Gender issues in solid organ donation and transplantation - Annals of ...

© Ann Transplant, 2013; 18: 508-514 DOI: 10.12659/AOT.889323

Received: 2013.04.24 Accepted: 2013.07.19 Published: 2013.09.25

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Review Paper

Gender issues in solid organ donation and transplantation Fangmin Ge1,2,3 , Tao Huang4 , Shunzong Yuan4, Yeqing Zhou5, Weihua Gong3,4 Hospital Administration Office, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, P.R. China 2 Department of Public Health, Charité University Medicine, Campus Virchow, Berlin, Germany 3 Department of Surgery, Transplant International Research Centre (TIRC), Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, P.R. China 4 Departments of Medicine, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 5 Department of Oral Medicine, Shaoxing People’s Hospital, Shaoxing City, Zhejiang Province, P.R. China 1

Source of support: The work was supported by the Department of Education of Zhejiang Province (Grant No. Y201226017), the National Natural Science Foundation of China (No. 81270323), the Qianjiang Talents Project of Zhejiang Province (Grant No.2012R10022), and Zhejiang Provincial Outstanding Youth Foundation (Grant No. LR13H020001).

Summary

Key words:

Gender as a critical, intrinsic, non-immunologic factor plays a pivotal role in the field of transplantation. The gender of donors and recipients is involved in the entire process, including organ donation and transplant surgery. This review article aims to summarize the literature related to the role of gender in solid organ donation and transplantation and to unveil the underlying mechanism by which gender mismatch between donor and recipient impacts transplant rejection. A systematic search was conducted through PubMed by using the following key words: “gender”, or “sex”, and “transplant”, “organ donation” for published articles. The prima facie evidence demonstrated that females are more likely to donate their organs and are less willing than males to accept transplant surgery; however, their donated liver organs will have a higher risk of graft failure compared with males. With respect to kidney, heart, and lung transplantations, the role of gender remains controversial. Results of animal studies support the negative impact of gender mismatch on allograft function. In conclusion, our present study advances the knowledge of gender issues in the field of solid organ donation and transplantation. In general, gender mismatch is not advantageous to transplant outcome, as evidenced by many aspects of biological investigations on immunogenicity of H-Y antigen to females. Therefore, gender issues should be highlighted and an a priori intervention is needed to improve graft survival in clinical practice. gender • organ donation • transplantation • transplant outcome • graft function

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Word count: 2288 Tables: 1 Figures: — References: 49 Author’s address: Weihua Gong, Department of Surgery, Transplant International Research Centre (TIRC), Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, P.R. China, e-mail: [email protected]

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Bacgkround With the rapid advance of surgical techniques and immunosuppressants, transplantation has become a routine treatment strategy for patients with end-stage disease to improve survival and quality of life. However, a growing gap between organ supply and demand has been a critical limiting factor for transplantation development, resulting in an expansion of donor procurement criteria and utilization of marginal donor organ pool such as the gender mismatched donor [1–3]. Accumulating evidence demonstrates that graft function can be affected by both immunologic parameters and intrinsic non-immunologic factors (including mismatch of race [4], size [5], age [6], weight [7], and even gender) [6]. Indeed, empirical organ donation is always determined by the specific situation. For instance, organs from most deceased donors are frequently procured from younger males who died due to trauma or accidents [8], whereas female donors more often died from cerebrovascular causes (such as stroke) in an older population. To some extent, utilization of gender-mismatched donors is forced in practice. Indeed, willingness of organ donation and acceptance for organ transplantation is different between female and males. Females have a greater tendency to donate their organs but are unwilling to receive organ transplantation [9,10]. Although the role of gender in heart [11], lung [12], kidney [13], and bone marrow transplantations [14] has been extensively studied, the, impact of gender-mismatch on transplant outcome remains controversial. Herein, we depict and analyze the effect of gender of donor and/or recipient on graft based on published data to better understand transplant immunobiology, provide better healthcare planning for transplant recipients, and improve transplant outcome.

Gender Disparity of Solid Organ Donation In gratuitous living donation, two-thirds of all organs were donated by women [15]. Furthermore, the gender imbalance is rising steadily as living organ donation has been continuously expanding. Women ages 19–60 are generally more altruistic than men. In 1988, the ratio of female to male donors was 1.2 in the United States and then reached 1.4 in 1998 [9]. A study from China reported that women were more willing to be living liver donors [16,17]. In 2007, a survey of 3 universities in Changsha, Hunan province, China,

Ge F. et l. – Gender in donation and transplantation

demonstrated that the proportion of female students willing to donate was nearly 5%, which was higher than that of male students. On the recipient’s side, female patients have previously been found to be less likely to accept either a living or deceased kidney transplant than are men [18]. There were 16% fewer females than males on waiting lists after diagnosis with end-stage renal disease. The rate of willingness to be placed on a waiting list or to be placed subsequently on a waiting list was 10% lower in females compared to males. In conclusion, women are less willing to accept a kidney transplant but are more willing to donate organs [10]. Multiple factors were assumed to account for these evident differences. Men have a higher incidence of end-stage diseases in need of a transplant and are more inclined to hypertension or ischemic heart disease, leading to their unsuitability as donors. The rate of progression of many renal diseases is faster in men than women and men show a 2-fold higher standardized mortality rate [10]. In addition, women were considered to have less knowledge about transplantation diagnosis and therapy and are less likely to receive aggressive treatment. The fact that women are more willing to donate a kidney excludes the reason of fear of surgery. It is necessary to determine whether a disparity of knowledge between men and women exists. Indeed, women and men have different social, economic, and cultural roles [15]. Psychological research showed that, in general, women have more altruism and sympathy than men [9]. Women tend to be caregivers due their own sense of responsibility. Because of the psychological factors described above, women are much more likely to be living organ donors than men. In fact, this altruism of women also has contributed to living liver transplantation and bone marrow transplantation [9,10]. Due to the traditional role of women in the family, women are obligated to take care of sick family members [19]. The nature of maternity gives women a duty to volunteer for donation to save their spouses, children, and other family members. Sisters, mothers, and wives more frequently donate their living organs to brothers, fathers, and husbands, respectively [9]. A report from the United Network for Organ Sharing (UNOS) stated that wife-to-husband transplants accounted for 73% of 360 spousal pairs of living organ donation [20]. Economic factors should also be taken into account. In fact, prior to organ donation, expense reimbursement and lost income can influence the decision-making. Income differences

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by gender suggest that the financial impact of organ donation from lost wages may be greater in donation by men/fathers [21]. Although improved reimbursement is neutral (not a genderspecific approach), this measure will have different effects on men and women [19]. With regard to gender selection for waiting patients in practice, its existence has hampered females from being added to waiting lists. Prior to transplantation, health professionals need to assess the condition of patients, such as steroid-induced osteoporosis, which is more common in females. Furthermore, gender bias arises in the family, friendships, and economic or other situations [10]. Nevertheless, the registry data of the International Society for Heart and Lung Transplantation showed different findings, in which the frequency of female cardiac transplant recipients was 20–23% between 1992 and 2009. Women are also less likely to accept cardiac transplantation [2]. The United Network for Organ Sharing data from 1994 through 2005 shows that, among 62 643 deceased donors, more males donated their organs [22].

Role of Gender in Human Transplantation In general, the aforementioned worldwide studies show that women are more likely to donate their organs. Therefore, it is of great interest to inquire whether donated organs from women or men will be more advantageous to the transplant hosts. Liver transplantation In deceased liver transplantation, it is well accepted that a female-to-male liver transplant has high risk for graft failure, as evidenced by poor survival rate and low transplant success [3,23–25]. However, a single-center database of gender-incompatible orthotopic liver transplantation was examined for overall survival of 1355 recipients, in which no any statistical difference of patient survival was observed for gender-mismatching [26]. It was also reported that gender is not associated with postoperative complications [27] or post-transplant survival for those recipients with fulminant hepatic failure [28]. Kidney transplantation In kidney transplantation, the gender of both donor and recipient can distinctly affect graft

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function and allograft survival over time. The adverse role of the female donor is controversial and needs to be determined, although female donor kidneys have a worse 5-year survival [6,29]. To achieve better transplant outcome, it was suggested to use the combination of male donor and female recipient, particularly for longterm survival [6,30]. Compared to females, male grafts are less susceptible to nephrotoxic effects of some immunosuppressants (e.g., cyclosporine A) [29]. However, no study has yet demonstrated the extent to which this exerts the effect of gender-mismatch on graft function. Opelz et al reported that, compared to males, incidence of graft loss for female donor kidneys was significantly higher after 1 and 10 years [31]. Opposing data showed that female recipients of male kidneys may have a greater risk of early graft loss compared to all other gender combinations [32]. Apart from these 2 different findings, neutral observations have found that a female kidney can function as well as a male donor kidney without any detrimental effects in living donor transplantation (Table 1) [33,34]. Heart transplantation Overall, gender-mismatching of organs is inclined to negatively impact heart transplant outcome and increase early mortality. A research group from Heidelberg analyzed 25 432 cardiac transplants in which female-to-male graft survival was inferior, but no statistical significance was observed [13]. Intriguingly, a retrospective analysis of 1000 cardiac transplant cases demonstrated that the combination of male-to-female favored short-term (1-year) graft outcome (73.7% vs. 90.9%). Conversely, with respect to long-term (10-year) follow-up, female donors have better survival, especially when recipients are female (90% vs. 72%) [2]. Although evidence of the effect of receiving an organ from a female donor is not entirely consistent, a multi-institutional prospective data set (from 1999 to 2007) collected by the United Network for Organ Sharing showed a significant improvement of short- and long-term graft survival by using same-sex pairings and there was no graft survival advantage of a female-female pairing [11]. Lung transplantation Because fewer patients are receiving this procedure, data are scarce. Male donor organs were found to be superior at 15- and 20-year followup [35]. Consistent data displayed no obvious

Ann Transplant, 2013; 18: 508-514


Table 1. The role of gender-mismatching on different transplant models. Likely to reject

Human & animal

Transplant model

Publication year

Reference

Gender mismatch

Human

Cardiac transplantation

2012

[2]

Female recipient

Human

Cardiac transplantation

2012

[4]

Female donor

Human

Renal transplantation

2008

[31]

Liver transplantation

2007

[25]

2004

[49]

Female-to-male

Rat

Small-for-size liver transplantation

2005

[5]

Human

Deceased liver transplantation

2012

[3]

2002

[24]

1996

[23]


2011

[6]

Female-to-female

Rat

Kidney transplantation

2008

[42]

Male-to-female

Human


2011

[32]

Mice

Skin homograft

1955

[36]

Human


2011

[33]

2004

[12,34]

Lung transplantation

2011

[35]

Renal transplantation in ovariectomized females

1999

[46]

No effect

Testosterone treated recipient

Rat

influence of sex pairing of donor and recipient on early transplant outcome after lung transplant surgery [12,35].

Role of Gender in Animal Transplantation As early as 1955, an interesting observation was made that isogeneic skin engrafted from a male onto a female had a poorer survival [36], implying that gender mismatch might affect graft acceptance. In renal transplantation, there is a mismatch between reduced female nephron mass and increased functional demand of male recipient, causing poor graft function [37]. Similarly, in a liver transplant model, the cumulative survival rate of the female-to-male group was significantly lower, irrespective of graft size and incidence of spontaneous death. Postoperative complications of female-to-male transplants, such as confluent hepatic necrosis or biliary obstruction, were relatively higher than in the male-to-male group [5]. Therefore, males are routinely used for most transplant models, acting as donor and recipients [38–40]. Indeed, owing to an antagonistic effect of the female sex hormone estradiol on the

immunosuppressive activity of cyclosporine [41], gender difference between donor and recipient can result in altered recipient response to cyclosporine A (CsA) immunosuppression in a rat kidney transplant model, indicating that a higher dose of CsA is required to prevent early graft loss in females [42].

Biological Basis for the Effect of Gender Mismatch on Transplant Rejection Graft immunological destruction mainly results from recognition by the recipient’s lymphocytes of major and minor histocompatibility (H) antigens, which are expressed by cells of the transplanted organ [43]. An early report described that a male isogeneic skin graft could be chronically rejected by genotypically identical female mice, accounting for the male-specific transplantation antigen, H-Y. Males can express the H-Y antigen immunogenic to females. However, other transplant models, including male-to-male, female-to-male, and female-to-female grafts, can successfully survive without rejection [36]. Scott et al., in 1995, were the first to explain the influence of gender in transplantation [44]. The H-Y

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epitopes deriving from intracellular proteins can be detected by T cells and present on the cell surface with major histocompatibility complex (MHC) molecules. In mice, the Hya spermatogenesis gene, is located on the short arm of the Y chromosome and can control H-Y expression. Smcy is another important gene in the same region; it encodes an H-YKk epitope, an octamer peptide, which is the counterpart of the human HLA B7 major histocompatibility class I molecule [43,44]. This MHC class II-restricted H-Y epitope, particularly Y gene-encoded peptide VIKVNDTVQI presented by HLA-DRbeta3*0301, can be recognized by CD4+ T-helper and then these T cells facilitate the process of maturation of dendritic cells, leading to an expansion of MHC class I-restricted cytotoxic CD8+ T lymphocytes [45]. Nevertheless, the role of H-Y epitope as a minor histocompatibility antigen is still disputed [31]. Apart from genetic disparity between males and females, the endocrine system of the transplant host also contributes to the effect of gender mismatch on transplant outcome. The kidney is per se characterized by its hemodynamics and immune responses between females and males [46]. An interesting study was performed, in which female or male F344 kidney grafts were transplanted into ovariectomized female Lewis rats. The recipients received treatment with estradiol, testosterone, or vehicle to address the beneficial effect of estradiol on the rejection progression. The findings revealed that use of testosterone could increase urinary protein excretion, interstitial fibrosis, severe vascular lesions, and extended glomerular sclerosis, regardless of donor gender. Conversely, estradiol treatment can improve graft function, preserve graft architecture, and diminish cellular infiltration, including mononuclear cell infiltration [46]. The protective effect of high estradiol level condition in the host was observed irrespective of donor gender [46]. Indeed, some immunosuppressants such as Sirolimus are capable of increasing FSH and LH and decreasing testosterone levels in adult male patients [47]. Therefore, postoperative immunosuppressants might act as a confounder factor affecting accurate evaluation of the impact of gender-mismatch on graft survival in the aforementioned transplant studies. In addition, anatomic studies have shown a larger total kidney weight in males, but there is no significant difference when a correction is made

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for body surface are [48]. Androgen and estrogen complexes influence the function of many cell types, which is probably responsible for the immunologic differences between men and women and contributes to worse renal graft survival using female donor kidneys [30,32]. Based on animal research data, gender can also affect various metabolic processes and responses of different organs. Ischemia is one of key steps in transplantation, in which female livers displayed significant accumulation of tissue lactate and H+, leading to a greater degree of intracellular acidosis and tissue injury and negatively affecting transplant outcome [25,49].

Conclusions Taken together, the information presented in this article suggests that gender mismatch does not provide any obvious advantages to transplant outcome. The gender issue should be highlighted not only in organ donation, but also in transplant pairing. Suitable intervention should be taken to alter the fact that women are likely to donate organs but are unwilling to accept transplant therapy. Indeed, gender-mismatch might cause a high risk of overall poorer graft survival. Anticipatory care planning is suggested to identify biomarkers and to monitor graft function and pre-treatment [42]. Declaration We declare that there is no conflict of interest.

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