- Email: [email protected]
Induction versus noninduction therapy in kidney transplantation: considering different PRA levels and different induction therapies
Induction Versus Noninduction Therapy in Kidney Transplantation: Considering Different PRA Levels and Different Induction Therapies M.C.R. Castro, L.M.P. Araujo, W.C. Nahas, S. Arap, E. David-Neto, and L.E. Ianhez ABSTRACT To evaluate the rate of acute cellular rejection (ACR) and long-term results in different levels of anti-HLA sensitization, using noninduction or different induction therapies, 763 patients who underwent transplantation from January 1995 to December 2001 were evaluated: 213 patients received induction therapy, 71 received Thymoglobulin (Thymo), 66 Simulect, and 44 OKT3. Follow-up time was at least 1 year for all groups. The Simulect group included older recipients and the OKT3 group had more female patients. Simulect and OKT3 groups had more black patients; Thymo and OKT3 groups had more retransplantations. PRA was low in the noninduction group (mean, 7%) and about the same in the Simulect and Thymo groups (mean, 30%). OKT3 was the most sensitized group (mean ⫽ 59%). Dialysis during the first posttransplantation week was more frequent among the induction groups (43% vs 65%; P ⬍ .005). Fewer patients experienced rejection episodes in the Thymo group (20% vs 50%; P ⫽ .02). Patients were classified according to their level of sensitization, and the Thymo group showed the lower rejection rates in all levels (mean, 20%; P ⫽ .001). When analyzing PRA ⬎50%, the Thymo group showed lower rejection rates (12% vs 50%; P ⫽ .02). At this level of sensitization, there was no significant difference on graft loss and death with a functioning graft. There was a trend to more cytomegalovirus (CMV) disease in the Thymo group (33% vs 23%; P ⫽ .08). Two PTLD were diagnosed, both in the noninduction group. Renal function was better in the Thymo group (1.3 mg/dL). In conclusion, Thymo showed lower ACR rates in all PRA groups. No significant differences in CMV infection, tumors, and patient survival were observed.
G
raft survival and acute cellular rejection (ACR) rates are influenced by the presence of anti-HLA antibodies.1 Patients can be immunized by blood transfusions, pregnancy, rejection of a previous allograft, and, less frequently, by cross reactivity to environmental antigens.2 Nowadays, about 30% of the patients awaiting a cadaver kidney are highly sensitized. Anti-HLA immunization may have severe consequences for the graft and the patient, namely, humoral rejection, accelerated rejection, and increased frequencies of delayed graft function as well as acute and chronic rejection.3– 6 Management of these highly sensitized patients is often difficult, using antibody removal by radiation, plasma exchange, or immunoadsorption.7 Regulation of antibody secreting clones (by polyclonal immunoglobulin)8,9 is a promising adjunct. The use of induction therapy remains controversial in kidney transplantation, although published studies favor induction.10 –13 There is no consensus about the best induction protocol for 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.03.084 874
immunized patients. To evaluate the rate of ACR and the long-term results in patients with different levels of antiHLA sensitization, using noninduction or different induction therapies, 763 patients who underwent transplantation in our unit were evaluated retrospectively. PATIENTS AND METHODS From January 1995 to December 2001, 763 adults (older than 18 years of age), received single, non-HLA-identical kidney transplants. Three hundred seventy-five patients received no induction treatment and 213 (36%) received some kind of induction therapy: 71 patients received anti-thymocye globulin, Thymoglobulin From the Renal Transplantation Unit, Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil. Address reprint requests to *Maria Cristina Ribeiro de Castro, MD, Rua Maria da Gra˜ 333, c.8, 05465-040, Sa˜o Paulo-SP, Brazil. E-mail: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 874 – 876 (2004)
INDUCTION VS NONINDUCTION THERAPY (Thymo; Imtix-SangStat, Lyon, France), 66 received the chimeric monoclonal anti interleukin (IL)-2 receptor antibody, Basiliximab (Simulect, Novartis Pharmaceuticals), and 44 an anti-CD3 monoclonal antibody (Orthoclone-OKT3, ORTHO). The 32 patients who received either Daclizumab-Zenapax (Hoffmann La Roche) or a locally produced anti-lymphocytic globulin were excluded because of the low number of cases. Thymo was given at an initial dose of 1.5 mg/kg/d for 7 to 10 days with the daily dose adjusted to keep peripheral lymphocytes ⬍150/mm3. OKT3 was given in a fixed dose of 5 mg/d for 7 to 10 days. Simulect was given at a fixed dose of 20 mg/d at the first and the fourth postoperative day (POD). All patients received Prednisone (1 mg/kg/d, weekly reduced until 10 mg/d), Azathyoprine (2 mg/kg/d) or Mycophenolate mofetil (30 mg/kg/d) corrected according to peripheral blood leucocytes counts and side effects, and Neoral (10 mg/kg/d) or Prograf (0.20 mg/kg/d) with trough levels between 250 and 350 ng/mL and 12–15 ng/mL, respectively, during the first postoperative month. When induction with Thymo or OKT3 was used, calcineurin inhibitors were initiated on average on the 10th POD. In the noninduction and Simulect groups, these agents were initiated on the first POD. OKT3 and Thymo patients received cytomegalovirus (CMV) prophylaxis with intravenous ganciclovir for 3 months. Rejection was diagnosed clinically, but frequently confirmed using a kidney biopsy. Rejections classified as Banff Ia, Ib, and IIa were treated with methylprednisolone 8 –15 mg/kg/d for 3 days. Those classified as Banff IIb or III were treated with Thymo or OKT3. Follow-up time was different for the 4 groups (56, 38, 14, and 27 months, respectively), but at least 1 year for all groups. The Simulect group had older recipients (46 vs 41, P ⫽ .0006), and the OKT3 group had more female patients (65% vs 39%, P ⫽ .017). The Simulect and OKT3 groups had more black patients (25% and 22% vs. 14%; P ⬍ .001), and the Thymo and OKT3 groups had more retransplantations (46% vs 7%; P ⬍ .001). Patients who received induction also had longer dialysis time (63 vs 38 months; P ⬍ .001). PRA was low in the noninduction group (mean, 7%) and about the same in the Simulect and Thymo groups (mean, 30%). OKT3 was the most sensitized group (mean, 59%). There were no differences in the prevalence of patients with diabetes and in the cold ischemia time. Patients in the induction group were more frequently recipients of cadaveric kidneys (92% vs 75%). Statistical analysis used chi-square and Fisher test to identify differences between groups. For continuous variables, treatment groups were compared using the standard two-sample t test. For highly skewed data, the Wilcoxon rank-sum test was used. The analysis was based on the intent to treat population and P ⬍ .05 was considered statistically significant.
RESULTS
Dialysis in the first week post– cadaveric transplantation was more frequent in the induction (65%) as compared with the noninduction group (43%; P ⬍ .005). The same event was observed among the living donor group (12% vs 40%; P ⫽ .01). Fewer patients had rejection episodes in the Thymo group (22%) compared with noninduction (48%), Simulect (51%), and OKT3 groups (36%) for cadaveric transplant recipients (P ⫽ .02). Also, fewer patients had rejection episodes in the Thymo group (20%) compared with noninduction (43%), Simulect (50%), and OKT3 groups (33%; P ⫽ .02) for living donor transplant recipi-
875
ents. A second episode of rejection was also less frequent among the Thymo group up (7%) compared with noninduction (21%), Simulect (19%) and OKT3 (18%) groups (P ⬍ .05); also it occurred significantly later (59 days versus 23 days P ⬍ .01). The number of rejection episodes per patient was lower in the Thymo group (0.2) compared with the other 3 groups (0.7, P ⬍ .02). Patients were classified according to their level of sensitization (⬍10%, 10 –50%, and ⬎50%). The Thymo cohort showed lower rejection rates at all levels (mean, 20%; P ⫽ .001). When specifically analyzing those patients with PRA ⬎50%, the Thymo group showed significantly lower rejection rates (16%) than the noninduction (70%), Simulect (42%), and OKT3 groups (47%; P ⫽ .02). The relative risk of rejection was reduced 2.3-fold with Thymo versus noninduction among these hyper-immunized patients. At this level of sensitization, after 4 years there was no significant difference in graft loss, namely, 41% with no induction, 41% with Thymo, 50% with Simulect, and 52% with OKT3 (P ⫽ .91) or patient death with a functioning graft, namely 8% with noninduction, 25% with Thymo, 37% with Simulect, and 29% with OKT3 (P ⫽ .44). Death in the Thymo group was caused equally by infection and cardiovascular disease (47% vs 41%; P ⫽ ns). There was only a trend to more CMV disease in the Thymo group (33% vs 23%; P ⫽ .08), but no death was related to CMV, probably due to prophylactic ganciclovir use in patients who received anti-lymphocytic therapy. The two patients who displayed posttransplantation lymphoproliferative diseases were both in the noninduction group and had received OKT3 and Thymo to treat resistant rejection. There were 3 cases of Kaposi’s sarcoma: 1 received no induction after transplantation, 1 received Simulect, and 1 received OKT3 as induction therapy. Nine carcinomas were equally frequent among the 4 groups. One patient in the Thymo group developed an esophageal cancer, detected at the second month after transplantation, which was probably present but not diagnosed at the time of transplantation. Renal function at the end of the first year was better in the Thymo group (1.3 mg/dL) compared with 1.4 mg/dL in both the OKT3 and noninduction groups, and 1.6 mg/dL in the Simulect group. DISCUSSION
This retrospective study showed that living and cadaveric donor transplant recipients, who are considered low sensitized (PRA ⬍10%), showed high rates of ACR (46%) when treated only with triple therapy and no induction. Induction treatment with Simulect, Thymo or OKT3 was able to reduce ACR rates in low sensitized patients. Induction performed with Thymo or OKT3 improved the results of patients with moderate levels of sensitization (PRA between 10% and 50%) when compared with the noninduction and the Simulect groups. Only Thymo improved the results of patients considered highly sensitized (PRA ⬎50%) when compared with the other 3 groups. This drug kept ACR rates ⬍20% in this difficult group of patients.
876
Thymo also presented the lowest ACR rates at all levels of sensitization. In this highly sensitized group, 1-year patient survival was not different. There was a trend to higher CMV infection rates in the Thymo group, but no death in this group was related to CMV. No significant differences were observed in the prevalence of tumors. As reported by other authors,14,15 we also detected that in this very high-risk group of transplant reciptients, induction is essential and that Thymo was superior to other forms of induction therapy. REFERENCES 1. Ojo AO, Wolfe RA, Held P, et al: Transplantation 63:968, 1997 2. Keown PA: Transplant Proc 119:74, 1987 3. Halloran PF, Schlaut J, Solez K, et al: Transplantation 53:550, 1992 4. Mc Keena RM, Takemoto SK, Terasaki PI: Transplantation 69:319, 2000
CASTRO, ARAUJO, NAHAS ET AL 5. Monteiro F, Buelow R, Mineiro C, et al: Transplantation 63:542, 1997 6. Kerman RH, Susskind B, Kermann DH, et al: Transplant Proc 29:1515, 1997 7. Reisaeter AV, Leivested T, Albrechtsen D, et al: Transplantation 60:180, 1995 8. Glotz D, Haymann JP, Sansonetti N, et al: Transplantation 56:335, 1993 9. Peraldi MN, Higgins N, Britton R, et al: Transplantation 62:691, 1996 10. Cardella CJ, Cattran D, Fenton SA, et al: Transplant Proc 29:29S, 1997 11. Szczech LA, Berlin JA, Feldman HI: Ann Intern Med 128:817, 1998 12. Opelz G: Transplantation 60:1220, 1995 13. Shield CF, Edwards EB, Davies DB, et al: Transplantation 63:1257, 1997 14. Belitsky P, MacDonald AS, Lawen J, et al: Transplant Proc 29(Suppl 7A):16, 1992 15. Mourad G, Garrigue V, Squifflet JP, et al: Transplantation 72:1050, 2001
G
raft survival and acute cellular rejection (ACR) rates are influenced by the presence of anti-HLA antibodies.1 Patients can be immunized by blood transfusions, pregnancy, rejection of a previous allograft, and, less frequently, by cross reactivity to environmental antigens.2 Nowadays, about 30% of the patients awaiting a cadaver kidney are highly sensitized. Anti-HLA immunization may have severe consequences for the graft and the patient, namely, humoral rejection, accelerated rejection, and increased frequencies of delayed graft function as well as acute and chronic rejection.3– 6 Management of these highly sensitized patients is often difficult, using antibody removal by radiation, plasma exchange, or immunoadsorption.7 Regulation of antibody secreting clones (by polyclonal immunoglobulin)8,9 is a promising adjunct. The use of induction therapy remains controversial in kidney transplantation, although published studies favor induction.10 –13 There is no consensus about the best induction protocol for 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.03.084 874
immunized patients. To evaluate the rate of ACR and the long-term results in patients with different levels of antiHLA sensitization, using noninduction or different induction therapies, 763 patients who underwent transplantation in our unit were evaluated retrospectively. PATIENTS AND METHODS From January 1995 to December 2001, 763 adults (older than 18 years of age), received single, non-HLA-identical kidney transplants. Three hundred seventy-five patients received no induction treatment and 213 (36%) received some kind of induction therapy: 71 patients received anti-thymocye globulin, Thymoglobulin From the Renal Transplantation Unit, Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil. Address reprint requests to *Maria Cristina Ribeiro de Castro, MD, Rua Maria da Gra˜ 333, c.8, 05465-040, Sa˜o Paulo-SP, Brazil. E-mail: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 874 – 876 (2004)
INDUCTION VS NONINDUCTION THERAPY (Thymo; Imtix-SangStat, Lyon, France), 66 received the chimeric monoclonal anti interleukin (IL)-2 receptor antibody, Basiliximab (Simulect, Novartis Pharmaceuticals), and 44 an anti-CD3 monoclonal antibody (Orthoclone-OKT3, ORTHO). The 32 patients who received either Daclizumab-Zenapax (Hoffmann La Roche) or a locally produced anti-lymphocytic globulin were excluded because of the low number of cases. Thymo was given at an initial dose of 1.5 mg/kg/d for 7 to 10 days with the daily dose adjusted to keep peripheral lymphocytes ⬍150/mm3. OKT3 was given in a fixed dose of 5 mg/d for 7 to 10 days. Simulect was given at a fixed dose of 20 mg/d at the first and the fourth postoperative day (POD). All patients received Prednisone (1 mg/kg/d, weekly reduced until 10 mg/d), Azathyoprine (2 mg/kg/d) or Mycophenolate mofetil (30 mg/kg/d) corrected according to peripheral blood leucocytes counts and side effects, and Neoral (10 mg/kg/d) or Prograf (0.20 mg/kg/d) with trough levels between 250 and 350 ng/mL and 12–15 ng/mL, respectively, during the first postoperative month. When induction with Thymo or OKT3 was used, calcineurin inhibitors were initiated on average on the 10th POD. In the noninduction and Simulect groups, these agents were initiated on the first POD. OKT3 and Thymo patients received cytomegalovirus (CMV) prophylaxis with intravenous ganciclovir for 3 months. Rejection was diagnosed clinically, but frequently confirmed using a kidney biopsy. Rejections classified as Banff Ia, Ib, and IIa were treated with methylprednisolone 8 –15 mg/kg/d for 3 days. Those classified as Banff IIb or III were treated with Thymo or OKT3. Follow-up time was different for the 4 groups (56, 38, 14, and 27 months, respectively), but at least 1 year for all groups. The Simulect group had older recipients (46 vs 41, P ⫽ .0006), and the OKT3 group had more female patients (65% vs 39%, P ⫽ .017). The Simulect and OKT3 groups had more black patients (25% and 22% vs. 14%; P ⬍ .001), and the Thymo and OKT3 groups had more retransplantations (46% vs 7%; P ⬍ .001). Patients who received induction also had longer dialysis time (63 vs 38 months; P ⬍ .001). PRA was low in the noninduction group (mean, 7%) and about the same in the Simulect and Thymo groups (mean, 30%). OKT3 was the most sensitized group (mean, 59%). There were no differences in the prevalence of patients with diabetes and in the cold ischemia time. Patients in the induction group were more frequently recipients of cadaveric kidneys (92% vs 75%). Statistical analysis used chi-square and Fisher test to identify differences between groups. For continuous variables, treatment groups were compared using the standard two-sample t test. For highly skewed data, the Wilcoxon rank-sum test was used. The analysis was based on the intent to treat population and P ⬍ .05 was considered statistically significant.
RESULTS
Dialysis in the first week post– cadaveric transplantation was more frequent in the induction (65%) as compared with the noninduction group (43%; P ⬍ .005). The same event was observed among the living donor group (12% vs 40%; P ⫽ .01). Fewer patients had rejection episodes in the Thymo group (22%) compared with noninduction (48%), Simulect (51%), and OKT3 groups (36%) for cadaveric transplant recipients (P ⫽ .02). Also, fewer patients had rejection episodes in the Thymo group (20%) compared with noninduction (43%), Simulect (50%), and OKT3 groups (33%; P ⫽ .02) for living donor transplant recipi-
875
ents. A second episode of rejection was also less frequent among the Thymo group up (7%) compared with noninduction (21%), Simulect (19%) and OKT3 (18%) groups (P ⬍ .05); also it occurred significantly later (59 days versus 23 days P ⬍ .01). The number of rejection episodes per patient was lower in the Thymo group (0.2) compared with the other 3 groups (0.7, P ⬍ .02). Patients were classified according to their level of sensitization (⬍10%, 10 –50%, and ⬎50%). The Thymo cohort showed lower rejection rates at all levels (mean, 20%; P ⫽ .001). When specifically analyzing those patients with PRA ⬎50%, the Thymo group showed significantly lower rejection rates (16%) than the noninduction (70%), Simulect (42%), and OKT3 groups (47%; P ⫽ .02). The relative risk of rejection was reduced 2.3-fold with Thymo versus noninduction among these hyper-immunized patients. At this level of sensitization, after 4 years there was no significant difference in graft loss, namely, 41% with no induction, 41% with Thymo, 50% with Simulect, and 52% with OKT3 (P ⫽ .91) or patient death with a functioning graft, namely 8% with noninduction, 25% with Thymo, 37% with Simulect, and 29% with OKT3 (P ⫽ .44). Death in the Thymo group was caused equally by infection and cardiovascular disease (47% vs 41%; P ⫽ ns). There was only a trend to more CMV disease in the Thymo group (33% vs 23%; P ⫽ .08), but no death was related to CMV, probably due to prophylactic ganciclovir use in patients who received anti-lymphocytic therapy. The two patients who displayed posttransplantation lymphoproliferative diseases were both in the noninduction group and had received OKT3 and Thymo to treat resistant rejection. There were 3 cases of Kaposi’s sarcoma: 1 received no induction after transplantation, 1 received Simulect, and 1 received OKT3 as induction therapy. Nine carcinomas were equally frequent among the 4 groups. One patient in the Thymo group developed an esophageal cancer, detected at the second month after transplantation, which was probably present but not diagnosed at the time of transplantation. Renal function at the end of the first year was better in the Thymo group (1.3 mg/dL) compared with 1.4 mg/dL in both the OKT3 and noninduction groups, and 1.6 mg/dL in the Simulect group. DISCUSSION
This retrospective study showed that living and cadaveric donor transplant recipients, who are considered low sensitized (PRA ⬍10%), showed high rates of ACR (46%) when treated only with triple therapy and no induction. Induction treatment with Simulect, Thymo or OKT3 was able to reduce ACR rates in low sensitized patients. Induction performed with Thymo or OKT3 improved the results of patients with moderate levels of sensitization (PRA between 10% and 50%) when compared with the noninduction and the Simulect groups. Only Thymo improved the results of patients considered highly sensitized (PRA ⬎50%) when compared with the other 3 groups. This drug kept ACR rates ⬍20% in this difficult group of patients.
876
Thymo also presented the lowest ACR rates at all levels of sensitization. In this highly sensitized group, 1-year patient survival was not different. There was a trend to higher CMV infection rates in the Thymo group, but no death in this group was related to CMV. No significant differences were observed in the prevalence of tumors. As reported by other authors,14,15 we also detected that in this very high-risk group of transplant reciptients, induction is essential and that Thymo was superior to other forms of induction therapy. REFERENCES 1. Ojo AO, Wolfe RA, Held P, et al: Transplantation 63:968, 1997 2. Keown PA: Transplant Proc 119:74, 1987 3. Halloran PF, Schlaut J, Solez K, et al: Transplantation 53:550, 1992 4. Mc Keena RM, Takemoto SK, Terasaki PI: Transplantation 69:319, 2000
CASTRO, ARAUJO, NAHAS ET AL 5. Monteiro F, Buelow R, Mineiro C, et al: Transplantation 63:542, 1997 6. Kerman RH, Susskind B, Kermann DH, et al: Transplant Proc 29:1515, 1997 7. Reisaeter AV, Leivested T, Albrechtsen D, et al: Transplantation 60:180, 1995 8. Glotz D, Haymann JP, Sansonetti N, et al: Transplantation 56:335, 1993 9. Peraldi MN, Higgins N, Britton R, et al: Transplantation 62:691, 1996 10. Cardella CJ, Cattran D, Fenton SA, et al: Transplant Proc 29:29S, 1997 11. Szczech LA, Berlin JA, Feldman HI: Ann Intern Med 128:817, 1998 12. Opelz G: Transplantation 60:1220, 1995 13. Shield CF, Edwards EB, Davies DB, et al: Transplantation 63:1257, 1997 14. Belitsky P, MacDonald AS, Lawen J, et al: Transplant Proc 29(Suppl 7A):16, 1992 15. Mourad G, Garrigue V, Squifflet JP, et al: Transplantation 72:1050, 2001