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Women and ESRD: Modalities, Survival, Unique Considerations
Women and ESRD: Modalities, Survival, Unique Considerations Kelly E. Guglielmi Women currently constitute 44.3% of prevalent patients on hemodialysis and 47% of those on peritoneal dialysis. Women on dialysis do not experience the survival benefit seen in those not on dialysis. This loss of a survival advantage is partially related to a lower cardiovascular survival benefit along with a higher noncardiovascular mortality rate compared with their male counterparts. Of particular concern is the markedly higher mortality rates seen in women less than 45 years of age on dialysis. There are several female hormonal abnormalities in the female dialysis patient that can result in menstrual irregularities, anovulation, infertility, sexual dysfunction, early menopause, accelerated bone loss, and potentially increased risk of cardiovascular complications. Although fertility is impaired in dialysis, conception occurs in 1% to 7% of women of childbearing years on dialysis. Hence, all women with a potential for pregnancy should be counseled regarding the risks of pregnancy and contraceptive options. There are specific gynecologic considerations unique to peritoneal dialysis, including hemoperitoneum, decreased fertility, and uterine prolapse. Sexual dysfunction is commonly seen in the female dialysis population and is associated with depression and a lower quality of life; however, despite the high prevalence, it is generally not assessed nor is it treated. Depression is also common in the female dialysis population. Like sexual dysfunction, depression is underdiagnosed and undertreated in this population. Q 2013 by the National Kidney Foundation, Inc. All rights reserved. Key Words: ESRD, Mortality, Women’s health, Female sexual dysfunction, Depression
Introduction As of 2010, in the United States, 376,352 patients were receiving hemodialysis, 29,733 patients were on peritoneal dialysis, and 174,136 were living with functioning kidney transplants. Of these patients, females constituted 44.3% of patients on hemodialysis, 47% of patients on peritoneal dialysis, and 40.5% of transplanted patients.1 Gender differences that affect patient outcomes, medical complications, and quality of life exist and warrant examination. This article will review what we currently know about the prevalence, modalities, survival, and mortality rates in the female ESRD population. Potential factors affecting survival and mortality will be explored. In addition, unique aspects of ESRD and dialysis affecting the female patient will be reviewed, including gynecologic considerations, reproductive hormone and sexual dysfunction, and gender-specific psychosocial factors. More detailed reviews of pregnancy in CKD and kidney bone disease in the female CKD patient are comprehensively addressed elsewhere in this issue.
Incidence, Prevalence, and Modalities On the basis of the U.S. Renal Data Service 2012 Annual Data Report, the rate of new ESRD cases decreased by 2% in 2010 to a rate of 348 per million population. The number of new patients starting hemodialysis in 2010 declined for the first time in over 30 years. Concurrently, the number of patients initiating peritoneal dialysis increased for the second year in a row to 6.6% of those with a known dialytic modality. The prevalence of ESRD as of December 31, 2010 was 1752 per million population, a 1.1% increase from 2009, which is encouraging because this demonstrates the slowest rate of growth in 30 years.1
The incidence rate for women initiating dialysis or receiving a transplant in 2010 was 274.5 patients per million compared with 440.5 male patients per million population. The prevalence rate for females with ESRD is 1422.6 per million population, which compares to 2167.7 for males. Broken down by modality, the prevalence of females is 920.2 per million for hemodialysis, 80.2 per million for peritoneal dialysis, and 422.2 per million for transplantation, which are respectively 65.7%, 78.8%, and 63.5% of the prevalence of men. This reflects a comparatively lower incidence and prevalence of ESRD in women, albeit women constitute a significant number of individuals receiving therapy for ESRD. It is interesting to note that women appear to receive pre-ESRD care significantly more often than men at 43.4% vs 20% at 0 to 12 months before initiation of dialysis and 42.8% vs 8% more than 12 months before initiation of dialytic support.1 At present, there is limited literature with regard to gender differences and various dialytic modalities. Nonetheless, there are a few observations that warrant mention. In standard hemodialysis, an overestimation of adequacy in females that is based on Kt/V has been suggested. This appears to be related to the difference between male and females in calculating the value of V, or the volume of urea distribution.2 Women appear to
From the Division of Nephrology, Department of Medicine, Advocate Christ Hospital and Medical Center, Evergreen Park, IL. There are no relevant conflicts of interest to disclose. Address correspondence to Kelly E. Guglielmi, MD, Southwest Nephrology Associates, 9125 South Pulaski Avenue, Evergreen Park, IL 60805. E-mail: [email protected] Ó 2013 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.05.003
Advances in Chronic Kidney Disease, Vol 20, No 5 (September), 2013: pp 411-418
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receive shorter treatment sessions and are less likely to receive arteriovenous fistulas.3,4 With regard to peritoneal dialysis, an unusual complication of peritoneal dialysis, encapsulating peritoneal sclerosis, appears to be more prevalent in females, particularly premenopausal women.5 In addition, there are unique complications of peritoneal dialysis related to the female reproductive system that are outlined later in this article.
coronary heart disease in women compared with men. This meta-analysis suggests that women with diabetes have higher blood pressures and a worse lipid profile compared with diabetic men. The meta-analysis also suggests that diabetic men were more likely to receive aspirin, statins, and more aggressive treatment of hypertension compared with their female counterparts.11 INTERHEART, a large worldwide case-control study of 15,000 patients with an acute myocardial infarction, identified women with diabetes as having over a 4-fold higher risk Survival and Mortality of myocardial infarction than diabetic men.12 Szalat and It is well established that women have a longer life expeccolleagues also suggest better control of diabetes and tancy than men in the general population. Females have lipids in males as compared with females.13 Most of the current literature on cardiovascular mortality and diabetes a life expectancy at birth of 81.1 years whereas men have is within the general population; thus, it is difficult to dia life expectancy of 76.3 years.6 This is generally believed to be primarily due to a lower prevalence of cardiovascurectly apply to the dialysis population. However, the data are compelling. Diabetes continues to be the leading lar disease in women. However, several studies have cause for ESRD. Thus, the consistent pattern of greater demonstrated that women on dialysis do not experience mortality in female diabetic patients may well be an ima longer life expectancy as compared with men receiving dialytic support.7-9 Carrero and colleagues examined portant factor in attenuating the cardiovascular survival the cardiovascular and nonbenefit seen in female hecardiovascular mortality modialysis patients as CLINICAL SUMMARY rates of nearly 109,000 male a whole. and females initiated on Perhaps as important, Women on dialysis have a mortality rate similar to men on and yet difficult to define, dialysis. Similar mortality dialysis. is the lack of survival benerates for women and men Reproductive hormone disturbances occur in women on fit in women due primarily on dialysis were noted. dialysis that affect the menstrual cycle, fertility, sexual Further defined, there was to a higher rate of noncarfunction, menopause, bone density, and potentially a smaller survival benefit diovascular death within cardiovascular health. seen in women compared all age categories. Particu Female sexual dysfunction is a complex disorder with with men on dialysis with larly surprising is this obpathophysiologic and psychosocial components regard to cardiovascular servation in younger commonly seen in the female dialysis population. women on dialysis. When mortality compared with Depression is common in the female dialysis population, broken down by age, the general population. but it is under-recognized and undertreated. women less than 45 years However, men initiating dialysis are twice as likely of age on dialysis were to have established cardioseen to demonstrate a higher vascular disease and are more likely to smoke.5 In addimortality risk as compared with men of similar age. This tion, men exhibit a higher prevalence of cardiovascular was most clearly apparent in women during the first calcification and hyperparathyroidism, both of which are year of dialysis and primarily due to noncardiovascular nontraditional risk factors linked to cardiovascular discauses.7 5 Factors contributing to the excess noncardiovascular ease. The observation that women on dialysis enjoy mortality seen in women are not well defined but wara less significant cardiovascular benefit would seem counterintuitive on the basis of these associations alone. Hence, rant further investigation. Nonetheless, several observathere are additional observations that may be useful to tions suggest potential associations. One pattern that consider as we attempt to understand this loss of gender has consistently emerged in the literature is the associaadvantage with initiation of dialysis. Gout has been idention of diabetes and all-cause mortality in women with tified as a nontraditional risk factor for cardiovascular disESRD. Women with diabetes mellitus initiating dialysis have been seen to demonstrate significantly higher allease. Women on dialysis demonstrate a higher incidence cause mortality rates as compared with men within all of gout as compared with men.10 Diabetes in the dialysis age groups.7-9,14 Why diabetes has a greater adverse and nondialysis population has frequently been seen to confer a higher mortality risk in females. There are several effect on female ESRD patients is not easily explained, studies comparing cardiovascular mortality in male and although several observations within the literature raise female diabetics in the general population. A metainteresting possibilities for further investigation. As analysis of 37 prospective studies by Huxley and colpreviously noted, better control of diabetes and lipids leagues demonstrates a 50% risk higher risk of fatal has been shown in males as compared with females.13
Women and ESRD: Unique Considerations
Diabetic females, in particular premenopausal women, appear to demonstrate a higher prevalence of oxidative stress and inflammation, both of which have been implicated in increased mortality on dialysis13 In contrast, Stenvinkel and colleagues have suggested that female reproductive hormones may confer a survival benefit in females with elevated C-reactive peptide levels as compared with their male counterparts on dialysis.15 Markers of protein-energy wasting and inflammation are strong predictors of mortality in ESRD patients. Compared with men, women on dialysis more commonly exhibit muscle atrophy, a marker of protein-energy wasting associated with inflammation, malnutrition, and a significant elevation in mortality.16 Women appear to be less likely to receive arteriovenous fistulas4 and may receive shorter dialysis.3 An increase in dialysis time may confer a survival advantage in women.17 Each of these factors, including diabetic control, lipid control, nutritional status, muscle mass, inflammation, adequacy of dialysis, and access type, have been implicated as potential markers or causative factors in the excess mortality seen in the ESRD population and may cumulatively result in the loss of a survival advantage in women once on dialysis. Women who initiate dialysis at an older age demonstrate a better cardiovascular survival benefit as compared with men of similar age. However, women initiating dialysis at a younger age demonstrate a higher mortality compared with younger men.7 This may well be related to the shortened exposure to reproductive hormones and their cardiovascular protective benefits. ESRD is associated with premature menopause, decreased production of reproductive hormones, and anovulation, as reviewed in the next section. In contrast, women who initiate dialysis at older ages have had a significantly greater lifetime exposure to reproductive hormones and their likely protective benefits.15 With these observations in mind, it would seem important as a next step to identify more specifically the noncardiovascular causes of death for women on dialysis and subsequently develop strategies to attenuate the risk factors known to affect these. Ultimately, this could positively affect mortality rates for this group of patients.
Gynecologic Considerations and Hormonal Abnormalities There are gender-specific medical and psychosocial conditions that affect the female ESRD patient. Abnormalities in fertility and reproduction, menstrual irregularities, anovulation, and sexual dysfunction are well recognized. Female sexual dysfunction appears to be a complex and multifactorial issue with several potential factors related to physiologic changes, associated medical conditions, and psychosocial considerations. To understand the pathophysiology of hormonal and menstrual abnormalities in kidney disease, a brief review
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of the normal menstrual cycle is important. The menstrual cycle begins with menarche at the age of 12 and commences with menopause at approximately age 51.18 The first day of menses is considered day 1 of the cycle. The normal menstrual cycle is composed of 3 phases— follicular or preovulatory, ovulatory, and luteal or postovulatory—and is typically 28 days in duration (range 21-40 days).18 Pulsatile hypothalamic release of gonadotropin releasing hormone regulates secretion of follicle stimulating hormone and luteinizing hormone (LH). Follicle stimulating hormone secretion begins in the late luteal phase of the previous cycle and continues into the early follicular phase, resulting in the growth of several follicles. LH increases slowly through the follicular phase. Estradiol levels rise approximately 7 to 8 days before and peak just before the preovulatory LH surge. The LH surge occurs as a result of a positive estradiol feedback pathway on LH secretion and becomes important as we work to understand what occurs in CKD. Several days before the LH surge, androgens and progestins increase, with progesterone increasing just before the LH surge. The surge in LH culminates in ovulation. With ovulation, estradiol levels decrease to a degree whereas progesterone levels continue to increase. The postovulatory or luteal phase duration is approximately 14 days and ends with the onset of menses. After release of the ovum, the follicle becomes the corpus luteum and continues to secrete progesterone. If the ovum is not fertilized the progesterone levels begin to decrease approximately 1 week before the onset of menses.18 The significance of ovulation and the effect on estrogen and progesterone levels becomes important when we consider the pathophysiological consequences of a disruption in this hormonal pattern. In women with advanced kidney failure, the secretion of gonadotropin releasing hormone appears to be disturbed as well as the LH surge.19,20 As a result, ovulation often fails to occur as is evidenced by the absence of the preovulatory rise and peak in LH and estradiol along with a lack of a rise in progesterone during the latter half of the menstrual cycle.19 This failure in ovulation appears to be related to abnormalities in the positive feedback pathway of estradiol on stimulation of LH release.19 Prolactin levels and biologic activity have been shown to be elevated in women with ESRD20 (Table 1). In the female ESRD population, this has been shown to contribute to decreased libido, infertility, amenorrhea or oligomenorrhea, and galactorrhea.20 There is a notable degree of variability in the literature with regard to the menstrual cycle of a patient on dialysis. Previous studies have suggested that women on dialysis are anovulatory and amenorrheic; however, there appears to be a significant variability of the menstrual pattern in premenopausal dialysis patients.20-22 Menstrual abnormalities described include amenorrhea, oligomenorrhea, polymenorrhea, or menorrhagia.20 Chronic anticoagulation may increase
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Table 1. Reproductive Hormone Abnormalities in ESRD Disturbance of GnRH Abnormalities in the positive feedback pathway of estradiol on LH secretion Lack of LH surge with resultant anovulation Low estradiol levels Low progesterone levels Elevated prolactin levels Abbreviations: GnRH, gonadotropin releasing hormone; LH, luteinizing hormone.
menstrual flow. The pattern of the menstrual cycle may have changed with the institution of erythropoietin therapy. To date, there are limited studies directly evaluating the pathophysiology of the menstrual cycle in dialysis patients. Of the limited studies available, most were performed in the pre-erythropoietin era.19,23,24 Recombinant erythropoetin was approved for use by the U.S. Food and Drug Administration in 1989. Since that time, a survey of women age 55 or younger on dialysis by Holley and colleagues in 1997 suggests that amenorrhea is less frequently seen as compared with older studies. Heavier menstrual flow was described by more women after initiating dialysis compared with prior studies.22 Jang and colleagues describe 10 of 15 premenopausal women on dialysis who experienced regular menses, most of who described premenstrual symptoms, raising the possibility that in fact their menstrual cycles may be ovulatory.21 Both studies only consisted of survey information, with no physiologic or hormonal data. Infertility has historically been well recognized in the female ESRD patient. Frequency of conception in women on dialysis appears to range from 0.3% to 1.5% per year.20 Others report pregnancy occurring in 1% to 7% of women of childbearing years while on dialysis.25,26 In contrast, for women actively attempting pregnancy, conception is estimated at 85% for the first year.27 Whether this number is changing within the current dialysis population has not been vigorously studied and warrants further evaluation. Women on peritoneal dialysis appear to become pregnant less frequently than those on hemodialysis, which is believed to be related to the inability of the ovum to reach the Fallopian tubes in the presence of peritoneal dialysate.28 The aforementioned survey by Holley describes 4 pregnancies while on dialysis in 4 of 76 patients surveyed 55 years of age or younger. Fifty percent of the women surveyed were sexually active whereas only 36% used contraception and only 13% had discussed contraception and pregnancy risks with their nephrologist.22 Although fertility rates likely remain low compared with the general population, counseling regarding conception and the significant risks of pregnancy on dialysis should be addressed in all sexually active women of childbearing age receiving renal replacement therapy. Intrauterine devices are not recommended as a first line for peritoneal dialysis patients because of reports of peritonitis. Estrogen-containing oral contraceptives are a reliable
form of contraception, although they may worsen hypertension and increase thrombotic risk. However, estrogen/progestin supplementation may carry a benefit because many dialysis patients are deficient in estradiol and progestins as outlined previously.29 Menopause occurs earlier in dialysis patients as compared with the general population. One cross-sectional survey found the average age of menopause in women on hemodialysis to be 47.7 years of age,21 consistent with another that noted 47 years of age,22 compared with the average in the general population of 51.3 years of age.30 The overall effect of early menopause in the dialysis population is not clearly defined, although it is intriguing to consider that age at menopause is inversely correlated with all-cause mortality in the general population.31 What are the potential pathologic ramifications and therapeutic options available to the female dialysis patient with abnormalities in the menstrual cycle? This question is complex and the answers are not clearly defined, particularly with regard to the most effective and safest therapeutic approaches. Nonetheless, the literature provides some basis for the importance of evaluating and considering therapy. On the basis of the variability in the hormonal and menstrual disturbances outlined above, the potential for pathology is based on the particular hormonal disturbance seen in a particular patient. In women with amenorrhea or oligomenorrhea, there is a risk for lower progesterone levels because of anovulation. If measured estradiol levels are seen to be normal with no evidence for ovulation, therapy with medroxyprogesterone acetate for 10 days of the month could be considered to avoid the risk of endometrial hyperplasia associated with unopposed estrogen effects on the endometrium.32 Hyperprolactinemia resulting in loss of libido, amenorrhea, oligomenorrhea, or galactorrhea may be responsive to bromocriptine, although this may not restore regular menses because the etiology for the abnormal menstrual cycle in the dialysis patient is complex with multiple factors affecting the cycle as discussed earlier. Approximately 30% of premenopausal women on dialysis have low serum estradiol levels, which can result in several pathophysiologic abnormalities. Low circulating estradiol levels can result in sexual dysfunction related to decreased libido, vaginal dryness and atrophy, dyspareunia, and a decreased ability to achieve orgasm. In addition, low estradiol levels can be an important factor in the accelerated bone loss seen in dialysis patients. Elevated prolactin levels are associated with lower serum estradiol. Matuszkiewics-Rowinska and colleagues’ study of premenopausal women on hemodialysis with amenorrhea and low serum estradiol levels demonstrated development of regular menses, remarkable improvement in libido and sexual activity, and improvement in bone mineral density at 12 months with administration of transdermal estrogen therapy coupled
Women and ESRD: Unique Considerations
with cyclic progesterone compared with a similar control group. Lowering of elevated prolactin levels were also noted, although not to normal levels. The study size was relatively small, with 13 patients in the treatment group; however, the results are encouraging. The risks associated with hormone replacement therapy were not assessed.29 Low estradiol levels can result in vaginal dryness and atrophy with resultant dyspareunia. Potential therapies include lubricants, local estrogen therapy, and estrogen supplementation. Estrogen deficiency does result in accelerated bone loss in the general as well as the dialysis population. There are certainly several additional factors involved in the pathogenesis of the complex and varied disorders of kidney bone disease.29,33 Elsewhere in this issue the complexities of kidney bone disease in the female CKD patient are explored. In amenorrheic women, reappearance of menses after initiating peritoneal dialysis is well described.28 Hemoperitoneum is a common occurrence in menstruating women on peritoneal dialysis. Valenzuela and colleagues noted that all menstruating women in their retrospective review had experienced at least 1 episode of hemoperitoneum. Several experienced recurrent episodes.34 A prospective multicenter review of patients describes a 50% incidence in menstruating peritoneal dialysis patients.35 Gynecologic causes are the most common causes for hemoperitoneum in the adult peritoneal patient. Menstruation with retrograde flow and ovulation with midcycle hemoperitoneum are the most common physiologic events resulting in hemoperitoneum.34,36 Ruptured ovarian cysts, follicular cysts or hemorrhagic luteal cysts, and endometriosis have been uncommonly reported28,37-39 (Table 2). Most often, a menstrual history will elucidate the likely etiology. Hemoperitoneum will typically resolve after a few rapid exchanges with dialysate. Hemoperitoneum can cause mild peritonitis due to blood in the peritoneum, but it is most often painless. Menses-related hemoperitoneum rarely results in intraperitoneal adhesions or catheter obstruction by clot. Rapid exchanges or intraperitoneal heparin can be used to treat or prevent these complications.28 Roomtemperature dialysate has been described as preferred because this induces vasoconstriction.40 Repeated or persistent hemoperitoneum may uncommonly require further evaluation and treatment. Treatment may be surgical or hormonal depending on the severity, etiology, and frequency of recurrence.36 Recurrent retrograde menstruation can be treated with tubal ligation or with Table 2. Gynecologic Causes of Hemoperitoneum in Peritoneal Dialysis Retrograde menstruation Midcycle follicular rupture with ovulation Ruptured ovarian cyst Endometriosis
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hormonal suppression of ovulation.36 All female premenopausal peritoneal dialysis patients should be counseled regarding the likelihood of cyclic hemoperitoneum. Additional gynecologic considerations unique to the peritoneal dialysis patients warrant consideration. ESRD patients are at increased risk for virus-associated malignancies, one if which is the well-known association of human papilloma virus with cervical cancer. Regular cervical cancer screening is important in the appropriate dialysis patient. Antibiotic prohylaxis is not indicated for a routine pelvic examination and PAP smear, although it is indicated for more invasive procedures such as a cervical cone or endometrial biopsy. These procedures should be performed with an empty peritoneal cavity and antibiotic prophylaxis appropriate for vaginal flora.28 Uterine prolapse related to increased intra-abdominal pressure in peritoneal dialysis is well described and may be managed with a change in dialysis prescription to use of a nocturnal cycler with low-volume daytime fills. Uncommonly, leakage of peritoneal fluid through a patent processus vaginalis can occur with resultant labial edema. Vaginal leak of peritoneal fluid through the thin layer of tissue between the peritoneum and the posterior vaginal dome has been rarely described.28
Sexual Dysfunction Sexual dysfunction is a complex disorder with multiple pathophysiologic and psychosocial components. It is assessed most commonly by the Female Sexual Function Index, a 19-point questionnaire that assesses 6 aspects of sexual function: desire, arousal, lubrication, orgasm, global satisfaction, and pain. Sexual dysfunction is commonly seen in the female hemodialysis and peritoneal dialysis populations with an estimated prevalence of up to 80%.41-46 Sexual dysfunction appears to be independently associated with age, symptoms of depression, lower education, menopause, diabetes mellitus, diuretic therapy, and not being waitlisted for kidney transplantation. Women with a partner are less likely to report sexual dysfunction but demonstrate a higher prevalence compared with the general population.46 Sexual dysfunction has been correlated with higher depression scores on the Beck Depression Inventory and lower quality-of-life scores.43-45,47 Despite the amount of data documenting a high prevalence of sexual dysfunction and its association with depression, anxiety, and quality of life, most patients do not discuss their concerns with their gynecologist, nephrologist, or primary care physician and treatment is not commonly provided.41 The evaluation and management of hormonal disturbances and sexual dysfunction in the female dialysis patient requires active involvement of a gynecologist with expertise and interest in this area in collaboration with the nephrology team. Much still needs to be defined with regard to the optimal management of this
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unique patient population. Kidney transplantation improves female sexual function and depression.48,49
Psychosocial Issues and Quality of Life Depression is the most common psychiatric finding in the hemodialysis population.50,51 Although it is a common a finding in both genders, it is significantly more prevalent in female hemodialysis patients compared with men.50-52 Lopes and colleagues have demonstrated a higher prevalence of depression among female hemodialysis patients on the basis of physician-diagnosed depression and scores on the Center for Epidemiological Studies Depression Index. Women on hemodialysis also score lower than their male counterparts on scales assessing health-related quality of life (HRQOL). Taken one step further, Lopes and colleagues have demonstrated an association among depressive symptoms, physician-diagnosed depression, and significantly lower HRQOL scores. This was seen to be significantly more pronounced in female hemodialysis patients. This association of depression with lower HRQOL scores was seen to affect scores on the physical and mental components of the Kidney Disease Quality of Life Short Form.52 Despite the high prevalence, depression is underdiagnosed and undertreated in the hemodialysis population as a whole.52 When we consider these findings, the clinical ramifications are significant. HRQOL is a significant predictor of hospitalization and mortality in the hemodialysis population independent of demographics and multiple co-morbid factors. Whether identifying and treating depression in the female hemodialysis population would have a positive effect on quality of life, hospitalization rates, and mortality requires further investigation. This has yet to be rigorously studied, but it could be a powerful opportunity to affect the care and outcome of hemodialysis patients. Of note, the prevalence of depression and the above noted associations have thus far not been studied in the peritoneal dialysis or home hemodialysis population. Additional interesting observations regarding psychosocial gender differences suggest that women take on more of the responsibility in family adaptation to ESRD than their male counterparts.53 Female African-American hemodialysis patients involved in couple relationships with greater dyadic satisfaction and less conflict demonstrate significantly lower mortality. However, this association was not found to be statistically significant in the male group.54 African-American hemodialysis women living in a complex household defined as a household that consists of a partner and others demonstrate higher mortality than women in a simple household (self or self and significant other). Of note, many of the complex households identified were multigenerational.50 However, social support has been associated with improved outcomes in chronic illness, and perception of social support is associated with improved survival in ESRD.50 It is possible that
a complex household may result in a higher level of stress and caregiving responsibilities for female patients on hemodialysis as opposed to men, thus negating the potential benefit of a larger support system. Behavioral compliance is an important predictor of dialysis outcome, but it does not appear to be significantly different between men and women.50,51 The psychosocial status of any individual on dialysis is certainly complex and unique, making sweeping population assessments difficult. Nonetheless, these observations are food for thought as clinicians attempt to understand and optimize the quality of life and outcomes for women on dialysis.
Conclusions Women currently constitute 44.3% of prevalent patients on hemodialysis and 47% on peritoneal dialysis in the United States. Women receive pre-ESRD care by a nephrologist significantly more often than men. However, despite this, women on dialysis do not enjoy the survival benefit compared with men that is seen in the general population. This loss of survival advantage is partially related to a lower cardiovascular survival advantage and more prominently related to a higher noncardiovascular mortality rate compared with their male counterparts. Particularly surprising is the markedly higher mortality rates seen in women younger than 45 years old on dialysis. Several factors have been implicated, although further research regarding the specific causes, the associated risk factors, and whether affecting these risk factors results in improved mortality is necessary. There are several gynecologic and hormonal irregularities that affect women on dialysis. Hormonal abnormalities seen in the female with ESRD can result in menstrual irregularities, anovulation, infertility, sexual dysfunction, early menopause, accelerated bone loss, and potentially increased risk of cardiovascular complications. Despite the frequency of reproductive hormone abnormalities with resultant morbidity and mortality, limited data are currently available with regard to optimal management strategies. Although fertility is impaired in dialysis, conception occurs in 1% to 7% of patients on dialysis. Thus, all women of childbearing age should be counseled regarding the risks of pregnancy and contraceptive options. There are specific gynecologic considerations unique to peritoneal dialysis. Peritoneal dialysis patients benefit from prophylaxis before undergoing invasive gynecologic procedures. Well-described complications unique to the peritoneal dialysis patient include hemoperitoneum, further decreased fertility, and uterine prolapse. Sexual dysfunction is common in the female hemodialysis as well as the peritoneal dialysis population. Female sexual dysfunction in ESRD is a complex disorder with multiple pathophysiologic and psychosocial components. It is seen to be associated with depression and lower quality of life. However, despite its high
Women and ESRD: Unique Considerations
prevalence, it is generally not assessed nor is it treated. Depression is prevalent in the female dialysis population. Depression and other psychosocial factors such as social support and stressors more profoundly affect the female dialysis patient compared with her male counterpart in terms of lower quality of life and mortality. Like sexual dysfunction, depression is under-recognized and undertreated in this population. As summarized, there are several gender-specific considerations and pathologies that occur in women with ESRD. Hopefully, bringing attention to several of these unique issues may increase the level of awareness within the nephrology community, positively affect how the multidisciplinary team cares for the female dialysis patient, and spur researchers to take our understanding to the next level.
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37.
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differs between genders. Nephron Clin Pract. 2009;112(4):c268c275. Stenvinkel P, Wanner C, Metzger T, et al. Inflammation and outcome in end-stage renal failure: does female gender constitute a survival advantage? Kidney Int. 2002;62(5):1791-1798. Carrero JJ, Chmielewski M, Axelsson J, et al. Muscle atrophy, inflammation and clinical outcome in incident and prevalent dialysis patients. Clin Nutr. 2008;27(4):557-564. Miller JE, Kovesdy CP, Nissenson AR, et al. Association of hemodialysis treatment time and dose with mortality and the role of race and sex. Am J Kidney Dis. 2010;55(1):100-112. Walsh PC. Diseases of the Prostate. In: Cecil Textbook of Medicine. Wyngaarden, Smith (eds). W. B. Saunders Company; 1988, p. 14211425. Lim VS, Henriquez C, Sievertsen G, Frohman LA. Ovarian function in chronic renal failure: evidence suggesting hypothalamic anovulation. Ann Intern Med. 1980;93(1):21-27. Rathi M, Ramachandran R. Sexual and gonadal dysfunction in chronic kidney disease: pathophysiology. Indian J Endocrinol Metab. 2012;16(2):214-219. Jang C, Bell RJ, White VS, et al. Women’s health issues in haemodialysis patients. Med J Aust. 2001;175(6):298-301. Holley JL, Schmidt RJ, Bender FH, Dumler F, Schiff M. Gynecologic and reproductive issues in women on dialysis. Am J Kidney Dis. 1997;29(5):685-690. Zingraff J, Jungers P, Pelissier C, Nahoul K, Feinstein MC, Scholler R. Pituitary and ovarian dysfunctions in women on haemodialysis. Nephron. 1982;30(2):149-153. Swamy AP, Woolf PD, Cestero RV. Hypothalamic-pituitary-ovarian axis in uremic women. J Lab Clin Med. 1979;93(6):1066-1072. Schmidt RJ, Holley JL. Fertility and contraception in end-stage renal disease. Adv Ren Replace Ther. 1998;5(1):38-44. Okundaye I, Abrinko P, Hou S. Registry of pregnancy in dialysis patients. Am J Kidney Dis. 1998;31(5):766-773. Gnoth C, Godehardt E, Frank-Herrmann P, Friol K, Tigges J, Freundl G. Definition and prevalence of subfertility and infertility. Hum Reprod. 2005;20(5):1144-1147. Dimitriadis CA, Bargman JM. Gynecologic issues in peritoneal dialysis. Adv Perit Dial. 2011;27:101-105. Matuszkiewicz-Rowi~ nska J, Sk orzewska K, Radowicki S, et al. The benefits of hormone replacement therapy in pre-menopausal women with oestrogen deficiency on haemodialysis. Nephrol Dial Transplant. 1999;14(5):1238-1243. Kato I, Toniolo P, Akhmedkhanov A, Koenig KL, Shore R, Zeleniuch-Jacquotte A. Prospective study of factors influencing the onset of natural menopause. J Clin Epidemiol. 1998;51(12): 1271-1276. Jacobsen BK, Heuch I, Kv ale G. Age at natural menopause and allcause mortality: a 37-year follow-up of 19,731 Norwegian women. Am J Epidemiol. 2003;157(10):923-929. Palmer BF. Sexual dysfunction in uremia. J Am Soc Nephrol. 1999;10(6):1381-1388. Silver J, Epstein E, Naveh-Many T. Oestrogen deficiency—does it have a role in the genesis of skeletal problems in dialysed women? Nephrol Dial Transplant. 1996;11(4):565-566. Valenzuela MP, Ponz E, Martınez Oca~ na JC, et al. Prognostic significance of hemoperitoneum in peritoneal dialysis. Nefrologia. 2008;28(1):73-76 (Spanish). Holley JL, Schiff M, Schmidt RJ, Bender FH, Dumler F. Hemoperitoneum occurs in over half of menstruating women on peritoneal dialysis. Perit Dial Int. 1996;16(6):650. Lew SQ. Hemoperitoneum: bloody peritoneal dialysate in ESRD patients receiving peritoneal dialysis. Perit Dial Int. 2007;27(3): 226-233. Harnett JD, Gill D, Corbett L, Parfrey PS, Gault H. Recurrent hemoperitoneum in women receiving continuous ambulatory peritoneal dialysis. Ann Intern Med. 1987;107(3):341-343.
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38. Fraley DS, Johnston JR, Bruns FJ, Adler S, Segel DP. Rupture of ovarian cyst: massive hemoperitoneum in continuous ambulatory peritoneal dialysis patients: diagnosis and treatment. Am J Kidney Dis. 1988;12(1):69-71. 39. Handa SP, Scarth H. Hemorrhagic luteal cyst with massive hemoperitoneum in a patient on CAPD. Perit Dial Int. 1993;13(1):65-66. 40. Goodkin DA, Benning MG. An outpatient maneuver to treat bloody effluent during continuous ambulatory peritoneal dialysis (CAPD). Perit Dial Int. 1990;10(3):227-229. 41. Seethala S, Hess R, Bossola M, Unruh ML, Weisbord SD. Sexual function in women receiving maintenance dialysis. Hemodial Int. 2010;14(1):55-60. 42. Navaneethan SD, Vecchio M, Johnson DW, et al. Prevalence and correlates of self-reported sexual dysfunction in CKD: a meta-analysis of observational studies. Am J Kidney Dis. 2010;56(4):670-685. 43. Lai CF, Wang YT, Hung KY, et al. Sexual dysfunction in peritoneal dialysis patients. Am J Nephrol. 2007;27(6):615-621. 44. Santos PR, Capote JR, Cavalcanti JU, et al. Quality of life among women with sexual dysfunction undergoing hemodialysis: a crosssectional observational study. Health Qual Life Outcomes. 2012;10:103. 45. Yazici R, Altintepe L, Guney I, et al. Female sexual dysfunction in peritoneal dialysis and hemodialysis patients. Ren Fail. 2009;31(5):360-364. 46. Strippoli GF, Vecchio M, Palmer S, et al. Sexual dysfunction in women with ESRD requiring hemodialysis. Clin J Am Soc Nephrol. 2012;7(6):974-981.
47. Lew-Starowicz M, Gellert R. The sexuality and quality of life of hemodialyzed patients–ASED multicenter study. J Sex Med. 2009;6(4):1062-1071. 48. Kettas¸ E, Cayan F, Akbay E, Kiykim A, Cayan S. Sexual dysfunction and associated risk factors in women with end-stage renal disease. J Sex Med. 2008;5(4):872-877. 49. Noohi S, Azar M, Behzadi AH, et al. Comparison of sexual function in females receiving haemodialysis and after renal transplantation. J Ren Care. 2010;36(4):212-217. 50. Kimmel PL, Patel SS. Psychosocial issues in women with renal disease. Adv Ren Replace Ther. 2003;10(1):61-70. 51. Lew SQ, Patel SS. Psychosocial and quality of life issues in women with end-stage renal disease. Adv Chronic Kidney Dis. 2007;14(4): 358-363. 52. Lopes GB, Matos CM, Leite EB, et al. Depression as a potential explanation for gender differences in health-related quality of life among patients on maintenance hemodialysis. Nephron Clin Pract. 2010;115(1):c35-c40. 53. Devins GM, Hunsley J, Mandin H, Taub KJ, Paul LC. The marital context of end-stage renal disease: illness intrusiveness and perceived changes in family environment. Ann Behav Med. 1997;19(4): 325-332. 54. Kimmel PL, Peterson RA, Weihs KL, et al. Dyadic relationship conflict, gender, and mortality in urban hemodialysis patients. J Am Soc Nephrol. 2000;11(8):1518-1525.
Introduction As of 2010, in the United States, 376,352 patients were receiving hemodialysis, 29,733 patients were on peritoneal dialysis, and 174,136 were living with functioning kidney transplants. Of these patients, females constituted 44.3% of patients on hemodialysis, 47% of patients on peritoneal dialysis, and 40.5% of transplanted patients.1 Gender differences that affect patient outcomes, medical complications, and quality of life exist and warrant examination. This article will review what we currently know about the prevalence, modalities, survival, and mortality rates in the female ESRD population. Potential factors affecting survival and mortality will be explored. In addition, unique aspects of ESRD and dialysis affecting the female patient will be reviewed, including gynecologic considerations, reproductive hormone and sexual dysfunction, and gender-specific psychosocial factors. More detailed reviews of pregnancy in CKD and kidney bone disease in the female CKD patient are comprehensively addressed elsewhere in this issue.
Incidence, Prevalence, and Modalities On the basis of the U.S. Renal Data Service 2012 Annual Data Report, the rate of new ESRD cases decreased by 2% in 2010 to a rate of 348 per million population. The number of new patients starting hemodialysis in 2010 declined for the first time in over 30 years. Concurrently, the number of patients initiating peritoneal dialysis increased for the second year in a row to 6.6% of those with a known dialytic modality. The prevalence of ESRD as of December 31, 2010 was 1752 per million population, a 1.1% increase from 2009, which is encouraging because this demonstrates the slowest rate of growth in 30 years.1
The incidence rate for women initiating dialysis or receiving a transplant in 2010 was 274.5 patients per million compared with 440.5 male patients per million population. The prevalence rate for females with ESRD is 1422.6 per million population, which compares to 2167.7 for males. Broken down by modality, the prevalence of females is 920.2 per million for hemodialysis, 80.2 per million for peritoneal dialysis, and 422.2 per million for transplantation, which are respectively 65.7%, 78.8%, and 63.5% of the prevalence of men. This reflects a comparatively lower incidence and prevalence of ESRD in women, albeit women constitute a significant number of individuals receiving therapy for ESRD. It is interesting to note that women appear to receive pre-ESRD care significantly more often than men at 43.4% vs 20% at 0 to 12 months before initiation of dialysis and 42.8% vs 8% more than 12 months before initiation of dialytic support.1 At present, there is limited literature with regard to gender differences and various dialytic modalities. Nonetheless, there are a few observations that warrant mention. In standard hemodialysis, an overestimation of adequacy in females that is based on Kt/V has been suggested. This appears to be related to the difference between male and females in calculating the value of V, or the volume of urea distribution.2 Women appear to
From the Division of Nephrology, Department of Medicine, Advocate Christ Hospital and Medical Center, Evergreen Park, IL. There are no relevant conflicts of interest to disclose. Address correspondence to Kelly E. Guglielmi, MD, Southwest Nephrology Associates, 9125 South Pulaski Avenue, Evergreen Park, IL 60805. E-mail: [email protected] Ó 2013 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.05.003
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receive shorter treatment sessions and are less likely to receive arteriovenous fistulas.3,4 With regard to peritoneal dialysis, an unusual complication of peritoneal dialysis, encapsulating peritoneal sclerosis, appears to be more prevalent in females, particularly premenopausal women.5 In addition, there are unique complications of peritoneal dialysis related to the female reproductive system that are outlined later in this article.
coronary heart disease in women compared with men. This meta-analysis suggests that women with diabetes have higher blood pressures and a worse lipid profile compared with diabetic men. The meta-analysis also suggests that diabetic men were more likely to receive aspirin, statins, and more aggressive treatment of hypertension compared with their female counterparts.11 INTERHEART, a large worldwide case-control study of 15,000 patients with an acute myocardial infarction, identified women with diabetes as having over a 4-fold higher risk Survival and Mortality of myocardial infarction than diabetic men.12 Szalat and It is well established that women have a longer life expeccolleagues also suggest better control of diabetes and tancy than men in the general population. Females have lipids in males as compared with females.13 Most of the current literature on cardiovascular mortality and diabetes a life expectancy at birth of 81.1 years whereas men have is within the general population; thus, it is difficult to dia life expectancy of 76.3 years.6 This is generally believed to be primarily due to a lower prevalence of cardiovascurectly apply to the dialysis population. However, the data are compelling. Diabetes continues to be the leading lar disease in women. However, several studies have cause for ESRD. Thus, the consistent pattern of greater demonstrated that women on dialysis do not experience mortality in female diabetic patients may well be an ima longer life expectancy as compared with men receiving dialytic support.7-9 Carrero and colleagues examined portant factor in attenuating the cardiovascular survival the cardiovascular and nonbenefit seen in female hecardiovascular mortality modialysis patients as CLINICAL SUMMARY rates of nearly 109,000 male a whole. and females initiated on Perhaps as important, Women on dialysis have a mortality rate similar to men on and yet difficult to define, dialysis. Similar mortality dialysis. is the lack of survival benerates for women and men Reproductive hormone disturbances occur in women on fit in women due primarily on dialysis were noted. dialysis that affect the menstrual cycle, fertility, sexual Further defined, there was to a higher rate of noncarfunction, menopause, bone density, and potentially a smaller survival benefit diovascular death within cardiovascular health. seen in women compared all age categories. Particu Female sexual dysfunction is a complex disorder with with men on dialysis with larly surprising is this obpathophysiologic and psychosocial components regard to cardiovascular servation in younger commonly seen in the female dialysis population. women on dialysis. When mortality compared with Depression is common in the female dialysis population, broken down by age, the general population. but it is under-recognized and undertreated. women less than 45 years However, men initiating dialysis are twice as likely of age on dialysis were to have established cardioseen to demonstrate a higher vascular disease and are more likely to smoke.5 In addimortality risk as compared with men of similar age. This tion, men exhibit a higher prevalence of cardiovascular was most clearly apparent in women during the first calcification and hyperparathyroidism, both of which are year of dialysis and primarily due to noncardiovascular nontraditional risk factors linked to cardiovascular discauses.7 5 Factors contributing to the excess noncardiovascular ease. The observation that women on dialysis enjoy mortality seen in women are not well defined but wara less significant cardiovascular benefit would seem counterintuitive on the basis of these associations alone. Hence, rant further investigation. Nonetheless, several observathere are additional observations that may be useful to tions suggest potential associations. One pattern that consider as we attempt to understand this loss of gender has consistently emerged in the literature is the associaadvantage with initiation of dialysis. Gout has been idention of diabetes and all-cause mortality in women with tified as a nontraditional risk factor for cardiovascular disESRD. Women with diabetes mellitus initiating dialysis have been seen to demonstrate significantly higher allease. Women on dialysis demonstrate a higher incidence cause mortality rates as compared with men within all of gout as compared with men.10 Diabetes in the dialysis age groups.7-9,14 Why diabetes has a greater adverse and nondialysis population has frequently been seen to confer a higher mortality risk in females. There are several effect on female ESRD patients is not easily explained, studies comparing cardiovascular mortality in male and although several observations within the literature raise female diabetics in the general population. A metainteresting possibilities for further investigation. As analysis of 37 prospective studies by Huxley and colpreviously noted, better control of diabetes and lipids leagues demonstrates a 50% risk higher risk of fatal has been shown in males as compared with females.13
Women and ESRD: Unique Considerations
Diabetic females, in particular premenopausal women, appear to demonstrate a higher prevalence of oxidative stress and inflammation, both of which have been implicated in increased mortality on dialysis13 In contrast, Stenvinkel and colleagues have suggested that female reproductive hormones may confer a survival benefit in females with elevated C-reactive peptide levels as compared with their male counterparts on dialysis.15 Markers of protein-energy wasting and inflammation are strong predictors of mortality in ESRD patients. Compared with men, women on dialysis more commonly exhibit muscle atrophy, a marker of protein-energy wasting associated with inflammation, malnutrition, and a significant elevation in mortality.16 Women appear to be less likely to receive arteriovenous fistulas4 and may receive shorter dialysis.3 An increase in dialysis time may confer a survival advantage in women.17 Each of these factors, including diabetic control, lipid control, nutritional status, muscle mass, inflammation, adequacy of dialysis, and access type, have been implicated as potential markers or causative factors in the excess mortality seen in the ESRD population and may cumulatively result in the loss of a survival advantage in women once on dialysis. Women who initiate dialysis at an older age demonstrate a better cardiovascular survival benefit as compared with men of similar age. However, women initiating dialysis at a younger age demonstrate a higher mortality compared with younger men.7 This may well be related to the shortened exposure to reproductive hormones and their cardiovascular protective benefits. ESRD is associated with premature menopause, decreased production of reproductive hormones, and anovulation, as reviewed in the next section. In contrast, women who initiate dialysis at older ages have had a significantly greater lifetime exposure to reproductive hormones and their likely protective benefits.15 With these observations in mind, it would seem important as a next step to identify more specifically the noncardiovascular causes of death for women on dialysis and subsequently develop strategies to attenuate the risk factors known to affect these. Ultimately, this could positively affect mortality rates for this group of patients.
Gynecologic Considerations and Hormonal Abnormalities There are gender-specific medical and psychosocial conditions that affect the female ESRD patient. Abnormalities in fertility and reproduction, menstrual irregularities, anovulation, and sexual dysfunction are well recognized. Female sexual dysfunction appears to be a complex and multifactorial issue with several potential factors related to physiologic changes, associated medical conditions, and psychosocial considerations. To understand the pathophysiology of hormonal and menstrual abnormalities in kidney disease, a brief review
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of the normal menstrual cycle is important. The menstrual cycle begins with menarche at the age of 12 and commences with menopause at approximately age 51.18 The first day of menses is considered day 1 of the cycle. The normal menstrual cycle is composed of 3 phases— follicular or preovulatory, ovulatory, and luteal or postovulatory—and is typically 28 days in duration (range 21-40 days).18 Pulsatile hypothalamic release of gonadotropin releasing hormone regulates secretion of follicle stimulating hormone and luteinizing hormone (LH). Follicle stimulating hormone secretion begins in the late luteal phase of the previous cycle and continues into the early follicular phase, resulting in the growth of several follicles. LH increases slowly through the follicular phase. Estradiol levels rise approximately 7 to 8 days before and peak just before the preovulatory LH surge. The LH surge occurs as a result of a positive estradiol feedback pathway on LH secretion and becomes important as we work to understand what occurs in CKD. Several days before the LH surge, androgens and progestins increase, with progesterone increasing just before the LH surge. The surge in LH culminates in ovulation. With ovulation, estradiol levels decrease to a degree whereas progesterone levels continue to increase. The postovulatory or luteal phase duration is approximately 14 days and ends with the onset of menses. After release of the ovum, the follicle becomes the corpus luteum and continues to secrete progesterone. If the ovum is not fertilized the progesterone levels begin to decrease approximately 1 week before the onset of menses.18 The significance of ovulation and the effect on estrogen and progesterone levels becomes important when we consider the pathophysiological consequences of a disruption in this hormonal pattern. In women with advanced kidney failure, the secretion of gonadotropin releasing hormone appears to be disturbed as well as the LH surge.19,20 As a result, ovulation often fails to occur as is evidenced by the absence of the preovulatory rise and peak in LH and estradiol along with a lack of a rise in progesterone during the latter half of the menstrual cycle.19 This failure in ovulation appears to be related to abnormalities in the positive feedback pathway of estradiol on stimulation of LH release.19 Prolactin levels and biologic activity have been shown to be elevated in women with ESRD20 (Table 1). In the female ESRD population, this has been shown to contribute to decreased libido, infertility, amenorrhea or oligomenorrhea, and galactorrhea.20 There is a notable degree of variability in the literature with regard to the menstrual cycle of a patient on dialysis. Previous studies have suggested that women on dialysis are anovulatory and amenorrheic; however, there appears to be a significant variability of the menstrual pattern in premenopausal dialysis patients.20-22 Menstrual abnormalities described include amenorrhea, oligomenorrhea, polymenorrhea, or menorrhagia.20 Chronic anticoagulation may increase
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Table 1. Reproductive Hormone Abnormalities in ESRD Disturbance of GnRH Abnormalities in the positive feedback pathway of estradiol on LH secretion Lack of LH surge with resultant anovulation Low estradiol levels Low progesterone levels Elevated prolactin levels Abbreviations: GnRH, gonadotropin releasing hormone; LH, luteinizing hormone.
menstrual flow. The pattern of the menstrual cycle may have changed with the institution of erythropoietin therapy. To date, there are limited studies directly evaluating the pathophysiology of the menstrual cycle in dialysis patients. Of the limited studies available, most were performed in the pre-erythropoietin era.19,23,24 Recombinant erythropoetin was approved for use by the U.S. Food and Drug Administration in 1989. Since that time, a survey of women age 55 or younger on dialysis by Holley and colleagues in 1997 suggests that amenorrhea is less frequently seen as compared with older studies. Heavier menstrual flow was described by more women after initiating dialysis compared with prior studies.22 Jang and colleagues describe 10 of 15 premenopausal women on dialysis who experienced regular menses, most of who described premenstrual symptoms, raising the possibility that in fact their menstrual cycles may be ovulatory.21 Both studies only consisted of survey information, with no physiologic or hormonal data. Infertility has historically been well recognized in the female ESRD patient. Frequency of conception in women on dialysis appears to range from 0.3% to 1.5% per year.20 Others report pregnancy occurring in 1% to 7% of women of childbearing years while on dialysis.25,26 In contrast, for women actively attempting pregnancy, conception is estimated at 85% for the first year.27 Whether this number is changing within the current dialysis population has not been vigorously studied and warrants further evaluation. Women on peritoneal dialysis appear to become pregnant less frequently than those on hemodialysis, which is believed to be related to the inability of the ovum to reach the Fallopian tubes in the presence of peritoneal dialysate.28 The aforementioned survey by Holley describes 4 pregnancies while on dialysis in 4 of 76 patients surveyed 55 years of age or younger. Fifty percent of the women surveyed were sexually active whereas only 36% used contraception and only 13% had discussed contraception and pregnancy risks with their nephrologist.22 Although fertility rates likely remain low compared with the general population, counseling regarding conception and the significant risks of pregnancy on dialysis should be addressed in all sexually active women of childbearing age receiving renal replacement therapy. Intrauterine devices are not recommended as a first line for peritoneal dialysis patients because of reports of peritonitis. Estrogen-containing oral contraceptives are a reliable
form of contraception, although they may worsen hypertension and increase thrombotic risk. However, estrogen/progestin supplementation may carry a benefit because many dialysis patients are deficient in estradiol and progestins as outlined previously.29 Menopause occurs earlier in dialysis patients as compared with the general population. One cross-sectional survey found the average age of menopause in women on hemodialysis to be 47.7 years of age,21 consistent with another that noted 47 years of age,22 compared with the average in the general population of 51.3 years of age.30 The overall effect of early menopause in the dialysis population is not clearly defined, although it is intriguing to consider that age at menopause is inversely correlated with all-cause mortality in the general population.31 What are the potential pathologic ramifications and therapeutic options available to the female dialysis patient with abnormalities in the menstrual cycle? This question is complex and the answers are not clearly defined, particularly with regard to the most effective and safest therapeutic approaches. Nonetheless, the literature provides some basis for the importance of evaluating and considering therapy. On the basis of the variability in the hormonal and menstrual disturbances outlined above, the potential for pathology is based on the particular hormonal disturbance seen in a particular patient. In women with amenorrhea or oligomenorrhea, there is a risk for lower progesterone levels because of anovulation. If measured estradiol levels are seen to be normal with no evidence for ovulation, therapy with medroxyprogesterone acetate for 10 days of the month could be considered to avoid the risk of endometrial hyperplasia associated with unopposed estrogen effects on the endometrium.32 Hyperprolactinemia resulting in loss of libido, amenorrhea, oligomenorrhea, or galactorrhea may be responsive to bromocriptine, although this may not restore regular menses because the etiology for the abnormal menstrual cycle in the dialysis patient is complex with multiple factors affecting the cycle as discussed earlier. Approximately 30% of premenopausal women on dialysis have low serum estradiol levels, which can result in several pathophysiologic abnormalities. Low circulating estradiol levels can result in sexual dysfunction related to decreased libido, vaginal dryness and atrophy, dyspareunia, and a decreased ability to achieve orgasm. In addition, low estradiol levels can be an important factor in the accelerated bone loss seen in dialysis patients. Elevated prolactin levels are associated with lower serum estradiol. Matuszkiewics-Rowinska and colleagues’ study of premenopausal women on hemodialysis with amenorrhea and low serum estradiol levels demonstrated development of regular menses, remarkable improvement in libido and sexual activity, and improvement in bone mineral density at 12 months with administration of transdermal estrogen therapy coupled
Women and ESRD: Unique Considerations
with cyclic progesterone compared with a similar control group. Lowering of elevated prolactin levels were also noted, although not to normal levels. The study size was relatively small, with 13 patients in the treatment group; however, the results are encouraging. The risks associated with hormone replacement therapy were not assessed.29 Low estradiol levels can result in vaginal dryness and atrophy with resultant dyspareunia. Potential therapies include lubricants, local estrogen therapy, and estrogen supplementation. Estrogen deficiency does result in accelerated bone loss in the general as well as the dialysis population. There are certainly several additional factors involved in the pathogenesis of the complex and varied disorders of kidney bone disease.29,33 Elsewhere in this issue the complexities of kidney bone disease in the female CKD patient are explored. In amenorrheic women, reappearance of menses after initiating peritoneal dialysis is well described.28 Hemoperitoneum is a common occurrence in menstruating women on peritoneal dialysis. Valenzuela and colleagues noted that all menstruating women in their retrospective review had experienced at least 1 episode of hemoperitoneum. Several experienced recurrent episodes.34 A prospective multicenter review of patients describes a 50% incidence in menstruating peritoneal dialysis patients.35 Gynecologic causes are the most common causes for hemoperitoneum in the adult peritoneal patient. Menstruation with retrograde flow and ovulation with midcycle hemoperitoneum are the most common physiologic events resulting in hemoperitoneum.34,36 Ruptured ovarian cysts, follicular cysts or hemorrhagic luteal cysts, and endometriosis have been uncommonly reported28,37-39 (Table 2). Most often, a menstrual history will elucidate the likely etiology. Hemoperitoneum will typically resolve after a few rapid exchanges with dialysate. Hemoperitoneum can cause mild peritonitis due to blood in the peritoneum, but it is most often painless. Menses-related hemoperitoneum rarely results in intraperitoneal adhesions or catheter obstruction by clot. Rapid exchanges or intraperitoneal heparin can be used to treat or prevent these complications.28 Roomtemperature dialysate has been described as preferred because this induces vasoconstriction.40 Repeated or persistent hemoperitoneum may uncommonly require further evaluation and treatment. Treatment may be surgical or hormonal depending on the severity, etiology, and frequency of recurrence.36 Recurrent retrograde menstruation can be treated with tubal ligation or with Table 2. Gynecologic Causes of Hemoperitoneum in Peritoneal Dialysis Retrograde menstruation Midcycle follicular rupture with ovulation Ruptured ovarian cyst Endometriosis
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hormonal suppression of ovulation.36 All female premenopausal peritoneal dialysis patients should be counseled regarding the likelihood of cyclic hemoperitoneum. Additional gynecologic considerations unique to the peritoneal dialysis patients warrant consideration. ESRD patients are at increased risk for virus-associated malignancies, one if which is the well-known association of human papilloma virus with cervical cancer. Regular cervical cancer screening is important in the appropriate dialysis patient. Antibiotic prohylaxis is not indicated for a routine pelvic examination and PAP smear, although it is indicated for more invasive procedures such as a cervical cone or endometrial biopsy. These procedures should be performed with an empty peritoneal cavity and antibiotic prophylaxis appropriate for vaginal flora.28 Uterine prolapse related to increased intra-abdominal pressure in peritoneal dialysis is well described and may be managed with a change in dialysis prescription to use of a nocturnal cycler with low-volume daytime fills. Uncommonly, leakage of peritoneal fluid through a patent processus vaginalis can occur with resultant labial edema. Vaginal leak of peritoneal fluid through the thin layer of tissue between the peritoneum and the posterior vaginal dome has been rarely described.28
Sexual Dysfunction Sexual dysfunction is a complex disorder with multiple pathophysiologic and psychosocial components. It is assessed most commonly by the Female Sexual Function Index, a 19-point questionnaire that assesses 6 aspects of sexual function: desire, arousal, lubrication, orgasm, global satisfaction, and pain. Sexual dysfunction is commonly seen in the female hemodialysis and peritoneal dialysis populations with an estimated prevalence of up to 80%.41-46 Sexual dysfunction appears to be independently associated with age, symptoms of depression, lower education, menopause, diabetes mellitus, diuretic therapy, and not being waitlisted for kidney transplantation. Women with a partner are less likely to report sexual dysfunction but demonstrate a higher prevalence compared with the general population.46 Sexual dysfunction has been correlated with higher depression scores on the Beck Depression Inventory and lower quality-of-life scores.43-45,47 Despite the amount of data documenting a high prevalence of sexual dysfunction and its association with depression, anxiety, and quality of life, most patients do not discuss their concerns with their gynecologist, nephrologist, or primary care physician and treatment is not commonly provided.41 The evaluation and management of hormonal disturbances and sexual dysfunction in the female dialysis patient requires active involvement of a gynecologist with expertise and interest in this area in collaboration with the nephrology team. Much still needs to be defined with regard to the optimal management of this
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unique patient population. Kidney transplantation improves female sexual function and depression.48,49
Psychosocial Issues and Quality of Life Depression is the most common psychiatric finding in the hemodialysis population.50,51 Although it is a common a finding in both genders, it is significantly more prevalent in female hemodialysis patients compared with men.50-52 Lopes and colleagues have demonstrated a higher prevalence of depression among female hemodialysis patients on the basis of physician-diagnosed depression and scores on the Center for Epidemiological Studies Depression Index. Women on hemodialysis also score lower than their male counterparts on scales assessing health-related quality of life (HRQOL). Taken one step further, Lopes and colleagues have demonstrated an association among depressive symptoms, physician-diagnosed depression, and significantly lower HRQOL scores. This was seen to be significantly more pronounced in female hemodialysis patients. This association of depression with lower HRQOL scores was seen to affect scores on the physical and mental components of the Kidney Disease Quality of Life Short Form.52 Despite the high prevalence, depression is underdiagnosed and undertreated in the hemodialysis population as a whole.52 When we consider these findings, the clinical ramifications are significant. HRQOL is a significant predictor of hospitalization and mortality in the hemodialysis population independent of demographics and multiple co-morbid factors. Whether identifying and treating depression in the female hemodialysis population would have a positive effect on quality of life, hospitalization rates, and mortality requires further investigation. This has yet to be rigorously studied, but it could be a powerful opportunity to affect the care and outcome of hemodialysis patients. Of note, the prevalence of depression and the above noted associations have thus far not been studied in the peritoneal dialysis or home hemodialysis population. Additional interesting observations regarding psychosocial gender differences suggest that women take on more of the responsibility in family adaptation to ESRD than their male counterparts.53 Female African-American hemodialysis patients involved in couple relationships with greater dyadic satisfaction and less conflict demonstrate significantly lower mortality. However, this association was not found to be statistically significant in the male group.54 African-American hemodialysis women living in a complex household defined as a household that consists of a partner and others demonstrate higher mortality than women in a simple household (self or self and significant other). Of note, many of the complex households identified were multigenerational.50 However, social support has been associated with improved outcomes in chronic illness, and perception of social support is associated with improved survival in ESRD.50 It is possible that
a complex household may result in a higher level of stress and caregiving responsibilities for female patients on hemodialysis as opposed to men, thus negating the potential benefit of a larger support system. Behavioral compliance is an important predictor of dialysis outcome, but it does not appear to be significantly different between men and women.50,51 The psychosocial status of any individual on dialysis is certainly complex and unique, making sweeping population assessments difficult. Nonetheless, these observations are food for thought as clinicians attempt to understand and optimize the quality of life and outcomes for women on dialysis.
Conclusions Women currently constitute 44.3% of prevalent patients on hemodialysis and 47% on peritoneal dialysis in the United States. Women receive pre-ESRD care by a nephrologist significantly more often than men. However, despite this, women on dialysis do not enjoy the survival benefit compared with men that is seen in the general population. This loss of survival advantage is partially related to a lower cardiovascular survival advantage and more prominently related to a higher noncardiovascular mortality rate compared with their male counterparts. Particularly surprising is the markedly higher mortality rates seen in women younger than 45 years old on dialysis. Several factors have been implicated, although further research regarding the specific causes, the associated risk factors, and whether affecting these risk factors results in improved mortality is necessary. There are several gynecologic and hormonal irregularities that affect women on dialysis. Hormonal abnormalities seen in the female with ESRD can result in menstrual irregularities, anovulation, infertility, sexual dysfunction, early menopause, accelerated bone loss, and potentially increased risk of cardiovascular complications. Despite the frequency of reproductive hormone abnormalities with resultant morbidity and mortality, limited data are currently available with regard to optimal management strategies. Although fertility is impaired in dialysis, conception occurs in 1% to 7% of patients on dialysis. Thus, all women of childbearing age should be counseled regarding the risks of pregnancy and contraceptive options. There are specific gynecologic considerations unique to peritoneal dialysis. Peritoneal dialysis patients benefit from prophylaxis before undergoing invasive gynecologic procedures. Well-described complications unique to the peritoneal dialysis patient include hemoperitoneum, further decreased fertility, and uterine prolapse. Sexual dysfunction is common in the female hemodialysis as well as the peritoneal dialysis population. Female sexual dysfunction in ESRD is a complex disorder with multiple pathophysiologic and psychosocial components. It is seen to be associated with depression and lower quality of life. However, despite its high
Women and ESRD: Unique Considerations
prevalence, it is generally not assessed nor is it treated. Depression is prevalent in the female dialysis population. Depression and other psychosocial factors such as social support and stressors more profoundly affect the female dialysis patient compared with her male counterpart in terms of lower quality of life and mortality. Like sexual dysfunction, depression is under-recognized and undertreated in this population. As summarized, there are several gender-specific considerations and pathologies that occur in women with ESRD. Hopefully, bringing attention to several of these unique issues may increase the level of awareness within the nephrology community, positively affect how the multidisciplinary team cares for the female dialysis patient, and spur researchers to take our understanding to the next level.
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