Impact of sex on clinical outcomes according to immunologic risk in spousal donor kidney transplantation
Article information
Abstract
Background
The aim of this study is to investigate the impact of sex on the clinical outcomes of spousal donor kidney transplantation.
Methods
We analyzed 456 spousal donor kidney transplantation recipients and categorized them into standard or high immunological risk groups according to panel-reactive antibody ≥50% or less. There were 366 recipients in the standard-risk group and 89 recipients in the high-risk group.
Results
When comparing biopsy-proven allograft rejection within 1 year from kidney transplantation, husband-to-wife recipients showed significantly higher incidence than wife-to-husband recipients in the high-risk group. By contrast, there was no significant difference between wife-to-husband and husband-to-wife recipients in the standard-risk group. Allograft function recovery was better in husband-to-wife recipients than in wife-to-husband recipients in each group, while husband-to-wife recipients in the high-risk group showed a more rapid decline than other recipients. The long-term patient and allograft survival rates showed no difference between husband-to-wife recipients and wife-to-husband recipients within the same groups.
Conclusion
The husband-to-wife recipients with high immunological risk showed a higher risk of biopsy-proven allograft rejection compared to wife-to-husband recipients, so careful monitoring and management may be required.
Introduction
Kidney transplantation (KT) is widely accepted as the optimal treatment for end-stage kidney disease (ESKD) patients [1,2]. Securing kidney donors is a crucial aspect of providing patients with opportunities for transplantation. Trends in donor type in KT can vary between different countries, and they can also change even within a country according to the sociocultural characteristics of different regions [3,4]. For example, in Korea, most transplants use organs from living donors, in contrast to the United States and European countries; moreover, within living donors, the proportion of spousal donor KT (SDKT) shows a marked increase with a decrease in living-related donors (LRD) [5]. This increase in SDKT can be attributed to several factors. In a modern nuclear family system, it is natural to prefer SDKT, and spousal donors are not limited by legal and ethical problems. Moreover, allograft outcomes from spousal donors are as good as those from LRDs or other living-unrelated donors [6,7].
However, in SDKT, it is important to consider the following two additional aspects. First, the sex difference that may exist between the donor and recipient in SDKT is important to consider. Sex has not only a biological aspect that includes genetic, physiologic, and endocrine features [8,9], but also a character that affects immune response by genetic, environmental, and hormonal mediators [9]. Therefore, many previous studies have demonstrated that allograft outcomes such as the development of allograft rejection or the change in allograft function can be affected by the sex of donor and recipient [10-13]. Second, when the recipient is female, and if they have been pregnant, which is a sensitization event, particularly multiple times, it can induce an adverse impact on allograft outcomes through immunologic mechanisms [14]. These special factors in SDKT associated with donor and recipient sex are believed to affect prognosis after KT, but the impact of sex in SDKT has yet to be comprehensively investigated, as it has only been sporadically reported on until now.
Based on the background detailed above, the aim of the current study is to investigate the impact of sex on clinical outcomes in SDKT. For this, we divided the SDKT recipients into wife-to-husband (W2H) recipients and husband-to-wife (H2W) recipients and then compared their clinical outcomes, including allograft rejection, long-term patient and allograft outcomes, and infectious complications.
Methods
Study population
We analyzed KT from spousal donors performed in The Catholic University of Korea, Seoul St. Mary’s Hospital from August 2005 to December 2022 (Fig. 1). Among 594 initially eligible SDKT cases, 139 cases were excluded for the following reasons: insufficient data for immunologic risk (n = 83) or re-transplantation cases (n = 56). Sex differences affect the immune response, and the rejection according to immunological risk also has an impact on graft outcome. Panel-reactive antibody (PRA) is associated with graft survival [15]. Patients with PRA ≥50% showed about half the graft survival compared to patients with a PRA level <50% [16-18]. Therefore, we categorized the enrolled patients using not only sex but also immunological risk according to PRA. We divided the recipient into four groups based on their immunological risk classified with PRA and type of SDKT. SDKT recipients with PRA under 50% were classified as the standard-risk group with standard immunological risk, while SDKT recipients with PRA over 50% were allocated as a high-risk group with high immunological risk. Among the 366 standard-risk group recipients, there were 291 W2H SDKT recipients and 75 H2W SDKT recipients. In the 89 high-risk group SDKT recipients, there were 34 W2H SDKT recipients and 55 H2W SDKT recipients.
Numbers and proportions of SDKT recipients.
In total, 594 SDKTs were conducted in The Catholic University of Korea, Seoul St. Mary’s Hospital from January 2009 to December 2022. Among 594 SDKTs, 83 cases without panel-reactive antibody (PRA) data and 56 re-transplantation cases were excluded. Of the remaining 455 SDKTs, 89 cases were allocated as the immunological high-risk group and the other 366 cases were classified as the immunological standard-risk group according to their PRA level.
SDKT, spousal donor kidney transplantation.
This study was approved by the Institutional Review Board of The Catholic University of Korea, Seoul St. Mary’s Hospital (No. KC23RISI0326) and has been conducted according to the principles expressed in the Declaration of Helsinki. The informed consent was not required because this study was retrospective analysis and involves no more than minimal risk to the subjects.
Pretransplant immunologic test and desensitization protocol
The immunological workup protocol used in our center has been reported in detail previously [19,20]. In all recipients and donors, human leukocyte antigen (HLA) typing was performed using LIFECODES HLA-A, B, C, DRB1, and DQB1 Sequence-Specific Oligonucleotide Typing Kits (Immucor Transplant Diagnostics). All living donor KT (LDKT) candidates underwent the baseline tests of PRA screening and crossmatch (XM) tests. XM results were reported using T-/B-complement dependent cytotoxicity crossmatch (CDC-XM) and T-/B-cell flow cytometry crossmatch (FCXM) tests. The CDC-XM and FCXM tests were conducted using standard procedures as detailed previously [21,22]. In patients with positive PRA screening or XM test results, we investigated the presence of anti-HLA antibody. Anti-HLA antibody was identified by the single antigen assay using LABScreen single antigen HLA class I-combi and class II-group 1 kits (One Lambda). The criterion for positivity was a median fluorescent intensity (MFI) value of >1,000. If the single antigen assay-detected anti-HLA antibody in the recipient was found to correspond to the HLA type of the donor, it was classified as a donor-specific anti-HLA antibody (HLA-DSA).
The desensitization protocol for LDKT consisted of rituximab, plasmapheresis, and intravenous immunoglobulin or bortezomib-based regimen. Rituximab was given in a single dose of 375 mg/m2 at the initiation of their program. Bortezomib was administered four times at a dose of 1.3 mg/m2, if needed. Pretransplant plasmapheresis was routinely performed in all patients with HLA-DSA. One plasma volume was exchanged with either albumin solution or fresh frozen plasma using the conventional method. Intravenous immunoglobulin (100 mg/kg) was administered after plasmapheresis. The target anti-A/B antibody titer on the transplant day was under 1:16. A tacrolimus-based triple immunosuppressant was administered to all patients. The target trough level of tacrolimus during the first posttransplant month was 8 to 12 ng/mL, while it was 5 to 8 ng/mL afterward. The dose of mycophenolate mofetil during the first month was a tolerable dose up to 1.5 g/day in most patients. Interleukin-2 receptor blockade (basiliximab) or antithymocyte globulin was used as an induction treatment.
Assessment of clinical outcomes
The clinical outcome of SDKT was evaluated in terms of the biopsy-proven allograft rejection (BPAR) occurrence rate, BPAR-free survival rate, change in allograft function as assessed by the estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [23,24], and patient and graft survival rate. Allograft kidney biopsy was performed in cases involving unexpected allograft dysfunction (when the serum creatinine level was 20% above the baseline), the unexpected development of proteinuria, and the occurrence of de novo DSA. Allograft kidney biopsy findings were interpreted according to the 2019 Banff classification [25,26]. BPAR was diagnosed via allograft biopsy for acute T-cell mediated rejection (TCMR), acute antibody-mediated rejection (ABMR), chronic active TCMR, chronic active ABMR, and chronic ABMR. Calcineurin inhibitors toxicity and BK virus nephropathy were diagnosed based on the Banff classification [25-27]. BPAR-free survival was defined as the time from transplantation to the first episode of BPAR. The development of de novo DSA until BPAR occurrence was analyzed. Serum creatinine levels were analyzed at the time of discharge as well as 1, 3, 5, and 10 years after transplantation, and the eGFR for each concordant time was assessed using the CKD-EPI equation. Patient and graft survival was defined as the time from transplantation until graft failure or death from any cause. The incidence and types of infection within 1 year after KT were analyzed.
Statistical analyses
Continuous data were presented in the form of mean ± standard deviation. The data were compared using the Student t test. Categorical data were compared using chi-square tests or Fisher exact tests. Kaplan-Meier curves and log-rank tests were used to describe and compare the BPAR-free survival rate as well as the allograft and patient survival rate. To define the risk factors affecting the allograft rejection, clinical parameters including SDKT type with immunologic risk, recipient age, and cause of ESKD were explored using Cox proportional regression analysis. To define the risk factors affecting the patient and graft survival, a Cox proportional hazards regression analysis was conducted with SDKT type with immunologic risk, recipient age, cause of ESKD, and donor body mass index (BMI). A p-value of <0.05 was considered statistically significant. All of the statistical analyses were performed using IBM SPSS version 24.0 (IBM Corp.).
Results
Baseline characteristics of spousal donor kidney transplantation recipients
The mean age was younger in H2W recipients than in W2H recipients in both groups. There were no differences in donor age, cause of ESKD, or pre-KT renal replacement therapy modalities between W2H recipients and H2W recipients within each group. The HLA mismatch number did not differ significantly between W2H recipients and H2W recipients within each group. The positivity and MFI level of HLA-DSA did not differ significantly between W2H recipients and H2W recipients within each group, but B-FCXM positivity was higher in H2W recipients than in W2H recipients in the high-risk group. There was no difference in the use of induction treatment between W2H recipients and H2W recipients. The proportion of ABO-incompatible KT was similar between W2H recipients and H2W recipients within each group. The details of the baseline characteristics are presented in Table 1.
Baseline characteristics of spousal donor KT recipients
Comparison of allograft rejection and development of de novo donor-specific anti-human leukocyte antigen antibody
In the standard-risk group, the incidences of total BPAR, ABMR, and TCMR did not differ significantly within 1 year after KT (8.0% vs. 5.7%, p = 0.10) (Fig. 2A) between W2H recipients and H2W recipients. However, the incidence of BPAR within 1 year after KT was higher in H2W recipients than it was in W2H recipients in the high-risk group (3.1% vs. 20.4%, p = 0.03), and all of BPAR was acute ABMR (Fig. 2B). Further, we compared BPAR-free survival rate by SDKT type and immunological risk. H2W recipients with high immunological risk showed the worst survival rate until 1 year from KT (Fig. 2D). To define the risk factor for BPAR in the first year after KT, we conducted Cox proportional regression analyses, while correlating the type of SDKT with immunological risk, recipient age, and cause of ESKD. H2W recipients with high immunological risk were associated with BPAR (hazard ratio [HR], 2.4; p = 0.03) (Table 2). In terms of the development of de novo DSA, it was highest in H2W recipients with high immunological risk, but it did not reach statistical significance (Fig. 2C).
Comparisons of BPAR incidence, BPAR-free survival rate, and development of de novo DSA of SDKT according to the type of SDKT and immunological risk.
(A) Graph depicting the incidence of BPAR in the standard-risk group. (B) Graph depicting the incidence of BPAR in the high-risk group. (C) Graph depicting the development of de novo DSA in all included patients. (D) Diagram depicting 3-year BPAR-fee survival of enrolled patients according to the type of SDKT along with immunological risks. H2W recipients showed a higher incidence of BPAR than W2H recipients in the high-risk group. High-risk H2W recipients showed the worst BPAR-free survival probability. *p < 0.05 by chi-square test or log-rank test.
ABMR, antibody-mediated rejection; BPAR, biopsy-proven allograft rejection; DSA, donor-specific antibody; H2W, husband-to-wife recipients; SDKT, spousal donor kidney transplantation; TCMR, T-cell mediated rejection; W2H, wife-to-husband recipients.
Predictors for acute rejection within 1 year after kidney transplantation
Comparison of infectious complications
We observed no difference in the frequency of infectious complications that required hospitalization between W2H recipients and H2W recipients in each group (Table 3). Thirty-seven out of 291 W2H recipients and seven out of 75 H2W recipients in the standard-risk group suffered from infections including complicated urinary tract infection (UTI), BK virus nephropathy, and cytomegalovirus disease. Seven out of 34 W2H recipients and 11 out of 55 H2W recipients in the high-risk group suffered from an infection other than lower UTI.
Incidence of infectious complication requiring hospitalization according to type of SDKT and immunological risk
Comparison of allograft function and long-term clinical outcomes
In the standard-risk group, 1-year eGFR was better in H2W recipients than it was in W2H recipients (Fig. 3A). However, there was no significant difference in long-term allograft function between W2H recipients and H2W recipients in each group (Fig. 3A, B). Long-term patient and allograft survival until 10 years posttransplant did not differ significantly in all included recipients (p = 0.90) (Fig. 3C, D).
Comparisons of allograft function and allograft and patient survival rate of SDKT according to the type of SDKT and immunological risk.
(A) Diagram depicting estimated glomerular filtration rate (eGFR) between wife-to-husband (W2H) recipients and husband-to-wife (H2W) recipients in the standard-risk group. (B) Diagram depicting eGFR between W2H recipients and H2W recipients in the high-risk group. Early graft function was better in H2W recipients than in W2H recipients. However, later graft function did not show a significant difference. (C) Diagram depicting 10-year patient and allograft survival rates of enrolled patients. (D) Diagram depicting 10-year patient survival rates of enrolled patients. There were no significant differences in patient and allograft survival rates. *p < 0.05 and **p < 0.01 by Student t test or according to the log-rank test.
SDKT, spousal donor kidney transplantation.
Discussion
Alongside substantial social and cultural changes, SDKT is becoming a major source of LDKT. However, donor-recipient sex mismatch is a basic consideration in SDKT, and the effect of sex on transplant outcome can be a concern in conducting SDKT. However, there have only been sporadic studies regarding the impact of sex on transplant outcomes, and many of these have shown contradictory results. In the current study, we explored the impact of sex on clinical outcomes of SDKT according to immunologic risk at baseline, and we found that the risk for BPAR could be increased, particularly in patients with high immunologic risk, but that it did not affect the long-term allograft outcomes.
First, we analyzed the effect of sex on allograft outcomes along with immunological risk in SDKT. That is because female recipients tend to develop greater immunologic responses [9] and are likely to be exposed to HLA during pregnancy [28]. Enhanced immune reactions can lead to more frequent allograft rejection episodes in female recipients [13]. Accordingly, we divided SDKT recipients by immunological risk allocated by PRA ≥50% or not, along with donor-recipient sex. We then compared the allograft outcomes between W2H recipients and H2W recipients in each immunological risk group. As a result, the incidence of BPAR within the first year was found to be similar between W2H recipients and H2W recipients with standard immunological risk (8.0% vs. 5.7%, p = 0.10). On the other hand, H2W recipients with high immunological risk showed a higher rate of BPAR than W2H recipients in the same group (3.1% vs. 20.4%, p = 0.03), all of which were acute ABMR. H2W recipients with high immunological risk was a risk factor of BPAR within 1 year after KT (HR, 2.4; p = 0.03). However, in terms of late allograft rejection including chronic ABMR, there was no significant difference between H2W recipients and W2H recipients within each group (p = 0.53 for the standard-risk group and p = 0.24 for the high-risk group; data not shown).
Highly sensitized female recipients showed a higher incidence of acute rejection in this study, and a possible explanation for this could be the alloimmunization by HLA-specific memory B cell [14,29-31]. Quiescent memory B cell circulates in peripheral blood and rapidly responds to reencountered same HLA [31]. Recently, the presence of donor-reactive memory B cell has been shown to have negative effects on allograft outcomes [29]. Female recipients also tend to generate a robust immune response compared to male recipients [9], and they could have been sensitized by pregnancy before KT. In addition, sex-determined minor histocompatibility antigen (H-Y antigen) could also lead to a higher risk of loss of graft function [32]. As described above, alloimmunization and memory B cell may influence the occurrence of rejection. The assessment and validation of memory B cells in SDKT recipients should be further evaluated in the context of pretransplant immunological risk stratification.
As has been shown in previous reports [33,34], H2W recipients in both groups, who underwent male-to-female KT, showed better allograft function according to eGFR comparison at the time of discharge after transplantation than W2H recipients. In terms of physiological aspects, male donors for H2W recipients had higher BMI than female donors for W2H recipients. The sex difference influences kidney graft outcome through different metabolic demands and different body sizes [35]. Physical differences such as a female’s smaller body surface area and smaller mass of nephrons, could affect graft outcomes [36]. Moreover, H2W recipients had lower BMI than W2H recipients. It led to a lower recipient/donor BMI ratio for H2W recipients than W2H recipients, regardless of the immunological risks. Therefore, this physical difference could be a cause of an allograft function difference at the time of discharge. Although this allograft function difference was found to be maintained for 1 year in the standard-risk group, among the high-risk group, allograft functions in the first year became similar between W2H recipients and H2W recipients. In the high immunological risk group, there was a donor BMI disparity (Supplementary Table 1, available online), but this advantage was believed to be offset by a higher incidence of BPAR in H2W recipients than in W2H recipients. By contrast, 3, 5, and 10 years after transplantation, allograft functions compared by eGFR were found to be similar between W2H recipients and H2W recipients in each group.
Among all included recipients, long-term patient and graft survival rate showed similar results. The acceptable long-term graft survival rates found in all included recipients indicated that the spouse can be considered an appropriate donor source, despite the higher incidence of acute rejection in H2W recipients with high immunological risk, compared to W2H recipients. Donor BMI was associated with long-term patient and graft survival rate (HR, 1.1; p = 0.02) (Supplementary Table 2, available online), while the type of SDKT with immunological risk was not related to long-term patient and graft survival. The appropriate treatment for BPAR may also have favorably affected graft survival. Moreover, the incidence of serious infectious complications requiring hospitalization showed no significant difference between H2W recipients and W2H recipients in each group.
This study has some limitations that are important to note. Although pretransplant evaluations for alloreactive memory B cell are expected to help determine immunological risk [29,31], we were not able to perform an HLA-specific memory B cell assay. Further, sensitization among female recipients is influenced by pregnancy history; however, the number of patients with detailed pregnancy history in this study was only 43 and was not available for analysis. Unfortunately, the current study did not analyze the correlations between allograft outcomes and memory B cell or pregnancy history. Graft outcomes related to gravidity or alloreactive memory B cell should be further evaluated in future research.
In conclusion, we revealed the risk of acute rejection in H2W recipients with high immunological risk compared to W2H recipients with similar immunological risk. Although a pretransplantation evaluation did not show any difference in immunological risk, the incidence of BPAR was higher in sensitized H2W recipients. Although the long-term graft and patient survival showed no difference, acute ABMR is still a significant complication after KT [37]. Desensitized recipients have a higher risk of opportunistic infection compared to compatible KT recipients. The risk of infection is proportional to the intensity of desensitization [38,39]. Also, highly sensitized recipients are at risk of acute rejection, especially acute ABMR [15,40]. Identification and treatment of ABMR in highly sensitized H2W recipients might be important for improving allograft survival. Along with the traditional immunological risk, we found that H2W recipients were related to the incidence of acute ABMR. From our experience, we suggest that individualized desensitization treatment and precise surveillance of rejection after KT are required for highly sensitized H2W recipients of SDKT.
Supplementary Materials
Supplementary data are available at Kidney Research and Clinical Practice online (https://doi.org/10.23876/j.krcp.24.128).
Notes
Conflicts of interest
All authors have no conflicts of interest to declare.
Funding
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI22C1529), and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00209312), and also supported by the Alumni of The Catholic University of Korea Division of Nephrology grant (2023RADN020901)
Data sharing statement
The data presented in this study are available from the corresponding author upon reasonable request.
Authors’ contributions
Conceptualization, Formal analysis: SC, BHC
Data curation: SC, HL, CWY
Funding acquisition: SC, HL, BHC
Investigation: SC, SHE, JWM
Methodology: SC, HEY
Writing–original draft: SC, HL, BHC
Writing–review & editing: All authors
All authors read and approved the final manuscript.