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ARTICLE
Alemtuzumab Induction Reduces Early Rejection in Female Renal Allograft Recipients: A Single Center Study

Objectives: Previous research studies have highlighted differences in rejection and graft survival across sexes that favor men. We compared delayed graft function, rejection, graft survival, and overall patient survival between sexes following alemtuzumab induction.

Materials and Methods: After Internal Review Board approval, a retrospective analysis of kidney transplants completed at the University of Toledo Medical Center between March 2004 and November 2015 was conducted.

Results: During the study period, 675 transplants were performed. This included 429 male patients (63.6%) and 246 female patients (36.4%). Recipient sex was not associated with delayed graft function. Acute rejection occurred less frequently in women than in men at 3 months (12.6% vs 20.7%; P = .009) and at 6 months (15.9% vs 24.6%; P = .008). Cumulative patient survival was superior in women (P = .032). Female recipient death-censored graft survival was inferior at 3 years (85.4% vs 91.6%; P = .034) and at 5 years (77.7% vs 86.9%; P = .019) versus male patients.

Conclusions: Compared with men, early female rejection is reduced and overall female survival is longer after alemtuzumab induction. However, intermediate-term female graft survival is less.


Key words : Fusion proteins, Immunosuppressant, Immunosuppressive regimens, Kidney transplantation, Monoclonal antibodies

Introduction

Disparities between female and male patients continue to plague the field of renal transplantation. Previous studies have reported reduced female allograft survival1 and higher rates of acute rejection compared with men.2 However, others dispute sex disparities with regard to graft and patient survival.3 Women are less likely to be placed on wait lists and less likely to receive an allograft.1,4,5 Together, female patients with end-stage renal disease continue to face substantial challenges.

Induction protocols are widely used to improve a variety of posttransplant parameters.6 However, whether a single agent (or combination therapy) has the potential to nullify sex disparities remains unknown. One induction agent that has shown promise, especially in preventing rejection among high-risk patients, is alemtuzumab (Campath®, Bayer HealthCare Pharmaceuticals, Berlin, Germany).7 Alemtuzumab is a humanized immunoglobulin G1 monoclonal antibody against CD52, a receptor found on the majority of leukocytes. Binding of CD52 by alemtuzumab targets the cell for antibody-directed cell death.8 After the administration of alemtuzumab, lymphocyte counts remain significantly reduced for up to 9 months.9 This sustained reduction has simplified immediate posttransplant immunosup­pressive regimens.10 For these reasons, alemtuzumab induction has been adopted at our institution and is utilized in roughly 13% of kidney transplant procedures in the United States.11 Unfortunately, few investigators have reported on outcomes in men versus women after alemtuzumab induction. The present study was undertaken to study delayed graft function (DGF), acute rejection, patient survival, and death-censored graft survival across biological sexes after alemtuzumab induction. Based on previous reports, we hypothesized that female recipient grafts would perform less favorably.

Materials and Methods

After Internal Review Board approval was granted, a retrospective analysis of all living-donor and deceased-donor renal transplants performed at the University of Toledo Medical Center between March 1, 2004 and November 30, 2015 was completed. All patients included in the study received a single dose of alemtuzumab. Data were collected using TransChart electronic medical record software (TransChart LLC, Dublin, OH, USA). Donor information collected included age, sex, ethnicity, presence of hypertension, presence of diabetes mellitus, type of donation (living or deceased), weight, body mass index (BMI), terminal creatinine, and whether the donor was considered an extended criteria donor. We also obtained similar recipient information, including age, sex, ethnicity, blood type, type of graft (living or deceased), weight, BMI, body surface area (BSA), panel reactive antibody (PRA), and number of previous transplant procedures (Table 1).

All recipients were cross-matched for T- and B-cell status via flow cytometry. The participants included in our study all had negative cross-matches. All cases of acute rejection were biopsy proven.

Patients were treated with 25 mg of diphenhy­dramine intravenously (IV), 500 mg of meth­l­prednisolone IV, and 30 mg of alemtuzumab IV before incision. Additionally, in most cases, 540 mg of mycophenolate sodium was administered by mouth (PO) in the preoperative area.

Postoperatively, a steroid taper was administered. This consisted of the following: methylprednisolone 250 mg IV on postoperative day 1, methylpred­nisolone 125 mg IV on postoperative day 2, prednisone 60 mg PO on postoperative day 3, prednisone 40 mg PO on postoperative day 4, and finally prednisone 20 mg PO on postoperative day 5. Most patients were ultimately treated with a steroid-free regimen.

Starting on postoperative day 1, tacrolimus at 1.5 mg PO twice daily and mycophenolate sodium at 540 mg PO twice daily were administered. Tacrolimus levels were measured immediately before the morning dosing. Levels were then titrated to between 4 and 11 ng/dL and were monitored on routine follow-up. If side effects permitted, mycophenolate sodium was increased to 720 mg PO twice daily at discharge.

Antimicrobial prophylaxis consisted of sulfamethoxazole 800 mg and trimethoprim 160 PO 3 times per week and clotrimazole troche 10 mg dissolved in the mouth 4 times per day following oral care. Daily valganciclovir at 450 mg PO was prescribed depending on risk factors.

Statistical analyses were performed using SPSS software (IBM Corporation, Armonk, NY, USA). Cross-tabulation and chi-square analyses were performed where applicable. For continuous variables, independent t tests were carried out. P values ≤ .05 were considered significant.

Results

Over the study period, 675 transplants were completed. Our study cohort included 246 female patients (36.4%) and 429 male patients (63.6%). Patients with white race/ethnicity constituted most of both the female and male recipient populations (69.5% and 71.8%, respectively). African Americans comprised the second-most common race/ethnicity in both our female and male groups (25.6% and 20.7%, respectively). Female recipients were younger than their male counterparts (50.6 vs 53.1 y; P = .05). Donor age was not significantly different between recipient sexes. Women received a female allograft 47.6% of the time, and men received a male allograft 56.6% of the time (P = .291).

Analysis of donor-recipient weight mismatch showed that 34.6% of women received a kidney from a similar weight donor (ie, < 10 kg absolute weight difference). In the male patients, 27.2% had similar weight donors (P = .004). We observed that 42.0% of female recipients and 27.2% of male recipients were mismatched with donors who weighed at least 10 kg more (P = .004) and that 23.5% of female recipients and 45.6% of male recipients were mismatched with donors who weighed at least 10 kg less (P = .004). These results are summarized in Table 1.

Compared across sexes, recipient BMIs were similar (27.1 kg/m2 in female patients vs 27.5 kg/m2 in male patients; P = .585). However, female recipient weight was substantially less (158.5 kg for female vs 190.2 kg for male patients; P < .001), and female recipient BSA was also less (1.67 m2 for women versus 1.90 m2 for men; P < .001). Female and male donor BMIs were similar (26.4 vs 27.4 kg/m2, respectively; P = .359). We also found that 73.0% of patients were first-time recipients, with retransplants accounting for 30.5% of female and 24.9% of male transplant recipients (P = .118). Donor race, rate of donor hypertension, and presence of donor diabetes mellitus were similar across sexes. Table 1 summarizes these demographics.

Female recipients received allografts with lower terminal creatinine levels versus male recipients (0.92 vs 1.25 mg/dL; P = .05). Female and male recipients received similar percentages of expanded criteria donations, including donations after neurologic death and donations after cardiac death. In addition, the percentage of donations after neurologic death and cardiac death from standard donors did not differ (Table 1). The Kidney Donor Profile Indices were similar (50% female vs 45% male; P = .294).

Diabetes mellitus constituted the most common reason for transplant among both female and male patients, occurring at a similar percentage (Table 1). Cold ischemia times were comparable between female and male patients (12.68 vs 12.94 hours, respectively). Similar rates of living donors (P = 1.0), elderly recipients (P = .905), and time on dialysis (P = .974) were seen in both sexes (Table 1). The mean PRA score was significantly higher in female recipients than in male recipients (18.2 vs 8.03; P < .001) (Table 1). However, the median PRA score for both sexes was 0.

Both women and men experienced similar rates of DGF (P = .219; Table 2). Rejection within 90 days was seen less frequently in women than in men (12.6% vs. 20.7%; P = .009) (Table 2). Women also experienced lower rates of rejection at 6 months than men (15.9% vs 24.6%; P = .008) (Table 2). In fact, reduced rejection was seen in the female population until roughly 40 months after transplant at which time the Kaplan-Meier curves met (Figure 1). Cumulatively, over the 90-month study period, no differences in rejection rates were seen across female and male patients (P = .254). Acute T-cell rejection constituted the dominant rejection type for both female (65.2%) and male patients (70.4%; P = .331). Furthermore, the most prevalent classification of rejection was Banff type II for women (79.6%) and men (77.3%; P = .55), followed by Banff type I and Banff type III. The most common cellular infiltrate was monocytes in women (34.8%) and lymphocytes in men (30.4%; P = .622).

Subset analysis of the rejection population divulged several important findings. A PRA score of 25 or greater was seen in 36.2% of female patients with graft rejection but only 13.6% of male patients with graft rejection (P < .001). Body surface area greater than 1.7 m2 was seen in 50.0% of women and 82.5% of men with rejection (P = .009). In addition, women less than 45 years old (compared with women > 45 years old) were at higher risk of rejection (41.4% chance over the study period) compared with 20.8% chance in women over age 45 years (P = .001).

Patient survival rates at 1, 3, and 5 years after transplant for the female versus male populations were 96.6% versus 95.3%, 92.7% versus 87.9%, and 88.5% versus 81.6%, respectively (Table 2). No differences in survival were seen at these time points (P = .457, .097, and .077, respectively). However, overall survival for the cumulative study period favored women (P = .032; Figure 2).

Cardiovascular disease accounted for a large (but statistically similar) percentage of deaths in both female and male patients (34.7% of female deaths vs 17.2% of male deaths). Infectious processes, however, caused a statistically larger percentage of female (27.6%) than male (9.7%) deaths (P = .022). Therefore, the leading causes of death were infection and cardiovascular disease in the female and male populations. Subset analysis showed that a PRA score of greater than 25 was seen in 45.6% of women but only 23.9% of men with infectious complications (P = .014). In addition, 25.0% of female patients and 86.7% of male patients with a BSA greater than 1.7 m2 experienced an infectious complication (P < .001).

Death-censored graft survival at 1, 3, and 5 years after transplant for the female versus male populations were 93.9% versus 95.6%, 85.4% versus 91.6%, and 77.7% versus 86.9%, respectively (Table 2). Death-censored graft survival at 3 and 5 years favored men (P = .034 and P = .019, respectively), whereas graft survival at 1 year was similar between sexes (P = .37; Table 2). Overall, death-censored graft survival for the cumulative study period was significantly better in men (P = .018; Figure 3).

In a subset analysis of patients who experienced graft loss, body surface area > 1.7 m2 did not affect death-censored graft survival in either the female (88.9%) or male (94.6%) populations at 5 years after transplant (P = .231). African American female patients compared with female patients who were not African American did not have inferior death-censored graft survival outcomes at 1, 3, or 5 years (Table 3). In addition, they experienced similar infectious complications (39.7% vs 47.0%; P = .314).

Women undergoing transplant before the age of 45, in addition to having higher rejection rates, had lower 3-year (83.5% vs 92.7%; P = .036) and 5-year (78.5% vs 89.8%; P = .023) death-censored graft survival. One-year death-censored graft survival and rates of infectious complications were not different between younger and older women (Table 3). Women and men over 45 years of age had comparable graft survival. However, older women experienced more infectious complications than older men (49.7% over the entire follow-up period vs 27.8%; P < .001). Infectious complications were defined as infections during the postoperative hospitalization period or during any patient encounter after transplant surgery (eg, urinary tract infections, an incision infection [including cellulitis or abscess], pneumonia requiring antibiotics, and polyoma viral infection requiring treatment beyond that of standard prophylaxis). Across sexes, women who experienced DGF were at higher risk of infection (62.5%) than men (30.0%; P = .024), but death-censored graft survival rates were similar. We also found that female patients with DGF, compared female patients without DGF, did not experience reduced death-censored graft survival or increased infectious complications (Table 3). Women with PRA score above 25 had worsened 3-year death-censored graft survival (80.8%) versus women with lower PRA scores (92.1%; P = .021).

Repeat transplant did not alter graft survival across sexes. However, after retransplant, women were more likely than men to have infectious complications (36.0% versus 24.3%, respectively; P < .001).

Donor-recipient weight mismatch was analyzed after stratifying groups into donor weight more than 10 kg greater than recipient, weight within 10 kg of recipient, and weight at least 10 kg less than recipient weight. We observed no differences in 1-year, 3-year, or 5-year death-censored graft survival for any of the donor-recipient weight categories compared across sexes (Table 4).

Analysis of women and men transplanted without organs matched by sex showed a reduced 5-year death-censored graft survival in women (85.5% vs 93.3%; P = .036). No differences were found in death-censored graft survival between women and men transplanted with organs matched by sex at 3 years (89.9% vs 94.6%; P = .127) and 5 years (85.9% vs 91.2%; P = .153). Within the female recipient population, women with organs matched by sex did not have superior death-censored graft survival versus women who had organs not matched by sex at 1 year (97.0% vs 94.9%; P = .442), 3 years (89.9% vs 89.9%; P = .810), and 5 years (85.9% vs 85.5%; P = 0.935). Within the male recipient population, donor-recipient matching did not alter 1-year (96.1% vs 97.3%; P = .532), 3-year (94.6% vs 94.6%; P = .999), or 5-year (91.2% vs 93.3%; P = .476) death-censored graft survival or infectious complication rates (26.7% vs 24.7%; P = .636) compared with mismatched individuals.

Death was the most common cause of graft failure in both women (n = 19) and men (n = 59) (28.4% vs 55.1%, respectively; P = .001). In addition, acute rejection was the cause of graft loss in 16 female patients (23.9%) and 10 male patients (9.3%; P = .009) (see Table 2). Other causes of graft failure that did not differ significantly between sexes included chronic rejection, recurrent disease, primary nonfunction, and allograft pathology.

Discussion

Previous studies have shown that female renal allograft recipients experience higher rates of acute rejection and reduced long-term graft survival than male patients.1,2,12 This analysis was undertaken to determine how alemtuzumab induction alters DGF, acute rejection, patient survival, and death-censored graft survival across sexes.

Delayed graft function is an important prognostic indicator of renal allograft success. The presence of DGF is known to strongly affect both short- and long-term outcomes.13 Classically, male recipients experience higher rates of DGF.14 The reason remains unclear. However, the protective effect of estrogen on ischemia/reperfusion injury remains a popular hypothesis.14 Interestingly, in our population, this disparity was not seen and DGF rates across sexes were similar (and low). This represents an improve­ment for men and likely helped male 3- and 5-year graft survival rates.

Biopsy-proven acute rejection (BPAR) within 90 days after transplant was seen less frequently in our female recipient pool. Kaplan-Meier analysis demonstrated sustained superiority in the female population up to 40 months after transplant (Figure 1). These findings are contrary to previous reports showing higher rates of BPAR in female renal allograft recipients when alemtuzumab is not used.15,16 However, studies that included men and women have shown reduced BPAR after alemtuzumab induction.7 The current report is the first to find sex-specific improvements in BPAR that favor female recipients after alemtuzumab induction despite significantly higher female recipient PRAs. We attribute these findings to enhanced potency of alemtuzumab on female patients who, on average, have smaller BSAs than men. It should be noted that, during the writing of this manuscript, rejection rates at 90 days and 180 days were noted at our center, which ranged from 12.6% to 24.6%. After analysis of the data included herein, patients at high risk for rejection were started on low-dose, indefinite prednisone therapy. High risk included patients with PRA greater than 20, having retransplant or DGF, and African American race/ethnicity. This sole implementation lowered our acute rejection rates to less than 10% (data not shown).

During subset analysis of the rejected population, donor and recipient BMI and BSA results were evaluated. Historically, donor and recipient obesity has been correlated with less favorable outcomes.17,18 Our female and male recipient BMIs were similar. However, female recipients had smaller weights and BSAs. We argue that recipient BSA better reflects a drug's volume of distribution. Because the same dose was given to both women and men, the potency of alemtuzumab could have been enhanced in the female population as a result of their physical characteristics. This remains one explanation for the lower early rejection rates seen in our female population. We found women younger than 45 years of age to be more likely to have graft rejection versus their older counterparts. By virtue of age, younger women are more likely to be premenopausal with higher levels of circulating estrogens. Estrogen's enhancement of humoral immunity via inhibitory effects on T-suppressor cells would therefore predispose premenopausal women to rejection.19

In our study, we used monocytes as a surrogate for humoral immunity. Monocytes are known to respond to the deposition of C3a and C5.20 As expected, monocytes were the most common infiltrate seen in female patients with rejection. In men, lymphocytes (ie, cell-mediated immunity) predominated. Interestingly despite estrogen enhancement of humoral immunity among women, the rejection types were similar between men and women and occurred in proportions similar to previously shown.21 Female patients, as a result of their reduced graft survival, would be expected to have higher Banff classifications,22 yet alemtuzumab did not preferentially improve the Banff classification for either women or men.

Regarding all-cause mortality, previous reports have shown similar rates across sexes after renal transplant.23-25 However, our analysis showed that female recipient survival was improved with alemtuzumab induction. We attributed this to a younger female population in the current study and known longer life expectancies among American women versus men.26 Nonetheless, subset analysis was performed with the hope of correlating recipient characteristics with posttransplant complications. Specifically, it was noted that women, rather than men, with BSAs less than 1.7 m2 were prone to infection. In addition, we found that female patients with DGF or retransplant experienced more infectious complications than matched men. Women are more likely to receive a higher dose of alemtuzumab per body mass when considering mean weight. A weight-based dose of alemtuzumab (0.4 mg/kg) has recently been shown to be as effective in preventing acute rejection while reducing the number of infectious complications as shown in patients who received less than 30 mg of alemtuzumab.27 The reason for these findings remains unclear. However, because of these findings, we recommend close follow-up in women, especially those with DGF or retransplant.

Reports outlining allograft survival across sexes have revealed mixed results. A report in 2003 that analyzed the United States transplant database indicated that graft survival after living-donor renal transplant was inferior in female recipients.1 Alternatively, other analyses have demonstrated equal graft survival between women and men.28,29 In our study, death-censored graft survival among female recipients at 3 and 5 years was worse. Variables affecting these results should be noted. Specifically, a higher mean female PRA placed them at increased risk for rejection. Alemtuzumab induction likely mitigated early immunologic risk. Over time, however, higher female PRAs predominated and affected midterm (ie, 3- and 5-year) allograft parameters. Retransplant, which is known to carry a greater risk of graft failure,30 occurred (although not statistically) more in our female population. Previous reports have noted higher female retransplant rates,31 which are believed to be secondary to H-Y mismatch.32 As an aside, patients with African American heritage did not show worse graft survival after alemtuzumab induction. This finding confirms published research showing the equalization of graft failure between ethnicities after alemtuzumab.33 Our group at the University of Toledo Medical Center recently demonstrated equal rates of rejection, graft survival, and overall survival across ethnicities following induction with alemtuzumab.34

Other factors affecting graft survival include donor-recipient sex mismatch.1,28 In female-to-male mismatch, the smaller allograft mass is unable to withstand the metabolic demands of the male recipient.35 Alternatively, male-to-female mismatch is affected by the aforementioned H-Y mismatch.32 In our study, mismatched female recipients had inferior 5-year posttransplant graft survival versus mismatched male recipients. This is presumably secondary to H-Y mismatch as discussed above. Interestingly, survival of sex-mismatched female recipient grafts was not inferior to matched female recipients grafts. Thus, alemtuzumab induction may benefit female recipients undergoing donor-recipient sex-mismatched surgery.

Regarding donor-recipient size mismatch, reduced renal allograft survival has been shown in recipients who received kidneys smaller than their body size.36,37 At our center, male recipients were paired with smaller donors more frequently; however, male recipient graft survival was not worse over the course of the study. Conversely, female recipients received kidneys from larger donors more often. However, this did not improve female graft survival, representing a departure from previous reports,38 including one that concluded that donor-recipient weight mismatch and donor-recipient sex mismatch are additive and can result in higher graft loss compared with either sex or weight mismatch alone.39 Our findings suggest that alemtuzumab eliminates the deleterious effects of both donor-recipient weight mismatch and donor-recipient sex mismatch.

This report provides new insights into the associations between alemtuzumab induction and sex-specific renal allograft outcomes. Because midterm female graft survival continues to be of concern in women, we recommend close follow-up and a low threshold for biopsy in this population. Furthermore, we continue to advocate the use of alemtuzumab in high-risk populations, including African American recipients and sex-mismatched and weight-mismatched individuals, as alemtuzumab showed a potential benefit for each of these populations in the present study. To what degree alemtuzumab benefits younger women who are at increased risk of rejection remains unknown. Furthermore, it remains unknown whether dose escalation of alemtuzumab in patients with a BSA above 1.7 m2 should occur. To answer these questions, further studies are needed.

The strengths of this study include the large patient population, the consistency of the medical regimen, and the consistent surgical technique provided almost exclusively by 2 surgeons. Limitations include the retrospective nature of the analysis at only a single site. Additionally, other parameters, including pre- or postmenopausal status, allograft mass, and allograft volume, were not captured. Furthermore, not all recipients required a protocol biopsy, and this may have limited the number of enrollees and power of the study. A requirement for patients to consent for protocol biopsy likely would predispose a selection bias, as only a subset of the true population would be included. However, protocol biopsies have been shown to improve the prognosis and detection of subclinical rejection.40 Data regarding rehos­pitalization rate, the specific nature of infections, including BK viral reactivation, and mean calcineurin inhibitor (tacrolimus) trough serum levels were not captured, although our target range was defined and monitored. To better understand sex-specific outcomes after renal transplant, a large, multicenter study is needed.

Conclusions

The present analysis highlights reduced early rejection and improved overall patient survival for women after alemtuzumab induction. Thus, alemtuzumab shows benefit among high-risk populations, including women and racial minorities. However, midterm death-censored graft survival in women was inferior. The similar rate of DGF seen between sexes after alemtuzumab induction is a promising finding. Future research is needed to better understand female factors affecting renal transplant and to develop a medical regimen aimed at ameliorating mid- and long-term female graft loss.


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DOI : 10.6002/ect.2017.0225


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From the 1Department of Urology and the 3Department of Surgery, University of Toledo, College of Medicine and Life Sciences, Toledo, Ohio; and the 2College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, USA
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. *Jonathan Demeter and Bradley Buck contributed equally.
Corresponding author: Jonathan H. Demeter, The University of Toledo College of Medicine and Life Sciences, Department of Urology, Mailstop 1091, 3000 Arlington Avenue, Toledo, OH 43614, USA
Phone: +1 419 383 3505
E-mail: jhdemeter@gmail.com