State-of-the-art Meeting on Sex and Gender in Transplantation: The Female Perspective

BACKGROUND AND AIMS Sex- and gender-based inequities in organ transplantation represent a critically relevant, yet under-appreciated aspect that impacts on patient and graft outcomes. Biologic factors (sex), as well as psychological-, social-, and economic factors (gender) all contribute to these disparities. Although such disparities are observed consistently worldwide, access to care and differences in allograft and patient outcomes by sex and gender differ between countries, emphasizing the necessity to engage the global community. Moreover, as in many other professional areas, gender disparities exist among professionals in transplantation science and medicine. To address the need for global recognition of the interplay between sex and gender in transplantation and to define unmet needs, Anette Melk (Hannover Medical School), Bethany Foster (McGill University), Germaine Wong (University of Sydney), and Louise Lerminiaux (patient representative) initiated the international hybrid symposium “Sex and Gender in Transplantation: The Female Perspective,” which took place from October 5 to 7, 2022, in Hannover, Germany. The interdisciplinary symposium connected clinicians, researchers, and patients from around the globe. Instead of taking the traditional male perspective, efforts were made to ensure a female perspective and approach to both the content and organization of the symposium. The symposium had 3 aims. First, we aimed to identify areas pertaining to sex and gender where more research is needed, with an emphasis on creating evidence to inform guidelines and policies. Second, we integrated patients’ perspectives and experiences in the execution of patient-centered research. Last, the symposium focused on achieving equity in access to careers in transplantation, defining metrics of success and strategies to accelerate progress in this area. ABOUT THE MEETING The symposium was an interactive hybrid event (on site and virtual), enabling broad participation, with special efforts to invite (early-career) investigators from multiple continents and disciplines, ensuring multifaceted contributions and perspectives. Two hundred thirty-four participants from 40 countries registered; 78 individuals (20 countries) made active contributions with 67 individuals (14 countries) attending in person. Figure 1 provides further details on the meeting’s participants. Participation of a science journalist throughout the meeting, who also served as a facilitator of a panel discussion, was a novel and effective means to create an overall comfortable atmosphere, allowing any question to be asked—critical with such a diverse group of attendees—and ensuring that the discussion was accessible to all attendees.FIGURE 1.: Distribution of participants’ field of expertise and country of origin. A, Map of participants’ countries of origin. B, Clinicians, clinician-scientists, and scientists in addition to a science journalist and patient representatives actively participated in the meeting. Of those with a research background, two-thirds were early- or mid-career investigators. Patients and early level, mid-level, and senior investigators coming from low- or middle-income countries were granted travel grants enabling attendance in person. C, Participants’ field of expertise and particular topics discussed during the meeting. Color and font size were assigned randomly.The meeting included lectures (available at https://diversity-in-transplantation.org/symposium-2022/), interactive panel discussions, and oral and poster presentations. To ensure diverse representation and inclusion, the following novel measures were taken: (1) there were independent panel discussions for both the Eastern and Western hemispheres, enabling participants to join at a reasonable time of day; (2) active involvement of patients at all stages of the meeting from the planning phase through to the postmeeting discussion ensured that topics of importance to patients were highlighted; (3) early-career and established investigators were matched, creating mentor-mentee partnerships as a strategy to sustainably boost research in the field, in addition to providing individual career advice to early-career investigators; (4) practical sessions with guidance on physical exercise and relaxation techniques were implemented and addressed sex-/gender-specific requirements; and (5) real-time translators, available throughout the symposium, enabled speakers and participants to be fully engaged and interactive. KEY ISSUES AND FUTURE DIRECTIONS Sex and gender impact multiple aspects of transplantation in critical and relevant ways. The interacting influences of sex and gender are illustrated in Figure 2. The symposium covered each of the areas below in detail. Recommendations for future research, compiled by attendees, are highlighted in Table 1. Table 1. - Future research areas in transplantation medicine as outlined for each dimension of biology (sex), psychosocial and cultural (gender), and the interaction of both Cells/tissues/organs Organism/individual Population Basic/clinical research Clinical/observational/qualitative research Observational/qualitative research Sex as biologic factor Interaction/combined contribution of sex and gender Gender as psychosocial, cultural, economic factor Sex differences in cell repair and regeneration Identifying differences in graft and patient survival Understanding reasons for differences in donation Sex differences in inflammatory responses Impact of sex mismatch Identifying disparities in access to transplant, retransplant, and posttransplant care in different countries with regard to medical care and cultural aspects Characterization of sex-specific immune reactivity at different stages across the lifespan Identifying differences in all-cause- and specific-excess mortality between sexes Understanding physicians’ decisions regarding transplant eligibility/delisting and if this differs with regard to patients’ gender in different countries Addressing the interaction of sex and age in experimental models Understanding how sex modifies the impact of risk factors and the progression of comorbidities Understanding patients’ decisions regarding transplantation and whether this differs amongst genders Identifying sex-specific biomarkers regarding cardiovascular morbidity Immunosuppressive/medication adherence (behavioral modification) High-quality data to identify the proportion of transplant-eligible women and men on waitlists in different countries Understanding sex differences in pharmacokinetics and pharmacodynamics Identifying sex/gender differences in quality of life/life participation posttransplant Understanding recipients’ decisions on family planning Impact of pregnancy on access to transplantation and posttransplant outcomes Models of care for pregnancy planning FIGURE 2.: Interaction of sex and gender on transplantation. Biology (sex), psychosocial, and cultural (gender) factors interact to influence outcomes. Given the complex interaction of donor and recipient, in addition to the different dimensions of sex and gender, their impact on transplantation outcomes must be addressed using basic science, clinical, observational, and population studies. A deeper understanding of the root causes for existing disparities in transplantation must be addressed through quantitative and qualitative research.Donation and Access Women donate organs more often than men but are less likely to receive a transplant. This phenomenon is strongly related to societal/cultural norms that place women in caregiving or helping roles, both in their families and in the larger society. Women with certain medical conditions (eg, type 2 diabetes1 and obesity2), ethnicities (non-Hispanic White and Black women3), or advanced age are disadvantaged in access to transplantation.4 Although women are less likely to be waitlisted than men, older women show better transplantation outcomes than older men. This may be driven in part by waitlist selection bias, with healthier women being more likely to be listed.4 Further studies must address sex and gender differences in the decision-making processes of donors, patients, and physicians involving organ donation and wait-listing, with careful consideration for cultural and religious factors. Graft and Patient Survival Graft survival differs by sex. In kidney5 and liver6 transplantation, among recipients of male donors, young women showed a higher risk of graft failure than young men.7 In heart transplantation, female recipients of all ages had higher graft failure risks than men in the setting of a male donor.8 Female recipients demonstrate greater variability in tacrolimus trough levels than men,9 raising the possibility that drug metabolism may vary through the menstrual cycle and thus impact the adequacy of controlling alloreactivity. This highlights an urgent need for pharmacokinetic and pharmacodynamic studies to understand sex differences that may affect graft outcomes. In pediatric kidney transplant recipients when compared with boys, girls demonstrate a higher burden of cardiovascular abnormalities. Postpubertal girls develop higher blood pressure when exposed to cyclosporine A trough levels ≥120 µg/L,10 girls with obesity demonstrate higher prevalence of left ventricular hypertrophy11 (an association also seen in healthy girls12), and girls are more susceptible to faster progression of arterial stiffness.13 These findings suggest that girls with end-stage kidney disease lose more potential life-years than boys. In adult kidney transplant recipients, men show higher absolute cardiovascular death rates than women, but the excess risk of cardiovascular mortality (risk above that in the age- and sex-matched general population) is substantially higher in women than in men.14 Women experience an increase in left ventricular mass index (LVMI) by 1-y after transplantation, whereas men show a decreasing LVMI.15 Despite growing evidence that women are more susceptible to cardiovascular damage than men, there are no sex-specific treatment or prevention strategies for transplant recipients. Differences Arising From Biologic Factors Biological sex differences are determined by gonadal hormones and sex chromosomes. In addition, over 90% of genes show sex-specific expression, illustrating that sex differences are present at molecular and organismal levels.16 Sex differences in lifespan are well recognized, indicating the role of sex in the accumulation of senescent cells resulting in sex-specific aging rates. Sex-specific gene expression and sex hormones influence immune reactivity—with relevance to graft outcomes. Estrogens tend to enhance the inflammatory immune response, possibly resulting in higher rejection rates; interestingly, women of postmenopausal age7,16,17 have lower graft failure rates than men. Despite a lower rate of primary graft dysfunction (possibly related to enhanced repair mechanisms), a sustained proinflammatory response is seen in female lung transplant recipients.18 Preclinical mouse models suggest that the development of ABO blood group natural antibodies is significantly affected by sex and age, suggesting a potential role for sex hormones.19,20 Mouse models allow the contribution of genes encoded in the sex chromosomes to be dissected from the impact of sex hormones and their receptors.21 Furthermore, the sensitizing effects of pregnancy on humoral immunity contrasted with T cell tolerance to the allogeneic fetus was discussed, with implications for multiparous women who face reduced access to transplantation.22 This discussion highlighted that sex differences in immune reactivity and cell regeneration will need to be delineated across the lifespan. More studies are needed to better understand sex differences and their interaction with age regarding immune reactivity and regenerative potential. Patient-oriented Research and Clinical Care Mental health, which may affect women and girls differently from men and boys, is often overlooked in transplant care. Matters such as “how long do I get to live,” survival guilt, or feeling unworthy of receiving such a precious gift are considerable mental burdens; relationship dynamics that result in higher divorce rates, financial difficulties, body image, and myths add extra strain. Sexual health and the impacts of sexually-transmitted infections such as human papilloma virus must also be considered in long-term care. Female recipients are particularly burdened when facing reproductive decisions.23 Discussions focused on the need for family planning with a shift away from counseling against pregnancy toward supporting a well-informed choice. Access to reproductive care is critical.24,25 Awareness among transplant professionals toward holistic long-term care is necessary, as well as more targeted research in areas of most importance to women transplant recipients. Intersectionality Intersectionality refers to a way in which a person’s identity can expose them to vulnerability and overlapping forms of discrimination and marginalization. As an example, women with kidney failure from lower socioeconomic backgrounds and from some ethnic backgrounds are less likely to be referred for transplantation, and if listed, they are less likely to receive a transplant. Intersectionality has recently been recognized as relevant in transplantation. An intersectionality framework offers a comprehensive approach to better understand complex interactions amongst a variety of disadvantaging mechanisms.26 This framework untangles different layers of inequity that are associated with one’s identity, including but not limited to sex, age, gender, religion, ethnicity, disability, sexual orientation, class, and socioeconomic status, that result in a cumulative adverse impact. This approach goes beyond the mere description of inequities in transplantation, also helping to uncover root causes. Equity and Diversity in Professional Development Professionals in the field of medicine are becoming more diverse. However, despite these encouraging developments, there are still major challenges. More than a third of respondents to a survey initiated by the International Liver Transplantation Society state that they have experienced discrimination, with gender discrimination being the most frequent.27 Almost half of women professionals report not having received mentoring during their careers.27 Despite equal gender distribution of medical school graduates, the “leaky pipeline” (ie, women are less likely to advance to higher positions) exists worldwide. Disparities are even more pronounced in low- and middle-income countries. It is therefore one of the mandates of international organizations such as Women in Transplantation to work to reduce inequities globally (https://www.tts-wit.org/).28 Ethical Considerations Traditional ethical principles like autonomy, justice, beneficence, and nonmaleficence are classically referenced in organ donation policies and transplantation ethics. However, there is room for other approaches like feminist bioethics,29 which addresses ethical issues impacting marginalized groups, including but not limited to women. As an extension to “mainstream” transplantation ethics, a feminist bioethics viewpoint offers novel solutions to neglected or persisting ethical issues through a deeper understanding of the relationships between donors and recipients. CONCLUSION AND OUTLOOK This meeting highlighted gaps in existing data and outlined future research directions. Existing research lacks consistency and transparency in methodology and reporting, and high-quality data are often missing. Additional investigation, including patient-centered research, is needed to advocate for policy changes to ensure equitable access to transplantation and to improve outcomes for women and men around the world. Aspects regarding patients’ mental health, intersectionality, and pretransplantation and posttransplantation patient education should be incorporated into clinical training. Concerted efforts are needed to establish a collaborative research consortium with the goal of collecting, collating, and sharing high-quality global data. Prompt knowledge transfer must be assured for education and training. A rapid pipeline implementing new findings into patient care is indispensable.

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