Early acute rejection (between transplantation and hospital discharge) was 3.8%. This proportion was highest without induction (4.8%) and lowest with alemtuzumab (1.3%; P < 0.001, Table 2). Differences in early rejection remained significant in multivariable models, indicating that relative to patients treated with thymoglobulin, patients without induction had 82% greater adjusted likelihood (adjusted odds ratio [AOR], 1.82, 95% confidence interval [95% CI], 1.48–2.25), and patients with IL-2 RB had over twofold likelihood (AOR, 2.40; 95% CI, 1.76–3.28) of early acute rejection (Table 3). Patients receiving alemtuzumab had significantly reduced likelihood of early acute rejection (AOR, 0.45; 95% CI, 0.25–0.81) compared to thymoglobulin. The proportion of patients treated for acute rejection within 1 year was 9.0% and did not significantly differ by induction group in unadjusted (Table 2) or multivariable models (Table 3).
One-Year Renal Function
The average 1-year serum creatinine level in the study population was 1.44 mg/dL, there were no differences in unadjusted levels by induction group (Table 2). However, in the adjusted models, significantly lower levels were associated with no induction treatment (Table 3). Estimated GFR was similar between groups in unadjusted models, but with adjustment, the no induction group had significantly higher estimated GFR at 12 months (61.5 mL/min/1.73 kg/m2).
Malignancy within 1 year of transplantation occurred in 1.24%. This proportion was not significantly different by induction group in unadjusted models (Table 2). However, on multivariable analysis, the highest risk was associated with IL-2 RB relative to patients on thymoglobulin. Patients with no induction had the lowest likelihood of malignancy (AOR, 0.55; 95% CI, 0.33–0.90; Table 3).
One-Year BK Virus
The overall proportion of patients treated for BK virus (BKV) within 1 year was 3.8%. There were no differences in this proportion between induction groups in unadjusted (Table 2) or multivariable models (P = 0.82, Table 3).
The proportion of patients hospitalized at 1 year was 39%. This proportion varied significantly by induction group with the highest proportion of patients among patients treated with thymoglobulin (42%, Table 2). In the multivariable model, significant differences persisted. No induction (AOR, 0.79; 95% CI, 0.72–0.86) and alemtuzumab (AOR, 0.77; 95% CI, 0.64–0.92) were associated with lower likelihood of hospitalization relative to thymoglobulin.
Graft and Patient Survivals
Median follow-up for recipients in the study was 4.0 years. Overall graft survival was significantly different by induction group (Table 2). Five-year graft survival was lowest with alemtuzumab (74.0%) and highest with IL-2 RB (79%). After multivariable adjustment, patients with alemtuzumab had significantly higher hazard for overall graft loss relative to patients treated with thymoglobulin (adjusted hazard ratio [AHR], 1.19; 95% CI, 1.01–1.40, Table 3) but no other statistically significant differences between treatment groups. These results were similar, restricting the study population to deceased donor recipients (AHR, 1.25; 95% CI, 1.03–1.51); however, there were no differences in adjusted graft survival between study groups among living donor recipients including alemtuzumab (AHR, 1.08; 95% CI, 0.78–1.48). There were no significant differences in patient survival in Kaplan-Meier plots or multivariable models between treatment groups.
Modifying Effect of Induction Use During Primary Transplantation
Of 9,755 patients that were within one of the induction study groups at primary transplantation and the primary transplant occurred after 1987, representing the time period that Scientific Registry of Transplant Recipients (SRTR) data is available, 2,569 (26%) used the same induction therapy during both transplants. This included 83% without induction, 12% IL-2 RB, 18% thymoglobulin, and 8% alemtuzumab. Among patients on thymoglobulin for the retransplant, patients with IL-2RB in the primary transplant had significantly higher 1-year acute rejection rates (12.5% vs. 7.0%, P = 0.01). There were no differences in rates of graft loss, patient survival, DGF, BK virus, hospitalizations, or malignancies. Among patients on IL-2 RB for retransplant, there were higher rates of BK virus for patients that were on thymoglobulin for their primary transplantation (14.3% vs. 5.9%, P = 0.02) but no differences for any of the other endpoints. Adjusted graft survival was similar for patients on the same induction therapy during the repeat transplantation (AHR, 1.01; 95% CI, 0.87–1.18).
The primary outcomes of the study indicate variations in certain clinical outcomes among adult kidney retransplants associated with use and type of induction. DGF, 1-year acute rejection, and 1-year BKV were not significantly different between patients that did or did not receive induction or between types of induction. Early acute rejection episodes were less common with thymoglobulin and alemtuzumab. Patients without induction had the lowest 1-year serum creatinine levels and malignancy rates. Patients receiving thymoglobulin had the highest likelihood of 1-year hospitalizations, and patients with alemtuzumab had the highest risk of overall graft loss. Patient survival was not significantly different between treatment groups. Cumulatively, the study seems to indicate a different risk profile associated with induction regimens but no evidence of an effect on patient mortality within the median follow-up of 4 years.
Part of the motivation for this study was to evaluate outcomes in a subset of the transplant population often excluded from research studies.7 A retrospective analysis may provide novel insights into the outcomes for this substantial and growing subset of the renal transplant population. Furthermore, given that retransplant recipients may often have unique clinical considerations and are generally at higher risk for complications and graft loss relative to primary transplant recipients, it is possible induction protocols have a differential effect in this group. From a clinical perspective, findings may also inform caregivers how much, if any, weight to place on previous induction use in a repeat transplant setting.
Some outcomes of the study parallel findings depicted in studies evaluating primary transplant recipients. In an UNOS analysis of deceased donor KTX, Sureshkumar et al.20 reported significantly higher risks of graft loss among patients induced with alemtuzumab and IL-2 RB relative to thymoglobulin. Additionally, among higher-risk patients, differences between thymoglobulin and IL-2 RB were no longer evident. Our findings complement these findings because alemtuzumab was associated with higher adjusted risks for graft loss, but among retransplant recipients, differences between IL-2 RB and thymoglobulin were no longer evident. There have been different reported effects of induction on the risk of malignancies, but most studies suggest that use of any induction agent has a numerically higher risk than without induction.14,15,21 The association of induction with malignancies was consistent in the present study, although no differences could be determined between induction type. Most studies indicate a reduced incidence of rejection with the use of induction compared to no induction but effects generally do not translate to differences in graft survival.12,17,22,23 Other studies have also found differences in rejection rates by type of induction, but again, generally, these differences did not lead to differences in graft loss rates.10-12,24 In this study, early rejection rates were lower with thymoglobulin and alemtuzumab, but 1-year rates were similar for all regimens, suggesting that among higher risk KTX, the effects of induction for reducing rejection may only be observed early.
There is mixed evidence regarding the role of specific immunosuppression agents and BKV.25-30 In this population of re-transplant recipients, there were no differences in treatment of BKV with the caveat that treatment may be selective based on other clinical conditions. Findings did indicate significantly better renal function at 1 year among patients without induction treatment, in contrast to findings compiled in a large meta-analysis of prospective trials.13 Although differences in renal function were relatively small in this study and did not translate into differences in graft loss, further investigation of whether the effects of induction treatment on renal function in the retransplant population may be warranted. Consideration of retransplant recipient inclusion in research studies is needed given that they comprise a significant proportion of the transplant population and given their relatively higher event rate, retransplant recipients may help improve evaluation of novel therapeutic agents.31,32
Several limitations should be considered with the interpretation of our results. There is significant potential for selection bias and residual confounding associated with this observational analysis and potential systematic use of therapies for select patients that may impact outcomes. We attempted to minimize bias with use of a propensity score analysis; however, this does not account for factors unavailable in UNOS data.33,34 There is substantial variation in use of induction agent at the transplant center level. As such, some differences could be attributed to the relative experience with each of the induction agents within individual centers or a “learning curve” associated with use of induction in a relative small proportion of patients treated at centers. Despite adjustment for maintenance agents, some effects may be associated with the entire medication regimen rather than induction alone. These data do not include information on dose administration which may significantly modify the effects of specific agents. Information about cause of graft loss may also be associated with use of specific induction protocols and outcomes after transplantation; however, these data are lacking in the UNOS database. Results may only be interpreted as associations and cannot be inferred to delineate a direct cause and effect relationship due to the retrospective observational study design. Finally, some of the outcome variables in this study are subject to both clinical treatment patterns or judgment (e.g., delayed graft function, treatment for BK virus, and acute rejection) and may also represent center-level variation in treatment.35
Induction treatment is associated with variation in clinical outcomes among adult kidney retransplant recipients in the United States. Variations in early acute rejection, renal function and malignancies significantly vary based on induction treatment at the time of transplantation. In addition, overall graft loss rates were higher among patients treated with alemtuzumab, which was evident among deceased but not living donor recipients. There is no evidence of significant variations in long-term patient survival for this population associated with induction treatment. These findings may help to characterize the benefits and risks associated with induction regimens among retransplant recipients and guide future practice for tailoring treatment to individual patients’ clinical profile.
MATERIALS AND METHODS
The study used data from the SRTR. The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the United States, submitted by the members of the OPTN, and has been described elsewhere.36 The Health Resources and Services Administration, U.S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors.
The study population consisted of adult re-transplant kidney recipients in the SRTR database. Exclusions were unknown immunosuppression information at the time of transplantation, graft loss before initial discharge, induction agent other than those in the study groups, and less than 7-day follow-up (n = 1662). Study groups were defined based on induction medication coded during the initial hospital stay. Patients were not categorized to a study group based on medications coded as maintenance or treatment for rejection. Transplant and demographic characteristics were compared between groups based on chi-square tests for categorical variables and analysis of variance tests for continuous variables. For 1-year outcomes (acute rejection, serum creatinine, malignancy, BKV and hospitalization), models only included patients with at least 1 year of graft survival based on being at risk for these events, given that no exact date is available for these outcomes in the database. Both acute rejection and BKV were defined as treatment for the events as coded in follow-up forms at 6 months or 1 year. Overall graft survival was defined as the minimum of time to graft failure or patient death.
Multivariable logistic models were used for non–time-dependent dichotomous outcomes. Hosmer-Lemeshow tests were used to evaluate adequate model fit for these models. Cox proportional hazard models were used for time to overall graft loss and patient death. For these models, complementary log-log plots were examined along with martingale residual plots to evaluate the proportional hazard assumption. All multivariate models were adjusted for recipient and donor age, sex, race, recipient body mass index, primary diagnosis, human leukocyte antigen mismatching (during primary and repeat transplantation), panel reactive antibody level (categorized as 0, 1–9, 10–29, 30+), functional status, waiting time on dialysis, year of repeat transplantation, early acute rejection during primary transplant, length of primary transplant graft survival, and maintenance immunosuppression (categorized as tacrolimus and mychophenalate mofetil or other). All models other than for the outcome of delayed graft function were also adjusted for donor type. The model for delayed graft function was limited to deceased donor transplants and was additionally adjusted for donor cause of death, hypertension, diabetes, terminal creatinine, cold ischemia time, donation after circulatory death and expanded criteria status. In addition, we evaluated whether induction treatment during patients primary transplant modified the effects of induction use during the retransplant event.
To help mitigate potential selection bias associated with the use of and type of induction treatment, we used a propensity score analysis for each of the outcome models. We initially created a multivariable logistic model for the outcome of any use of induction (yes or no). We then incorporated the probability for an individual patient to receive induction treatment as an inverse probability treatment weight in each of the outcome models. Probability weights that were considered to be outliers (>99.5th or <0.5th percentile) were excluded. All analyses were conducted using SAS (v.9.2, Cary, NC). The study was approved by the Cleveland Clinic Institutional Review Board.
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