Keywords: AKI, CKD, dialysis, ESKD, gender difference, GN
Abstract
Key Points
Women are under-represented in high-impact nephrology trials.
Trends remain consistent over the past 20 years and on the basis of target condition.
Addressing the imbalanced enrollment of women in trials could improve disparities in care and outcomes of kidney disease.
Background
Gender disparities in the incidence and complications of kidney diseases are well described. However, analysis to elucidate gender disparities in enrollment in nephrology randomized clinical trials (RCTs) has not been performed.
Methods
We performed a systematic review and meta-analysis of high-impact nephrology RCTs published between 2000 and 2021. We included RCTs enrolling participants aged 18 years and older in the following categories: (1) CKD, (2) AKI, (3) GN, (4) maintenance dialysis, and (5) kidney transplantation. We summarized trial characteristics according to reporting and enrollment of participants, enrollment site, publication year, trial category, and intervention type. Outcomes of interest include the proportion of enrolled male and female participants overall and according to trial category. In addition, we compared enrollment trends in the United States and globally to estimates of kidney disease prevalence.
Results
Most qualifying trials (373/380, 98%) reported the distribution of male and female participants. Enrollment was imbalanced overall with male participants accounting for 62% (n=215,850) of the enrolled participants and female participants for just 38% (n=133,082). Male participants formed most of trial cohorts in AKI (65%), CKD (62%), dialysis (55%), and transplant trials (65%), whereas women were majority enrollees in GN trials (61%). CKD trials under-represented women in both US trials and worldwide.
Conclusions
Women are under-represented in high-impact nephrology trials with the exception of GN trials. This imbalance may contribute to disparities in outcomes and gaps in the care of women with kidney disease.
Introduction
Adequate representation of women in clinical trials is crucial to understanding the relationship between disease progression and gender and to guide the development of new treatments. Nonetheless, there has been gross under-enrollment of women in general clinical trials for decades,1,2 perhaps stemming from a historical 1977 US Food and Drug Administration (FDA) recommendation for the exclusion of women of childbearing potential from all phase I and early phase II clinical research.3 Although the National Institutes of Health (NIH) Revitalization Act of 1993 attempted to rectify this information loss by mandating adequate inclusion of women in NIH-sponsored clinical trials, the proportion of women enrolled in clinical trials overall remains suboptimal.3–5
Representative enrollment of women in kidney disease trials may be particularly important for ensuring that standard therapies are effective for patients of all sexes and genders and in reducing disparities in care. It is important to consider this within the context of the gender disparities that exist in the global burden of CKD. For example, in a 2016 study, there was a markedly lower prevalence of CKD in men than women, with a male to female ratio of 0.81; however, the incidence of progression to kidney replacement therapy and mortality was lower.6 Several hypotheses have been proposed to explain sex-related differences in kidney disease morbidity and mortality, including hormonal influences on inflammatory and immunological responses, resistance to oxidative stress, and differences in fat storage.7,8 In particular, reproductive hormones play a key role in “sexual dimorphism” (gender and sex differences) in a variety of organs, including the kidneys, where they regulate various structural and functional aspects of kidney function and response to pharmacologic agents.7,9 However, to the best of our knowledge, the enrollment of women in nephrology trials in high-impact journals over the past 20 years has not been systematically evaluated. To understand sex-specific trends in nephrology trial enrollment, we performed a systematic review and meta-analysis of the reporting and enrollment of male and female participants in nephrology clinical trials.
Methods
Study Selection
We used a recently assembled database including high-impact nephrology trials. Study selection and search strategy for this dataset have been previously reported in detail.10 In brief, we identified randomized clinical trials (RCTs) published between 2000 and 2021 in ten high-impact journals, with the objective of identifying trials most likely to influence standards of care. We included RCTs enrolling participants aged 18 years and older with the following target population: (1) CKD, (2) AKI, (3) GN, (4) maintenance dialysis (hemodialysis and peritoneal dialysis), and (5) kidney transplantation. Trials were required to have hard clinical outcome measures, including mortality/survival, CKD progression, cardiovascular events, relapse and remission for GN trials, and renal recovery, response to therapy, and rejection for transplant trials. For AKI trials, additional outcomes such as intensive care unit, ventilation or dialysis free days, and intensive care unit discharge were allowed. Trials with <50 participants and those not meeting the adult age cutoff were excluded.
Search Strategy
A medical librarian (J. Nicholson) designed the literature search criterion in collaboration with the other authors. Search terms are listed in Supplementary Table 1. We searched PubMed/MEDLINE on January 27, 2022, with search terms designed to capture RCTs for the five kidney disease–related conditions described above. To focus on trials likely to influence standards of care, we limited our search to studies published in ten high-impact journals with high impact factors: American Journal of Kidney Diseases, American Journal of Transplantation, The British Medical Journal, CJASN, The Journal of American Medical Association, JASN, Kidney International, The Lancet, Nephrology Dialysis and Transplantation, and The New England Journal of Medicine, between January 1, 2000, and December 31, 2021.
Screening and Data Collection
Study screening was performed independently by at least two authors using data collection and processing software (Covidence, Veritas Health Innovation, Melbourne, Australia). The initial stage screened studies on the basis of titles and abstracts only. Studies were then identified for eligibility using full-text review of published articles. Disagreements were resolved by consensus and finalized by the first and last authors. Data were abstracted for key variables by two authors (Q.H. Soomro and A. McCarthy), including demographics, study design and target condition, sample size, study geographical region/location (defined below), and outcomes of interest. Data were abstracted from original papers, supplementary material, protocol papers, and the ClinicalTrials.gov website. As needed, authors were contacted for clarification regarding demographics, funding agency, and trial sites.
Interventions were categorized as drug, device, dialysis prescription, procedure or surgery, care delivery, exercise/mindfulness, or other. Funding sources were categorized as NIH, non-NIH government (i.e., non-US governmental funding or funding by the US FDA or Department of Veteran Affairs), industry, foundation, or other. Trial enrollment was also categorized according to region as the United States only, international (outside of the United States only), Europe, Asia, and global (both US and international enrollment). Publication year was categorized as 2000–2006, 2007–2011, 2012–2016, or 2017–2021. Trial quality was analyzed using the Cochrane tool.11
Statistical Analysis
Trial characteristics are summarized according to reporting and enrollment of participants, enrollment sites, publication year, target condition, and intervention type. Outcomes of interest included the proportion of enrolled male and female participants according to target condition categories. Additional analyses included proportions across enrollment site and publication date categories. Descriptive statistics are reported as n (%), mean±SD, or median (interquartile range).
Meta-analytic estimates of the proportion of participants were performed using the metaprop command in STATA.12 Pooled effect size estimates were calculated using random effects models with restricted maximum likelihood as the heterogeneity estimator. Confidence intervals for the binomial proportion were calculated using exact or Clopper–Pearson methods.12
The primary category of interest was the target medical condition (CKD, AKI, GN, maintenance dialysis, and kidney transplantation). We additionally performed a priori planned subgroup analyses according to publication date, enrollment site, and intervention using the random effects model to further explore heterogeneity. Finally, we compared global and US trial enrollment with estimates of global sex-specific population estimates using the United Nations world population estimates,13 US and global sex-specific CKD prevalence estimates using data from the Global Burden of Disease study6 and the National Health and Nutrition Examination Survery data,14 and ESKD and transplant data from the United States Renal Data System.15 Statistical analysis was performed using STATA version 17 (StataCorp, College Station, TX) and Microsoft excel. P < 0.05 was considered significant.
Results
Overall Results
As reported previously,10 the search strategy identified 4494 articles. Of these, 1200 were included in the full-text screening, and 380 randomized controlled trials met all inclusion criteria, 86 (23%) of included trials were CKD, 69 (18%) were AKI, 56 (15%) were ESKD on dialysis, etc. Despite publication in high-impact journals, there were numerous deficiencies in reporting quality (Supplementary Table 2). Most trials that reported the distribution of male and female participants was 373 of 380 (98%); one trial reported that most participants were men without providing an actual count. Enrollment was imbalanced overall with male participants accounting for 62% (n=215,850) of the enrolled participants and female participants for 38% (n=133,082), with a male to female ratio of 1.62. Randomization was stratified on the basis of sex in 23 of 373 trials (6.1%), and subgroup analysis on the basis of sex was performed in the primary outcome articles in 66 of 373 trials (17.6%).
Gender Distribution According to Target Condition and Additional Trial Characteristics
Male participants accounted for most of the enrolled participants (61%–65%) in all trial categories with the exception of GN trials where female participants accounted for 61% of enrollees (Figure 1 and Table 1). Overall disparities in enrollment were particularly notable for AKI (65% male participants), CKD (62% male participants), and transplant trials (65% male participants) with less dramatic disparities in dialysis trials (55% male participants). There were marked differences in enrollment according to the region of trial conduct. Male participants accounted for 63% of trial populations in global, 62% in international (outside of the United States only), and 63% in European trials, but for just 56% in US and Asian trials. Overall, enrollment trends did not differ according to funding type and were qualitatively unchanged between 2000 and 2021 with male participants accounting for >60% of all trial participants in each period. As shown in Table 2, there were not trends for differential enrollment according to enrollment period and target condition. Men accounted for 67% of AKI, 61% of CKD, 35% of GN, 52% of dialysis, and 64% of trial population in 2000–2006 and 63%, 63%, 38%, 53%, and 65% of participants in 2017–2021, respectively. Interestingly, trials with procedure/surgery as an intervention enrolled relatively higher proportions of male participants (72%) compared with other categories, whereas male (54%) and female (46%) enrollment were more similarly distributed in device trials.
Figure 1.
Distribution of male and female participants in kidney disease trials according to location, publication year, and trial category. International=non-US trial. HD, hemodialysis; PD, peritoneal dialysis.
Table 1.
Overall characteristics of trials
| Characteristic | Trials N (%)a Total=380 |
Male N (%) 374 (98%) No. Men Enrolled=215,850 |
Female N (%) 373 (98%) No. of Women Enrolled=133,082 |
|---|---|---|---|
| Enrollment site | |||
| Global | 82 (22) | 110,355 (63) | 63,383 (37) |
| United States only | 61 (16) | 24,266 (56) | 19,393 (44) |
| International (non-US) | 41 (11) | 25,325 (62) | 15,677 (38) |
| Europe | 154 (40) | 49,109 (63) | 29,324 (37) |
| Asia | 41 (11) | 6795 (56) | 5305 (44) |
| Trial category | |||
| AKI | 69 (18) | 60,029 (65) | 32,757 (35) |
| CKD | 86 (23) | 92,205 (62) | 55,865 (38) |
| GNb | 25 (6) | 1421 (39) | 2266 (61) |
| HD/PD | 56 (15) | 29,157 (55) | 24,024 (45) |
| Transplant | 144 (38) | 33,038 (65) | 18,170 (35) |
| Publication year | |||
| 2000–2006 | 94 (25) | 18,450 (61) | 11,947 (39) |
| 2007–2011 | 78 (20) | 30,171 (62) | 18,451 (38) |
| 2012–2016 | 95 (25) | 54,828 (63) | 32,438 (37) |
| 2017–2021 | 113 (30) | 112,401 (62) | 70,246 (38) |
| Funding source | |||
| NIH | 31 (8) | 19,597 (60) | 15,444 (40) |
| Non-NIH governmental | 56 (15) | 49,687 (67) | 24,016 (33) |
| Industry | 183 (48) | 127,767 (62) | 78,204 (38) |
| Foundation | 58 (15) | 28,928 (61) | 18,392 (39) |
| Otherc | 82 (22) | 20,310 (64) | 11,327 (36) |
| Intervention | |||
| Care delivery | 36 (9) | 39,506 (57) | 29,213 (43) |
| Device | 4 (1) | 466 (54) | 399 (46) |
| Dialysis | 34 (9) | 10,652 (59) | 7505 (41) |
| Drug | 281 (74) | 153,552 (62) | 92,678 (38) |
| Procedure/surgery | 9 (2) | 5611 (72) | 2144 (28) |
| Exercise/meditation | 2 (0.5) | 280 (61) | 179 (39) |
| Other | 8 (2) | 5783 (86) | 964 (14) |
Global=US+international trials. HD, hemodialysis; PD, peritoneal dialysis; NIH, National Institutes of Health.
Column percentages.
Total GN trials 25, all seven lupus nephritis trials had more women than men enrolled, and 3 of 9 IgA trials conducted in Asia had more women than men enrolled.
Other=investigator/university funded. Some studies had more than one funding source.
Table 2.
Enrollment by trial type and year
| Target Condition | Trials N (%) Total=380 |
Male N (%) 374 (98%) No. of Men Enrolled=215,850 |
Female N (%) 373 (98%) No. of Women Enrolled=133,082 |
|---|---|---|---|
| AKI | |||
| 2000–2006 | 15 (4) | 2051 (67) | 1033 (33) |
| 2007–2011 | 9 (2) | 2616 (64) | 1441 (36) |
| 2012–2016 | 20 (5) | 15,466 (69) | 6986 (31) |
| 2017–2021 | 25 (7) | 39,896 (63) | 23,297 (37) |
| CKD | |||
| 2000–2006 | 15 (4) | 4452 (61) | 2904 (39) |
| 2007–2011 | 22 (6) | 16,114 (62) | 9820 (38) |
| 2012–2016 | 23 (6) | 25,967 (61) | 16,811 (39) |
| 2017–2021 | 26 (7) | 45,672 (63) | 26,330 (37) |
| GN | |||
| 2000–2006 | 7 (2) | 203 (35) | 377 (65) |
| 2007–2011 | 3 (1) | 292 (41) | 422 (59) |
| 2012–2016 | 2 (0.5) | 64 (52) | 58 (48) |
| 2017–2021 | 13 (3) | 862 (38) | 1409 (62) |
| Dialysis | |||
| 2000–2006 | 14 94) | 3093 (52) | 2832 (48) |
| 2007–2011 | 11 (3) | 4311 (59) | 3052 (41) |
| 2012–2016 | 15 (4) | 7514 (59) | 5321 (41) |
| 2017–2021 | 16 (4) | 14,329 (53) | 12,819 (47) |
| Kidney transplant | |||
| 2000–2006 | 43 (11) | 8651 (64) | 4801 (36) |
| 2007–2011 | 34 (9) | 7093 (65) | 3828 (35) |
| 2012–2016 | 35 (9) | 5817 (64) | 3262 (36) |
| 2017–2021 | 32 (8) | 11,477 (65) | 6279 (35) |
Meta-Analytic Estimates
All trials reporting enrollment information on sex of the participants were included in a meta-analysis to better estimate proportional enrollment after accounting for the number of trials and trial size. As shown in Table 3, overall and subgroup estimates were qualitatively similar in the crude and meta-analytic analyses. Overall pooled results were similar to the raw proportions with male enrollment estimated at 62% (95% CI, 60% to 64%) overall and for 67%, 61%, 48%, 59%, and 65% of AKI, CKD, GN, dialysis, and kidney transplant trials, respectively. In the weighted estimates, enrollment rates were stable across time, with only modest variation according to type of intervention. Trial disease category (P < 0.001) and region of enrollment (P = 0.02) were significantly associated with the proportion of women enrolled. Results of meta-regression analyses were similar with trial category significantly associated with the proportion of women enrolled (P = 0.01). By contrast, enrollment proportions were not associated with publication year, enrollment site, and intervention type (Table 4).
Table 3.
Meta-analytic estimates of proportion of male and female participants in nephrology trials according trial characteristics
| Trial Category | No. of Studies Included in the Model | Weight, % | Random Pooled ES for Proportion of Male Enrollment | 95% CI | Random Pooled ES for Proportion of Female Enrollment | 95% CI | Test for Heterogeneity Between Subgroups |
|---|---|---|---|---|---|---|---|
| AKI | 69 | 18.6 | 0.67 | 0.63 to 0.70 | 0.33 | 0.30 to 0.37 | P = <0.001 |
| CKD | 85 | 23.2 | 0.61 | 0.57 to 0.65 | 0.39 | 0.35 to 0.43 | |
| GN | 25 | 6.5 | 0.48 | 0.37 to 0.58 | 0.52 | 0.42 to 0.63 | |
| HD/PD | 55 | 14.8 | 0.59 | 0.56 to 0.61 | 0.41 | 0.39 to 0.44 | |
| Kidney transplant | 139 | 36.8 | 0.64 | 0.63 to 0.65 | 0.36 | 0.35 to 0.37 | |
| Publication year | P = 0.84 | ||||||
| 2000–2006 | 91 | 24.1 | 0.61 | 0.59 to 0.64 | 0.39 | 0.36 to 0.41 | |
| 2007–2011 | 77 | 20.6 | 0.63 | 0.58 to 0.68 | 0.37 | 0.32 to 0.42 | |
| 2012–2016 | 94 | 25.2 | 0.63 | 0.59 to 0.67 | 0.37 | 0.33 to 0.41 | |
| 2017–2021 | 111 | 29.9 | 0.61 | 0.59 to 0.64 | 0.39 | 0.36 to 0.41 | |
| Enrollment site | P = 0.02 | ||||||
| United States only | 60 | 15.7 | 0.61 | 0.54 to 0.67 | 0.39 | 0.33 to 0.46 | |
| Global | 82 | 22.6 | 0.61 | 0.59 to 0.64 | 0.39 | 0.36 to 0.41 | |
| Europe | 149 | 39.6 | 0.63 | 0.62 to 0.65 | 0.37 | 0.35 to 0.38 | |
| Asia | 41 | 10.8 | 0.57 | 0.53 to 0.61 | 0.43 | 0.39 to 0.47 | |
| International (non-US) | 41 | 11.0 | 0.64 | 0.62 to 0.66 | 0.36 | 0.34 to 0.38 | |
| Intervention type | P = 0.83 | ||||||
| Drug | 280 | 75 | 0.67 | 0.53 to 0.81 | 0.38 | 0.36 to 0.40 | |
| Device | 4 | 1.0 | 0.58 | 0.50 to 0.65 | 0.42 | 0.35 to 0.50 | |
| Dialysis | 34 | 9.1 | 0.64 | 0.60 to 0.68 | 0.36 | 0.32 to 0.40 | |
| Procedure/surgery | 9 | 2.4 | 0.61 | 0.50 to 0.71 | 0.39 | 0.29 to 0.50 | |
| Exercise/meditation | 2 | 0.5 | 0.61 | 0.57 to 0.66 | 0.39 | 0.34 to 0.43 | |
| Care delivery | 36 | 9.7 | 0.61 | 0.55 to 0.67 | 0.39 | 0.33 to 0.45 | |
| Other | 8 | 2.1 | 0.67 | 0.53 to 0.81 | 0.33 | 0.19 to 0.47 |
I2 trial categories=76%–99%, I2 publication year=95%–99%, I2 enrollment site=95%–99%. ES, estimated proportion; CI, confidence interval; HD, hemodialysis; PD, peritoneal dialysis.
Table 4.
Meta-regression with the proportion of participants enrolled who were categorized as women as the dependent variable
| Proportion of Women | Coefficient | SD | P Value |
|---|---|---|---|
| Publication year | −0.0034 | 0.02 | 0.87 |
| Trial target condition | 0.06 | 0.02 | 0.01 |
| Enrollment site | 0.01 | 0.02 | 0.62 |
| Intervention - drug | −0.06 | 0.09 | 0.47 |
| Intervention - dialysis | −0.15 | 0.10 | 0.14 |
| Intervention - device | −0.09 | 0.21 | 0.67 |
N=373 trials. Model Akaike information criterion=0.93, Bayesian information criterion=214.
Comparisons with Global and US Disease Prevalence
Women constitute roughly half of the world's population, and CKD has been shown to be more common in women globally at 55% compared with men 45%.6,13 As shown in Figure 2, global enrollment of women was disproportionately low in CKD trials relative to both the proportion of women in the world population and estimates of CKD prevalence. Although women account for roughly half of the US population and for a higher proportion of patients with CKD, the proportion of women on dialysis or receiving a transplant was lower compared with men. Differences between US disease prevalence and enrollment proportion in transplant trials were negligible, whereas women were enrolled at a disproportionately high rate in dialysis trials. By contrast, the proportion of women enrolled in US CKD trials (38%) was disproportionately low relative to CKD prevalence (52%) Figure 3.
Figure 2.
Comparison of worldwide population sex distribution, global CKD prevalence, and CKD trial enrollment for all CKD trials worldwide.
Figure 3.
Proportion of women enrolled in US trials compared with the proportion of female patients with the disease in the population. Blue bars show prevalence of disease and red bars show proportion of women enrolled in trials.
Discussion
Underrepresentation of women in clinical trials is pervasive and reflects a history of policies and misplaced fears that have resulted in exclusion of women from trial enrollment and may negatively affect care where sex-related differences in biology affect responses to therapy.3 Although gender differences in the epidemiology of kidney disease are well described, the enrollment of women in kidney disease trials has not been comprehensively reported. To better understand the representation of women in nephrology trials, we performed a comprehensive review and meta-analysis of high-impact nephrology RCTs published over a 20-year period.
Our analysis has several important findings: Male participants account for most (62%) of the trial participants overall and across multiple nephrology trial categories, with the exception of GN trials in which women were enrolled at marginally higher rates than men. This trend was true throughout the world, but notably US trials tend to enroll relatively higher proportions of female participants (male to female ratio of 1.7 globally versus 1.2 in the United States). Male-dominant enrollment has been persistent without qualitative changes and has remained at a proportion at or above 60% between 2000 and 2021. Imbalances were particularly striking in AKI and transplant trials in which men accounted for approximately two of every three trial participants. Gender-related enrollment disparities were also notable in CKD trials in which women accounted for <40% participants despite accounting for more than half of the background population of patients with CKD. This pattern was similar in the United States and the rest of the world. By contrast, in trials conducted in the United States, enrollment of women in transplant trials was qualitatively in line with estimates of gender-specific disease prevalence, and women were enrolled in disproportionately higher numbers relative to ESKD prevalence in dialysis trials. Trial condition type seems to be the most important factor explaining the variation in enrollment of women.
In 1993, FDA guidelines were published that lifted previous restrictions on the participation of women with childbearing potential from entering phase I and II trials. In addition to emphasizing fair representation of women in drug trials, the guidelines identified three specific pharmacokinetic issues of concern meriting study in women, including the effect of stages of menstrual cycle, oral contraceptives, and the effect of drug on the oral contraceptives.16 Despite these revised guidelines, enrollment of women in trials in general has continued to lag. For instance, one recent study reported the participation to disease prevalence ratio of women enrolled in recent landmark trials published in the New England Journal of Medicine, examining sodium glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and nonsteroid mineralocorticoid antagonists. Women comprised a minority of the study populations with enrollment ranging from 30% to 36% of participants, with a participation to prevalence ratio ranging from 0.56 to 0.72.17 Our analysis is consistent with these findings while extending them further with a longer period included, beyond a single journal, to diseases other than diabetic CKD.
The stark disparities we observed in enrollment of women compared with men in nephrology trials are likely to affect generalizability of the trial findings and may contribute to differences in outcomes of kidney disease in men and women, particularly for CKD, AKI, and transplant trials in which women accounted for <40% of trial participants worldwide. Several studies have demonstrated key sex-related differences in the metabolism, handling, toxicity, and efficacy profile of commonly used drugs, often on post hoc analysis of original trial data.18,19 Indeed, heterogeneous pharmacodynamics and differences in the risk of adverse reactions between men and women20 may put women at a disadvantage for understanding the efficacy and safety of treatment options if women are not represented in trials. For instance, ten prescription drugs have been withdrawn from the US market since 1997, with eight of ten posing greater risks for women than men.21 Understanding the biologic differences in diseases and response to therapies, especially in areas where women tend to face a higher burden of disease is thus particularly crucial. In addition to the higher burden of CKD in women than men, sex differences in the expression of drug transporters and carriers in kidney have been identified that may contribute to CKD-specific, sex-related changes in pharmacokinetics of kidney-targeted drugs in men and women. For example, a preclinical study showed a higher rate of clearance of furosemide in male rats compared with female rats with important implications for dosing and toxicity.22
Understanding the heterogeneity in efficacy and safety profiles of therapies requires enrolling women in sufficient numbers in kidney disease trials, ideally in large enough numbers to perform sex-specific subgroup analyses that are powered adequately to identify differential beneficial or harmful effects of kidney disease therapies. Our analysis suggests that with the exception of GN trials, kidney disease trials do not achieve this goal overall, although performance is better in US transplant and dialysis trials.
The relatively higher percentage of women enrolled in the GN trials likely reflect the high proportion of lupus nephritis trials which enrolled a majority of female patients, reflecting the higher prevalence of disease in women than men (85% women).23 In addition, many IgA trials were conducted in Asia where the prevalence of disease is high in women—for example, the ratio of men to women in biopsy-proven IgA in Asia is 2:1 in contrast to Northern Europe and the United States where the ratio is 6:1.24 Indeed, the region of enrollment seemed to be important more broadly. Although there is a male predominance in nephrology trial enrollment globally, there was a distinctly different pattern in trials conducted in the United States alone in which women are enrolled in slightly higher proportions. There were marked differences, for example, in the characteristics of dialysis trials conducted globally compared with those conducted solely in the United States where women were enrolled in higher numbers than men despite a lower prevalence of ESKD. Similarly, enrollment in US transplant trials within the United States seems to match the overall prevalence of kidney transplantation in men and women.
How to increase the enrollment of women in nephrology trials is uncertain. Ensuring a diverse pool of investigators and clinical trial staff may be critical. Several studies have shown that the trials with female first or last authors have a higher proportion of female enrollment and sex-specific analysis.25,26 While reporting of the sex of participants was nearly universal (98%) in our analysis, universal requirements for reporting sex and gender at publication could also help improve understanding and increase awareness of important sex-specific disparities. Training of research staff and investigators in recruitment strategies, and alleviating any fears in participation could also help. Working with patient advocacy groups, community organizations, and community health care providers to raise awareness regarding trials might also encourage more equitable enrollment. While not the focus of our analysis, in addition to enrollment, overall efforts from research team and community providers should likely include efforts to ensure equal retention of men and women. Dedicated reporting on sex-based dropout and loss to follow-up rates would be helpful, and it is likely that lessons on recruitment and retention can be learned from successful studies with high or universal inclusion of women, such as the Women's Health Initiative.27 Strategies to enhance equity in trial enrollment are summarized in Supplementary Figure 1.
A few limitations of our study should be noted. We recorded sex as a binary variable because that is the way it has been historically recorded. In the future of clinical trials, sex and gender may be recorded as nonbinary variables. A two-step approach, where trial participants are asked their sex assigned at birth and their current gender identity might be considered because the prevalence of kidney disease is disproportionately higher in transgender individuals and differs in transgender women and transgender men.28 In addition, we restricted our systematic review to trials published in ten high-impact journals to focus on trials with the greatest likelihood of publishing practice-changing results. Some trials that collectively play a role in advancing the field of nephrology may have been missed with this methodology. In addition, because we did quantify treatment efficacy or compare effects of alternative therapies and focused on trials that specifically chose those most likely to be practice changing, we did not analyze enrollment trends according to trial quality. However, this may be an area worth exploring in the future.
The make-up of clinical trial enrollment should ideally mirror the prevalence of kidney disease conditions in the population. Our analysis suggests that the body of nephrology trials in the last few decades has consistently failed to meet this standard. Addressing the marked disparities in the enrollment of women and men would improve understanding of discrepancies in kidney progression in men and women and how best to address them. To generate study populations that are more reflective of the kidney disease population, substantial effort is needed to enroll women and under-represented genders in clinical trials.
Supplementary Material
Disclosures
D.M. Charytan reports consultancy agreements with Allena Pharmaceuticals (DSMB), Amgen, AstraZeneca, CSL Behring, Eli Lilly/Boehringer Ingelheim, Fresenius, Gilead, GSK, Medtronic, Merck, Novo Nordisk, Renalytix, and Zogenix; research funding from Amgen, Gilead, Medtronic-clinical trial support, and Novo Nordisk; royalties from UpToDate for authorship/editors on reviews; advisory or leadership role in CJASN; and expert witness fees related to proton-pump inhibitors. All remaining authors have nothing to disclose.
Funding
Q.H. Soomro: ASN Foundation for Kidney Research (Donald E. Wesson).
Author Contributions
Conceptualization: David M. Charytan, Joey Nicholson, Qandeel H. Soomro.
Data curation: Amalya M. Charytan, Colin Keane, Angela McCarthy, Joey Nicholson, Giana Ramos, Qandeel H. Soomro, Dalila Varela, Javaughn Ways.
Formal analysis: Qandeel H. Soomro.
Methodology: Qandeel H. Soomro.
Supervision: David M. Charytan.
Visualization: Qandeel H. Soomro.
Writing – original draft: Qandeel H. Soomro.
Writing – review & editing: Amalya M. Charytan, David M. Charytan, Colin Keane, Angela McCarthy, Joey Nicholson, Giana Ramos, Qandeel H. Soomro, Dalila Varela, Javaughn Ways.
Data Sharing Statement
Anonymized data created for the study are or will be available in a persistent repository on publication. Compiled Data. Other. Excel file.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/KN9/A395.
Supplemental Table 1. Search strategy.
Supplemental Table 2. Bias assessment of trials included.
Supplemental Figure 1. Suggested ways to improve enrollment of women participants in nephrology randomized clinical trials.
References
- 1.Steinberg JR Turner BE Weeks BT, et al. Analysis of female enrollment and participant sex by burden of disease in US clinical trials between 2000 and 2020. JAMA Netw Open. 2021;4(6):e2113749. doi: 10.1001/jamanetworkopen.2021.13749 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Harris DJ, Douglas PS. Enrollment of women in cardiovascular clinical trials funded by the national heart, lung, and blood institute. N Engl J Med. 2000;343(7):475–480. doi: 10.1056/NEJM200008173430706 [DOI] [PubMed] [Google Scholar]
- 3.Liu KA, Mager NA. Women's involvement in clinical trials: historical perspective and future implications. Pharm Pract (Granada). 2016;14(1):708. doi: 10.18549/PharmPract.2016.01.708 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Institute of Medicine (US) Committee on Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies. In: Mastroianni AC, Faden R, Federman D, eds. B, NIH Revitalization Act of 1993 Public Law 103-43 Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Volume I. National Academies Press (US); 1994. https://www.ncbi.nlm.nih.gov/books/NBK236531/ [PubMed] [Google Scholar]
- 5.NIH Inclusion Outreach Toolkit: How to Engage, Recruit, and Retain Women in Clinical Research. 2019. https://orwh.od.nih.gov/toolkit/recruitment/history [Google Scholar]
- 6.Bikbov B, Perico N, Remuzzi G. on behalf of the GBD Genitourinary Diseases Expert Group. Disparities in chronic kidney disease prevalence among males and females in 195 countries: analysis of the global burden of disease 2016 study. Nephron. 2018;139(4):313–318. doi: 10.1159/000489897 [DOI] [PubMed] [Google Scholar]
- 7.Sabolić I, Asif AR, Budach WE, Wanke C, Bahn A, Burckhardt G. Gender differences in kidney function. Pflugers Arch. 2007;455(3):397–429. doi: 10.1007/s00424-007-0308-1 [DOI] [PubMed] [Google Scholar]
- 8.Schaum N, Lehallier B, Hahn O. Tabula Muris Consortium. Ageing hallmarks exhibit organ-specific temporal signatures. Nature. 2020;583(7817):596–602. doi: 10.1038/s41586-020-2499-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Berg UB. Differences in decline in GFR with age between males and females. Reference data on clearances of inulin and PAH in potential kidney donors. Nephrol Dial Transplant. 2006;21(9):2577–2582. doi: 10.1093/ndt/gfl227 [DOI] [PubMed] [Google Scholar]
- 10.Soomro QH McCarthy A Varela D, et al. Representation of racial and ethnic minorities in nephrology clinical trials: a systematic review and meta-analysis. J Am Soc Nephrol. 2023;34(7):1167–1177. doi: 10.1681/ASN.0000000000000134 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Higgins JP Altman DG Gøtzsche PC, et al. Cochrane Bias Methods Group, Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi: 10.1136/bmj.d5928 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health. 2014;72(1):39. doi: 10.1186/2049-3258-72-39 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.United Nations, Department of Economic and Social Affairs, Population Division (2022). World Population Prospects 2022: Summary of Results. UN DESA/POP/2022/TR/NO. 3. 2022. Accessed December 5, 2023. https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/wpp2022_summary_of_results.pdf [Google Scholar]
- 14.Florea A, Jacobs ET, Harris RB, Klimentidis YC, Thajudeen B, Kohler LN. Chronic kidney disease unawareness and determinants using 1999-2014 national health and nutrition examination survey data. J Public Health (Oxf). 2022;44(3):532–540. doi: 10.1093/pubmed/fdab112 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.United States Renal Data System Annual Report 2020. 2020 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2020. [Google Scholar]
- 16.Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs. FDA Guidance Document. 1993. Accessed December 5, 2023. https://www.fda.gov/media/71107/download [Google Scholar]
- 17.Vinson AJ, Collister D, Ahmed S, Tennankore K. Underrepresentation of women in recent landmark kidney trials: the gender gap prevails. Kidney Int Rep. 2022;7(11):2526–2529. doi: 10.1016/j.ekir.2022.08.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Mauvais-Jarvis F Berthold HK Campesi I, et al. Sex- and gender-based pharmacological response to drugs. Pharmacol Rev. 2021;73(2):730–762. doi: 10.1124/pharmrev.120.000206 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Joseph S, Nicolson TJ, Hammons G, Word B, Green-Knox B, Lyn-Cook B. Expression of drug transporters in human kidney: impact of sex, age, and ethnicity. Biol Sex Differ. 2015;6:4. doi: 10.1186/s13293-015-0020-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Tran C, Knowles SR, Liu BA, Shear NH. Gender differences in adverse drug reactions. J Clin Pharmacol. 1998;38(11):1003–1009. doi: 10.1177/009127009803801103 [DOI] [PubMed] [Google Scholar]
- 21.Drug Safety. Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women. 2001. Accessed December 5, 2023. https://www.gao.gov/products/gao-01-286r [Google Scholar]
- 22.Cerrutti JA, Quaglia NB, Brandoni A, Torres AM. Effects of gender on the pharmacokinetics of drugs secreted by the renal organic anions transport systems in the rat. Pharmacol Res. 2002;45(2):107–112. doi: 10.1006/phrs.2001.0912 [DOI] [PubMed] [Google Scholar]
- 23.Wang H, Ren YL, Chang J, Gu L, Sun LY. A systematic review and meta-analysis of prevalence of biopsy-proven lupus nephritis. Arch Rheumatol. 2018;33(1):17–25. doi: 10.5606/ArchRheumatol.2017.6127 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Deng W Tan X Zhou Q, et al. Gender-related differences in clinicopathological characteristics and renal outcomes of Chinese patients with IgA nephropathy. BMC Nephrol. 2018;19(1):31. doi: 10.1186/s12882-018-0829-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Nielsen MW, Andersen JP, Schiebinger L, Schneider JW. One and a half million medical papers reveal a link between author gender and attention to gender and sex analysis. Nat Hum Behav. 2017;1(11):791–796. doi: 10.1038/s41562-017-0235-x [DOI] [PubMed] [Google Scholar]
- 26.Sugimoto CR, Ahn YY, Smith E, Macaluso B, Larivière V. Factors affecting sex-related reporting in medical research: a cross-disciplinary bibliometric analysis. Lancet. 2019;393(10171):550–559. doi: 10.1016/S0140-6736(18)32995-7 [DOI] [PubMed] [Google Scholar]
- 27.Hays J Hunt JR Hubbell FA, et al. The Women's Health Initiative recruitment methods and results. Ann Epidemiol. 2003;13(9 suppl l):S18–S77. doi: 10.1016/s1047-2797(03)00042-5 [DOI] [PubMed] [Google Scholar]
- 28.Eckenrode HE, Gutierrez OM, Osis G, Agarwal A, Curtis LM. Kidney disease prevalence in transgender individuals. Clin J Am Soc Nephrol. 2022;17(2):280–282. doi: 10.2215/CJN.04660421 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Data Availability Statement
Anonymized data created for the study are or will be available in a persistent repository on publication. Compiled Data. Other. Excel file.