Suppression of allograft rejection is central to successful organ transplantation; thus, immunosuppressive agents are crucial for successful allograft function. Immunosuppressive drugs are used for induction (intense immunosuppression in the initial days after transplantation), maintenance, and reversal of established rejection. This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.

https://www.nejm.org/doi/pdf/10.1056/NEJMra033540

Immunosuppressive Drugs for Kidney Transplantation

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(04)17406-0.pdf

Delayed graft function in kidney transplantation.

Background Induction therapy reduces the frequency of acute rejection and delayed graft function after transplantation. A rabbit antithymocyte polyclonal antibody or basiliximab, an interleukin-2 receptor monoclonal antibody, is most commonly used for induction. Methods In this prospective, randomized, international study, we compared short courses of antithymocyte globulin and basiliximab in patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor. Patients taking cyclosporine, mycophenolate mofetil, and prednisone were randomly assigned to receive either rabbit antithymocyte globulin (1.5 mg per kilogram of body weight daily, 141 patients) during transplantation (day 0) and on days 1 through 4 or basiliximab (20 mg, 137 patients) on days 0 and 4. The primary end point was a composite of acute rejection, delayed graft function, graft loss, and death. Results At 12 months, the incidence of the composite end point was similar in the two groups (P=0.34). The antithymocyte globulin group, as compared with the basiliximab group, had lower incidences of acute rejection (15.6% vs. 25.5%, P=0.02) and of acute rejection that required treatment with antibody (1.4% vs. 8.0%, P=0.005). The antithymocyte globulin group and the basiliximab group had similar incidences of graft loss (9.2% and 10.2%, respectively), delayed graft function (40.4% and 44.5%), and death (4.3% and 4.4%). Though the incidences of all adverse events, serious adverse events, and cancers were also similar between the two groups, patients receiving antithymocyte globulin had a greater incidence of infection (85.8% vs. 75.2%, P=0.03) but a lower incidence of cytomegalovirus disease (7.8% vs. 17.5%, P=0.02). Conclusions Among patients at high risk for acute rejection or delayed graft function who received a renal transplant from a deceased donor, induction therapy consisting of a 5-day course of antithymocyte globulin, as compared with basiliximab, reduced the incidence and severity of acute rejection but not the incidence of delayed graft function. Patient and graft survival were similar in the two groups. (ClinicalTrials.gov number, NCT00235300 [ClinicalTrials.gov].).

https://www.nejm.org/doi/pdf/10.1056/NEJMoa060068

Rabbit antithymocyte globulin versus basiliximab in renal transplantation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-6143.2011.03754.x

Delayed Graft Function in the Kidney Transplant

From the Hematology Branch (P.S., O.N., B.W., P.S., N.S.Y.) and Office of Biostatis- tics Research (C.O.W.), National Heart, Lung, and Blood Institute; and the Trans- NIH Center for Human Immunology, Auto- immunity, and Inflammation, National In- stitutes of Health (A.B., N.S.Y.) — both in Bethesda, MD. Address reprint requests to Dr. Scheinberg at 10 Center Dr., Bldg. 10 CRC, Rm. 3E-5140, MSC 1202, Bethes- da, MD 20892-1202, or at scheinbp@mail .nih.gov. A B S T R AC T A large, unexpected difference was observed in the rate of hematologic response at 6 months in favor of horse ATG (68%; 95% confidence interval (CI), 56 to 80) as compared with rabbit ATG (37%; 95% CI, 24 to 49; P<0.001). Overall survival at 3 years also differed, with a survival rate of 96% (95% CI, 90 to 100) in the horse- ATG group as compared with 76% (95% CI, 61 to 95) in the rabbit-ATG group (P = 0.04) when data were censored at the time of stem-cell transplantation, and 94% (95% CI, 88 to 100) as compared with 70% (95% CI, 56 to 86; P = 0.008) in the re- spective groups when stem-cell-transplantation events were not censored. Conclusions In a randomized study, rabbit ATG was inferior to horse ATG as a first treatment for severe aplastic anemia, as indicated by hematologic response and survival. (Funded by the Intramural Research Program of the National Institutes of Health; ClinicalTrials.gov number, NCT00260689.)

/pdf/horse-versus-rabbit-antithymocyte-globulin-in-acquired-3jokclvu37.pdf

Horse versus Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia

Background The aim of this study was to compare the efficacy and safety of Thymoglobulin (a rabbit-derived polyclonal antibody) to Atgam (a horse-derived polyclonal antibody) for induction in adult renal transplant recipients Methods Transplant recipients (n=72) were ran domized 2:1 in a double-blinded fashion to receive Thymoglobulin (n=48) at 15 mg/kg intravenously or Atgam (n=24) at 15 mg/kg intravenously, intraopera tively, then daily for at least 6 days Recipients were observed for at least 1 year of follow-up Results By 1 year after transplantation, 4% of Thymoglobulin-treated patients experienced acute rejection compared with 25% of Atgam-treated patients (P=0014) The rate of acute rejection was lower with Thymoglobulin than Atgam (relative risk=009; P=0009) Rejection was less severe with Thymoglobulin than Atgam (P=002) No recurrent rejection occurred with Thymoglobulin compared with 33% with Atgam (P=NS) Patient survival was not different, but the composite end point of freedom from death, graft loss, or rejection, the event-free survival, was superior with Thymoglobulin (94%) compared with Atgam (63%; P=00005) Fewer adverse events occurred with Thymoglobulin (P=0013) Leukopenia was more common with Thymoglobulin than Atgam (56% vs 4%; P<00001) during induction The mean absolute lymphocyte count remained below baseline with Thymoglobulin throughout the study (P<0007), but with Atgam, significant lymphocyte reductions occurred only at day 7 The incidence of cytomegalovirus disease was less with Thymoglobulin than Atgam at 6 months (10% vs 33%; P=0025) Conclusions Brief (7-day) induction with Thymoglobulin resulted in less frequent and less severe rejection, a better event-free survival, less cytomegalovirus disease, fewer serious adverse events, but more frequent early leukopenia than induction with Atgam These results may in fact be explained by a more profound and durable beneficial lymphopenia

Sara Dolan

Papers

A randomized, double-blinded comparison of thymoglobulin versus atgam for induction immunosuppressive therapy in adult renal transplant recipients