP)
2Filo et al[51], 1980Prospective, randomised, single centre, United States; First rejectioneATG 10 mg/kg/d for 15 d (n = 35) vs MP 30 mg/kg every other day up to 5 doses (n = 43)Reversal – 32/35 (ATG) vs 29/43 (MP); Recurrent rejection – 16/35 (ATG) vs 15/43 (MP); Graft survival (91% vs 62%); Faster recovery (6.9 d vs 8.9 d); Graft loss – 15/35 vs 25/43 (MP)At 12 mo – 1/24 (ATG) vs 0/29 (MP)
3Hoitsma et al[52], 1982Prospective, randomised, single centre, Netherlands; First rejectionrATG initially 4 mg/kg followed by 2-7 mg/kg for 21 d (n = 20) vs prednisolone 200 mg/d, tapered to 25 mg/d in 2 wk (n = 20)Reversal – 43/50 (ATG) vs 35/50 (Prednisolone); Recurrent rejection – 28/50 (ATG) vs 35/50 (Prednisolone); Graft loss – 15/50 (ATG) vs 28/50 (Prednisolone)At 12 mo – 0/20 (ATG) vs 1/20 (Prednisolone)Infection – 9/20 (ATG) vs 15/20 (Prednisolone)
4Toledo-Pereyra et al[53], 1985Prospective, randomised, single centre, United States; First rejectionALG 10 to 20 mg/kg for 10 d (n = 20) vs ATG 10 to 20 mg/kg for 10 d (n = 20)Reversal – 15/20 (ALG) vs 16/20 (ATG)
6Alamartine et al[54], 1994Prospective randomised, single centre, France; Steroid-resistant rejectionMuromonab-CD3 5 mg/d for 10 d (n = 27) vs rATG: 1.5 mg/kg/d for 10 d (n = 32)Reversal – 25/26 (Muromonab-CD3) vs 27/32 (ATG); Recurrent rejection – 25/32 (ATG) vs 24/27 (Muromonab-CD3); Graft loss at 12 mo – 11/32 (ATG) vs 4/26 (Muromonab-CD3)CMV infection – 8/27 (Muromonab-CD3) vs 18/32 (ATG)
7Tesi et al[55], 1997 Prospective, randomised, multi-centre n = 163 (82 Thymoglobulin, 81 ATGAM); First rejectionrATG 1.5 mg/kg vs ATGAM 15 mg/kg (both for 7 to 14 d)65% treated with THYMO had histology grade improvement (vs 50% in ATGAM)Overall – 3/82 (rATG) vs 1/81 (eATG)CMV infection 20/82 in both groups
8Mariat et al[31], 1998Prospective, randomised, single centre, France; First rejectionMuromonab-CD3 5 mg/kg for 3 d followed by 2.5 mg/kg for 7 d (n = 29) vs rATG 25 mg/d if < 40 kg, 50 mg/d if 40-70 kg & 75 mg/d if > 70 kg; 10 d (n = 31)Reversal – 25/29 (Muromonab-CD3) vs 30/31 (ATG); Recurrent rejection – 11/29 (Muromonab-CD3) vs 9/31 (ATG); Graft loss at 12 mo – 6/29 (Muromonab-CD3) vs 4/31 (ATG)At 12 mo – 3/31 (ATG) vs 1/29 (Muromonab-CD3)CMV infection – 12/31 (ATG) vs 13/29 (Muromonab-CD3); Malignancy – 0/31 (ATG) vs 2/29 (Muromonab-CD3)
9Gaber et al[56], 1998 Prospective, randomised, multi centre, United States; First rejectionThymoglobulin (rATG) 1.5 mg/kg/d for 7-14 d (n = 82) vs ATGam (eATG) 15 mg/kg/d, for 7-14 d (n = 81)Reversal – 88% (Thymoglobulin) vs 76% (ATGAM); Recurrent rejection; 28/82 (rATG) vs 50/81 (eATG)Total 6/82 (rATG) vs 3/81 (eATG)Leukopenia – 57% (rATG) vs 30% (eATG); Bacterial infection – 29% (rATG) vs 37% e(ATG); Viral infection – 21% (rATG) vs 11% (eATG)
10Theodorakis et al[57], 1998Prospective, randomised, single centre, Germany; First rejectionATG 4 mg/kg for 7 d (n = 25) vs MP 250 mg/d for 3 d (n = 25)Recurrent rejection – 4/25 (ATG) vs 18/25 (MP); Graft loss – 5/25 (ATG) vs 3/25 (MP)
11Baldi et al[58], 2000 Prospective, randomised, single center, Belgium; First rejectionrATG 4 mg/kg day for 10 d (n = 28) vs Muromonab-CD3: 5 mg/d for 10 d (n = 28); MP for both groups: 500 mg/d for 3 dReversal – 21/28 (rATG) vs 14/28 (Muromonab-CD3); Recurrent rejection – 9/28 (ATG) vs 10/25 (Muromonab-CD3)Irreversible rejection in 3/28 OKT3, 2nd rejection in 33% ATG, 39% OKT3Fever – 21.4% (ATG) vs 92.8% (Muromonab-CD3); Headache – 3.5% (ATG) vs 46.4% (Muromonab-CD3); Infection – 9/28 (ATG) vs 10/28 (Muromonab-CD3); Malignancy 2/28 (ATG) vs 0/28 (Muromonab-CD3)
12Midtvedt et al[59], 2003 Prospective, randomised, single centre, Norway; First rejectionATG 2 mg/kg followed by 1 mg/kg if & when T cells > 50 (n = 27) vs muromonab-CD3: 5 mg, then 2.5 mg (n = 28)Reversal – 26/27 (ATG) vs 27/28 (Muromonab-CD3); Recurrent rejection – 12/27 (ATG) vs 14/28 (Muromonab-CD3); Grafts loss at 12 mo – 3/27 (ATG) vs 4/28 (Muromonab-CD3)At 12 mo – 2/27 (ATG) vs 1/28 (Muromonab-CD3)CMV infection – 14/27 (ATG) vs 11/28 (Muromonab-CD3); Malignancy – 1/27 (ATG) vs 1/28 (muromonab-CD3); Bacterial pneumonia – 3/27 (ATG) vs 3/28 (Muromonab-CD3)
ATG: Anti-thymocyte globulin; rATG: Rabbit Anti-thymocyte globulin, eATG: Equine Anti-thymocyte globulin; MP: Methylprednisone.
Table 2 Summary of non-randomized clinical studies
No
Ref.
Study design
ATG -dose/duration
Graft outcome
Death
Adverse events
1Hardy et al[60], 1980Prospective, non-randomised, single centre , United States, n = 20 (10 ATG)eATG – 15 mg/kg (max 750 mg) for 21 d + MP (750, 200 & 150 mg for 3 d) (n = 10) vs MP (750, 200 & 150 mg for 3 d) (n = 10)Reversal – 9/10 (ATG) vs 8/10 (control); Recurrent rejection 2/10 (ATG) vs 4/10 (control); Graft loss at 12 mo – 4/10 (ATG) vs 5/10 (control)0 in both groups3 serious complications in control group and 1 in ATG
2Richardson et al[30], 1989Prospective, non-randomised, single centre, United KingdomrATG (2-3 mg/kg for 5-10 d) reduced to 1-2 mg/kg if leukopenia or thrombocytopenia (n = 27)70.3% graft survival with mean follow-up time of 13.3 mo; 8 out of 27 failed (6 due to rejection, 1 death, and 1 renal artery stenosis)1 death6 UTIs, 1 pseudomembranous colitis, 8 CMV and 5 HSV, 2 deaths
3Clark et al[45], 1993Prospective, non-randomised, single centre, United KingdomGroup 1: rATG, 2.5-5 mg/kg/d) for 10-14 d (n = 10); Group 2: As per T cell count for 10-14 d (n = 17)76% graft survival at 1 year group 2 (vs 60% in group 1); Group 1 – (4 rejections); Group 2 – (4 rejections)2 deaths (group 1) vs 0 deaths (group 2)Group 1: 3 serious viral infection, 6 minor infections; Group 2: 11 minor infections
4Uslu et al[61], 1997Retrospective, non-randomised, single centre, Turkey rATG 5 mg/kg for 13.7 ± 3.7 d (n = 9) OKT3 5 mg/d for 11.4 ± 1.9 d (n = 5)Graft survival: 78% ATG vs 20% OKT3 with median f/u 405 dOKT3 – 1 CMV, Fever > 38 in 80% pts in both groups, Leukopenia (35% ATG vs 0 in OKT3)
5Sharma et al[46], 2003Prospective, non-randomized, single centre, India ATG 1.5-1.8 mg/kg alternate d, mean duration 5 doses (n = 33)90% graft survival in first year and 73% at 20 mo. Graft loss in 4; Recurrent rejection in 8/33 at 3 mo1 death11 pneumonia, 3 UTI, 1 peritonitis, 2 CMV, 5 leukopenia
6Colak et al[62], 2008Retrospective, non-randomised, single-centre, TurkeyATG 3-5 mg/kg/d 10-14 d (Dose adjusted with other parameters) (n = 23)Graft function improved in 19 cases (83%)1 death9 infections (3 pulmonary aspergillosis, 2 CMV, 4 pulmonary/urinary bacterial infections)
7Kainz et al[33], 2009Retrospective, non- randomised, multi centre, AustriaN/A n = 399 (368 ATG, 31 OKT3)Median actual graft survival 9.5 yr ATG vs 4.5 yr OKT3N/AN/A
8van der Zwan et al[38], 2018Retrospective, non-randomised, single centre, Netherlands rATG – 4 mg/kg repeated after 4 d if CD3 > 200, for 2 wk (n = 103)Median allograft survival 7.0 yr. At one yr 78.2% had functioning graft; At 5 yr 55.6% functioning graft; 49 lost graft in median f/u 6.8 yr17 deaths97 bacterial, 8 fungal, 27 CMV reactivation, 4 EBV reactivation, 6 BK viraemia), 14 malignancy (12 solid, 2 lymphoma)
ATG: Anti-thymocyte globulin; EBV: Epstein-Bar virus, CMV: Cytomegalovirus, rATG: Rabbit anti-thymocyte globulin; OKT3: Muromonab CD3, UTI: Urinary tract infection; N/A: Not applicable.