| Abstract|| |
The influence of steroid maintenance on the outcomes of repeat kidney transplant (RKT) recipients with respect to induction type is unclear. Using the Organ Procurement and Transplant Network/United Network of Organ Sharing (OPTN/UNOS) database, we identified patients (≥18 years) who underwent deceased donor RKT from January 2000 to December 2008 after receiving induction with rabbit-antithymocyte globulin (r-ATG), alemtuzumab or an IL-2 receptor blocker (IL-2B) and were discharged on a calcineurin inhibitor/mycophenolate mofetil regimen with or without steroids. Of 5634 patients, 3643 received r-ATG (steroid = 3157, no-steroid = 486), 448 alemtuzumab (steroid = 196, no-steroid = 252) and 1543 an IL-2B (steroid = 1465, no-steroid = 78). Unadjusted graft survivals were similar for the no-steroid versus steroid groups for induction with r-ATG [hazard ratio (HR) 0.85 and 95% confidence interval (95% CI) 0.70-1.03, P = 0.10], alemtuzumab (HR 0.76, 95% CI 0.51-1.14, P = 0.18) and IL-2B (HR 0.77, 95% CI 0.56-1.70, P = 0.23). In the adjusted model, steroid use improved graft survival in alemtuzumab (HR 0.44, 95% CI 0.25-0.76, P = 0.003) but not in the r-ATG (HR 0.86, 95% CI 0.68-1.09, P = 0.21) or IL-2B (HR 0.98, 95% CI 0.56-1.70, P = 0.94) groups. Steroid use was associated with inferior patient survival in unadjusted (HR 1.30, 95% CI 1.17-1.44, P <0.001) and adjusted (HR 1.29, 95% CI 1.14-1.45, P <0.001) models for r-ATG induction, whereas this was not observed with alemtuzumab (unadjusted HR 1.11, 95% CI 0.89-1.37, P = 0.36; adjusted HR 0.90, 95% CI 0.68-1.20, P = 0.49) or IL-2B (unadjusted HR 1.01, 95% CI 0.87-1.18, P = 0.87; adjusted HR 1.15, 95% CI 0.97-1.38, P = 0.12) inductions. Our study showed a graft survival benefit in the alemtuzumab- and patient death risk in the r-ATG-induced RKT recipients discharged on steroids.
|How to cite this article:|
Sureshkumar KK, Hussain SM, Nashar K, Marcus RJ. Steroid maintenance in repeat kidney transplantation: Influence of induction agents on outcomes. Saudi J Kidney Dis Transpl 2014;25:741-9
|How to cite this URL:|
Sureshkumar KK, Hussain SM, Nashar K, Marcus RJ. Steroid maintenance in repeat kidney transplantation: Influence of induction agents on outcomes. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 May 29];25:741-9. Available from: http://www.sjkdt.org/text.asp?2014/25/4/741/134954
Presented in part as a poster at the American Society of Nephrology Kidney Week, November 2011, Philadelphia, PA
| Introduction|| |
Despite impressive reductions in acute rejection (AR) rates and improvement in short-term graft survival, long-term graft survival has not improved correspondingly in renal transplantation. ,, Approximately 50% of grafts fail within 10 years of transplantation. Many patients with failed allografts will undergo repeat kidney transplantation (RKT). During the last decade, there has been a steady growth in re-listed and RKT patients. As of 2008, in the US, 18% of wait-listed and 13% of kidney transplant patients have received previous transplantation.  An analysis of the Canadian Organ Replacement Register has shown a 50% reduction in mortality for patients who failed their first renal allograft and went on to receive a repeat transplant as compared with continuing dialysis. 
Steroid avoidance protocols have been increasingly used in recent years in patients undergoing kidney transplantation. RKT recipients are generally considered higher immu-nologic risk related to factors such as sensi-tization from prior transplant and transplant nephrectomy. It is intuitive to think that higher degrees of immunosuppression, including intensive induction therapy, and maintenance steroids would be beneficial in RKT recipients. On the other hand, RKT recipients could be more vulnerable to complications of cumulative immunosuppression that begins with prior transplants. Over the last decade, greater than 70% of kidney transplant recipients in the United States have received peri-operative induction therapy. Induction immuno-suppression improved graft and patient outcomes for most organ transplants.  The most commonly used induction agents in the recent era can be divided into either depleting or non-depleting. The depleting agents used include either the polyclonal rabbit-antithymocyte globulin (r-ATG) or monoclonal alemtuzumab antibodies. The non-depleting agents used for induction are the interleukin-2 receptor bloc-kers (IL-2B, either basiliximab or daclizu-mab). The marketing authorization of daclizu-mab was withdrawn as of January 2009 and the product has been discontinued completely. It is unclear whether there are any graft or patient survival benefits for using maintenance steroids in RKT recipients with respect to the induction agents they received. Using the Organ Procurement and Transplant Network/ United Network of Organ Sharing (OPTN/ UNOS) database, we aimed to evaluate the influence of maintenance steroids on the outcomes of deceased donor RKT recipients stratified by induction type.
| Materials and Methods|| |
This study was approved by the Institutional Review Board and was performed in accordance with the ethical standards laid down by the Declaration of Helsinki as well as Declaration of Istanbul. Using the OPTN/UNOS database, we identified patients ≥18 years who underwent deceased donor RKT between January 1 2000 and December 31 2008 and received induction therapy with r-ATG, alem-tuzumab or an IL-2B agent (basiliximab or daclizumab) and were discharged on a calci-neurin inhibitor (CNI)/mycophenolate mofetil (MMF)-based maintenance immunosuppres-sion regimen with or without steroids. A transplant was considered as a RKT if there was a history of previous kidney transplant for the patient in the database. For each induction type, patients were divided into two groups: Those who underwent early steroid withdrawal before the hospital discharge (ESW group) and those who were discharged on steroid maintenance. We designated the latter as the chronic steroid maintenance (CSM) group. Patients who received live donor kidney or multi-organ transplants, no induction, more than one induction or induction therapy with a different agent were excluded from the analysis.
Demographic variables for the different induction groups were collected. Graft was considered failed when one of the following occurred: Need for maintenance dialysis, re-transplantation or patient death. An intention to treat method was used in the analysis. Graft and patient survivals were compared between the ESW and CSM groups for each induction type before and after adjusting for pre-spe-cified variables. The co-variates known to have an adverse impact on the graft outcome and included in the model were donor-related factors: Age, gender, expanded criteria donor (ECD) kidney, donation after cardiac death (DCD) kidney, death from cerebrovascular accident; recipient-related factors: Age, African American race, diabetes mellitus, dialysis duration, peak panel reactive antibody (PRA) titer, number of human leukocyte antigen (HLA) mismatches; and transplant-related factors: Cold ischemia time (CIT), delayed graft function (DGF, defined as the need for dialysis within the first week after transplantation), 12-month AR and transplant year. Treated rejection rates at 12 months post-transplantation were compared for the ESW versus CSM groups stratified by the induction type.
| Statistical Analysis|| |
Comparisons among groups were made using the two-tailed t-test for continuous variables and chi square test for categorical variables. Values were expressed as mean ± standard deviation and median with range or percentage. When there were missing data for different variables/risk factors, we assumed the absence of the risk factor for the purpose of analysis. Less than 2% of the data were missing for different variables (except for treated AR where 20-25% of data were missing) used in the analysis. Both unadjusted (univariate) and adjusted (multivariate, after correcting for the confounding variables listed above) overall graft and patient survivals were calculated and were compared between the CSM versus the ESW groups within each induction type using a Cox regression model. Hazard ratio (HR) and 95% confidence interval (CI) were calculated. A P-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS software version 14.
| Results|| |
The median follow-up for the entire group was 29.6 months (range 10.7-60.1 months). Trends in the use of induction agents in deceased donor RKT recipients from 2000 to 2008 are shown in [Figure 1]A and B. Alemtu-zumab was first used as an induction agent in 2003, with a gradual increase in its use over the subsequent years in the ESW group [Figure 1]A. The use of alemtuzumab was fairly stable from 2003 to 2008 in the CSM group [Figure 1]B. There was a gradual increase in the use of r-ATG in the CSM group with a corresponding decrease in the use of the IL-2 B agent from 2000 to 2008. In the CSM group, roughly 75% received r-ATG, 10% alemtuzumab and 15% an IL-2B agent in the year 2008. During the same year, about 55% of patients received r-ATG induction, 40% alemtuzumab and 5% an IL-B agent in the ESW group.
|Figure 1: Trends in the use of induction agents from 2000 to 2008 in the steroid withdrawal (A) and steroid maintenance (B) groups.|
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There were a total of 5634 patients who underwent deceased donor RKT during the study period and received induction with r-ATG, alemtuzumab or an IL-2B agent and discharged on a CNI/MMF-based maintenance immunosuppression with or without steroids. Among these patients, 3643 received r-ATG induction (CSM = 3157, ESW = 486), 448 alemtuzumab (CSM = 196, ESW = 252) and 1543 an IL-2 B agent (CSM = 1465, ESW = 78). Demographic characteristics of the CSM versus ESW groups by induction type are shown in [Table 1]. Among the patients who received r-ATG induction, the peak PRA titer was higher, with a higher prevalence of African Americans in the CSM group while in the ESW group, the recipient age was higher with a higher prevalence of ECD kidney use along with longer CIT and higher HLA mismatches. In the alemtuzumab induction group, recipient diabetes and DCD kidney use was higher in the CSM versus ESW groups. In patients who received an IL-2B induction, peak PRA was higher and more patients were on pre-transplant dialysis in the CSM group, whereas recipient age was higher with increased use of DCD kidneys in the ESW group. Almost all patients were on tacrolimus as their CNI agent.
When compared with ESW, unadjusted graft survivals were similar in the CSM group in patients who received induction with r-ATG (HR 0.85, 95% CI 0.70-1.03, P = 0.10), alemtu-zumab (HR 0.76, 95% CI 0.51-1.14, P = 0.18) and IL-2B agent (HR 0.77, 95% CI 0.56-1.70, P = 0.23). After adjustment for confounding variables, CSM was associated with significantly improved graft survival compared with ESW in the alemtuzumab group (HR 0.44, 95% CI 0.25-0.76, P = 0.003), but neither in the r-ATG (HR 0.86, 95% CI 0.68-1.09, P = 0.21) nor in the IL-2B (HR 0.98, 95% CI 0.56-1.70, P = 0.94) group [Figure 2]. Factors that emerged as significant predictors of graft failure for each induction type in the multi-variate model are shown in [Table 2]. Only delayed graft function (DGF consistently predicted adverse graft outcome among all induction types.
|Figure 2: Adjusted graft survival for maintenance steroid vs. no maintenance steroid groups in patients who received induction with r-ATG (A), alemtuzumab (B) and IL-2B (C).|
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In the unadjusted model, patient survival was inferior for the CSM (HR 1.30, 95% CI 1.17- 1.44, P <0.001) compared with the ESW group in patients who received r-ATG induction, and this finding persisted in the adjusted model (HR 1.29, 95% CI 1.14-1.45, P <0.001) [Figure 3]A. Unadjusted patient survivals were similar for the CSM versus ESW groups with alemtu-zumab (HR 1.11, 95% CI 0.89-1.37, P = 0.36) and IL-2B (HR 1.01, 95% CI 0.87-1.18, P = 0.87) inductions. After adjustment for confounding variables, patient survivals remained similar in the CSM versus ESW groups for both alemtuzumab (HR 0.90, 95% CI 0.68- 1.20, P = 0.49) and IL-2B (HR 1.15, 95% CI 0.97-1.38, P = 0.12) inductions [Figure 3]B and C. Factors that emerged as significant predictors of patient death in the multivariate model stratified by induction type are shown in [Table 3]. Recipient age, DGF, recipient diabetes and pre-transplant dialysis duration strongly predicted patient death for all induction types. Maintenance steroid use was a risk factor for death only in patients who received induction with r-ATG.
|Figure 3: Adjusted patient survival for maintenance steroid vs. no maintenance steroid groups in patients who received induction with r-ATG (A), alemtuzumab (B) and IL-2B (C).|
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Acute rejection Interpretation of data regarding treated rejection was limited due to missing data in up to 20-25% of the transplants. Taking this limitation into consideration, the reported treated rejection rates for the CSM versus ESW groups at 12 months were similar in patients who received induction with r-ATG (10.6% vs. 10.9%, P = 0.85), alemtuzumab (13.3% vs. 10.7%, P = 0.41) and IL-2B agent (10.1% vs. 6.4%, P = 0.29).
| Discussion|| |
Our study showed improved graft survival with steroid maintenance versus ESW in deceased donor RKT recipients undergoing induction therapy with alemtuzumab and discharged on a CNI/MMF-based regimen. This benefit was not apparent with r-ATG and IL-2B induction in such patients. Steroid maintenance was associated with decreased patient survival in patients who received r-ATG but not alemtuzumab or IL-2 B inductions.
Several studies have looked at the safety and effectiveness of steroid withdrawal in kidney transplantation with promising results. ,,, A randomized double-blind trial with five-year follow-up was reported by Woodle et al.  In this trial, 191 patients were randomized to steroid withdrawal at seven days after transplant and 195 patients to low-dose maintenance steroid (5 mg/day after 6 months post-transplant). All patients received induction therapy and were maintained on tacrolimus/MMF. There was an increase in Banff 1A biopsy-confirmed AR in the early steroid withdrawal group but similar patient, graft and death-censored graft survival at five years between the groups. The early steroid withdrawal group had a favorable effect on serum triglycerides, new-onset diabetes and weight gain. A meta-analysis involving 34 studies and 5637 patients showed increased AR risk but similar patient and graft survival with steroid avoidance or withdrawal when compared with maintenance steroids.  Cardiovascular risk factors including the incidence of hypertension, new-onset diabetes mellitus and hypercholesterolemia were reduced significantly by steroid avoidance or withdrawal. The 10-year outcome of rapid steroid withdrawal involving 1241 adult primary kidney transplants was recently reported from the University of Minnesota.  Compared with a historical control group of patients on maintenance steroids, patient, graft, death-censored graft and AR-free survivals were similar in the live donor (n = 791) and superior in the deceased donor (n = 450) transplant recipients. Rapid steroid withdrawal was associated with favorable effects on complications such as new-onset diabetes mellitus, cataracts, avas-cular necrosis and cytomegalovirus infections. Most of these studies primarily involved first transplant recipients who generally are at lower risk thus limiting their application in repeat transplant recipients. RKT was found to be a risk factor for AR in the group of patients undergoing early steroid withdrawal.  Risk for new initiation of steroids in deceased donor kidney transplant recipients initially discharged without maintenance steroids was higher if the patients were receiving RKT.  A single-center retrospective analysis showed similar actuarial graft survival at years 1, 2, 3 and 4 between groups of patients who got two kidney transplants versus those who received more than two transplants. However, these survival rates were significantly inferior when compared with the patients who received a first trans-plant.  A single-center study of 79 high-risk kidney transplant recipients including 22 re-transplants undergoing rapid steroid discontinuation showed a three-year actuarial graft and patient survival rates of 94% and 95%, res-pectively.  All patients in this study received induction with r-ATG followed by cyclos-porine/MMF maintenance. There has only been one study reported previously that was specifically comparing the outcomes of ESW (n = 59) versus CSM (n = 54) in RKT reci-pients.  This single-center retrospective analysis reported similar AR rates as well as excellent and similar five-year graft (88% vs. 84%) and patient (95% vs. 91%) survival rates. Compared with ESW, more patients in the CSM group required lipid-lowering therapy along with the need for more antihyper-tensive medications. All patients in this study received r-ATG induction followed by CNI/ MMF maintenance immunosuppression with or without steroids, and one-third of the patients received live donor kidney transplants.
To the best of our knowledge, our study is the first to analyze the influence of the induction type on the outcomes of RKT recipients stratified by steroid maintenance. A graft survival benefit for CSM versus ESW was seen in patients who received alemtuzumab induction but not in those who underwent induction with either r-ATG or IL-2B. The reasons for this observation are not entirely clear. Depleting agent induction, especially with alemtuzumab, can be associated with profound and prolonged leukopenia, which could drive reductions in the doses or discontinuation of anti-proliferative agents such as MMF that may increase the risk for immune-mediated allo-graft damage. CSM might confer protection in these situations through giving added immuno-suppression and also by enabling the use of MMF as CSM, through its myeloproliferative effect, is typically associated with higher levels of WBC count when compared with ESW.  However, there were no significant differences in the treated AR rates at 12 months between the CSM and ESW groups in the alemtuzumab-induced patients. Leuko-penia may also hamper the use of antiviral agents, adding to the risk for infectious complications. All these could potentially contribute to suboptimal outcomes, particularly in the alemtuzumab-induced group who subsequently underwent ESW. This point is especially important as more patients who received alemtuzumab induction were discharged on no steroid (n = 252) compared with CSM (n = 192), with the trend increasing over the years. Patient survival was inferior in the CSM versus the ESW groups in patients who underwent r-ATG induction, a finding that was not observed in patients who received induction with either alemtuzumab or the IL-2B agent. Again, the reasons for this finding are not entirely clear. One could speculate that r-ATG induction followed by triple immunosuppres-sion in CSM patients results in enhanced immunosuppression with increased vulnerability for infectious and neoplastic complications with adverse patient outcomes. Even though alemtuzumab also is a powerful depleting agent, increased patient death was not observed in alemtuzumab-induced patients continued on CSM versus ESW. As mentioned early, a considerable number of patients in the alemtuzumab induced group may not have continued MMF or may be on lower doses of it due to associated leukopenia. This could be attenuating the cumulative immunosuppres-sion and reducing patient complications.
Our study has several limitations. Retrospective analyses can prove the association but not causation. Despite using an adjusted model, residual confounding factors could exist. Selection bias to different induction agents and steroid maintenance could likely exist due to center-wise differences in practice patterns. Some early steroid withdrawal protocols withdraw steroids at seven days post-transplant. If these patients were discharged from the hospital in less than seven days, they would be wrongly categorized as being on steroids. Details on the doses of induction agents were not available, which may have an impact on the outcomes. Changes in maintenance immu-nosuppressive regimen since initial hospital discharge were not captured. This is particularly important as many patients initially discharged on no steroids get restarted on CSM, particularly after rejection episodes. Therapeutic levels of CNI and doses of MMF were not available that could have potentially influenced graft outcomes.
In summary, our analysis of a recent cohort of deceased donor RKT recipients using the OPTN/UNOS registry found a graft survival advantage for the addition of maintenance steroids to a CNI/MMF regimen in those who underwent induction with alemtuzumab but not r-ATG or IL-2B agent. On the other hand, there was an adverse association between patient survival and steroid maintenance in r-ATG-induced patients. The reasons for these observations are not completely understood and needs further studies.
| Acknowledgment|| |
This work was supported in part by the Health Resources and Services Administration contract 231-00-0115. 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.
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Kalathil K Sureshkumar
Division of Nephrology and Hypertension, Department of Medicine, Allegheny General Hospital, Pittsburgh, PA 15212
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]