Efficacy and Safety of Thymoglobulin and Basiliximab in Kidney Transplant Patients at High Risk for Acute Rejection and Delayed Graft Function

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1 ArtIcle Efficacy and Safety of Thymoglobulin and Basiliximab in Kidney Transplant Patients at High Risk for Acute Rejection and Delayed Graft Function Guodong Chen, 1 Jingli Gu, 2 Jiang Qiu, 1 Changxi Wang, 1 Jiguang Fei, 1 Suxiong Deng, 1 Jun Li, 1 Gang Huang, 1 Qian Fu, 1 Lizhong Chen 1 Abstract Objectives: To compare the efficacy and safety of thymoglobulin compared with basiliximab in patients who had kidney transplants and are at high risk for acute rejection and delayed graft function. Materials and Methods: A retrospective review of patients who had 1 or more risk factors for acute rejection and delayed graft function and who were given either thymoglobulin or basiliximab for induction therapy. Incidences of acute rejection, antibody-treated acute rejection, delayed graft function, chronic rejection, cancer, infection, leucopenia, and thrombocytopenia were compared between thymoglobulin and basiliximab groups. Serum creatinine levels within 1 year and long-term graft and patient survival also were compared. Results: A total of 327 patients were included. Incidences of acute rejection, antibody-treated acute rejection, delayed graft function, and chronic rejection were significantly lower in the thymoglobulin group than in the basiliximab group (P <.05). Serum creatinine levels were lower in the thymoglobulin group on postoperative days 7, 14, and 30 (P <.05). There were no statistically significant differences regarding long-term graft and patient survival, cancer, or total infection rate between the groups. Incidences of Cytomegalovirus infection, leucopenia, and thrombocytopenia were significantly higher in the thymoglobulin group (P <.05). From the 1 Organ Transplant Center and the 2 Department of Hematology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China Acknowledgements: The authors have no conflicts of interest to disclose. This study was supported by 5010 clinical research funding from Sun Yat-Sen University. Corresponding author: Lizhong Chen, MD, Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Rd II, Guangzhou, Guangdong, China, Phone: Fax: clz1@medmail.com.cn Experimental and Clinical Transplantation (2013) 4: Conclusions: Thymoglobulin may improve shortterm outcomes, compared with basiliximab, in patients who had kidney transplants and are at high risk for acute rejection and delayed graft function. However, long-term outcomes are similar with thymoglobulin and basiliximab. Key words: Thymoglobulin, Basiliximab, Kidney transplant Introduction In patients with kidney transplants, acute rejection has been shown to significantly reduce long-term graft survival. 1 Delayed graft function (DGF) may increase the incidence of acute rejection and have negative effects on long-term graft and patient survival. 2,3 Some risk factors have been reported to be related to acute rejection and DGF after kidney transplant, such as higher donor age, long cold ischemia time, repeat transplant, positive panel-reactive antibody test results, and mismatched histocompatibility leukocyte antigen (HLA). 4-6 Induction therapy has been widely used to reduce acute rejection and DGF after kidney transplants. Thymoglobulin and basiliximab are the most commonly prescribed medications in induction therapy. Several studies have shown that both thymoglobulin and basiliximab could significantly decrease the incidence of acute rejection and DGF after a kidney transplant. 7-9 However, whether these drugs have similar efficacy and safety in patients who are at high risk for acute rejection and DGF remains to be determined. In the present study, we retrospectively reviewed 327 patients who had kidney transplants and 1 or more risk factors for acute rejection and DGF and who were given either thymoglobulin or basiliximab for Copyright Başkent University 2013 Printed in Turkey. All Rights Reserved. DOI: /ect

2 Guodong Chen et al /Experimental and Clinical Transplantation (2013) 4: induction therapy. Drug efficacy and safety were compared between these 2 induction therapy groups. Materials and Methods The present study was a retrospective cohort study conducted at The First Affiliated Hospital of Sun Yat-Sen University in South China. The study protocol was approved by the Institutional Review Board of The First Affiliated Hospital of Sun Yat-Sen University. No prisoner organs were used in this study. All protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Inclusion criteria for patients included the following: (1) received deceased-donor kidney transplant at The First Affiliated Hospital of Sun Yat-Sen University between January 1998 and December 2005, (2) aged 18 to 65 years, (3) at least 1 risk factor for acute rejection and DGF as described in Table 1, and (4) received either thymoglobulin or basiliximab as induction therapy. The exclusion criteria included the following: (1) received multiple organ transplants, (2) received immunosuppressive therapy before kidney transplant, (3) received sirolimus or azathioprine as maintenance therapy, (4) seropositive for hepatitis B surface antigen or antibody against hepatitis C virus, and (5) cancer within 2 years before kidney transplant. table 1. Comparison of Risk Factors for Acute Rejection and Delayed Graft Function Between Thymoglobulin and Basiliximab Groups (N=327) Group* Risk Factor (n=149) (n=178) P Value Donor age > 50 y 10 (6.7%) 13 (7.3%).835 Cold ischemia time > 24 h 58 (38.9%) 72 (40.4%).779 Repeat transplant 67 (44.9%) 75 (42.1%).607 PRA > 10% 49 (32.9%) 59 (33.1%).906 HLA mismatched > 4 loci 13 (8.7%) 15 (8.4%).924 Risk factors, No. ± SD 2.3 ± ± Abbreviations: HLA, human leukocyte antigen; PRA, panel reactive antibody *Data presented as No. (%) unless otherwise indicated. Induction therapy Patients included in the study were divided into a thymoglobulin group or basiliximab group depending on whether they received thymoglobulin or basiliximab as induction therapy. Patients in the thymoglobulin group received thymoglobulin (1 mg/kg/d intravenously [IV]) during kidney transplant surgery and on days 1 and 2 after surgery. Patients in the basiliximab group received basiliximab (20 mg IV) during kidney transplant surgery and on day 4 after surgery. Methylprednisolone (500 mg/d IV) was administered in both groups during transplant surgery and on postoperative days 1 and 2. Maintenance immunosuppressive regimen Patients received mycophenolate mofetil (MMF) 750 mg orally twice daily immediately after kidney transplant, and MMF was tapered to 500 mg twice daily within 1 month and to 250 mg twice daily after 1 year. Tacrolimus and cyclosporine were started on postoperative day 3. The initial dosage of tacrolimus was 0.1 mg/kg daily. The tacrolimus trough level was 5 to 10 ng/ml within the first 6 months and then tapered to 4 to 6 ng/ml within 1 year, and 3 to 5 ng/ml after 1 year. The initial dose of cyclosporine was 5 mg/kg daily. Its trough level was 150 to 250 ng/ml within the first 6 months, then tapered to 130 to 180 ng/ml within 1 year and 120 to 150 ng/ml after 1 year. Prednisone 30 mg daily was stated on postoperative day 3 and tapered to 5 mg daily within 6 months. Diagnosis and treatment Acute rejection was diagnosed with such clinical manifestations as fever, oliguria, and serum creatinine elevation, and the diagnosis was confirmed by allograft biopsy. When acute rejection was diagnosed, methylprednisolone (500 mg/d IV) was administered for 3 days. If steroid therapy had no beneficial effect, anti-thymocyte globulin (rabbit) (1 mg/kg/d) or muromonab-cd3 (5 mg/d) was administered for 7 to 10 days. Prophylaxis All transplant recipients received intravenous ganciclovir sodium for cytomegalovirus (CMV) prophylaxis from postoperative day 1 to day 14. This administration was followed by maintenance therapy with oral ganciclovir for 90 days. Sulfamethoxazole was given orally for 3 months for Pneumocystis carinii prophylaxis. Primary endpoints The primary efficacy endpoints included acute rejection, antibody-treated acute rejection, DGF, chronic rejection, graft loss, and patient death. Longterm graft and patient survival, serum creatinine

3 312 Guodong Chen et al /Experimental and Clinical Transplantation (2013) 4: Exp Clin Transplant level within 1 year, infection, cancer, leucopenia, and thrombocytopenia also were analyzed. Definition Acute rejection and chronic rejection were confirmed by biopsy. Antibody-treated acute rejection was defined as acute rejection in which anti-thymocyte globulin or muromonab-cd3 steroids, were required for treatment. Delayed graft function was defined as a requirement for dialysis during the first week after kidney transplant. Statistical analyses All data were analyzed by SPSS statistical software (SPSS: An IBM Company, Windows version 16.0, IBM Corporation, Armonk, New York, USA). Graft and patient survival were calculated by the Kaplan-Meier method, and survival curves were compared using the log-rank test. Categorical variables were compared using the chi-square test or Fisher exact test. Continuous variables were compared using the t test. A value for P <.05 was considered significant. Results A total of 327 patients were included in the present study. Among these patients, 149 (45.6%) received thymoglobulin and 178 (54.4%) received basiliximab. The median follow-up was 8.2 years in the thymoglobulin group and 8.5 years in the basiliximab group. Risk factors for acute rejection and DGF in the thymoglobulin and basiliximab groups are compared in Table 1. Baseline demographic characteristics for patients in the thymoglobulin and basiliximab groups are summarized in Table 2. The data show that there were no significant differences in risk factors, sex, age, weight, dialysis, or maintenance therapy between the thymoglobulin and basiliximab groups. The acute rejection rate in the thymoglobulin group was 16.8%, compared with 30.3% in the basiliximab group (P =.004). Antibody-treated acute rejection rate was 5.4% versus 12.4% in the thymoglobulin group versus the basiliximab group (P =.029). These results show that thymoglobulin was significantly more effective than basiliximab in reducing acute rejection, especially antibody-treated acute rejection, after kidney transplant. Banff criteria suggest that biopsy-proven acute rejection was more severe in the basiliximab group than in the thymoglobulin group (Table 3), though chisquare test results indicated no statistically significant difference (P =.268). Incidences of DGF and chronic rejection were significantly lower in the thymoglobulin group than in the basiliximab group (26.2% vs 37.1%, 10.7% vs 19.1%; P <.05), as shown in Table 4. table 2. Baseline Demographic Characteristics of Thymoglobulin and Basiliximab Groups (N=327) Groups (N=327)* Characteristic (n=149) (n=178) P Value Sex Male 91 (61.1%) 122 (68.5%).158 Female 58 (38.9%) 56 (31.5%) Age, mean ± SD, y 43.9 ± ± Weight, mean ± SD, kg 57.2 ± ± Dialysis None 23 (15.4%) 25 (14.0%).769 Hemodialysis 78 (52.3%) 89 (50.0%) Peritoneal dialysis 48 (32.2%) 64 (36.0%) Maintenance therapy Tacrolimus + MMF + steroids 105 (70.5%) 128 (71.9%).774 Cyclosporine + MMF + steroids 44 (29.5%) 50 (28.1%) Abbreviations: MMF, mycophenolate mofetil *Data presented as No. (%) unless otherwise indicated. table 3. Comparison of Banff Classification in Biopsy-Proven Acute Rejection Between Thymoglobulin and Basiliximab Groups (N=79) Banff P Value Classification (n=25) (n=54) Type I A 10 (40.0%) 13 (24.1%).268 Type I B 7 (28.0%) 19 (35.2%) Type II A 4 (16.0%) 4 (7.4%) Type II B 3 (12.0%) 10 (18.5%) Type III 1 (4.0%) 8 (14.8%) Using R C (chi-square test) table 4. Comparison of Efficacy Endpoints Between Thymoglobulin and Basiliximab Groups (N=327) Endpoint (n=149) (n=178) P Value Delayed graft function 39 (26.2) 66 (37.1).035 Acute rejection 25 (16.8) 54 (30.3).004 Antibody-treated acute rejection 8 (5.4) 22 (12.4).029 Chronic rejection 16 (10.7) 34 (19.1).036 Graft loss 62 (41.6) 79 (44.4).614 Patient death 31 (20.8) 39 (21.9).808

4 Guodong Chen et al /Experimental and Clinical Transplantation (2013) 4: No statistically significant differences were found in long-term graft survival (Figure 1) or patient survival (Figure 2) between the thymoglobulin and basiliximab groups. The causes of graft loss were similar in both groups, including death with functioning grafts, chronic rejection, acute rejection, and recurrent nephropathy. The causes of patient death also were similar in both groups, with infection, cardiovascular disease, and renal function failure being the most common causes. common in the thymoglobulin group than in the basiliximab group (28.2% vs 15.7%; P <.05). The incidence of cancer was similar in both groups. The leucopenia and thrombocytopenia rates were significantly higher in the thymoglobulin group than in the basiliximab group (22.8% vs 11.8%, 8.1% vs 2.8%; P <.05) (Table 5). Figure 3. Comparison of Serum Creatinine Levels within 1 Year After Kidney Transplant Between Thymoglobulin and Basiliximab Groups. *P <.05 Figure 1. Comparison of Long-Term Graft Survival After Kidney Transplant Between Thymoglobulin and Basiliximab Groups Using the Kaplan-Meier Method and Log-Rank Test Cum Survival Figure 2. Comparison of Long-Term Patient Survival After Kidney Transplant Between Thymoglobulin and Basiliximab Groups Using the Kaplan-Meier Method and Log-Rank Test Cum Survival Days After Transplant table 5. Comparison of Complications After Transplant Between Thymoglobulin and Basiliximab Groups (N=327) Complication (n=149) (n=178) P Value Infections 96 (64.4) 111 (62.4).699 CMV 42 (28.2) 28 (15.7).006 Non-CMV 25 (16.8) 24 (13.5).406 Bacteria 67 (45.0) 73 (41.0).472 Fungi 17 (11.4) 20 (11.2).975 Protozoa 3 (2.0) 2 (1.1).663 Cancer 3 (2.0) 4 (2.2).597 Leucopenia 34 (22.8) 21 (11.8).008 Thrombocytopenia 12 (8.1) 5 (2.8).033 Abbreviations: CMV, Cytomegalovirus Discussion Days After Transplant Serum creatinine levels were significantly lower in the thymoglobulin group than in the basiliximab group on postoperative days 7, 14, and 30 (P =.023,.015, and.032) (Figure 3). There was no statistically significant difference in total infection rate between the thymoglobulin and basiliximab groups (64.4% vs 64.2%; P >.05), but CMV infection was more In the present retrospective cohort study, we found that thymoglobulin could reduce the incidence of DGF and acute rejection in patients with kidney transplants and who were at high risk for acute rejection and DGF compared with basiliximab. Based on Banff criteria for biopsy-proven acute rejection, the severity of acute rejection was lower in the thymoglobulin group than in the basiliximab group. Thus, it was logical that antibody-treated acute rejection also was significantly decreased in

5 314 Guodong Chen et al /Experimental and Clinical Transplantation (2013) 4: Exp Clin Transplant thymoglobulin group compared to the basiliximab group. These results demonstrate that thymoglobulin was more effective than basiliximab in controlling the immune response and inflammatory damage to grafts in these high-risk recipients. One prospective study also reported that thymoglobulin could significantly decrease the incidences of acute rejection and antibody-treated rejection compared with basiliximab, but that study found no difference in the incidence of DGF between the 2 drugs. 10 Our results also suggest that thymoglobulin could improve short-term renal function. Within the first month after kidney transplant, the serum creatinine level was much improved in the thymoglobulin group compared to the basiliximab group perhaps because thymoglobulin reduced the DGF and acute rejection rates in these high-risk transplant recipients. Furthermore, our results show that thymoglobulin could reduce the incidence of chronic rejection. Because many studies have shown that DGF, acute rejection, and chronic rejection are major risk factors for graft loss, thymoglobulin has the potential to improve long-term outcomes in kidney transplant recipients. However, our data show no differences in long-term graft and patient survival between the thymoglobulin and basiliximab groups. Additional prospective studies are needed to compare the long-term efficacy between thymoglobulin and basiliximab. There was no statistically significant difference in total infection rate between the thymoglobulin and basiliximab groups, but the CMV infection rate was higher in thymoglobulin group. Although routine CMV prophylaxis was used for all recipients after kidney transplant, CMV infection remained common among these recipients. This high infection rate may have been the result of the high dosages of immunosuppressive drugs used in these recipients to counter their risks for DGF and acute rejection. Another factor to consider is that thymoglobulin depleted the T cells, but basiliximab only suppressed the T cells. Thus, it is reasonable that CMV infection would be higher in the thymoglobulin group. Because the incidences of leucopenia and thrombocytopenia also were higher in the thymoglobulin group, it is advisable to pay attention to the white blood cell and platelet counts postoperatively, and to reduce the dose of thymoglobulin if the white blood cell count is lower than /L so as to decrease the infection rate. Because this is a retrospective cohort study, the patients were not randomized into thymoglobulin and basiliximab groups. We recognize that some selection bias may exist in this study. Additional prospective and randomized studies are warranted to further compare the efficacy of thymoglobulin and basiliximab in high-risk patients receiving kidney transplants. In conclusion, our study shows that thymoglobulin could significantly reduce the incidences of acute rejection, DGF, and chronic rejection, as well as decrease the severity of acute rejection, in kidney transplant recipients who are at high risk for acute rejection and DGF, compared with basiliximab. Short-term renal function was better in the thymoglobulin group than in the basiliximab group, but long-term outcomes were similar between the groups. References 1. de Fijter JW. Rejection and function and chronic allograft dysfunction. Kidney Int Suppl. 2010;119:S38-S Yarlagadda SG, Coca SG, Formica RN Jr, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. 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Pharmacotherapy. 2006;26(12): McKeage K, McCormack PL. Basiliximab: a review of its use as induction therapy in renal transplantation. Bio Drugs. 2010;24(1): Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D; Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355(19): Shrestha BM, Haylor JL. Factors influencing long-term outcomes following renal transplantation: a review. JNMA J Nepal Med Assoc. 2007;46(167): Yarlagadda SG, Klein CL, Jani A. Long-term renal outcomes after delayed graft function. Adv Chronic Kidney Dis. 2008;15(3): Cooper JE, Gralla J, Cagle L, Goldberg R, Chan L, Wiseman AC. Inferior kidney allograft outcomes in patients with de novo donorspecific antibodies are due to acute rejection episodes. Transplantation. 2011;91(10):