Objectives: Alemtuzumab (monoclonal anti-CD52 antibody) provides profound lymphocyte depletion and offers numerous advantages as an induction agent. Elderly recipients (> 65 years old) traditionally have inferior posttransplant outcomes versus younger recipients. We investigated short-term and long-term patient and graft survival rates following alemtuzumab induction in elderly recipients.
Materials and Methods: This retrospective analysis, which included 676 renal allograft transplant recipients with alemtuzumab induction, was conducted at the University of Toledo Medical Center between March 2006 and November 2015. We used 2-sided t test, Pearson chi-square test, Fisher exact test, and Cox proportional hazard regressions with 95% confidence interval for analyses. P < .05 was significant.
Results: Elderly recipients were more likely to receive a kidney from an inferior donor (deceased donor: 82% vs 72.4%; P = .030) and have higher mean kidney donor profile index (46.2 vs 38.4; P = .024) than nonelderly recipients. Elderly recipients were more likely to experience delayed graft function (15.1% vs 8.5%; P = 0.038). Elderly recipients demonstrated death-censored graft survival (1 year: 95.4% vs 93.1%; 3 years: 88.5% vs 93.3%; 5 years: 83.1% vs 86.4%) and rejection rates (1 year: 19.8% vs 21.2%; 3 years: 22.1% vs 25.3%; 5 years: 23.8% vs 26.9%) similar to nonelderly recipients. Elderly recipients had significantly higher overall mortality rates than recipients under 65 years old (29.8% vs. 13.2%; P = .001). Although 1-year patient survival was similar to younger recipients (94.8% vs 96.3%; P = .431), 3-year (80.0% vs 91.5%; P = .006) and 5-year (72.9% vs 86.2%; P = .19) rates were significantly decreased in elderly recipients.
Conclusions: Elderly age is not a predictor of rejection or death-censored graft loss in individuals who receive alemtuzumab induction. Despite elevated overall mortality, elderly recipients induced with alem-tuzumab demonstrated rejection, graft, and short-term patient survival rates similar to younger recipients.
Key words : Geriatric patients, Quality of life, Renal transplantation
According to the United Network for Organ Sharing, 23.3% of the population awaiting a kidney transplant is 65 years or older (n = 22 218), constituting the third largest group on wait lists.1 As of 2017, 19.4% of kidney transplant recipients were 65 years old and older (n = 6748), comprising the third largest reci-pient age group.1 Because the elderly have a higher incidence of end-stage renal disease, kidney transplant has become a promising therapy for improving overall quality and quantity of lives.2,3
The elderly population is traditionally reported as having decreased immune function with an elevated risk of negative outcomes (eg, infection, graft loss, death) and higher likelihood of receiving a lower-quality kidney.4,5 In addition, elderly age is directly associated with more frequent allograft loss.6 Despite these claims, some have found that elderly recipients have lower rates of rejection and improved death-censored graft survival.7 Thus, current research in posttransplant management of older patients has focused on optimization of immunosuppression to achieve outcomes more comparable to outcomes shown in younger recipients.
Alemtuzumab, a humanized monoclonal antibody targeting CD52 glycoprotein on the cell surface of lymphocytes, depletes T- and B-cell lymphocytic reserves and is utilized in approximately 13% of kidney transplant procedures.8,9 The profundity of immunosuppression, simple dosing schedule, side-effect profile, and potential for relative steroid-sparing regimens make alemtuzumab an attractive choice as an induction agent, particularly for elderly patients. However, research on the benefits of alemtuzumab induction in renal transplant is ongoing, and there are scarce clinical data pertaining to its use in older patients.
In this study, our aim was to elucidate whether alemtuzumab induction therapy in kidney transplant recipients was associated with better outcomes in elderly recipients. We hypothesized that elderly recipients who receive alemtuzumab induction would experience outcomes similar to those shown with other well-documented immunosuppression regimens and similar to nonelderly individuals.
Materials and Methods
We conducted an Internal Review Board-approved and Department for Human Research Protection-approved retrospective analysis of 676 renal allograft transplant recipients induced with alemtuzumab at the University of Toledo Medical Center (Toledo, OH, USA) between March 2006 and November 2015. Donor information was verified with data obtained from the United Network for Organ Sharing database, and data included age, sex, ethnicity, comorbidities, donor type, reason for transplant, rejection status, and infection status. All patient information adhered to ethical guidelines of the 1975 Helsinki Declaration, and informed consent was provided by each patient. Before transplant, patients were screened using flow cytometry to determine the cross-reactivity of T and B cells between donor and potential recipients. All patients had negative crossmatches for both T and B cells, and each case of acute rejection was confirmed with biopsy.
Preoperatively, graft recipients were pretreated with 25 mg of intravenous diphenhydramine, 500 mg of intravenous methylprednisone (Solu-Medrol, Pfizer, New York, NY, USA), and 30 mg of intravenous alem-tuzumab (0.5 mg/kg was used if patient was < 60 kg).
Postoperatively, a steroid taper was administered with 250 mg of intravenous methylprednisone on postoperative day 1, which was followed by 125 mg of intravenous methylprednisone on postoperative day 2, 60 mg of oral prednisone on postoperative day 3, 40 mg of oral prednisone on postoperative day 4, and 20 mg of oral prednisone on postoperative day 5. After June 2015, high-risk patients, such as African Americans, patients who had retransplants, recipients who experienced delayed graft function (DGF), or those with panel reactive antibody greater than 20%, were discharged with instructions for 5 to 10 mg of oral prednisone indefinitely.
On postoperative day 1, 1.5 mg of oral tacrolimus was delivered twice daily (Prograf, Astellas Pharma, Tokyo, Japan) and 540 mg of oral mycophenolate sodium was administered twice daily. Tacrolimus was titrated to the appropriate dose based on serum levels. If oral mycophenolate sodium was tolerated well, it was increased to 720 mg oral twice daily on discharge.
Antimicrobial prophylaxis was initiated post-operatively with sulfamethoxazole (800 mg) and trimethoprim (160 mg) at 3 times per week (Bactrim DS, AR Scientific, Philadelphia, PA, USA). Additionally, 10 mg of clotrimazole troche dissolved orally was administered 4 times/day following oral care for antifungal protection. Depending on established risk factors, valganciclovir (Valcyte, Hoffman-La Roche, Basel, Switzerland) was admin-istered for at least 3 months or longer for prophylactic cytomegalovirus protection.
Continuous variables (eg, age, body mass index, and kidney donor profile index [KDPI]) were assessed as medians and evaluated using 2-sided t tests. For categorical variables (eg, sex, education status, insurance status, ethnicity, rejection, and DGF), we used Pearson chi-square test or Fisher exact test for analyses. Survival curves were assessed using the life table method. Factors associated with survival were identified using Cox proportional hazards regression and were assessed with elderly status as a covariate. All tests were performed at a 95% confidence interval (95% CI), and a type I error level P value of < .05 was considered significant. Patient data were reviewed using TransChart electronic medical record software (TransChart LLC, Dublin, OH, USA). Statistical analyses were performed using SPSS version 21 (IBM, Armonk, NY, USA).
Of 676 study patients who received alemtuzumab induction, 122 (18.1%) were elderly and 554 (81.9%) were nonelderly patients. Age at time of transplant was significantly different between elderly and nonelderly patients (age of 68.6 ± 3.4 y vs. 51.4 ± 12.3 y; P < .001) (Table 1). Elderly recipients were significantly less likely to have private health insurance (P < .001), less likely to have achieved a higher level of education (P = .034), less like to have had a prior transplant/-retransplant (P = .005), and more likely to have type 2 diabetes mellitus (P = .004) (Table 1).
The elderly group had a significantly higher rate of transplants from deceased donors (P = .03) and a significantly higher mean KDPI (P = .024) (Table 1). Donors to the elderly population were significantly more likely to have hypertension (P = .013) and type 2 diabetes mellitus (P = .018) (Table 1). Further recipient and donor demographic data are outlined in Table 1.
Elderly patients were significantly more likely to require a transplant due to diabetes mellitus or hypertension and significantly less likely to have one due to nephritic/nephrotic pathology or polycystic kidney disease (Table 2). Rejection diagnosis and Banff classification were equivalent for young and elderly patients, with acute cellular rejection (ACR) and Banff II being the most common assessments (Table 2). We observed a significant difference in predominant cell type during rejection, with elderly patients demonstrating more neutrophils and nonelderly patients presenting with more plasma cells (Table 2).
The most common cause of elderly graft failure and graft failure for all patients was death (63.4% vs 39.6%; P < .05) (Table 2). Elderly patients were significantly less likely to lose their graft as a complication of acute (P < .05) or chronic rejection (P < .05) (Table 2). Elderly recipients had fewer deaths by cardiovascular causes than nonelderly recipients (P < .05); all other causes of death were equivocal (Table 2).
There were 29 elderly (23.8%) and 149 nonelderly (26.9%) patients who experienced rejection. We observed no significant differences in total rejection rates or interval rejection rates at 90 days, 1 year, 3 years, or 5 years (Table 3, Figure 1). Elderly age was not a significant risk factor for rejection (hazard ratio [HR] of 0.90; 95% CI, 0.6-1.33; P = .582) (Table 3). Only increased KDPI and private insurance were signi-ficant predictors of rejection (Table 3).
With regard to death-censored graft survival, we observed no significant accumulative or interval difference at 90 days, 1 year, 3 years, or 5 years between elderly and nonelderly recipients (Table 4, Figure 2). Elderly age was not a significant predictor of death-censored graft survival (HR of 1.07; 95% CI, 0.62-1.86; P = .806). Using elderly age as a covariate, we observed that retransplant status, donor hyper-tension, and increased KDPI were significant predictors of death-censored graft loss (Table 3).
Elderly patients had equivocal 90-day and 1-year patient survival but significantly inferior 3-year and 5-year patient survival rates (P = .006 and P = .019) compared with nonelderly recipients (Table 5, Figure 3). Elderly status was a significant predictor for patient death (HR of 2.26; 95% CI, 1.48-3.45; P < .001) (Table 5), with a decreased mean patient survival of 1488.5 ± 968.3 days compared with 1763.5 ± 1030.0 days (P = .012) (Table 2). There were no other significant predictors for death (Table 5).
Primary nonfunction was not statistically different between the 2 groups (2.5% vs 0.7%; P = .116) (Table 2). Delayed graft function was more likely to occur in the elderly group than in the nonelderly group (P = .038) (Table 2). Elderly patients were not more likely to experience an infection posttransplant than younger patients (P = .093) (Table 2).
As life expectancy increases and the proportion of elderly patients in the population grows, so will the total number of eligible geriatric kidney transplant candidates. When compared with younger can-didates, outcomes after kidney transplant in elderly patients have been documented as inferior; however, in carefully selected cohorts, mortality is decreased and life expectancy is increased compared with patients who are maintained on dialysis.5,10-16 Despite the known age burden on transplant recipients, outcomes in elderly kidney transplant recipients after alemtuzumab induction have not been clearly reviewed. Alemtuzumab is a useful adjuvant for modern immunosuppressive induction because it aims to equalize the outcome disparities between older and younger recipients.
The number of kidney transplants required by elderly patients is on the rise and is expected to increase as the “baby boomer” generation ages.1 Kidney transplant is viewed as an improvement in the quality of life for elderly dialysis patients but is not without ethical concerns.3 Elderly patients on dialysis inevitably develop hemodynamic, infectious, and metabolic complications, yet kidney transplant can effectively decrease morbidity and mortality.13 Despite the perception that age negatively influences graft and patient survival, kidney transplant still holds a strong survival advantage over conventional dialysis treatment in older patients.17 Denial of kidney transplant based solely on age has become less prevalent, as recent studies have shown that negative outcomes are not directly caused by advanced age.18-20
Schold and associates studied the effects of age on kidney transplant in African American patients and demonstrated a greater risk of graft loss in nonelderly compared with elderly recipients.21 Our analysis did not find such an association. Brooks and associates reported specifically reduced rejection rates in African American patients who are greater than 65 years old compared with White patients of equivalent age at 1, 3, and 5 years after alemtuzumab induction.22 Inferior outcomes would be expected in a cohort composed of patients of high-risk age and ethnic status, but our analyses concurred with the assertion of Brooks and associates regarding the positive effect of alemtuzumab on overall rejection in high-risk populations.
In our analysis, elderly recipients received organs with a significantly higher KDPI compared with KDPI of organs for nonelderly recipients. Despite this, the elderly and nonelderly recipients had similar outcomes. Elderly recipients were also less likely to have type 2 diabetes mellitus and less likely to have received a previous transplant. Consequently, the lower risk for both categories possibly contributed to a healthier individual with less immunologic and systemic concerns.
Aside from unspecified endogenous processes, sociocultural and socioeconomic factors such as education and insurance contributed to the outcomes shown in elderly recipients. Higher levels of education are associated with better outcomes.23,24 The superior outcomes shown with higher education can be attributed to better knowledge and insight into the care and management of grafts posttransplant. Our analysis showed that, although elderly patients had less advanced education, this fact did not have a deleterious effect on graft maintenance or survival. Private insurance provides patients with better health care access, financial stability, and effective monitoring of detrimental comorbidities that may damage grafts.24 Our analysis showed that elderly individuals had more private insurance, which could have contributed to similar rejection and short-term survival benefit.
Our analysis indicates that advanced age is not a significant risk factor for rejection. Because our overall rejection rate was comparatively high, the immunosuppressive protocol was altered in 2015 to provide maintenance steroid management for high-risk patient populations. It is unclear whether elderly recipients experience greater or lesser rates of acute rejection than younger patients. Previous reports have stated that elderly recipients have decreased acute rejection and attributed this decrease to reduced naïve T cells and total number of mature B lymphocyte precursors.3,25 In contrast, other studies have indicated increased rates of acute rejection and decreased graft and recipient survival among elderly recipients when induced with alemtuzumab.4,5 Hurst and associates and others showed that higher rates of rejection, death, and graft loss in the elderly population were associated with alemtuzumab therapy compared with other induction regimens.4,26 In contrast, the present analysis found no significant difference in overall and interval rejection but found significant differences in long-term patient survival.
Our present analysis showed that elderly individuals experienced less acute rejection than nonelderly recipients. The use of alemtuzumab may influence and/or normalize acute rejection and chronic rejection rates in elderly versus nonelderly patients. In addition, our experience indicates that, with alemtuzumab therapy, the overall rates of graft failure in the elderly population were comparable to nonelderly patients.
Coles and associates and Zhang and associates previously reported that certain cell types that predominant in the graft after transplant can influence recipient outcomes.27,28 Our review supported this notion by the presence of graft-damaging host neutrophils in the biopsies.29 Neutrophil expression of CD52 lends these cells susceptible to alemtuzumab induction; moreover, in individuals who presented with ACR, neutrophils can present in abundance.30 We report that elderly patients had increased rates of ACR compared with antibody-mediated rejection. This disproportionately higher rate of ACR is likely due to increased incidence of neutrophils among elderly patients.
Although our rates of transplant rejection were comparatively high, it is important to recognize that other studies detailing the use of alemtuzumab are related to increased 1-year rejection. Huang and associates previously reported significantly increased rates of acute rejection at 6 months and 12 months with alemtuzumab induction compared with no induction, induction with interleukin 2 receptor antagonists, and induction with rabbit antithymocyte globulin (rATG).31 Gill and associates demonstrated that alemtuzumab use in elderly patients was associated with increased risk of overall acute rejection, which was particularly higher in low-risk recipients with high-risk organs.5
Other investigations into elderly kidney transplant have resulted in a diversity of patient outcomes. Neri and colleagues reported DGF of 31%, ACR of 12.6%, infection of 34.3%, and death-censored graft survival and patient survival of 94.4% and 98.7%, 87.9% and 93%, and 81.4% and 89% at 1, 3, and 5 years, respectively, after induction with basiliximab or thymoglobulin at different centers.32 Iwamoto and associates, who studied the use of basiliximab, noted an ACR incidence of 25% and graft and patient survival of 100% and 91.7% and of 95.4% and 98.1% at 1 and 5 years, respectively.33 Gill and associates achieved ACR rates of 7.3% (rATG), 10.5% (interleukin 2 receptor antagonists), and 11.4% (alemtuzumab), whereas Palanisamy and associates described 1-year outcome results of 6% ACR, 22% infection, 94% graft survival, and 98% patient survival with rATG and 13% ACR, 25% infection, 90% graft survival, and 96% patient survival with daclizumab.3,5 Khanmoradi and colleagues reported that use of rATG significantly led to lower elderly DGF at 31.1% and lower patient survival; however, no differences in death-censored graft survival, graft function, and rejection rates were shown.10
As a whole, these findings are comparable with our reported 1-year graft and patient survival rates (95.4% and 99.2%), although our 5-year results (72.9% and 83.1%) are somewhat lower. Our decreased graft survival may be associated with our elevated rejection rates (19.8% at 1 year) discussed previously, whereas differences in patient survival may be due to variations in mean patient age and demographics.
One potential disadvantage of the immuno-depleting regimen (alemtuzumab with steroid minimization) described in this paper may be under-immunosuppression. We noted an overall rejection rate of 27%, higher than the national average and greater than other institutions that utilize alem-tuzumab. In addition, investigations into our rejection diagnoses determined a relatively rapid onset of rejection and more severe rejection diagnoses, characterized by high Banff classification. In the face of these findings, our institution is experimenting with long-term steroid maintenance in individuals preoperatively determined to be at greater risk for rejection.
Notably, our analysis demonstrated that elderly patients were significantly more likely to develop DGF. Increased DGF in elderly patients may result from the elderly patient’s inability to quickly rebound after traumatic burdens, such as surgery, anesthetic agents, transient hemodynamic instability, or chronic comorbidities.34,35 However, other studies investigating DGF have found no strong ties between advanced age and DGF incidence.36 Because of the association between DGF and subsequent rejection, further investigation into age, comor-bidities, and DGF are important aspects of future research in elderly transplant.
Prior reports have shown that recipients who are 65 years and older experience inferior graft and patient survival versus younger patients.17,37 In this study, we showed no differences in rate of graft survival between elderly and nonelderly patients at 90-day, 1-year, 3-year, and 5-year follow-up. We also found no differences in short-term patient survival at follow-up times of 90 days and 1 year.
The utility of providing a renal transplant to an elderly patient over a younger one is debatable due to the shortened life expectancy in older patients. Prior reports have stated that the benefits of transplant are seen at 1 to 2 years posttransplant.12,18 We found that elderly recipients do have a significantly worse mean patient survival (1488.5 days compared with 1763.5 days); with alemtuzumab, the elderly patients live long enough to witness beneficial effects. Saucedo-Crespo and associates detected no significant difference in death-censored graft survival.18 Our analysis also uncovered no significant variance in death-censored allograft survival rates between elderly and nonelderly patient populations. The elderly recipients may have decreased long-term patient survival, but the extent to which decreased survival is caused by transplant-related factors, as opposed to age-related comorbidities, was not established.
Rates of infection are a common complication associated with kidney transplant, and elderly recipients can develop cytomegalovirus, BK virus, and other opportunistic infections. In our study, we found no significant differences in rates of infection in elderly versus nonelderly patients.
Our current analysis has several significant strengths. Our findings support the well-documented assertion that alemtuzumab induction helps reduce disparities. Most studies fail to investigate the utility in elderly populations due to confounding factors and age-defining limitations. However, our report provides insight into how elderly kidney transplant recipients fare with factors other than age-defining limitations. Our use of a large data set and multiyear standardized protocol allowed a long-term evaluation of elderly and nonelderly recipient outcomes.
Despite our encouraging results, our investigation does have limitations. First, the retrospective nature of the review and database analyses versus a randomized trial provide little room for the control and flexibility shown with an experimental design study. Furthermore, the scope of this analysis was limited to a single transplant center, which may hinder translation to other transplant centers. Finally, the institutional induction protocol did not have an in-center control arm.
Alemtuzumab induction is associated with reduced negative outcomes after kidney transplant when we compared elderly versus nonelderly individuals. No differences were shown in death-censored graft survival and graft rejection throughout the follow-up period between elderly and nonelderly individuals. Importantly, elderly age was not a significant predictor for rejection or death-censored graft loss in individuals with alemtuzumab induction. Future prospective, multicentered, large sample-size studies are necessary to further expound on the present results to determine causation for reduced elderly patient outcomes.
DOI : 10.6002/ect.2018.0296
From the 1College of Medicine and Life Sciences, University of Toledo, the
2Department of Urology and Pathology, University of Toledo College of Medicine
and Life Sciences, and the 3Department of Surgery, University of Toledo College
of Medicine and Life Sciences, Toledo, Ohio, USA
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Anthony DeLeonibus, 3000 Arlington Ave., Toledo, OH 43614, USA
Phone: +1 410 991 5425
Table 1. Elderly and Nonelderly Recipient and Donor Demographic Information
Table 2. Patient Outcomes and Transplant Characteristics
Table 3. Outcomes of Rejection and Multivariate Analysis of Rejection Risk Factors in Elderly Patients
Table 4. Outcomes of Graft Survival and Multivariate Analysis of Graft Survival Risk Factors in Elderly Patients
Table 5. Outcomes of Patient Survival and Multivariate Analysis of Patient Survival Risk Factors in Elderly Patients
Figure 1. Rejection Rates by Age Cohort
Figure 2. Death-Censored Graft Survival by Age Cohort
Figure 3. Patient Survival by Age Cohort