Mortality risk for women on chronic hemodialysis differs by age

Women in the general population experience increased longevity relative to men. Furthermore previous reports have suggested higher mortality in younger woman on hemodialysis. Whether this is true in a Canadian population, after accounting for multiple confounders and the competing risk of kidney transplantation, remains unknown.

We found that women’s survival on chronic hemodialysis varies by age with higher mortality in women younger than 45 years old and lower mortality in woman older than 75 years of age compared to men and this was persistent after accounting for the competing risk of transplantation.

Women comprise a significant and increasing proportion of the worldwide dialysis population. Several studies have identified significant differences in prevalence and treatment of kidney disease between the sexes. Women appear less likely than men to start dialysis for treatment of kidney failure and less likely to receive a kidney transplant [1–4]. Upon initiation of dialysis, women are more likely to receive a lower dialysis dose, inferior treatment of anemia and mineral metabolism complications, and have a catheter as a vascular access [5–7]. Although, attempts to mitigate sex-based differences in renal care have been attempted; significant disparities still exist [5].

Despite clearly documented differences in the delivery of dialysis care, the questions of whether these differences adversely impact the outcome of women on dialysis remains unclear. A small number of previous studies suggest younger women on hemodialysis may have a higher mortality relative to men [2, 8, 9]. Furthermore, elderly women have been reported to have comparable survival to elderly men on hemodialysis [2, 8, 9]. Whether these findings are applicable to the Canadian dialysis population remains unknown. In populations with disparate rates of censoring and competing events, such as differences in transplantation in end stage renal disease (ESRD), appropriate analyses must be employed to account for these differences [10, 11]. The use of competing outcomes analyses has allowed considerable insight into sex based disparities in transplantation rates on hemodialysis demonstrating elderly women are less likely to receive a renal transplant and young African Americans on hemodialysis experience a higher mortality [3, 12]. Relatively healthy elderly women may remain on hemodialysis, as opposed to healthy elderly men who may receive a transplant, creating a survival disparity. Accounting for the competing event of transplantation may alter the survival estimates of elderly women on hemodialysis such that it mimics observations from the general population, where women experience a survival benefit and improved longevity compared to men.

In this regard we set out to examine sex-based differences on mortality among a chronic hemodialysis cohort utilizing a competing risk analysis and whether age was an effect modifier. We hypothesized that women would experience higher survival after accounting for the competing risk of transplantation and this would differ by age.

In this large national cohort of patients on chronic hemodialysis, substantial mortality differences were evident among the sexes based on age. Although overall mortality for men and women after comprehensive adjustment was similar, age was a significant effect modifier as women under the age of 45 years of age had a substantially higher mortality risk compared to men of a similar age. In contrast, women over the age of 75 years of age experienced a modestly lower mortality, an observation consistent with data in the general population. These differences persisted after accounting for the competing risk of transplantation and after comprehensive adjustment for confounders.

The finding that mortality is increased in women < 45 years of age on hemodialysis relative to men is congruent with finding from previous studies from Europe and the United States [2, 8, 9]. Crude mortality rates for hemodialysis patients from the United States Renal Data System (USRDS) show higher mortality in women under the age of 60 years of age compared to men with the largest disparity among those aged 20–29 years of age (Crude mortality rate male 4.93 women 6.29 per 100 patient years; relative rate 1.27). Similarly, data from the Renal Epidemiology and Information Network (REIN) registry in France reported an increase in the standardized mortality ratio in women relative to men, predominantly due to mortality in the first four years on dialysis. Our findings are consistent with these previous reports and demonstrate the mortality difference persists after adjustment for numerous confounders and after accounting for the competing outcome of transplantation.

We observed women greater than 75 years of age had a higher mortality compared to men. We found absolute mortality reductions of 2.3% and 4.2% in women 75 to 85 years of age and over 85 years of age relative to similar aged men. This observation mimics those seen in the Canadian general population where women experience, on average, an additional 4 years of longevity relative to men [13]. However it is unclear if the survival benefit is simply an extension of those observed in the general population or due to the possibility of a selection bias. There have been numerous reports that elderly women do not receive equal access to cardiovascular procedures, surgical interventions and kidney transplantation [14–16]. Elderly women may not choose or be offered chronic hemodialysis to the same extent as men thus altering the population on chronic hemodialysis. Further investigations regarding sex-based differences in acceptance and offer of dialysis treatment are required.

It is well known that kidney transplantation as a treatment for kidney failure is less frequent among women than men. In our cohort, we also found that the likelihood of receiving a kidney transplant was lower across all age categories in women. However, these differences do not explain the age-related mortality differences among the sexes since, after accounting for the competing risk of transplantation, there was little change in the observed mortality risk. Thus young women on dialysis are disadvantaged by both a higher risk of mortality and a reduced likelihood of receiving a renal transplant.

We did find several risk factors that may contribute to the higher mortality observed in younger woman on dialysis. Woman less than 45 years of age had an almost two-fold increase in malignancy, were more likely to have glomerulonephritis, obstruction or interstitial disease as their cause of renal failure, have a lower serum albumin and hemoglobin and were 5.7% less likely to initiate dialysis with a fistula. Of these only vascular access represents a potentially modifiable risk factor. Multiple studies have reported lower rates of AVF among women however it remains unclear if this represents actual differences in patient agreement for AVF, referral rates, AVF creation and/or maturation among the sexes [17–19]. Technical difficulties may include smaller vessel diameter or early thrombosis. Miller et al. reported post-AVF creation women are less likely to achieve fistula patency and are more likely to have early thrombosis and undergo more salvage procedures compared to men. A similar increase in complications and the need for more revascularization procedures has been reported in AVG in women compared to men [20]. It is possible that there may be important cosmetic considerations as young women may be less agreeable to AVF surgery. Attitudes towards vascular access suggest body image is an important consideration however whether it is sex-specific remains unclear [21].

The main strengths of our study are the use of a large national cohort with over 10 years of incident patient follow up. CORR captures data on almost all patients who initiate hemodialysis in Canada. We were able to perform more comprehensive covariate adjustment than previous studies including co-morbidities, modality, vascular access, laboratory parameters, geography, pre-dialysis care and distance to dialysis facility. We also accounted for the competing outcome of transplantation in our survival analysis.

Conversely, our study had limitations. As in any observational study, residual confounding cannot be ruled out as an alternative explanation for our findings. We lacked detailed information regarding the cause of death. We did not account for modality transitions namely initiation of dialysis on peritoneal and transitions to hemodialysis. Our vascular access measurements were taken at initiation of dialysis, did not reflect changes that occur over time and may not reflect access function. The distance from dialysis centre was direct linear distance and may not accurately reflect driving distances or travelling time. We lacked information on the source (living, deceased) of organ procurement.

In conclusion we found that age is an important effect modifier in survival of women on hemodialysis. Young women experienced a considerably higher mortality relative to men whereas older women appear to have a survival advantage. This was consistent after accounting for the competing risks of renal transplantation. Further sex-specific investigations are required into the mechanisms and possible prevention of these mortality disparities.