LIVER EXPERT FORUM – CONFERENCE REPORT Change in eGFR (mL/min/1.73m 2 ) 0 -5 -10 -15 -20 -25 -23.6 -21.2 -13.6 potency and can offer a renal benefit [34,35]. These trials did not include induction in the reduced- CNI cohorts, and it appears that induction is not required in medium-risk or low-risk patients given reduced-exposure CNI. CNI withdrawal Withdrawal of CNI therapy at approximately month 1 post-transplant, with introduction of a mammalian target of rapamycin (mTOR) inhibitor, does not increase the risk of BPAR if induction therapy has been given [36,37]. In the absence of induction, however, the rate of BPAR can increase substantially under CNI-free immunosuppression [35,38]. p=0.012 TAC/steroids TAC/MMF/steroids Delayed TAC/DAC/steroids Figure 5. Change in estimated GFR from baseline to 1 year after liver transplantation in 517 primary liver transplant patients randomized to tacrolimus with steroids, tacrolimus with mycophenolate mofetil (MMF) and steroids, or tacrolimus (TAC) from day 5 with daclizumab (DAC) and steroids [30] “Induction is prudent if patients are switched from CNI to mTOR inhibitor therapy early after liver transplantation.” EDUCATION improve early renal function after liver transplantation (Figure 5). Two large retrospective studies found that rATG with delayed tacrolimus versus standard therapy reduced the risk of BPAR versus standard therapy and was associated with significantly improved renal function [32,33]. Reduced CNI exposure Results from randomized trials indicate that reduced-exposure tacrolimus usage with MMF and steroids from the time of liver transplantation [34], or switching to reduced-exposure CNI at month 1 post-transplant [35] maintain immunosuppressive Can rATG ameliorate ischemiareperfusion injury? Prof. Gabriela Berlakovich (Vienna, Austria) considered the question of whether intraoperative rATG administration can attenuate ischemia-reperfusion injury (IRI) after liver transplantation, as has been suggested in kidney transplants [39]. A randomized trial in 22 liver transplant patients found that rATG (1.5 mg/kg given anhepatically and on days 2 and 4 post-transplant) was associ- 54
LIVER EXPERT FORUM – CONFERENCE REPORT Freedom from biliary complications Freedom from ischemic cholangiopathy 100 100 Patients (%) 80 60 40 rATG Basiliximab Patients (%) 80 60 40 rATG Basiliximab 20 20 0 0 0 90 180 270 360 0 90 180 270 360 Time post-transplant (days) Time post-transplant (days) Figure 6. Biliary complications and ischemic cholangiopathy in recipients of a liver graft donated after circulatory death given rATG (1.5 mg/kg anhepatically and on days 2 and 4 post-transplant, n=32) or basiliximab (on days 0 and 4) (n=54) [40] ated with fewer biliary complications and ischemic cholangiopathy than basiliximab (Figure 6), and with lower mean alanine transaminase (ALT) levels on day 2 [39]. A retrospective analysis of liver grafts donated after circulatory death has also indicated that rATG may offer a protective effect on the biliary epithelium, reducing ischemic stricture formation [40]. in infection rates versus induction-free patients. A Cochrane analysis of randomized trials in liver transplantation also found no increase in malignancy associated with induction generally, or when using either IL-2RA or rATG induction (Table 2) [16]. The same analysis showed no increase in the risk of post-transplant lymphoproliferative disease (PTLD) overall or with either type of induction. Safety issues in liver transplantation Historically, the main safety issues raised in relation to induction have been the risk of infection and post-transplant malignancies. Concerns about infection appear unfounded. A Cochrane analysis of liver transplant patients from 11 randomized trials of induction versus no induction found no effect on the risk of infections overall, or on the risk of cytomegalovirus infection specifically [16]. Individual studies of IL-2RA induction [29–31] or rATG [32,33] have also reported no difference Table 2. Cochrane analysis of relative risk for malignancy with induction versus no induction [16] Any induction (n=1,682) IL-2RA induction (n=1,302) rATG (n=1150) Induction Malignancy (%) No induction Relative risk (95% CI) 2% 3% 0.91 (0.49, 1.69) 2% 2% 1.27 (0.58, 2.77) 5% 10% 0.56 (0.15, 2.09) EDUCATION 55
