Alemtuzumab Induction and Antibody-Mediated Rejection in Kidney Transplantation T. Noureldeen, Z. Albekioni, L. Machado, N. Muddana, R.J. Marcus, S.M. Hussain, and K.K. Sureshkumar* Division of Nephrology and Hypertension, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
ABSTRACT Background. Induction therapy improves graft outcomes in kidney transplant recipients (KTRs). We aimed to compare the incidences of antibody-mediated rejection (AMR) and acute cellular rejection (ACR) as well as graft and patient outcomes in KTRs who underwent induction with alemtuzumab versus rabbit-antithymocyte globulin (r-ATG). Methods. This was a single-center retrospective study involving patients who underwent kidney transplantation between January 2009 and December 2011 after receiving induction therapy with either alemtuzumab or r-ATG. Maintenance immunosuppression included tacrolimus and mycophenolate mofetil with early steroid withdrawal. Acute rejection was diagnosed using allograft biopsy. Results. Among the 108 study patients, 68 received alemtuzumab and 40 got r-ATG. There was a significantly higher incidence of AMR (15% vs 2.5%; P ¼ .008) and similar incidence of ACR (4.4% vs 10%; P ¼ .69) for alemtuzumab versus r-ATG groups. One-year serum creatinine levels (l.68 0.8 mg/dL vs 1.79 1.8 mg/dL; P ¼ .66) as well as graft (91.1 3.5% vs 94.5 3.8%; P ¼ .48) and patient (93.8 3.0% vs 96.4 3.5%; P ¼ .92) survivals were similar for the alemtuzumab versus the r-ATG groups. Conclusion. Our study showed a higher incidence of AMR and similar incidence of ACR in KTRs who underwent induction with alemtuzumab compared with those who received r-ATG and were maintained on tacrolimus and MMF. This was despite a lower HLA mismatch in the alemtuzumab group. One-year graft survival, patient survival, and allograft function were similar. Inadequate B-cell suppression by alemtuzumab as well as altered phenotypic and functional properties of repopulating B cells could be contributing to heightened risk of AMR in these patients.
I
NDUCTION immunosuppression has been shown to improve graft outcomes in kidney transplant recipients (KTRs) [1]. The most commonly used depleting induction agents are alemtuzumab and rabbit-antithymocyte globulin (r-ATG). Alemtuzumab is a humanized monoclonal antibody to CD-52 expressed on circulating mononuclear cells. It causes cell lysis by complement deposition, membrane attack complex formation, antibody-dependent cellular cytotoxicity, and lymphocyte apoptosis [2]. r-ATG is a polyclonal rabbit antihuman T-cell antibody that causes cell lysis and apoptosis. Higher incidence of antibody-mediated rejection (AMR) was reported in KTRs who underwent induction therapy with alemtuzumab and were maintained on sirolimus-based immunosuppression [3,4]. We have previously reported the
results from registry analysis showing inferior graft outcomes in higheimmune risk KTRs who received induction therapy with alemtuzumab compared with r-ATG and who underwent early steroid withdrawal [5]. In a randomized trial, alemtuzumab induction was associated with higher incidence of delayed acute rejection [6]. The purpose of the current study was to compare the incidences of AMR and acute cellular rejection (ACR) as well as graft and patient outcomes for
*Address correspondence to K.K. Sureshkumar, MD, FRCP (Glasg), FASN, Division of Nephrology and Hypertension, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212, USA. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.08.037
Transplantation Proceedings, 46, 3405e3407 (2014)
3405
3406
alemtuzumab versus r-ATG induction in patients who underwent kidney transplantation at our center. PATIENTS AND METHODS This was a single-center retrospective study of adult patients who underwent kidney transplantation between January 2009 and December 2011 and received induction therapy with either alemtuzumab or rATG. The study protocol was approved by the Institutional Review Board. Alemtuzumab was used during the first 2 years and r-ATG during the last year of the study period as per institutional protocol. Patients who received a different induction agent or multi-organ transplants were excluded. Alemtuzumab was used as a single intravenous dose of 30 mg given intraoperatively. r-ATG was given in 4 divided doses with a cumulative dose of 6 mg/kg and the first dose given intraoperatively. Steroids were administered as follows: methyl prednisolone 500 mg intraoperatively, 250 mg on postoperative day (POD) 1, 125 mg on POD 2 followed by oral prednisone 60 mg on POD 3, and 30 mg on POD 4. At this point steroids were discontinued except in previously transplanted or sensitized patients in whom a low dose of prednisone was continued. Maintenance immunosuppression consisted of tacrolimus (target trough level 8e10 ng/mL) and mycophenolate mofetil (500e1000 mg bid). Infection prophylaxis was achieved with valgancyclovir for cytomegalovirus and trimethoprimsulfamethoxazole for Pneumocystis jeruvocii. Acute rejection was diagnosed using renal allograft biopsy and graded according to Banff 2007 criteria [7]. Criteria for diagnosing AMR included the presence of peritubular capillary C4d deposition along with histological evidence of allograft injury and positive donor specific antibody (DSA).
RESULTS
From a total of 201 patients screened, 108 fulfilled the inclusion criteria. Of this group, 68 patients received alemtuzumab induction and 40 received r-ATG. Median follow-up was 25.2 months for the alemtuzumab group and 12.6 months for the r-ATG group. Demographic characteristics of the groups are shown in Table 1. In the r-ATG group, there were more male donors and higher recipient age. A higher proportion of patients were on steroid maintenance in the r-ATG group (25% vs 3%; P < .001). HLA mismatch was higher in the r-ATGeinduced patients nearing statistical significance (4.4 0.9 vs 3.8 1.5; P ¼ .05). The incidence of DGF was similar between the groups. Of 35 biopsies performed in the alemtuzumab group, 13 had evidence for acute rejection (AMR ¼ 10; ACR ¼ 3). In the r-ATG group, 30 biopsies were performed with 5 showing evidence for acute rejection (AMR ¼ 1; ACR ¼ 4). There was a significantly higher incidence of AMR (15% vs 2.5%; P ¼ .008) and a similar incidence of ACR (4.4% vs 10%; P ¼ .69) for the alemtuzumab versus the r-ATG groups. Trough tacrolimus level was lower but therapeutic for the alemtuzumab versus the r-ATG groups at POD 7 (9.8 3.6 vs 11.7 3.7 ng/mL; P ¼ .01) but similar at months 3 (10.6 2.6 vs 11.4 2.5 ng/ mL; P ¼ .18) and 12 (9.4 2.6 vs 9.5 2.9 ng/mL; P ¼ .91). One-year serum creatinine levels (1.68 0.8 mg/dL vs 1.79 1.8 mg/dL; P ¼ .66) as well as graft (91.1 3.5% vs 94.5 3.8%; P ¼ .48) and patient (93.8 3.0% vs 96.4 3.5%; P ¼ .92) survivals were similar for the alemtuzumab versus the r-ATG groups.
NOURELDEEN, ALBEKIONI, MACHADO ET AL Table 1. Demographic Features of Study Population
Donor gender (M/F) (%) LDK/SCD/ECD/DCD kidney (%) Donor death from CVA (%) Recipient age (y) Recipient race (white/black/other) (%) Cold ischemia time (h) Panel-reactive antibody (%) HLA mismatch Cause of ESRD (DM/HTN/GN/other) (%) Previous transplantation (%) Pre-emptive transplantation (%) Tacrolimus maintenance (%) Mycophenolate mofetil maintenance (%) Prednisone maintenance (%) Delayed graft function (%)
Alemtuzumab (n ¼ 68)
r-ATG (n ¼ 40)
46/54 40/35/15/10 19 47 9.5 87/13/0
68/32 43/28/23/6 13 54 11.6 76/13/11
.03 .60 .37 .001 .42
10.6/8.6 18 32 3.8 1.5 25/9/25/41
11.6 6.9 23 38 4.4 0.9 33/8/25/34
.52 .51 .05 .85
16 22 99 99
25 28 98 100
.26 .23 .70 .44
3 9
25 18
ABSTRACT Background. Induction therapy improves graft outcomes in kidney transplant recipients (KTRs). We aimed to compare the incidences of antibody-mediated rejection (AMR) and acute cellular rejection (ACR) as well as graft and patient outcomes in KTRs who underwent induction with alemtuzumab versus rabbit-antithymocyte globulin (r-ATG). Methods. This was a single-center retrospective study involving patients who underwent kidney transplantation between January 2009 and December 2011 after receiving induction therapy with either alemtuzumab or r-ATG. Maintenance immunosuppression included tacrolimus and mycophenolate mofetil with early steroid withdrawal. Acute rejection was diagnosed using allograft biopsy. Results. Among the 108 study patients, 68 received alemtuzumab and 40 got r-ATG. There was a significantly higher incidence of AMR (15% vs 2.5%; P ¼ .008) and similar incidence of ACR (4.4% vs 10%; P ¼ .69) for alemtuzumab versus r-ATG groups. One-year serum creatinine levels (l.68 0.8 mg/dL vs 1.79 1.8 mg/dL; P ¼ .66) as well as graft (91.1 3.5% vs 94.5 3.8%; P ¼ .48) and patient (93.8 3.0% vs 96.4 3.5%; P ¼ .92) survivals were similar for the alemtuzumab versus the r-ATG groups. Conclusion. Our study showed a higher incidence of AMR and similar incidence of ACR in KTRs who underwent induction with alemtuzumab compared with those who received r-ATG and were maintained on tacrolimus and MMF. This was despite a lower HLA mismatch in the alemtuzumab group. One-year graft survival, patient survival, and allograft function were similar. Inadequate B-cell suppression by alemtuzumab as well as altered phenotypic and functional properties of repopulating B cells could be contributing to heightened risk of AMR in these patients.
I
NDUCTION immunosuppression has been shown to improve graft outcomes in kidney transplant recipients (KTRs) [1]. The most commonly used depleting induction agents are alemtuzumab and rabbit-antithymocyte globulin (r-ATG). Alemtuzumab is a humanized monoclonal antibody to CD-52 expressed on circulating mononuclear cells. It causes cell lysis by complement deposition, membrane attack complex formation, antibody-dependent cellular cytotoxicity, and lymphocyte apoptosis [2]. r-ATG is a polyclonal rabbit antihuman T-cell antibody that causes cell lysis and apoptosis. Higher incidence of antibody-mediated rejection (AMR) was reported in KTRs who underwent induction therapy with alemtuzumab and were maintained on sirolimus-based immunosuppression [3,4]. We have previously reported the
results from registry analysis showing inferior graft outcomes in higheimmune risk KTRs who received induction therapy with alemtuzumab compared with r-ATG and who underwent early steroid withdrawal [5]. In a randomized trial, alemtuzumab induction was associated with higher incidence of delayed acute rejection [6]. The purpose of the current study was to compare the incidences of AMR and acute cellular rejection (ACR) as well as graft and patient outcomes for
*Address correspondence to K.K. Sureshkumar, MD, FRCP (Glasg), FASN, Division of Nephrology and Hypertension, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212, USA. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.08.037
Transplantation Proceedings, 46, 3405e3407 (2014)
3405
3406
alemtuzumab versus r-ATG induction in patients who underwent kidney transplantation at our center. PATIENTS AND METHODS This was a single-center retrospective study of adult patients who underwent kidney transplantation between January 2009 and December 2011 and received induction therapy with either alemtuzumab or rATG. The study protocol was approved by the Institutional Review Board. Alemtuzumab was used during the first 2 years and r-ATG during the last year of the study period as per institutional protocol. Patients who received a different induction agent or multi-organ transplants were excluded. Alemtuzumab was used as a single intravenous dose of 30 mg given intraoperatively. r-ATG was given in 4 divided doses with a cumulative dose of 6 mg/kg and the first dose given intraoperatively. Steroids were administered as follows: methyl prednisolone 500 mg intraoperatively, 250 mg on postoperative day (POD) 1, 125 mg on POD 2 followed by oral prednisone 60 mg on POD 3, and 30 mg on POD 4. At this point steroids were discontinued except in previously transplanted or sensitized patients in whom a low dose of prednisone was continued. Maintenance immunosuppression consisted of tacrolimus (target trough level 8e10 ng/mL) and mycophenolate mofetil (500e1000 mg bid). Infection prophylaxis was achieved with valgancyclovir for cytomegalovirus and trimethoprimsulfamethoxazole for Pneumocystis jeruvocii. Acute rejection was diagnosed using renal allograft biopsy and graded according to Banff 2007 criteria [7]. Criteria for diagnosing AMR included the presence of peritubular capillary C4d deposition along with histological evidence of allograft injury and positive donor specific antibody (DSA).
RESULTS
From a total of 201 patients screened, 108 fulfilled the inclusion criteria. Of this group, 68 patients received alemtuzumab induction and 40 received r-ATG. Median follow-up was 25.2 months for the alemtuzumab group and 12.6 months for the r-ATG group. Demographic characteristics of the groups are shown in Table 1. In the r-ATG group, there were more male donors and higher recipient age. A higher proportion of patients were on steroid maintenance in the r-ATG group (25% vs 3%; P < .001). HLA mismatch was higher in the r-ATGeinduced patients nearing statistical significance (4.4 0.9 vs 3.8 1.5; P ¼ .05). The incidence of DGF was similar between the groups. Of 35 biopsies performed in the alemtuzumab group, 13 had evidence for acute rejection (AMR ¼ 10; ACR ¼ 3). In the r-ATG group, 30 biopsies were performed with 5 showing evidence for acute rejection (AMR ¼ 1; ACR ¼ 4). There was a significantly higher incidence of AMR (15% vs 2.5%; P ¼ .008) and a similar incidence of ACR (4.4% vs 10%; P ¼ .69) for the alemtuzumab versus the r-ATG groups. Trough tacrolimus level was lower but therapeutic for the alemtuzumab versus the r-ATG groups at POD 7 (9.8 3.6 vs 11.7 3.7 ng/mL; P ¼ .01) but similar at months 3 (10.6 2.6 vs 11.4 2.5 ng/ mL; P ¼ .18) and 12 (9.4 2.6 vs 9.5 2.9 ng/mL; P ¼ .91). One-year serum creatinine levels (1.68 0.8 mg/dL vs 1.79 1.8 mg/dL; P ¼ .66) as well as graft (91.1 3.5% vs 94.5 3.8%; P ¼ .48) and patient (93.8 3.0% vs 96.4 3.5%; P ¼ .92) survivals were similar for the alemtuzumab versus the r-ATG groups.
NOURELDEEN, ALBEKIONI, MACHADO ET AL Table 1. Demographic Features of Study Population
Donor gender (M/F) (%) LDK/SCD/ECD/DCD kidney (%) Donor death from CVA (%) Recipient age (y) Recipient race (white/black/other) (%) Cold ischemia time (h) Panel-reactive antibody (%) HLA mismatch Cause of ESRD (DM/HTN/GN/other) (%) Previous transplantation (%) Pre-emptive transplantation (%) Tacrolimus maintenance (%) Mycophenolate mofetil maintenance (%) Prednisone maintenance (%) Delayed graft function (%)
Alemtuzumab (n ¼ 68)
r-ATG (n ¼ 40)
46/54 40/35/15/10 19 47 9.5 87/13/0
68/32 43/28/23/6 13 54 11.6 76/13/11
.03 .60 .37 .001 .42
10.6/8.6 18 32 3.8 1.5 25/9/25/41
11.6 6.9 23 38 4.4 0.9 33/8/25/34
.52 .51 .05 .85
16 22 99 99
25 28 98 100
.26 .23 .70 .44
3 9
25 18
