Objectives: Our aim was to assess outcomes in White and African American kidney transplant recipients after induction with alemtuzumab.
Materials and Methods: We performed a retrospective study of 464 patients who received deceased-donor kidney transplants and were induced with alem-tuzumab between March 2006 and May 2015. We evaluated ethnic influences on patient and graft survival, delayed graft function, allograft failure, and rejection.
Results: There were 337 White (67.3%) and 127 African American (25.3%) patients. We observed no significant differences in 1-, 3-, 5-, and 7- year death-censored graft survival. We also observed no significant differences in 1-, 3-, and 5-year patient survival rates. Having African American ethnicity was not a significant predictor of rejection, graft survival, or patient survival.
Conclusions: Our results indicate that recipient ethnicity is not a predictor of rejection, graft survival, or patient survival. White and African American kidney transplant recipients induced with alemtuzumab experienced an equalization of outcomes.
Key words : Ethnicity, Immunosuppression, Renal transplantation
Induction immunosuppression in kidney trans-plantation is associated with improved graft and patient outcomes.1 Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein on the surface of lymphocytes and results in T- and B-cell depletion.2-8 It is used in approximately 13% of kidney transplant procedures.9,10 Hanaway and associates have suggested that, in high-risk patients, alemtuzumab can be equally as effective as rabbit antithymocyte globulin in preventing rejection.3
Patients with African American (AA) ethnicity are well-documented as being at higher risk for graft rejection and failure.11,12 Although the racial and ethnic disparities in kidney transplant outcomes have been well-documented, few studies have investigated the effects of alemtuzumab in different ethnicities.
Thus, our objective was to determine whether the use of alemtuzumab in kidney transplant recipients was associated with varied outcomes with respect to recipient ethnicity. We hypothesized that AA patients receiving alemtuzumab would experience worse outcomes than White patients.
Materials and Methods
We performed an Internal Review Board-approved, retrospective analysis on a database of 464 patients who received kidney transplants and were induced with alemtuzumab at the University of Toledo Medical Center (Toledo, OH, USA) between March 2006 and May 2015. We only included recipients of deceased-donor allografts to make outcomes more comparable. These were consecutive transplants. Patient data were reviewed using the TransChart electronic medical record software (TransChart LLC, Dublin, OH, USA). Donor information included age, ethnicity, presence of hypertension, presence of type 2 diabetes mellitus, and type of donor. Recipient information included sex, age, ethnicity, type of graft received, panel reactive antibody, and number of transplants (Table 1).
Before transplant, patient profiles were cross-matched for T- and B-cell status via flow cytometry. All patients included in our study were negative crossmatches for both T and B cells. All cases of acute rejection were biopsy proven.
Patients were pretreated with 25 mg of diphenhydramine intravenously (IV). At the time of the procedure, an induction immunosuppression regimen generally consisting of 500 mg IV methyl-prednisolone (Solu-Medrol, Pfizer, New York, NY, USA), 540 mg oral mycophenolate sodium (Myfortic, Novartis Pharmaceuticals, Basel, Switzerland or CellCept, Genentech, San Francisco, CA, USA), and 30 mg IV alemtuzumab was administered. From 2006-2010, we used alemtuzumab, tacrolimus, and mycophenolate sodium. Since 2010, the steroid bolus and then taper were added to the protocol.
The postoperative steroid taper consisted of 250 mg IV methylprednisolone on postoperative day 1, 125 mg IV methylprednisolone on postoperative day 2, 60 mg prednisone orally on postoperative day 3, 40 mg prednisone orally on postoperative day 4, and, finally, 20 mg prednisone orally on postoperative day 5. Patients at high risk for rejection were continued indefinitely on 5 to 10 mg oral prednisone.
On postoperative day 1, patients began receiving 1.5 mg oral tacrolimus (Prograf, Astellas Pharma, Tokyo, Japan) and 540 mg oral mycophenolate sodium twice per day. Tacrolimus levels were measured and titrated to the correct dose. If adverse effects were tolerable and allowable, mycophenolate sodium was administered at 2/3 dose until the white blood cell count returned to normal levels.
Antimicrobial prophylaxis was started post-operatively with sulfamethoxazole (800 mg) and trimethoprim (160 mg tablet by mouth; Bactrim DS, AR Scientific, Philadelphia, PA, USA) 3 times per week and 10 mg clotrimazole troche dissolved in the mouth 4 times per day following oral care. Daily valganciclovir (Valcyte, Hoffman-La Roche, Basel, Switzerland) was prescribed for cytomegalovirus prophylaxis.
Continuous variables such as age, length of dialysis, cold ischemia time, and kidney donor profile index (KDPI) are presented as medians and compared using t tests or the Mann-Whitney U test when appropriate. Categorical variables including sex, ethnicity, education level, delayed graft function, and early rejection are presented as percentage of the total number within the group. These factors were compared with the Pearson chi-square or Fisher exact test. Survival curves were generated using the life table method, with statistical comparisons computed with the log-rank method. Multivariate survival analysis was done using Cox regression analysis with multivariate factors selected from univariate results and with patient ethnicity included for comparison. Type I error level was set at 0.05. All statistical analyses were conducted using IBM SPSS version 23 software (IBM Corp., Armonk, NY, USA).
A total of 464 patients received alemtuzumab induction. There were 337 White (67.2%) and 127 AA (25.3%) patients. White recipients were significantly older at time of transplant (57.7 vs 52.8 years; P = .001). White recipients had a significantly shorter time on dialysis (777 vs 1115 days; P < .001). White recipients were more likely to live farther from our medical center (51.6 vs 29.2 miles; P < .001). All other recipient demographics are listed in Table 1. There were no significant differences in donor variables (Table 1). In addition, there were no significant differences in insurance or education variables between White and AA recipients (Table 1).
Of patients in our study group, 136 (27.1%) experienced rejection. There were no significant differences in White and AA recipients in cumulative rejection rate or rejection rate at 90 days, 1 year, 3 years, or 5 years (Table 2, Figure 1). African American ethnicity was not a significant risk factor for rejection (hazard ratio [HR] of 1.127, 95% confidence interval [CI], 0.766-1.659; P = .544) (Table 2). Panel reactive antibody greater than 20%, donor age, KDPI, and AA donor type were all significant predictors of rejection, whereas recipient age was protective (Table 2). With AA ethnicity as a covariate, the same trend held true except that panel reactive antibody greater than 20% was no longer a significant predictor (HR of 1.38, 95% CI, 0.915-2.08; P = .124) (Table 2).
Regarding death-censored graft survival, there were no significant differences in 1-, 3-, 5- and 7-year survival between White and AA recipients (Table 3, Figure 2). African American race/ethnicity was not a significant predictor of death-censored graft survival (HR of 1.024, 95% CI, 0.597-1.756; P = .931) (Table 3). Significant predictors of death-censored graft survival are listed in Table 3. With the use of AA ethnicity as a covariate, only expanded criteria donor type (HR of 2.598, 95% CI, 0.1498-4.506; P = .001), donor age (HR of 1.034, 95% CI, 1.017-1.051; P < .001), donor diabetes mellitus (HR of 2.023, 95% CI, 1.002-4.086; P = .049), and KDPI (HR of 1.016, 95% CI, 1.007-1.025; P < .001) were significant predictors of death-censored graft survival (Table 3).
There were no significant differences in 1-, 3-, or 5-year patient survival between White and AA recipients (Table 4, Figure 3). In addition, there was no significant difference in total patient survival between the 2 cohorts. African American ethnicity was one of the only factors that was not a significant predictor of patient survival (HR of 0.885; 95% CI, 0.505-1.55; P = .669) (Table 4). Significant predictors of patient survival are listed in Table 4.
Ethnic disparities in outcomes after kidney transplant are well documented. However, few reports have been published on outcomes in different ethnicities with the use of alemtuzumab induction therapy. Patients with AA heritage have been identified as high risk because of poor outcomes after kidney transplant compared with White individuals.11,13-20 In contrast, the present analysis found no significant differences in death-censored allograft survival rates between AA and White patients. In addition, our multivariate analysis did not indicate that AA ethnicity was a significant predictor of graft survival.
Many have demonstrated that AA individuals are at a particularly high risk for acute rejection.11,21-23 A prospective study of 901 recipients indicated that, in patients given tacrolimus and mycophenolic acid maintenance therapy, the rate of biopsy-proven acute rejection was almost twice as high in individuals with AA compared with non-AA ethnicity.23 Schold and associates suggested that this effect was predominately observed in younger (age 18-33 years) AA recipients and that there was no difference in rejection rate between AA and other groups over the age of 65 years.24 In contrast, we found no significant difference in rates of graft rejection between White and AA patients. Furthermore, AA ethnicity was not a significant predictor of rejection. Regarding age differences, AA recipients over the age of 65 years exhibited rejection less frequently than Whites at 1, 3, and 5 years (18% vs 26%, 30%, and 33%, respectively). However, only 3 AA recipients over the age of 65 years experienced rejection; thus there is likely not significant statistical power to these results.
Others have written that patient survival after kidney transplant is also lower in AA than in White patients.17,18 However, our analysis suggests that there is no difference in the rate of patient survival between AA and White individuals after kidney transplant. In addition, AA ethnicity was one of the only factors that was not a significant predictor of patient survival.
With the development of modern induction agents, outcomes after kidney transplant in AA have improved, but they still typically lag behind others.19,20 The present analysis suggests that, in recipients induced with alemtuzumab, these disparities are diminished. We are not the first to show the reduction of ethnic disparities between AA and White recipients beyond the first posttransplant year after induction with alemtuzumab.25 Smith and associates found that, in patients who did not receive alemtuzumab, White recipients had significantly lower rates of graft failure than AA recipients (14.9% vs 44.4%; P = .0156).25 However, in patients who received alemtuzumab, no significant differences in allograft failure rates between White and AA patients existed (5.7% vs 9.4%; P = .8248). Our results correlate with and expand on their findings. Our analysis included a larger number of patients induced with alemtuzumab and analysis of risk factors for rejection, graft, and patient survival.
Many have attempted to elucidate the possible explanations regarding why AA patients typically experience worse outcomes than White patients. Some posit that socioeconomic factors play a role.13,14,26 For example, Butkus and associates propounded that the major factors predicting lower long-term graft survival in AA included lower socioeconomic status and lower rates of private insurance coverage.14 We found no significant differences in insurance or education between White and AA patients. Thus, the equalization of outcomes that we have observed is likely not due to socioeconomic differences.
Others have indicated that specific genetic polymorphisms in the apolipoprotein L1 gene could contribute to ethnic disparities in outcomes after kidney transplant.27-29 Patients with AA ethnicity who carry these polymorphisms are more likely to develop chronic kidney disease and end-stage renal disease versus those who do not carry them.30,31 Locke and associates recently developed a novel method of determining future CKD risk based on apolipoprotein L1 risk variants in patients with no other absolute contraindications.32 They demonstrated that this risk is particularly prominent in young AA patients. We are unfortunately unable to provide information on potential genetic risk variants in our AA recipients. However, it is possible that genetic factors influenced the outcomes that we observed.
Our data suggest that, in kidney transplant recipients induced with alemtuzumab, there are no significant differences in graft and patient outcomes between White and AA patients. Given that most recipient variables, all donor variables, education level, and insurance status were not significantly different, it is possible that alemtuzumab induction has played some role in equalizing outcomes between White and AA patients after kidney transplant. There are a number of possible explanations for these findings. Smith and associates proposed that the simplicity of alemtuzumab induction therapy (a one-time, perioperative dose) could have an effect on increasing patient adherence and thereby increasing favorable outcomes.25 As mentioned previously, genetic factors seem to play a role in increasing the risk of chronic kidney disease and end-stage renal disease in AA patients.27-31 Therefore, it is plausible that genetic factors could also be partially responsible for improving outcomes in AA patients induced with alemtuzumab. There are, however, other possible explanations for the equalization of outcomes between White and AA patients. White patients were significantly older at time of transplant compared with AA patients, and age at time of transplant was a significant predictor of patient survival. Thus, the older age of White recipients could have influenced the equalization of outcomes that we witnessed between White and AA recipients.
It is important to note that, although our rates of rejection are relatively high, there are other examples of alemtuzumab being associated with an increase in rejection after 1-year. Huang and associates, for example, found that there were significantly higher rates of acute rejection at both 6 months and 1 year after induction with alemtuzumab compared with no induction, induction with rabbit antithymocyte globulin, and induction with interleukin 2 receptor antagonists.33 We have since altered our protocol to include maintenance steroids for AA and other high-risk groups.
Our analysis has a number of strengths. It provides insight into the association between alemtuzumab and the reduction of previously well-documented ethnic disparities after kidney trans-plant. In addition, it expands on results shown by others regarding the effects of alemtuzumab on outcomes in different ethnicities. Furthermore, our analysis used a relatively large patient population with a similar protocol throughout its entirety. Although our results are promising, our analysis does have a few limitations. First, the retrospective nature of our study is a possible limitation. Our sample also lacks a control for comparison. We also were unable to analyze genetic risk variants in our population. Finally, the results from our single-center study may not be applicable to all centers.
This analysis demonstrated that alemtuzumab induction therapy could be associated with the elimination of the ethnic disparities between White and AA recipients commonly observed with kidney transplant. In particular, we found that, in patients induced with alemtuzumab, there were no significant differences in graft and patient survival between White and AA recipients. More importantly, our data suggest that, in patients induced with alemtuzumab, recipient ethnicity is not a significant predictor of rejection, graft survival, or patient survival. Further studies with a larger sample size are needed to determine the exact reasons for the elimination of these disparities.
Volume : 17
Issue : 2
Pages : 196 - 201
DOI : 10.6002/ect.2017.0065
From the 1College of Medicine and Health Sciences, University of Toledo, the
2Department of Surgery, and the 3Departments of Urology and Pathology,
University of Toledo College of Medicine and Health Sciences, Toledo, Ohio, USA
Acknowledgements: The authors received no funding for this study and have no conflicts of interest to disclose. Contributions of authors are as follows: J. Brooks and A. DeLeonibus wrote the paper; G. Mitro and W. Qu performed statistical analysis; M. Nazzal and M. Rees reviewed the paper; J. Ortiz designed the study and reviewed and edited the paper.
Corresponding author: Joseph Brooks, 9633 Kelly Drive, Loveland, OH 45140, USA
Phone: +1 513 600 3049
Table 1. Recipient and Donor Demographic Characteristics
Table 2. Rejection Outcomes and Multivariate Analysis of Rejection Risk Factors
Table 3. Graft Survival Outcomes and Multivariate Analysis of Graft Survival Risk Factors
Table 4. Patient Survival Outcomes and Multivariate Analysis of Patient Survival Risk Factors
Figure 1. Rejection Rate by Race/Ethnicity
Figure 2. Death-Censored Graft Survival by Race/Ethnicity
Figure 3. Patient Survival by Race/Ethnicity