Sex and Gender in Science, Medicine, and Nephrology

Sex and gender in science and medicine have gained significant attention over the past decade. With the increasing focus on precision medicine, understanding the complex interactions between biology and the physical and social environment in the context of global health cannot be overstated. Understanding sex differences may help address disparities in outcomes, arising from the lack of recognition of these differences.

Sex and Gender: Nomenclature

Sex is a biological construct, while gender refers to psychological and social behavior and roles guiding interactions with communities and health care systems. The binary classification of sex as female or male has been challenged, and terms such as intersex, hermaphrodite, or nonbinary have been used.¹

Health is affected by the interaction of biological and environmental factors. Biological factors include genetics, epigenetics, sex chromosomes, and hormones, while environmental factors comprise geography; chemical exposure; pollution; and social environments, such as communities, health care systems, and cultural norms. It is within this context that gender is defined. These components determine not only disease expression but also health-seeking behavior, responsiveness of medication, and adherence to treatment strategies.

In science and engineering, multiple examples highlight the value of attention to sex differences, modifying the manufacturing of protective gear, and improving product engineering for equity and safety.²

Sex Differences in Disease Prevalence and Expression

Sex and gender affect disease prevalence, expression, diagnosis, treatment choices, health care system interactions, and outcomes.¹ For instance, autoimmune diseases are more prevalent in women, while neurodegenerative diseases are more common in men. Data reveal underdiagnosis, different risk factors, outcomes, and clinical presentations for many chronic conditions, including heart, lung, and CKDs.

Cardiovascular function differs between sexes, raising questions about the appropriateness of specific cutoffs for hypertension throughout the lifespan. Moreover, complications also differ: Women are prone to heart failure with preserved ejection fraction and atrial fibrillation, while men tend to develop heart failure with reduced ejection fraction.³ In acute coronary syndrome, failure to use sex-appropriate troponin levels can result in missed diagnosis, affecting mortality. Challenges for women undergoing coronary artery bypass graft placement include delays in diagnosis, referral bias, test inaccuracies, perception, non–guideline-based care, different anatomy and tools, and lower clinical trial participation.³

The assessment of eGFR using creatinine may be less accurate for women versus men when compared with cystatin C–based measurements. In the era of gender-affirming hormone therapy for transgender people, the accuracy of eGFR assessment using creatinine and assignment of sex for eGFR calculations add complexity. The effect of interpreting or misinterpreting common laboratory tests on CKD diagnosis and treatment decisions remains unclear.⁴

Sex differences in drug pharmacokinetics exist: Differences in the volume of distribution, metabolism, gastric emptying, gastric pH, and kidney clearance contribute to why women report more adverse drug reactions and related hospitalizations.⁵ Many drug doses are not weight based, further contributing to inappropriate dosing and higher side-effect profiles in women.

Women are less likely to receive angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or sodium-glucose cotransporter 2 inhibitors (SGLT2is) despite similar indications.⁵

Sex Differences in Prevalence and Outcomes of CKD

There are international sex differences in CKD prevalence and lower all-cause mortality in women at similar GFR values. In both lower and higher income countries, women have less access to kidney disease diagnosis and treatment, partly because of increases in costs of services, which increase from CKD screening to treatment for kidney failure to transplantation. Even in Sweden, which has a universal health care system, sex differences in CKD recognition, referral, and follow-up are lower in women than men.⁶

CKD progression has been demonstrated to be faster in men than women.⁶ Biological explanations include estrogen's protective effect on vasculature and kidney hemodynamics, as well as testosterone's adverse effect. Premenopausal women experience a slower decline in GFR compared with men and postmenopausal women, likely attributable to inter-related factors: lower hypertension incidence, less microvascular disease, and higher estrogen levels, but differences in adherence to medical therapies and health care system exposure may also play a role.

In transplantation, significant sex differences exist: Women are more likely to donate kidneys to men but less likely to receive living donations. They are also less likely to be listed for transplantation and often wait longer once listed. Women have shown better follow-up adherence and drug compliance.⁶

Biological Differences in Kidney Structure and Function

Men have larger kidneys than women, attributed to greater body surface area, glomerular mass, and volume, as well as other structural differences. Endothelin receptor density is higher in women, and there are sex differences in sodium reabsorption and SGLT2i expression (women greater than men).⁷

Sex differences in kidney transporters exist, with functional consequences likely based on the need for appropriate electrolyte and water balance during pregnancy. Different androgen and estrogen receptors exist in specific tubular and cellular locations.⁷ Men and women with diabetes show differences in the regulation of kidney hemodynamics, leading to hyperfiltration in women. In translational studies, differences in men and women with diabetes regarding energy metabolism are described: Women tend to favor pyruvate metabolism and generate less oxidative free radicals than men, potentially explaining part of the differential progression and responsiveness to injury.⁸

There are differences in angiotensinogen expression, renin, and angiotensin-converting enzyme activity; angiotensin II receptor regulation; and interactions with estrogen.⁷ Although it is beyond the scope of this review to detail these, their complexity and variability over the lifespan are noteworthy.

Pregnancy, preeclampsia, and the importance of fetal and maternal health are also beyond the scope of this paper. Note that preeclampsia is a unique contributor as a cause of CKD.

Clinical Care of Women with CKD

There is limited knowledge about attitudes and awareness regarding the clinical care of women with CKD. A survey of more than 240 healthcare professionals across four countries found that knowledge, ability, and willingness to discuss these topics varied depending on the healthcare professional's sex.

Underrepresentation of Women in Clinical Trials

Women represent only 35%–45% of participants in all clinical trials, although chronic conditions, such as cardiovascular disease, diabetes, and CKD, affect both sexes. This underrepresentation is evident in CKD trials involving nonsteroidal mineralocorticoid receptor antagonists, SGLT2is, and glucagon-like peptide-1 receptor agonists.¹⁰

There are many barriers to female trial participation, including difficulty in fulfilling contraception requirements, education and literacy issues, time pressures due to caregiving roles, burden of visits, and sociocultural issues such as fear and mistrust of the health care system. Other factors include the underrepresentation of women as principal investigators and lead authors in publications. While more women are entering nephrology academia and clinical settings, this may not be fully reflected yet.

Throughout the research spectrum, the representation of sexes is different: Male rodents are used more than female rodents; in phase 1 and 2 studies, men are enrolled more than women to assess benefits, doses, and titration schedules. In phase 3 studies, the enrollment of men exceeds that of women. Subsequently, postmarketing surveillance demonstrates women are more likely to report adverse events and stop medications over the long term.⁵ We speculate that this inattention to sex differences early in the research cycle may in part explain some of the adverse reactions and discontinuations.

Implications: Improved Understanding of and Attention to Sex and Gender in Medicine

Guidance to improve understanding of sex differences exists: Basic science, genetics, and translational work should consider the sex of the cells and animals and consciously seek differences in biological processes.² Studies should be designed with an initial consideration of whether the phenomenon or product under investigation would affect organisms with biological sex differences. If so, it is important to identify an adequate number of participants from the sexes for inclusion and analyze the data by sex. Any observed sex differences should be analyzed to determine the source of the differences: whether environmental, genetic, hormonal, anthropometric, or possibly due to experimenter–participant interactions. The onus is then to report the findings by sex and explain the underlying mechanism(s).² A priori attention to the possibility of sex differences allows appropriate collection of information and biological samples, to contextualize results.

There are biological differences between men and women in anatomy and function, mediated by sex chromosomes, hormones, and epigenetic phenomena. Thus, the pathophysiology and presentation of specific conditions may differ. These have led to different practices of detection, recognition, referral, monitoring, and prescribing for men and women. Evidence shows that men and women have different health-seeking behaviors and that perceptions and confidence of health care professionals of different sexes influence treatment decisions and interactions. The underrepresentation of women in clinical trials limits the evidence base for informed care. This complex interplay of biological and behavioral factors may help explain differential outcomes between men and women, although these differences are underappreciated.

We suggest that in this era of personalized and precision medicine, we should start with more systematic attention to sex and gender, to improve understanding and recognize differences between women and men, ultimately optimizing therapies for both. Changes in education, institutional and regulatory policies, study design, reporting, and clinical curiosity are all essential to improving outcomes for all.

Supplementary Material

cjasn-20-1283-s001.pdf ^{(1.3MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C167.

Funding

None.

Author Contributions

Conceptualization: Adeera Levin.

Data curation: Adeera Levin, Farah Wehbe.

Project administration: Adeera Levin.

Resources: Farah Wehbe.

Writing – original draft: Adeera Levin.

Writing – review & editing: Adeera Levin, Farah Wehbe.