Examination of sex/gender disparities across the continuum of kidney transplant steps

To the Editor,

Women with end-stage kidney disease (ESKD) are less likely to be waitlisted for or to receive a kidney transplant as compared with men, even after adjustment for several demographic and clinical factors [1–5] and despite similar or better post-transplant survival [4, 6–8]. The reasons for this disparity have not been delineated, in part because the critical and necessary early transplant steps of referral to and evaluation at a transplant center (steps necessary for eventual waitlist and transplant) are not captured in national surveillance data. A comprehensive assessment of sex/gender inequities across all steps in the complex transplant process is essential to guide the development of policies and interventions focused on reducing sex/gender disparities that will target the right population at the right transplant step. Therefore, in this study, our primary was to examine sex/gender disparities across all transplants steps from referral to transplant utilizing the novel Early Steps to Transplant Access Registry (E-STAR) [9, 10] across three states in the Southeastern USA (Georgia, North Carolina and South Carolina; see Supplementary methods for detailed description of this data source). Our secondary aim was to examine the potential effect modification of age, race and obesity based on prior work [11].

RESULTS

Baseline characteristics

At dialysis initiation, women (vs men) were more likely to be Black (56.24% vs 50.09%), obese [mean body mass index (BMI) 31.6 kg/m² vs 29.8 kg/m²], have Medicaid insurance (27.70% vs 16.95%), have diabetes as primary cause of ESKD (48.08% vs 44.93%), have pre-ESKD care (80.82% vs 78.16%), and to live in a neighborhood with a higher poverty level (42.28% vs 38.73%) and greater average proportion of Black residents (35.39% vs 33.09%) (Supplementary data, Table S1). Men and women were similarly likely to be informed of transplant as a treatment option, to have similar dialysis-facility level factors (i.e. for-profit status, facility type and size, and patient-to-social worker ratio), and to have similar neighborhood-level education. In addition, comorbidities were similar between men and women, excluding diabetes which was more common among women (63.08% vs 58.82%) and prior tobacco use which was more common among men (10.07% in men vs 7.03% in women).

As you move through each transplant step, the overall population becomes more male, younger, less obese, less likely to have diabetes as the primary cause of ESKD, less likely to have most comorbidities, less likely to have Medicaid or Medicare as the primary insurance, less likely to come from a higher poverty neighborhood, and more likely to have been informed of transplant as a treatment option and to come from a large dialysis facility (Supplementary data, Table S2).

Sex/gender and referral, evaluation, waitlisting and transplant

Overall, median [interquartile range (IQR)] time to referral, evaluation, waitlisting and transplant was 57 (1–191), 44 (15–90), 87 (1–248) and 370 (141–864) days in women, and 66 (1–200), 45 (17–886), 101 (1–267) and 371 (138–852) days in men, respectively. In crude models, women were 10% [hazard ratio (HR) 0.90 (95% confidence interval 0.88–0.93)] less likely to be referred within 12 months, 7% [0.93 (0.89–0.96)] less likely to start the evaluation within 6 months among those referred, yet similarly likely to be waitlisted among those evaluated [0.98 (0.93–1.03)] and transplanted among those waitlisted [1.02 (0.95–1.10)] (Table 1). Patterns were similar in multivariable models, but effect sizes reduced.

Table 1:

Association between sex/gender and transplant referral, evaluation, waitlisting and transplant in the Southeastern USA, 2015–19 with follow-up through 2020.

Outcome a	Crude HR (95% CI)	Adjusted HR (95% CI) b
Referred within 1 year (among all incident dialysis patients)	0.90 (0.88–0.93)	0.97 (0.94–1.00)
Evaluation started within 6 months (among referred patients)	0.93 (0.89–0.96)	0.96 (0.93–1.00)
Waitlisted (among evaluated patients)	0.98 (0.93–1.03)	1.02 (0.97–1.08)
Transplanted (among waitlisted patients)	1.02 (0.95–1.10)	1.04 (0.95–1.13)

^aHR compares rates of each outcome in women vs men

^bMultivariable analysis adjusted for age, race, obesity, insurance status, comorbidities, attributed cause of ESKD, informed of transplant, neighbourhood poverty, neighbourhood % Black, neighbourhood % high school graduate, dialysis facility for-profit status, facility size, freestanding facility status and patient-to-social worker ratio.

CI, confidence interval.

Sex/gender and transplant access, by age, race and obesity

Significant interactions were found between sex/gender and age (P < .001), race (P = .007) and obesity (P < .001), and 12-month referral. By age, women aged 60–69 and 70–79 years were 10% [0.90 (0.86–0.95)] and 28% [0.72 (0.67–0.79)] less likely to be referred compared with men of the same age, respectively, while women aged 30–39 years were more 13% [1.13 (1.03–1.23)] more likely to be referred (Fig. 1A and Supplementary data, Table S3). For all other age groups, there were no significant differences in referral rates between men and women. By race, non-Hispanic white and Black women were 16% [0.84 (0.80–0.88)] and 7% [0.93 (0.90–0.97)] less likely to be referred, respectively, compared with men of the same race, while no sex/gender disparity was observed for Hispanic and “other” races (Fig. 1B and Supplementary data, Table S3). For obesity, a graded response was observed: increasing BMI was associated with a widening in the sex/gender disparity such that women in obese class III were 24% [0.76 (0.70–0.82)] less likely to be referred compared with men of the same weight (Fig. 1C and Supplementary data, Table S3) compared with an 8% [0.92 (0.87–0.97)] reduced likelihood in women vs men who were considered overweight.

Figure 1:

Crude association between sex and 12-month referral (red), 6-month evaluation start (blue), waitlisting (green), and transplant (black) by (A) race and ethnicity, (B) age and (C) obesity. Note: the reference line of 1 (dotted line) indicates equity (i.e. no difference in rates of each outcome between men and women) whereas <1 indicates a transplant access disparity for women.

Significant interactions were also observed between sex/gender and age for evaluation (P = .13) and waitlisting (P = .001), and sex/gender and obesity for evaluation (P = .001) and waitlisting (P = .002). Specifically, referred women aged 18–29, 50–59, 60–69 and 70–79 years were 17% [0.83 (0.71–0.97)], 8% [0.92 (0.86–0.99)], 10% [0.90 (0.84–0.96)] and 14% [0.86 (0.77–0.97)] less likely to start the evaluation compared with referred men of the same age (Fig. 1B and Supplementary data, Table S3). For waitlisting, young women aged 18–29 years were 32% [0.68 (0.56–0.83)] less likely to be waitlisted once evaluated compared with men of the same age (and 20% less likely in fully adjusted models), while women aged 50–59 years were 9% [1.09 (1.00–1.20)] more likely to be waitlisted once evaluated compared with men. For both evaluation and waitlisting, increasing obesity levels were generally associated with an increase in the sex/gender disparity (Fig. 1C and Supplementary data, Table S3), though this reached a level of statistical significance only for evaluation in obese classes II and III.

Sensitivity analysis

When examining waitlisting among all incident dialysis patients (as compared with those who started the evaluation as in primary analyses), women were 14% [HR 0.86 (0.83–0.90)] less likely to be waitlisted compared with men, Supplementary data, Table S4. Patterns were similar to overall findings when adjusting for pre-ESKD nephrology care and calendar year, and accounting for competing risks (Supplementary data, Table S4).

DISCUSSION

This study builds on extant literature documenting sex/gender disparities in access to waitlisting and eventual transplant, and demonstrates that the sex/gender disparity, at least in the Southeastern USA, is in fact greatest at earlier transplant steps of referral and evaluation. This disparity may relate to conscious or unconscious provider biases, differential comorbidity burden or frailty distribution, possible differences in candidate self-selection, caregiving burden, concerns regarding pregnancy-induced sensitization or a combination of these factors (see expanded discussion in Supplementary data for more information) [12].

Limitations

Key limitations include the lack of generalizability outside the Southeastern USA and to people with late-stage chronic kidney disease who may be referred for transplant, but are not captured in US Renal Data System. Furthermore, this study is limited to data routinely captured in dialysis and transplant centers and does not include reasons why people were not referred, evaluated or waitlisted (see Supplementary data for expanded detail on study limitations).

Conclusions

In conclusion, in the Southeastern USA, women with ESKD are 10% and 7% less likely to be referred and start the evaluation, respectively, but similarly likely to be waitlisted once evaluated as compared with men. This disparity differs by age, obesity and race. Understanding the underlying mechanisms driving these disparities is needed to inform the design of interventions and policies aimed at reducing gender inequities. Addressing sex/gender inequities as early in the process as possible (i.e. at referral) is likely to have the greatest impact.

DISCLAIMER

The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US Government.

FUNDING

This project and The Reducing Disparities in Access to kidNey Transplantation Regional Study was funded in part by the National Institute on Minority Health and Health Disparities award U01MD010611. Support for the preparation of this document was funded by Centers for Medicare and Medicaid Services (an agency of the US Department of Health and Human Services) ESRD Network 6 contract HHSM-500-2013-NW006C. This project was also funded in part by an Emory University Health Services Center Pilot Award (recipient J.L.H.) and an American Society of Transplantation Career Development Award (recipient J.L.H.).

AUTHORS’ CONTRIBUTIONS

J.L.H. conceived the study, contributed to study design, oversaw analysis and wrote the manuscript. M.D. conducted all analyses and reviewed/edited the manuscript. S.O.P. contributed to funding and data acquisition, provided intellectual input and reviewed/edited the manuscript. N.D. assisted in analysis and reviewed/edited the manuscript. D.D., T.R. and A.R. contributed to study design, provided intellectual input and reviewed/edited the manuscript. R.E.P. contributed to data acquisition, study conceptualization, provided intellectual input and reviewed/edited the manuscript. All authors approve the final version of this manuscript. J.L.H. is the guarantor of this work and takes responsibility for final responsibility for the decision to submit for publication.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.