Use of daclizumab as initial immunosuppression in liver transplant recipients with impaired renal function

Abstract

The addition of daclizumab (a human immunoglobulin G1 monoclonal antibody that blocks interleukin-2 receptors on T lymphocytes) to mycophenolate mofetil (MMF) and steroids is a new option for initial immunosuppression in patients undergoing liver transplantation (LT) with impaired renal function. We evaluated the efficacy and safety of daclizumab in preventing rejection in 25 patients with impaired kidney function undergoing LT. Patients with serum creatinine (Cr) levels greater than 2 mg/dL immediately before LT were administered initial immunosuppression with daclizumab, 1 mg/kg, in addition to MMF, 2 g/d, and methylprednisolone. Tacrolimus was added after kidney function improved (when Cr levels improved by >25% of initial value). Daclizumab-treated patients were compared retrospectively with 2 other groups of patients who underwent LT with kidney impairment (Cr > 2 mg/dL): 56 patients were administered OKT3 induction, and 48 patients were administered lowdose tacrolimus. The incidence of rejection and infection (bacterial, fungal, and viral), need for preoperative and postoperative dialysis, Cr level immediately post-LT and at 3 months, and graft and patient survival were analyzed. There was no difference among the groups in 3-month Cr levels or the incidence of rejection or fungal or viral infection. The daclizumab group had fewer bacterial infections (n ‫؍‬ 13) than the tacrolimus group (n ‫؍‬ 28) and significantly fewer than the OKT3 group (n ‫؍‬ 58; P ‫؍‬ .006). Only 1 patient (4%) in the daclizumab group required dialysis post-LT versus 13 patients in each of the other groups (OKT3, 23.21%; P < .05; tacrolimus, 27%). In the daclizumab group, 2-year patient and graft survival rates were statistically significant compared with the lowdose tacrolimus group (89% and 81% v 73% and 69%, respectively; P ‫؍‬ .06). There were no side effects related to daclizumab use, and all patients tolerated the drug well. In patients with impaired renal function before LT, daclizumab-based initial immunosuppression can be used safely to reduce the risk for infection and need for dialysis post-LT, with improved long-term graft and patient survival. (Liver Transpl 2001;7:220-225.)T here is no agreement on initial immunosuppressive regimens in patients undergoing liver transplantation (LT) with impaired renal function. [1][2][3] Suggested regimens include OKT3 induction in combination with azathioprine and steroids, with or without low doses of calcineurin inhibitors. [4][5][6] A new option in this circumstance is the use of daclizumab with mycophenolate mofetil (MMF) and steroids. Daclizumab is a human immunoglobulin G1 monoclonal antibody that blocks the ␣ chain of interleukin-2 receptors on activated T lymphocytes. [7][8][9] Previous studies have shown the efficacy of daclizumab in preventing rejection in kidney transplantation and LT without immediate side effects. [7][8][9][10][11] In particular, daclizumab does not cause cytokine release syndrome, neurotoxicity, or nephrotoxicity, which makes it an appealing alternative t...

Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors

“…18 Although delaying initiation of CNI with interleukin-2 receptor (IL-2R) antagonists basiliximab and daclizumab has been associated with acceptable short-term outcomes, long-term benefits in renal function have not been observed. 16,17,20,29,30 In comparison with our current study, the lack of apparent long-term renal function benefits from the use of IL-2R antagonists to delay CNI initiation may be related to the differences in the patient populations studied and the pharmacology of these antibodies. In previous studies that used IL-2R antagonists to delay initiation of CNI, most patients did not have preexisting renal dysfunction and were not critically ill. 16,19,29 In this study, all patients had preexisting renal dysfunction (Ն1.5 mg/dL), and most were critically ill at the time of transplant, as evident by the high MELD score and high percentage of patients hospitalized prior to transplant.…”

Long-term Safety, Tolerability and Efficacy of Daclizumab (Zenapax®) in a Two-dose Regimen in Liver Transplant Recipients

“…Recently, different dosing regimens (five doses or singleshots) have been tested in liver-transplanted patients in order to limit the use calcineurin inhibitors in the early postoperative period in patients with impaired renal function; with good success (32,33). However, daclizumab application without calcinurin inhibitors was not effective in liver transplantation (34).…”

Structural basis of immunosuppression by the therapeutic antibody daclizumab

“…It is a humanized IgG1 form of murine anti-IL-2Rα mAb anti-Tac and retains the murine complementarity determining regions (CDRs) and some key residues of the framework regions (FWRs) for high specificity and high affinity [23]. Daclizumab has been successfully used in the treatment of renal transplantation [24][25][26][27][28] and liver transplantation [29][30][31][32], and is promising for the treatment of acute graft-versus-host disease [33,34], multiple sclerosis [35], and malignancies such as T cell leukemia [19]. The non-randomized large multi-center trials in phase I/II showed that the safe and efficacious dosages of basiliximab and daclizumab are quite different (basiliximab in two 20 mg/kg doses and daclizumab in five 2 mg/kg doses) [36].…”