Associations of Estradiol With Mortality and Health Outcomes in Patients Undergoing Hemodialysis: A Prospective Cohort Study

Abstract

Background: Both lower and higher estradiol (E2) levels have been associated with increased mortality among women with kidney failure. However, robust data are still lacking. Objective: We investigated the interaction of diabetes and age on linear and nonlinear associations between E2 levels, adverse outcomes, and health-related quality of life (HRQOL) in Canadian women undergoing hemodialysis (HD). Design: Population-based cohort study; data from Canadian Kidney Disease Cohort Study (CKDCS). Setting & patients: A total of 427 women undergoing HD enrolled in the CKDCS. Measurements: Baseline E2 (in pmol/L) and E2 tertiles (95 pmol/L). Methods: Cox-proportional hazards used for all-cause and cardiovascular disease (CVD) mortality. Fine-Gray models used for incident CVD. Mixed models used for Health Utilities Index Mark 3 (HUI3), Kidney Disease Quality of Life Physical Component Scores (KDQOL12-PCS), and Mental Component Scores (KDQOL12-MCS). Results: Over a median follow-up of 3.6 (interquartile range [IQR]: 1.6-7.5) years, 250 (58.6%) participants died; 74 deaths (29.6%) were CV-related. Among 234 participants without prior CV events, 80 (34.2%) had an incident CVD event. There were no significant linear associations between E2 and all-cause mortality, CVD mortality, and incident CVD. However, E2 showed a significant concave association with all-cause mortality, but not with CVD mortality and incident CVD. Among patients aged ≥63 years, higher E2 levels were associated with lower HUI3 scores, mean difference (MD) = –0.062 per 1 – SD pmol/L, 95% confidence interval (CI) = –0.112 to –0.012, but the opposite was observed in younger patients (<63 years) in whom higher E2 levels were associated with higher HUI3 scores (MD = 0.032 per 1 – SD pmol/L, 95% CI = 0.008-0.055), P interaction = .045. No associations were observed among E2, KDQOL12-PCS (MD = –0.15 per 1 – SD pmol/L, 95% CI = –1.15 to 0.86), and KDQOL12-MCS (MD = –0.63 per 1 – SD pmol/L, 95% CI = –1.82 to 0.57). Limitations: Unmeasured confounding and small sample size. Conclusions: The association between E2 and all-cause mortality may be nonlinear, while no association was observed for CVD mortality, incident CVD, KDQOL12-PCS, and KDQOL12-MCS. Furthermore, the association between serum E2 and HUI3 was modified by age: Higher levels were associated with higher utility among women aged <63 years and the converse observed among older women.