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Influence of Induction Modality on the Outcome of Deceased Donor Kidney Transplant Recipients Discharged on Steroid-Free Maintenance Immunosuppression

Sureshkumar, Kalathil K.1,3; Thai, Ngoc L.2; Hussain, Sabiha M.1; Ko, Tina Y.1; Marcus, Richard J.1

doi: 10.1097/TP.0b013e3182472898
Clinical and Translational Research
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Background. Over last several years, alemtuzumab induction has been increasingly used in kidney transplantation especially in patients maintained on steroid-free immunosuppression. It is unclear which induction agent is associated with better graft and patient outcomes in these patients.

Methods. Using Organ Procurement and Transplant Network/United Network of Organ Sharing database, graft and patient survivals were compared with multivariate analysis for deceased donor kidney transplant recipients from January 2000 to December 2008 who received induction with rabbit-antithymocyte globulin (r-ATG), alemtuzumab, or an interleukin-2 (IL-2) receptor blocker and were discharged on a calcineurin inhibitor/mycophenolate mofetil/steroid-free immunosuppression.

Results. When compared with r-ATG (n=5348), adjusted graft survival was inferior with alemtuzumab (n=2428, hazards ratio [HR] 1.26, 95% confidence interval [CI] 1.10–1.43, P=0.001) and IL-2 receptor blocker (n=1396, HR 1.19, 95% CI 1.01–1.39, P=0.04) inductions and patient survival was inferior with alemtuzumab (HR 1.29, 95% CI 1.08–1.55, P=0.006). Alemtuzumab induction was associated with higher adjusted graft failure risks in patients with panel reactive antibody more than 20% (HR 1.30, 95% CI 1.01–1.68, P=0.04), recipients of expanded criteria donor kidneys (HR 1.58, 95% CI 1.23–2.02, P<0.001), and kidneys with cold ischemia time more than 24 hr (HR 1.31, 95% CI 1.04–1.65, P=0.02) and higher patient death risks in recipients of expanded criteria donor kidney (HR 1.66, 95% CI 1.20–1.30, P=0.002) and kidneys with cold ischemia time more than 24 hr (HR 1.44, 95% CI 1.04–2.00, P=0.03). Adjusted graft survival rates were similar for different induction agents in the low-immune risk group.

Conclusions. When compared with alemtuzumab and IL-2 receptor blocker, r-ATG induction seems to be associated with superior outcomes in deceased donor kidney transplant recipients maintained on calcineurin inhibitor/mycophenolate mofetil/steroid-free regimen.

1Division of Nephrology and Hypertension, Allegheny General Hospital, Pittsburgh, PA.

2Division of Abdominal Transplantation, Allegheny General Hospital, Pittsburgh, PA.

This work was supported in part by Health Resources and Services Administration contract 231-00-0115.

The authors declare no conflict of interest.

The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Presented (in part orally) at the American Transplant Congress 2011, Philadelphia, PA.

Address correspondence to: Kalathil K. Sureshkumar, M.D., F.R.C.P. (Glasg), F.A.S.N., Division of Nephrology and Hypertension, Allegheny General Hospital, Pittsburgh, PA. E-mail: ksureshk@wpahs.org

K.K.S. participated in research design, performance of the research, data analysis and writing of the manuscript; R.J.M. participated in research design, performance of the research, and data analysis; S.M.H. participated in research design and data analysis; N.L.T. participated in research design and data analysis; and T.Y.K. participated in data analysis.

Received 9 September 2011. Revision requested 12 November 2011.

Accepted 16 December 2011.

Over the last decade, more than 70% of kidney transplant recipients in the United States have received perioperative induction therapy. Induction immunosuppression improved graft and patient outcomes for most organ transplants (1). Agents used for induction can be broadly divided into depleting or nondepleting. The most common currently used depleting induction agents are rabbit-antithymocyte globulin (r-ATG) and alemtuzumab. r-ATG is a polyclonal agent that contains antibodies to a wide variety of human T-cell surface antigens including major histocompatibility complex antigens and cause cell lysis and apoptosis. Alemtuzumab initially approved by the US Food and Drug Administration for the treatment of B-cell chronic lymphocytic leukemia in 2001 is a monoclonal humanized IGG1 antibody that can recognize CD-52 expressed on circulating mononuclear cells. It causes cell lysis by a variety of mechanisms including complement deposition, membrane attack complex formation, antibody-dependent cellular cytotoxicity, and lymphocyte apoptosis (2). The nondepleting agents commonly used in kidney transplantation include interleukin-2 (IL-2) receptor blockers basiliximab and daclizumab. Basiliximab is a chimeric, and daclizumab a humanized monoclonal antibody that inhibits IL-2 receptor binding on activated T-cells and cause altered IL-2 signal transduction. As of January 2009, the marketing authorization of daclizumab has been withdrawn and the product discontinued.

Steroid-free maintenance immunosuppression is increasingly used in kidney transplantation. Over the last few years, the use of alemtuzumab as an induction agent has been increasing especially in recipients subsequently maintained on steroid-avoidance protocols. It is unclear which induction agent is associated with optimal graft and patient outcomes in deceased donor kidney (DDK) transplant recipients maintained on a calcineurin inhibitor (CNI)/mycophenolate mofetil (MMF)/steroid-free immunosuppression.

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RESULTS

Demographic Features

Median follow-up was 29.6 months (range, 10.7–60.1 months). Trends in the use of different induction agents are shown in Figure 1. There has been a gradual decrease in the use of IL-2 receptor blocker from the year 2000 to 2006. Alemtuzumab use for induction began in 2003 with increase in its use over the subsequent years. Among the patients who received the above induction agents in the year 2008, approximately 50% received r-ATG, 35% alemtuzumab, and 15% an IL-2 receptor blocker.

FIGURE 1

FIGURE 1

There were 42,851 patients who received DDK transplant between January 2000 and December 2008 by using induction with r-ATG, alemtuzumab, or an IL-2 receptor blocker and were maintained on a CNI/MMF regimen. Among these patients, 33,679 were discharged on steroids after the initial transplant admission and 9172 patients were discharged without maintenance steroids. We defined the latter cohort as the early steroid withdrawal group. Table 1 shows the distribution of patients in the early steroid withdrawal group according to the induction type. During the study period, 5348 patients received r-ATG induction, 2428 alemtuzumab, and 1396 patients an IL-2 receptor blocker. In the alemtuzumab group, donor age was higher with higher prevalence of expanded criteria donor (ECD)/donation after cardiac death (DCD) kidneys, donor death from cerebrovascular accident and longer cold ischemia time (CIT). There were also higher prevalence of African American recipients and second transplants in the alemtuzumab group and patient were on pretransplant dialysis for longer duration. A higher proportion of patients in this group experienced delayed graft function (DGF) and more patients were on tacrolimus. r-ATG group had a higher level of peak panel reactive antibody (PRA) titer and human leukocyte antigen mismatches. Recipient age was highest in the IL-2 receptor blocker group with a higher proportion of patients older than 60 years and males.

TABLE 1

TABLE 1

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Impact of the Type of Induction Agent on Graft Survival

Adjusted graft survival (AGS) in the multivariate model is shown in Figure 2(A). When compared with r-ATG, there was significantly higher risk of graft failure in patients who received induction with alemtuzumab (hazards ratio [HR] 1.26, 95% confidence interval [CI] 1.10–1.43, P=0.001) and IL-2 receptor blocker (HR 1.19, 95% CI 1.01–1.39, P=0.04).

FIGURE 2

FIGURE 2

Influence of confounding factors on allograft outcome in the multivariate model is shown in Table 2. The strongest six predictors of graft failure in the multivariate model were DGF, acute rejection in the first 6 months, previous transplant, recipient diabetes, alemtuzumab versus r-ATG induction, and IL-2 receptor versus r-ATG induction. There were 6111 patients in the high and 3061 patients in the low immune risk groups. In the high-immune risk group, AGS was inferior with alemtuzumab (n=1815, HR 1.18, 95% CI 1.06–1.31, P=0.003) and IL-2 receptor blocker (n=772, HR 1.06, 95% CI 1.002–1.12, P=0.043) inductions when compared with r-ATG (n=3524). AGS rates were similar for alemtuzumab (n=613, HR 0.98, 95% CI 0.76–1.28, P=0.92) and IL-2 receptor blocker (n=624, HR 1.09, 95% CI 0.99–1.20, P=0.10) inductions when compared with r-ATG (n=1824) in the low-immune risk group. Further analysis of individual subgroups within the high-immune risk group showed the following results: when compared with r-ATG, induction with alemtuzumab was associated with increased risk of adjusted graft failure in subgroups with PRA more than 20% (HR 1. 30, 95% CI 1.01–1.68, P=0.04), ECD kidney recipients (HR 1.58, 95% CI 1.23–2.02, P<0.001), and CIT more than 24 hr (HR 1.31, 95% CI 1.04–1.65, P=0.02). Induction with an IL-2 receptor blocker was not associated with increased graft failure risk when compared with r-ATG in any of these high-risk subgroups (Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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Impact of the Type of Induction Agent on Patient Survival

Adjusted patient survival for the different induction groups are shown in Figure 2(B). When compared with r-ATG, patient survival was inferior for induction with alemtuzumab (HR 1.29, 95% CI 1.08–1.55, P=0.006) and trended lower with IL-2 receptor blocker (HR 1.23, 95% CI 1.00-1.52, P=0.05). The top six predictors of patient death in the multivariate model were as follows: recipient diabetes (HR 1.72, 95% CI 1.47–2.01, P<0.001), DGF (HR 1.61, 95% CI 1.36–1.90, P<0.001), previous transplant (HR 1.36, 95% CI 1.02–1.82, P=0.04), alemtuzumab versus r-ATG induction (HR 1.29, 95% CI 1.08–1.55, P=0.006), IL-2 receptor blocker versus r-ATG induction (HR 1.23, 95% CI 1.00–1.52, P=0.05), and recipient age per year (HR 1.045, 95% CI 1.037–1.053, P<0.001). Alemtuzumab was associated with similar adjusted patient survival versus r-ATG induction when patients were split into high (HR 1.11, 95% CI 0.96–1.28, P=0.16) and low (HR 1.002, 95% CI 0.72–1.39, P=0.99) immune risk groups. Adjusted patient survival was inferior with IL-2 receptor blocker versus r-ATG induction in both high (HR 1.08, 95% CI 1.004–1.17, P=0.04) and low (HR 1.16, 95% CI 1.02–1.31, P=0.03) immune risk groups. Adjusted patient survivals in different high-immune risk subgroups are shown in Table 3. When compared with r-ATG, patient survival was inferior with alemtuzumab induction in those who received an ECD kidney (HR 1.66, 95% CI 1.20–1.30, P=0.002) or a kidney with CIT more than 24 hr (HR 1.44, 95% CI 1.04–2.00, P=0.03). IL-2 receptor blocker use was associated with inferior patient survival in ECD kidney recipients (HR 1.52, 95% CI 1.03–2.26, P=0.04) when compared with r-ATG induction.

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Impact of the Type of Induction Agent on Acute Rejection

Interpretation of data regarding treated rejection was limited due to missing data in up to 20% to 25% of the transplants. Taking this limitation into consideration, the reported treated rejection rates trended lower at 6 months in the alemtuzumab versus r-ATG versus IL-2 receptor blocker inductions (6.5% vs. 8.1% vs. 8.4%, P value=0.06). At 12-months, the respective treated rejection rates were 9.1% vs. 9.5% vs. 9.5% (P=0.85).

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DISCUSSION

Our study showed overall inferior graft and patient survival associated with alemtuzumab induction and inferior graft survival with IL-2 receptor blocker when compared with induction with r-ATG in adult DDK transplant recipients discharged on a CNI/ MMF/steroid-free maintenance immunosuppression. When compared with r-ATG, alemtuzumab induction was associated with inferior graft and patient survival in the subgroups of patients who received ECD kidneys and kidneys with CIT more than 24 hr and inferior graft survival in sensitized patients. In low-immune risk recipients, graft survival rates were similar among induction agents. IL-2 receptor blocker induction was associated with inferior patient survival in subgroups of patients who received ECD kidneys. The over all observed superiority of r-ATG seems to be due to the benefits in high-immune risk patients.

The potential mechanisms by which induction agents reduce the risk of graft failure may involve the reduction in acute rejection rates and induction of allo-tolerance in transplant recipients (1). Knechtle et al. (3,4) demonstrated excellent graft survival in rhesus monkeys by using T-cell depleting anti-CD3 immunotoxin as an induction agent before kidney transplantation and true tolerance as evidenced by the survival of subsequent skin allografts from same donors. Induction therapy allowed patients to use lower amount of immunosuppression in the study by Calne et al. (5).

Steroid-sparing maintenance immunosuppression has been increasingly used over the last few years in kidney transplant recipients. Induction therapy is generally considered an important factor for achieving optimal results with early steroid withdrawal (6). However, it is not clear which induction agent is associated with optimal outcome in those patients. Several single center retrospective studies compared different induction strategies in kidney transplantation. The study by Kaufman et al. (7) reported similar 1-year patient and death-censored graft survival for induction with alemtuzumab versus basiliximab in living and DDK transplant recipients on a steroid-free tacrolimus/MMF-based maintenance immunosuppression. Similar patient and graft survivals were also reported by Shapiro et al. (8) for living and DDK transplant patients who received induction with alemtuzumab or r-ATG and maintained on tacrolimus monotherapy. The single-center study by Schadde et al. (9) looked at the outcomes in patients who received DCD kidneys and maintained on triple immunosuppression including CNI, MMF and steroid. The 3-year graft survival rates were similar between alemtuzumab and r-ATG inductions in high-immune risk group and between alemtuzumab and IL-2 receptor blocker inductions in low-immune risk group. Patient survival was inferior with alemtuzumab versus r-ATG induction in high-immune risk group. Similar patient and superior graft survival with alemtuzumab compared with r-ATG and IL-2 receptor blocker was reported by Knechtle et al. (10) in living and DDK transplants. A previous registry analysis showed better graft and rejection-free-survival in DDK transplant recipients after alemtuzumab induction if they were maintained on a CNI-based immunosuppression compared with CNI-free regimens (11). A higher incidence of graft failure was observed in live donor kidney recipients who received alemtuzumab induction compared with an IL-2 receptor blocking agent (12).

To date, there have only been few prospective studies that compared different induction agents in kidney transplantation. A randomized three-arm trial conducted by Ciancio et al. (13) compared induction with alemtuzumab, r-ATG, and daclizumab in 30 first DDK transplant recipients in each arm with greater than 50% of the patients being African American or Hispanic. Patients who received r-ATG or daclizumab were maintained on tacrolimus (target trough level 8–10 ng/mL), MMF (1 g twice daily), and steroids and those who received alemtuzumab were maintained on lower dose tacrolimus (target trough level 4–7 ng/mL) and MMF (500 mg twice daily) with early steroid withdrawal. At a median follow-up of 6 months, there were no significant differences in acute rejection rates, patient or graft survival, renal function, infections or the development of diabetes and hyperlipidemia. A 24-month follow-up of same patient groups however showed an inferior death-censored graft survival with a higher incidence of biopsy-proven chronic allograft nephropathy and lower calculated creatinine clearance in the alemtuzumab group (14). A single-center prospective randomized trial comparing induction with alemtuzumab (n=113) versus r-ATG (n=109) in kidney transplant recipients (84% DDK and 34% ECD kidneys) maintained on CNI/MMF reported higher biopsy-proven acute rejection (BPAR) with r-ATG (26% vs. 14%, P=0.02) but similar graft and patient survivals at a median follow-up of 2 years (15).

A recently published multicenter randomized prospective study compared the outcomes of alemtuzumab (n=70) versus r-ATG (n=69) induction in high risk (repeat transplant, PRA value of ≥20%, black race) and alemtuzumab (n=164) versus basiliximab (n=171) induction in low risk groups (16). All patients received tacrolimus and MMF with early steroid withdrawal as maintenance therapy. BPAR was lower in alemtuzumab versus basiliximab induction in low risk group at 6 months (2% vs. 18%, P<0.001), 12 months (3% vs. 20%, P<0.001), and 36 months (10% vs. 20%, P=0.003) whereas BPAR rates were similar between alemtuzumab and r-ATG induction among high risk group at 6 months (6% vs. 9%, P=0.40), 12 months (10% vs. 13%, P=0.53), and 36 months (18% vs. 15%, P=0.63). There were no significant differences in 3-year patient and graft survival rates between the induction types in low- and high-risk groups. It should be noted that approximately 60% of the study patients received living donor kidneys and ECD/DCD kidneys were not included in the study and thus limiting the generalization of the results. A previously published small open label randomized study involving 21 high immunological risk patients (PRA >20% or repeat transplant) showed similar 1-year graft survival (85.7% vs. 87.5%) comparing alemtuzumab induction with tacrolimus monotherapy to r-ATG induction with triple immunosuppression including tacrolimus/MMF/prednisone (17).

Large number of patients involving multiple transplant centers nationally and inclusion of high risk cohort increases the validity of our findings. The reasons for observed graft survival benefits of r-ATG or the lack there of with alemtuzumab induction are not clear. We used an intention-to-treat analysis. Maintenance immunosuppression could have likely altered over the follow-up period. T-cell depletion especially with alemtuzumab has been associated with more pronounced and prolonged leukopenia which may drive reductions in the doses of antiproliferative agents such as MMF with resultant increase in the risk of immune allograft damage. Leukopenia may also hamper the use of antiviral agents adding to infectious complication risks. All these could potentially contribute to suboptimal outcomes particularly in the alemtuzumab group. Late BPAR rate (between 12 and 36 months after transplantation in patients who did not have BPAR within the first 12 months) was significantly higher with alemtuzumab induction in a recently published prospective study (16). Many patients initially withdrawn from steroids could be back on steroids at a later point. This usually happens after acute rejection episodes and likely affected all groups. There is evidence that r-ATG can reduce ischemia-reperfusion injury (IRI) that develops soon after the release of arterial clamp during kidney transplantation. IRI plays an important role in the development of DGF that can increase the risk of late graft failure. The mechanism of r-ATG in reducing IRI result primary from blocking the cell-to-cell interactions, reducing the degree of leukocyte rolling and adherence along capillary endothelial surfaces (1820). A higher incidence of biopsy-proven chronic allograft nephropathy was noted in patients who received alemtuzumab induction in one study which could be contributing to inferior graft survival in those patients when compared with r-ATG induction (14).

Our study has several limitations. It is difficult to prove cause and effect relationships in a retrospective analysis. Selection bias to different induction agents could likely exist due to center-wise differences in practice patterns. Some early steroid withdrawal protocols withdraw steroids at 7 days posttransplant. If these patients were discharged from hospital in less than 7 days, they would be wrongly categorized as being on steroids. Details on the doses of induction agents were not available. Changes in maintenance immunosuppressive regimen since initial hospital discharge were not captured. Therapeutic levels of CNI and doses of MMF were not available that could have potentially influenced graft outcomes. Influence of other unidentified confounders could also exist. Safety and tolerability of different induction strategies were not evaluated. The possibility of a type 1 error can not be excluded especially in subgroup analysis of the high-immune risk groups.

In summary, our study showed graft and patient survival benefits associated with r-ATG induction compared with alemtuzumab and a graft survival benefit compared with IL-2 receptor blocker for adult DDK transplant recipients discharged on a CNI/MMF-based maintenance immunosuppression with early steroid withdrawal. These observations seem to be related to the favorable effects of r-ATG induction in high-immune risk patients. It seems reasonable to consider induction with r-ATG in sensitized recipients, and recipients of ECD kidneys and kidneys with CIT more than 24 hr based on our findings. Prospective randomized trials of sufficient size and follow-up with inclusion of high-risk patients will be needed to definitively evaluate the safety and efficacy of different induction strategies in kidney transplant recipients.

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MATERIALS AND METHODS

Using Organ Procurement and Transplant Network/United Network of Organ Sharing database, we identified patients older than 18 years who underwent DDK transplantation between January 1, 2000, and December 31, 2008, and received induction therapy with r-ATG, alemtuzumab, or an IL-2 receptor blocking agent (basiliximab or daclizumab) and were discharged on a CNI/MMF-based maintenance immunosuppression regimen. These patients were then divided into two groups: those who underwent early steroid withdrawal and those who were continued on maintenance steroid. Patients were included in the early steroid withdrawal group if they were discharged from the initial transplant admission without steroid. Patients were excluded from the analysis if they received multiorgan transplants, no induction, more than one induction or induction therapy with a different agent.

Demographic variables for the different induction groups were collected. Graft was considered failed when one of the following occurred: need for maintenance dialysis, retransplantation or patient death. An intention to treat method was used in the analysis. Because demographic characteristics in the induction groups varied substantially, we decided to use an adjusted model in the analysis. Graft and patient survivals were compared between the groups after adjusting for prespecified variables. The covariates known to have adverse impact on the graft outcome and included in the model were donor-related factors: age, gender, ECD kidney, DCD kidney, death from cerebrovascular accident; recipient-related factors: age, African American race, diabetes mellitus, dialysis duration, peak PRA titer, number of human leukocyte antigen mismatches; and transplant-related factors: CIT, DGF (dialysis need within first week), 6-month acute rejection, previous transplant, and transplant year. Because majority of patients in all three induction groups were on tacrolimus versus cyclosporine, we did not include the type of CNI agent in the model. Adjusted graft and patient survivals were also compared among different induction types for both high- and low-immune risk groups. Patients were included in the high-immune risk group if they met any of the following criteria: repeat transplant, African American race, peak PRA titer more than 20%, ECD/DCD kidney recipients, or CIT more than 24 hr. A further analysis was performed subsequently to compare the adjusted graft and patient survivals between the different induction agents for each of the individual high-immune risk subgroups. Treated rejection rates at 6 and 12 months posttransplantation were compared among the induction groups.

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Statistical Analysis

Comparisons among groups were made using one-way analysis of variance for continuous variables and chi square test for categorical variables. Values were expressed as mean±standard deviation, median with range or percentage. When there were missing data for different variables/risk factors, we assumed absence of the risk factor for the purpose of analysis. Less than 2% of the data were missing for different variables (except for treated acute rejection where 20% to 25% of data were missing) used in the analysis. Adjusted over all graft and patient survivals were calculated after correcting for the confounding variables (listed above) and were compared among the induction groups using a Cox regression model. This was done for the whole patient group, then for both high and low immune risk groups (defined above) and for each of the subgroups within the high immune risk group. Multivariate analysis was used with calculation of HR and 95% CIs to evaluate the relative risks of various confounding variables and induction agents in predicting both graft and patient outcomes. A P value of less than 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software version 14.

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Keywords:

Induction agent; Steroid free; Graft failure risk

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