In the present study, by employing various statistical approaches, we clearly demonstrated a survival advantage of women over men independent of all-cause and infection-related deaths in patients undergoing HD. Regarding all-cause mortality, the effect of being female was smaller in patients with diabetic nephropathy or higher serum levels of creatinine or albumin. Moreover, in the subgroup analysis of infection-related mortality, the impact of being female was smaller in younger patients or patients with diabetic nephropathy, history of CVD, higher blood hemoglobin, and higher serum levels of creatinine, total cholesterol, or albumin. Taken together, our results suggest a potential survival benefit for female patients undergoing maintenance HD.
The present study has provided evidence that women have a survival advantage during HD. To the best of our knowledge, our study is the first to demonstrate that the female survival advantage is consistent regarding infection-related mortality in HD patients. This relationship remains statistically significant even after adjustment for potential confounding factors, PS-matching, or IPTW adjustment. Furthermore, when non-infection-related death was considered a competing risk, the infection-related mortality rate in women was significantly lower than that in men. As for all-cause death, a report from the Dialysis Outcomes Practice Patterns Study (DOPPS) demonstrated that the HR (95% CI) of all-cause mortality in men (versus women) was 1.09 (1.04–1.14) after adjusting for age and time on dialysis16, consistent with our current observations. Taken together, our data and previous reports strongly suggest that women have a survival advantage over men during maintenance HD.
Several potential mechanisms might explain the survival advantage of women over men undergoing HD. Previous studies reported that, in comparison to female patients undergoing HD, men might be more susceptible to inflammation-induced anorexia and can exhibit more severe symptoms (e.g., handgrip strength decline9) and deterioration over time, as evidenced by nutritional and inflammatory variables such as albumin, body weight, CRP, and interleukin-610. It has also been demonstrated in regards to inflammation that women have better outcomes than men11. These results suggest that men are more vulnerable than women in the HD population. In the general population, mounting evidence has also shown a survival advantage of women that is related to genetic and physiological factors. Inactivation of the disadvantageous X chromosome3, longer telomeres4, a lower resting metabolic rate20, estrogen21, and mitogenome-nuclear genome interactions6 might play a role in the longer longevity of women. These factors could partly explain the underlying mechanism of our observations. Furthermore, the heightened immune response in women is generally considered to make them more resistant to infections7, 8, 22. Our study confirmed a similar relationship in patients undergoing maintenance HD.
The subgroup analysis of all-cause mortality revealed that the effect of being female was enhanced in patients with diabetic nephropathy or higher serum levels of creatinine or albumin. Additionally, the subgroup analysis of infection-related mortality revealed that the effect of being female was attenuated in older patients, or patients with diabetic nephropathy, a history of CVD, lower blood hemoglobin, serum levels of creatinine, or albumin or higher levels of total cholesterol. In our analysis, the protective effect of being female in diabetic nephropathy was different in each outcome. Previous studies have shown that the age-related decline of immune cells and inflammatory mediators were slower in women than in men7, 8. Furthermore, sex hormones might reduce antioxidants20, and women are more resistant to anorexia and lower malnutrition9, 10. However, recent observational studies demonstrated an inverse association between sex and a high death rate in younger patients undergoing HD14, 23. Hence, further studies are necessary to elucidate whether the effects of the baseline factors observed in the current study are present across a variety of HD populations and whether their underlying mechanisms are related to sex hormones.
Despite the accumulation of these findings to date, the advantage of being female regarding human life expectancy of patients undergoing HD is still controversial. Sex-dependent differences in the proportion of types of vascular access might partially explain the inconsistency. The results from the DOPPS have revealed that the selection of vascular access showed sex-dependent differences, with less frequent catheter use in male HD patients (12.2%) than that in female HD patients (18.4%); subgroup analyses indicated that HD catheter use was associated with a higher risk of all-cause mortality in female patients undergoing HD16. As catheter users are likely to develop catheter-related infections and resulting persistent inflammation followed by malnutrition, it is possible that they are at increased risks of infection-related and all-cause death. In this regard, sex differences in the proportion of types of vascular access may be important confounders that might have nullified the natural specific advantage of women. Importantly, a national survey conducted in 2008 in Japan reported that more than 90% of the patients undergoing maintenance HD used arteriovenous fistula while only 0.5% used a catheter17. Additionally, there was no sex discrepancy in the proportion of types of vascular access in Japanese patients in the DOPPS16. This result suggests that catheter users were presumed to be minor in our study and that there is no sex discrepancy in the proportion of types of vascular access. In the present study, even when PS-matching or IPTW adjustment was employed, the survival advantage of women was statistically significant, particularly regarding all-cause and infection-related death. This indicates that catheter use during HD might diminish the natural specific advantage of women. However, it is impossible to assess this in the present study, because we had no direct data regarding the type of vascular access. Therefore, further studies with data regarding the type of vascular access are necessary to determine whether women undergoing HD have a survival advantage regardless of the type of vascular access.
The strength of our study was its large-scale and wide-ranging inclusion criteria. As such, our results are generalizable to real-world HD patients. However, some limitations in our study should be noted. First, the measurements of baseline parameters might have been insufficient. For instance, data regarding the use of steroid or immunosuppressive agents and the acceptance rate of renal replacement therapy were missing. Recent studies indicate that elderly women are more likely to choose conservative care than renal replacement therapy, and the female survival advantage diminished among HD patients24. However, our results obtained with PS-based methodologies for adjusting this selection bias revealed a female survival advantage. Second, we had no data on the serum levels of sex hormones. A previous study showed that women undergoing HD had lower serum estradiol levels than those in the general population25. Thus, the activity of sex hormones might hardly explain the discrepancy in mortality. The length of exposure to female hormones before HD initiation may determine the impact of the female advantage on survival. Third, the participating patients in this study were all Japanese, and thus our results might not be applicable to other ethnic groups. Despite these limitations, we believe that this study provides further evidence that women have a survival advantage over men during HD.
In conclusion, our findings on patients undergoing maintenance HD suggest that women have a survival advantage over men. Further studies are required to confirm this female survival advantage and its underlying mechanisms during HD.