Objectives: This study explored the safety of early steroid withdrawal in recipients of expanded criteria deceased-donor kidney transplants.

Materials and Methods: Using the Organ Procurement and Transplant Network-United Network of Organ Sharing database, we identified patients who underwent expanded criteria deceased-donor kidney transplant between January 2000 and December 2008 after receiving induction with rabbit-antithymocyte globulin (n = 3717), alemtuzumab (n = 763), or interleukin 2 blocking agent (n = 2600) followed by calcineurin inhibitor and mycophenolate mofetil-based maintenance with and without steroid therapy.

Results: Adjusted overall graft survival (hazard ratio 1.32; 95% confidence interval, 1.1-1.56; P = .002) and patient survival (hazard ratio 1.46, 95% confidence interval, 1.16-1.83, P = .001) were inferior, whereas death-censored graft survival (hazard ratio 1.13; 95% confidence interval, 0.87-1.47; P = .35) was similar for chronic steroid maintenance versus early steroid withdrawal groups in rabbit-antithymocyte globulin-induced patients. Graft and patient outcomes were similar for chronic steroid maintenance versus early steroid withdrawal groups among alemtuzumab and interleukin 2 blocking agent-induced patients. Among rabbit-antithymocyte globulin-induced patients, adjusted overall graft survival (hazard ratio 1.57; 95% confidence interval, 1.2-2.0; P < .001) and patient survival (hazard ratio 1.5; 95% CI, 1.15-2.1; P = .004) were inferior, whereas death-censored graft survival (hazard ratio 1.5; 95% confidence interval, 0.97-2.43; P = .07) trended inferior for chronic steroid maintenance versus early steroid withdrawal groups in recipients > 60 years old (n = 1729).

Conclusions: Our study showed safety of early steroid withdrawal in recipients of expanded criteria deceased-donor kidney transplants who underwent perioperative induction followed by calcineurin inhibitor and mycophenolate mofetil maintenance. Among rabbit-antithymocyte globulin-induced patients, chronic steroid maintenance was associated with inferior graft and patient outcomes, an effect limited to older recipients.

Key words : Graft failure risk, Induction agent, Patient death risk, Steroid maintenance

Introduction

The growing organ shortage represents a major challenge in kidney transplant. Currently, in the United States, around 120 000 patients are on the wait list for a kidney transplant.¹ One strategy used to address the supply-demand mismatch in kidney transplant is the use of expanded criteria donor (ECD) kidneys. Expanded criteria donor kidneys comprise about 15% to 20% of all deceased-donor kidney transplants.¹ The transplant of ECD kidneys is generally associated with inferior graft outcomes compared with standard criteria donor kidneys.² Recipients of ECD kidneys have higher risks for developing delayed graft function and acute rejection, factors associated with inferior graft outcomes. A meta-analysis of 34 studies by Yarlagadda and associates showed an association between delayed graft function and higher risk of experiencing acute rejection.³ Renal allografts from older donors have impaired ability to repair tissue injury, leading to persistent inflammation and increased immune recognition.⁴ A multivariate analysis by de Fitzer and associates showed increased incidence of acute rejection episodes in patients receiving a renal allograft from donors older than age 50 years.⁵ Because ECD kidneys appear more immunogenic, it is intuitive to think that enhanced immunosuppression such as steroid maintenance would be beneficial in recipients of such kidneys. On the other hand, ECD kidneys are generally transplanted into older recipients who are more prone to the adverse consequences of enhanced immunosuppression. With the availability and use of powerful induction agents such as rabbit antithymocyte globulin (r-ATG) and potent maintenance immunosuppressive medications such as tacrolimus and mycophenolate mofetil, early steroid withdrawal has been gaining popularity over the past decade. It is unclear whether steroid therapy can be safely withdrawn from ECD kidney recipients who have undergone perioperative induction therapy. In this study, we aimed to explore the safety and feasibility of early steroid withdrawal among recipients of ECD kidneys who underwent perioperative induction therapy followed by calcineurin inhibitor and mycophenolate mofetil maintenance therapy.

Materials and Methods

This study was approved by our Institutional Review Board and performed in accordance with the ethical standards outlined by the Helsinki Declaration and the Istanbul Declaration. Using the Organ Procurement and Transplant Network-United Network of Organ Sharing database, we identified patients ≥ 18 years old who had undergone deceased ECD kidney transplant between January 2000 and December 2008 after receiving perioperative induction therapy with r-ATG, alemtuzumab, or an interleukin 2 (IL-2) receptor blocker (interleukin 2B [IL-2B], daclizumab, or basiliximab) and who were discharged on a calcineurin inhibitor and mycophenolate mofetil-based main­tenance immunosuppression with or without steroid. An extended criteria donor was defined as any donor ≥ 60 years of age or a donor ≥ 50 years of age with 2 of the following 3 features: history of hypertension, terminal serum creatinine ≥ 1.5 mg/dL, and death from cerebrovascular accident. Patients who received living-donor kidney or multiorgan transplants, no induction, more than 1 induction, or induction therapy with a different agent were excluded from the analyses.

Demographic variables for the different induction groups were collected. Grafts were considered failed when 1 of the following occurred: need for maintenance dialysis, retransplant, or patient death. An intention-to-treat analysis was performed. Groups were defined based on the immuno­suppressive regimen at the time of initial hospital discharge after the kidney transplant. For each induction type, patients were divided into 2 groups: those who underwent early steroid withdrawal (defined as discontinuation of steroid therapy at time of first discharge after the kidney transplant) and those who were discharged on steroid maintenance therapy. We designated the latter group as the chronic steroid maintenance group (defined as continuation of maintenance steroids at time of first discharge after the kidney transplant). Overall and death-censored graft survival and patient survival were compared between early steroid withdrawal and chronic steroid maintenance groups for each induction type after adjusting for prespecified variables. An adjusted model was used in the analysis to account for substantial variations in the demographic features for early steroid withdrawal versus early steroid withdrawal in each induction type. The covariates that can adversely affect graft outcomes and that were included in the model were donor-related factors (age, sex, kidney donation after cardiac death, death from cerebrovascular accident), recipient-related factors (age, African American race, type 2 diabetes mellitus, dialysis duration, peak panel reactive antibody titer, number of HLA antigen mismatches), and transplant-related factors (cold ischemia time, delayed graft function [defined as the need for dialysis within first week of transplant], 12-month acute rejection, previous transplant, and transplant year). A further analysis was performed to compare the overall and death-censored graft survival and patient survival between early steroid withdrawal and chronic steroid maintenance groups for r-ATG-induced recipients by dividing them into younger age (≤ 60 y) and older age (> 60 y) groups.

Statistical analyses
Comparisons among groups were made using 2-tailed t test for continuous variables and chi-square test for categorical variables. Values are expressed as means ± standard deviation, median with range, or percentage. For the purpose of our analyses, the risk factors were considered absent when data for them were missing. Fewer than 2% of the data were missing in the registry except for the variable “treated acute rejection,” for which 20% to 25% of the data were missing. Cox regression model was used for multivariate analysis, and hazard ratios (HR) along with 95% confidence intervals (CI) were calculated. A P value < .05 was considered statistically significant. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 14.0, IBM Corporation, Armonk, NY, USA).

Results

Demographic characteristics
Median follow-up with interquartile ranges for different induction groups were as follows: 34.4 months (19.5-49.7 mo) for r-ATG, 24.0 months (12.1-45.9 mo) for alemtuzumab, and 35.9 months (18.8-61.4 mo) for IL-2B. Trends in the use of induction agents in chronic steroid maintenance and early steroid withdrawal groups in recipients of ECD kidneys are shown in Figure 1. Alemtuzumab was used as an induction agent starting in year 2003. Since then, its use in patients who have early steroid withdrawal has gradually increased and has remained somewhat unchanged in patients who receive chronic steroid maintenance. In 2008, in the early steroid withdrawal group, roughly 45% of the patients were induced with r-ATG, 40% with alemtuzumab, and 15% with IL-2B. During the same year in the chronic steroid maintenance group, about 50% received r-ATG, 10% alemtuzumab, and 40% IL-2B as an induction agent. There has been a gradual increase in the use of r-ATG as an induction agent from 2000 to 2008 in the chronic steroid maintenance group. Demographic features of the patient groups by induction type are shown in Table 1. Of 7080 patients included in the analysis, 3717 received r-ATG (chronic steroid maintenance = 2720, early steroid withdrawal = 997), 763 received alemtuzumab (chronic steroid maintenance = 252, early steroid withdrawal = 511), and 2600 received an IL-2B (chronic steroid maintenance = 2382, early steroid withdrawal = 218). Among the r-ATG-induced patients, there was higher prevalence of patients with type 2 diabetes mellitus, repeat transplant, longer duration of dialysis, African American race, higher panel reactive antibody, and greater development of delayed graft function in the chronic steroid maintenance group, whereas prevalence of donation after cardiac death kidney and older recipient was higher in early steroid withdrawal group. Prevalence of delayed graft function and HLA antigen mismatch was higher in the chronic steroid maintenance group among alemtuzumab-induced patients. Among IL-2-induced patients, prevalence of donor death from cerebrovascular accident and peak panel reactive antibody was higher in the chronic steroid maintenance group, whereas the prevalence of donation after cardiac death kidney, older recipient, and longer dialysis duration was higher in the early steroid withdrawal group.

Graft outcomes for chronic steroid maintenance versus early steroid withdrawal groups
Adjusted overall graft survival was significantly inferior for chronic steroid maintenance versus early steroid withdrawal groups in patients who received induction with r-ATG (HR 1.32; 95% CI, 1.1-1.56; P = .002) (Figure 2). However, adjusted death-censored graft survival was similar between the groups (HR 1.13; 95% CI, 0.87-1.47; P = .35). Adjusted overall graft survival (HR 1.02; 95% CI, 0.72-1.45; P = 0.91 and HR 0.89; 95% CI, 0.66- 1.19; P = .42) and death-censored graft survival (HR 0.99; 95% CI, 0.51-1.58; P = .9 and HR 1.12; 95% CI, 0.65-1.9; P = .68) were similar for chronic steroid maintenance versus early steroid withdrawal groups for patients who received induction with alemtuzumab and IL-2B (Figure 2). A further analysis was performed for r-ATG-induced recipients by dividing them into younger age (≤ 60 y) and older age (> 60 y) groups. Among the 3717 ECD kidney recipients who underwent r-ATG induction, 1988 were ≤ 60 years old and 1729 were older than 60 years. In the older age group, adjusted overall graft survival was significantly inferior (HR 1.57; 95% CI, 1.2-2.0; P < .001) and death-censored graft survival trended inferior (HR 1.5; 95% CI, 0.97-2.43; P = .07) for chronic steroid maintenance versus early steroid withdrawal groups (Figure 3). On the other hand, both adjusted overall graft survival (HR 1.17; 95% CI, 0.88-1.42; P = .36) and death-censored graft survival (HR 0.97; 95% CI, 0.7-1.33, P = .83) for chronic steroid maintenance versus early steroid withdrawal groups were similar in the younger age groups (Figure 3).

Patient outcomes for chronic steroid maintenance versus early steroid withdrawal groups
Adjusted patient survival was inferior for chronic steroid maintenance versus early steroid withdrawal groups in r-ATG-induced (HR 1.46; 95% CI, 1.16-1.83; P = .001) but similar in alemtuzumab-induced (HR 0.91; 95% CI, 0.58-1.4; P = .69) and IL-2B-induced (HR 0.89; 95% CI, 0.63-1.25; P = .49) patients (Figure 2). Among the patients who received r-ATG induction, adjusted patient survival for chronic steroid maintenance versus early steroid withdrawal groups remained inferior in older patients (HR 1.5; 95% CI, 1.15-2.1; P = .004) but similar in younger patients (HR 1.3; 95% CI, 0.92-1.88; P = .14) (Figure 3).

Discussion

Our study showed safety of early steroid withdrawal in recipients of ECD kidneys who underwent perioperative induction therapy followed by calcineurin inhibitor and mycophenolate mofetil maintenance. In fact, adjusted overall graft and patient survival results were inferior in ECD kidney recipients who were continued on chronic steroid maintenance compared with early steroid withdrawal in those who underwent r-ATG induction. Similar death-censored graft survival for chronic steroid maintenance versus early steroid withdrawal group following r-ATG induction suggests increased death with functioning graft in the chronic steroid maintenance group. This effect was limited to recipients of ECD kidneys who were older than 60 years.

Steroid withdrawal within the first week of transplant could be safe in low immune risk patients who received induction therapy. Meta-analyses of randomized controlled trials of steroid withdrawal have demonstrated similar transplant outcomes despite an increased risk for acute rejection with early steroid withdrawal when compared to steroid maintenance.^8-10 A registry analysis by Luan and associates showed a reduced risk for graft failure and patient death at 1 and at 4 years in kidney transplant recipients continued on a steroid-free regimen.¹¹ The 5-year prospective randomized trial by Woodle and associates demonstrated reductions in weight gain, new onset of type 2 diabetes mellitus after transplant, and hypertriglyceridemia in kidney transplant recipients randomized to early steroid withdrawal following antibody induction and calcineurin inhibitor and mycophenolate mofetil maintenance.¹² A large single-center retrospective analysis by Rizzari and associates involving 1241 adult primary kidney transplant recipients showed similar patient and graft survival rates at 10 years for rapid steroid discontinuation group compared with historic controls on maintenance steroids.¹³ In the subgroup of patients who received deceased-donor kidney transplants, patient and graft survival results were significantly higher in the rapid steroid discontinuation group. There were significant reductions in the incidence of new onset of type 2 diabetes mellitus after transplant, as well as cataracts and avascular necrosis in the rapid steroid discontinuation group. A recent Organ Procurement and Transplant Network database analysis of repeat kidney transplant recipients by Sureshkumar and associates failed to show patient or graft survival benefits with steroid maintenance in the group that received perioperative induction with r-ATG.¹⁴ None of these studies specifically reported the outcomes of steroid withdrawal in recipients of ECD kidneys or elderly kidney transplant recipients.

During the past decade, the proportion of transplant recipients > 60 years of age reported to United Network of Organ Sharing has grown from 14% in 1999 to 25% in 2009.¹⁵ With preferential allocation of organs, elderly recipients are more likely to receive ECD kidneys. Based on Scientific Registry of Transplant Recipients data analysis, Schold and associates proposed a model toward efficient use of resources in which older patients can substantially reduce their wait time with receipt of ECD kidneys.¹⁶ The 5-year analysis of the Eurotransplant Senior Program Registry favored the allocation of ECD kidneys to elderly recipients.¹⁷ A key feature of the recently adopted Organ Procurement and Transplant Network kidney allocation policy is the concept of longevity matching in which best quality kidneys will be preferentially allocated to wait list candidates with longest predicted survival.¹⁸ Under the new kidney allocation policy, terms such as ECD and standard criteria donor are replaced by a more continuous grading of donor kidney quality by using the Kidney Donor Profile Index, which ranges from 0% to 100% with a score of 0 representing the best quality kidney. A traditional ECD kidney would generally have a Kidney Donor Profile Index score of > 85% and will likely be offered to elderly candidates on the wait list.

As mentioned earlier, ECD kidneys are at higher risks for experiencing delayed graft function and acute rejection.^4,5 Analysis of United Network of Organ Sharing registry by Gill and associates demonstrated a higher risk for acute rejection and trend toward poor allograft survival in elderly kidney transplant recipients who received induction with IL-2B agents compared with r-ATG.15 The authors recommended the use of r-ATG in elderly patients receiving high-risk donor kidneys including ECD or donation after cardiac death kidneys and kidneys with cold ischemia time > 24 hours. A previous registry analysis reported by our group showed superior patient and graft outcomes with r-ATG induction compared with induction with either alemtuzumab or IL-2B in deceased-donor kidney transplant recipients discharged on a calcineurin inhibitor and mycophenolate mofetil regimen without maintenance steroids.¹⁹ r-ATG is a powerful polyclonal-depleting induction agent that contains antibodies to numerous T-cell surface antigens and causes apoptosis and cell lysis. Induction with r-ATG results in severe lymphocyte depletion and prolonged immunosuppression with detectable blood levels of the drug 3 months later.²⁰ Elderly recipients are more prone to the consequences of enhanced immunosuppression such as infection, malignancy, or metabolic complications.²¹

A recent study by Ducloux and associates showed an association between r-ATG use and increased risk for cardiovascular events.²² The authors postulated that r-ATG induced infectious risk burden with activation of CD8-positive T cells and immune reconstitution with expansion of proinflammatory cytokine producing CD8-positive T cells as factors contributing to atherosclerosis burden. Older transplant recipients in general are at much higher risk of dying as a result of infectious complications than younger recipients.²² The risk of dying of infection increases in older transplant recipients to a much greater degree than patients of the same age on the wait list. These observations indicate that higher infectious complications are likely due to immunosuppressive medications rather than merely an age-related trend.²³

Our study showed inferior adjusted overall graft and patient survival results in elderly kidney transplant recipients continued on steroid maintenance following r-ATG induction compared to older recipients who had discontinuation of steroids at the time of hospital discharge. This could possibly be related to the cumulative enhanced immunosuppression related to r-ATG induction and steroid containing triple maintenance therapy. In a large study, Opelz and associates reported a highly significant association between maintenance steroid dose and death with functioning graft related to cardiovascular causes beyond the first year after deceased-donor kidney transplant.²⁴ Interestingly, such an association was not seen with either tacrolimus or mycophenolic acid. Death-censored graft survival for older recipients (> 60 y) on maintenance steroids trended inferior in our study when compared with older patients who were not on maintenance steroids, suggesting that higher graft loss could have been due to nonimmunologic reasons.

Results of our study have practical implications. With the new allocation system, kidneys from older donors are more likely to be offered to older recipients. These kidneys are at higher risk of developing both delayed graft function and acute rejection. Induction with r-ATG could be beneficial in these patients based on previous reports.^15,19 In our analysis, 53% of all ECD kidney recipients underwent r-ATG induction, with 73% on chronic steroid maintenance. The results of our study suggest that one has to be cautious in using chronic steroid maintenance in r-ATG-induced ECD kidney recipients especially those over 60 years of age.

The results of this analysis need to be interpreted in the context of the limitations inherent to a retrospective registry analysis. Retrospective design can confirm association but not prove causation. Residual confounding can exist despite using an adjusted model. Selection bias likely exists due to center-wide variations in practice patterns involving use of induction agents and steroid maintenance. Information on dosing of induction agents and maintenance medications was not available in the database. Immunosuppressive medications could have likely changed after the discharge of the patients, which was not captured, likely resulting in misclassification of some patients. A previous registry analysis by Schold and associates showed a reduction in the proportion of early steroid withdrawal patients restarted on steroid therapy at 6 months from 47% in 2002 to 16% in 2008.²⁵ Some patients initially discharged on steroids may have undergone late steroid withdrawal depending on transplant center practice patterns. These misclassifications likely had minimal effects on the results since such influence is nondifferential, which tend to deflate the results toward the null.26 The possibility of type I error cannot be excluded.

In summary, our study showed safety of early steroid withdrawal in recipients of ECD kidneys who underwent perioperative induction followed by calcineurin inhibitor and mycophenolate mofetil maintenance. In addition, chronic steroid maintenance was associated with increased death with functioning graft in the subgroup of elderly recipients of ECD kidneys who underwent r-ATG induction. These clinically relevant findings need to be further explored in future studies.

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