Introduction Because differences in men's and women's physiology have widely been recognized [1], researchers are encouraged to evaluate clinical study data by sex [2],[3]. Important sex-specific distinctions have been recognized in several of the most prevalent medical conditions, such as obesity [4], type 2 diabetes mellitus [5],[6], cardiovascular disease [7],[8], and depression [9]. Many of these conditions coexist with, or may have contributed to, chronic kidney disease [10]. Chronic kidney disease in itself raises numerous gender questions, for example, regarding sex-dependent prevalence [11] and disease awareness [12]. Sex-specific differences in the characteristics, treatment, and outcomes for individuals on renal replacement therapy have, however, only once previously been the primary theme in an international study, and with focus on mortality patterns at the start of dialysis [13]. Here we present a large adult male-to-female comparison of patient and treatment characteristics as well as mortality risk, using evidence from participants in the international Dialysis Outcomes and Practice Patterns Study (DOPPS). We also compare the adult male-to-female mortality risk with that of the general population, as deduced from the Human Mortality Database life tables. We aimed to describe current hemodialysis practice patterns, and identify patient variables or hemodialysis practices that can be modified in order to improve the care of women and men with end-stage renal disease by assessing (1) hemodialysis prevalence among study participants, overall and by country, (2) national differences in sex-dependent hemodialysis patient mortality, (3) sex-dependent differences in hemodialysis characteristics, and (4) the presence of a sex interaction in the associations between hemodialysis characteristics and mortality. Methods Patients and Data Collection DOPPS data The DOPPS is an international prospective cohort study of adult patients (ages ≥18 y) undergoing hemodialysis treated in representative facilities of each participating country (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the United Kingdom, and the United States). Phase 1 of the DOPPS collected data from June 1996 to October 2001, Phase 2 from February 2002 to February 2005, Phase 3 from June 2005 to January 2009, and Phase 4 from March 2009 to March 2012. Data collection in Australia, Belgium, Canada, New Zealand, and Sweden did not begin until Phase 2. Due to the small number of DOPPS facilities recruited in New Zealand (n = 2), patients in this country were combined with those in Australia (n = 18 facilities) in subsequent analyses. DOPPS facilities were enrolled randomly from a list of all hemodialysis facilities within each nation at the beginning of each phase of data collection between 1996 and 2012, as described previously [14],[15]. In the current study, we analyzed the following patient populations: (1) 206,374 DOPPS census patients from the initial cross-section of patients in each study phase, i.e., all patients dialyzing in the DOPPS facilities at study start, having data on demographics and mortality; (2) 35,964 prevalent patients (subset of patient population #1 above, based on a random selection of 20–40 hemodialysis patients per participating facility); and (3) 14,941 incident patients from patient population #1 above who were enrolled in the DOPPS within 90 d after initiation of hemodialysis therapy between March 2009 and March 2012. Study approval was received annually from a central institutional review board. Additional national and local ethics committee approvals and written patient consents were obtained as required. Demographic data (including race), comorbid conditions, laboratory values, and medications for sampled patients were abstracted from patient records. Mortality events were collected during study follow-up. Estimated glomerular filtration rate (eGFR) at dialysis initiation was calculated among a subset of population #3 (described above) using the Modification of Diet in Renal Disease Study (MDRD) formula [16]. The Human Mortality Database To compare mortality rates for the general population with those of the DOPPS population, data from the Human Mortality Database was used [17]. Country- and age-group-specific mortality rates were calculated using data from January 2000–December 2009. Individuals aged 90 d dialyzing 3× weekly. bCoronary artery disease, cerebrovascular disease, congestive heart failure, hypertension, peripheral vascular disease, other cardiovascular disease. cCancer, gastrointestinal bleed, lung disease, neurologic disorder, psychologic disorder, recurrent cellulitis. dEuropean countries = Belgium, France, Germany, Italy, Spain, Sweden, UK. eEducation, employment, marital status, smoking status, predialysis systolic blood pressure, blood flow rate, serum potassium, medication prescriptions (erythopoiesis-stimulating agent, phosphate binder, vitamin D, antihypertensive, antibiotic), prior parathyroidectomy, and prior transplant. A/NZ, Australia/New Zealand; BMI, body mass index; CV, cardiovascular; HD, hemodialysis; IDWG, interdialytic weight gain; N. America, North America; PTH, parathyroid hormone. 10.1371/journal.pmed.1001750.g004 Figure 4 Analysis of sex interaction in the associations between hemodialysis patient characteristics and mortality. p-Value is for interaction with sex, shown for variables with p 90 d. Bold indicates p 90 d. Bold indicates p 90 d differ from those of the CHOICE study, which used as-treated analyses for incident patients and showed that catheter use was associated with mortality risk among men but not among women [58]. Thus, hemodialysis vascular access by sex deserves more study to also consider whether our sex-specific findings on vascular access and mortality are partly explained by selection. The present study on hemodialysis patients is shedding light on several sex-dependent issues that have also been addressed in the general population [59]–[61]. Among these issues, smoking and marriage prevalence differed by sex in hemodialysis patients, and may have an effect on outcomes. Our finding of higher rates of clinician-diagnosed depression in women agrees with a previous DOPPS analysis showing that women have a significantly higher prevalence of depressive symptoms according to the Center for Epidemiologic Studies Depression Scale [62]. Access to transplantation has also been previously shown to be lower in women [63], as reinforced by the data presented in Tables 2 and 3. Several limitations need to be acknowledged. The presented analyses of adjusted mortality risk can show only associations, not causation, and can thus merely hint at the mechanisms that render mortality rates similar in men and women on hemodialysis. Likewise, our descriptive findings of hemodialysis prevalence by sex cannot answer why the prevalence of hemodialysis treatment is higher for men than women. However, the large national differences we identified strongly suggest that the reasons go beyond biological ones. After careful review of the present data and the literature, we believe the data suggest that women with end-stage renal disease are less likely than men to receive hemodialysis treatment, perhaps because of psychosocioeconomic factors. It also is possible that women are less likely than men to receive hemodialysis because the severity of their disease is not recognized by their caregivers, they are less aware of their disease and the degree of its severity [12], or they are more reluctant to undergo treatment. The present large study followed a suggestion made many years ago that hemodialysis mortality for women should be analyzed internationally [64]. Despite limitations, it may now open a window of subsequent research opportunities and possibilities to improve patient care. In conclusion, we showed among patients treated with hemodialysis for end-stage renal disease that women differ from men in a vast number of variables, some of which appear related to biology, some to patient care or to society. The finding that the general survival advantage for women is virtually lost for all adult age groups of individuals on dialysis is striking. Variation among the DOPPS regions in the very small survival advantage for women on hemodialysis might be partly explained by similar variations in the general population. The impact of different levels of adjustments on adult male-to-female mortality as well as other sex-related factors (in our statistical interaction studies) points to higher catheter-related mortality risk for women than observed for men, and suggests an opportunity to improve hemodialysis practices. Whether men and women differ by dialysis initiation and chronic kidney disease care is perhaps the most important question raised by the present study. This question is not novel, as national data have been available for decades, but may not previously have been asked as clearly as by the present analysis with a large sample size and international perspective. Future international studies should concentrate on considering sex differences as a factor for treating patients with end-stage renal disease, not only for improving outcomes, but also for equalizing women's access to renal replacement therapy. Supporting Information Figure S1 Adjusted hazard ratios for the adult male-to-female mortality risk in hemodialysis patients, by region (order of case mix and “modifiable” adjustments reversed from Figure 3 ). aStratified by country (including US black race and US non-black race) and phase; n = 36,216 patients (n = 8,258 deaths) among patients with time on dialysis >90 d dialyzing 3× weekly. bCoronary artery disease, cerebrovascular disease, congestive heart failure, hypertension, peripheral vascular disease, other cardiovascular disease. cCancer, gastrointestinal bleed, lung disease, neurologic disorder, psychologic disorder, recurrent cellulitis. dEuropean countries = Belgium, France, Germany, Italy, Spain, Sweden, UK. eEducation, employment, marital status, smoking status, predialysis systolic blood pressure, blood flow rate, serum potassium, medication prescriptions (erythropoiesis-stimulating agent, phosphate binder, vitamin D, antihypertensive, antibiotic), prior parathyroidectomy, and prior transplant. A/NZ, Australia/New Zealand; BMI, body mass index; CV, cardiovascular; HD, hemodialysis; IDWG, interdialytic weight gain; N. America, North America; PTH, parathyroid hormone. (TIF) Click here for additional data file. Table S1 Percentage of patients that are women in the hemodialysis population from national registry data compared to DOPPS. (DOCX) Click here for additional data file. Table S2 Patient characteristics, by sex and country. (DOCX) Click here for additional data file. Table S3 Analysis of sex interaction in the associations between hemodialysis patient characteristics and mortality, by region. (DOCX) Click here for additional data file. Checklist S1 STROBE Statement checklist of items that should be included in reports of observational studies. Responses to the STROBE Statement recommendations are provided in bold italic. (DOCX) Click here for additional data file.
