The theme of World Kidney Day 2018 is 'kidneys and women's health: include, value, empower'. To mark this event, Nature Reviews Nephrology asked four leading researchers to discuss key considerations related to women's kidney health, including specific risk factors, as well as the main challenges and barriers to care for women with kidney disease and how these might be overcome. They also discuss policies and systems that could be implemented to improve the kidney health of women and their offspring and the areas of research that are needed to improve the outcomes of kidney disease in women.
QWhy is the topic of 'kidneys and women's health' particularly important?
Gloria E. Ashuntantang. Acute kidney injury (AKI) and chronic kidney disease (CKD) are growing public health problems that are associated with adverse clinical and psychosocial outcomes1. Globally, CKD is more prevalent in women (∼272 million) than in men (∼226 million)2, and sex differences exist in all aspects of kidney health, from epidemiology, pathogenesis and care to outcomes. In addition to risk factors in common with men, such as diabetes mellitus and hypertension, the specific biology of women exposes them to unique risk factors for AKI and CKD. Systemic lupus erythematosus (SLE), HIV infection and urinary tract infections (UTIs) are known risk factors for kidney disease that are more frequent in women than in men3,4,5,6. Pregnancy places an additional burden on the kidney health of women, and complications of pregnancy are a frequent cause of kidney disease7. Women have less access to kidney care, especially renal replacement therapy (RRT), than do men8. Poor kidney function is associated with higher mortality in women, and as kidney function declines, mortality increases in women but not in men9,10. In the USA, CKD was the ninth leading cause of death in adult women and the eighth leading cause of death in black women in 201411.
Vesna D. Garovic. Data from the 2016 US Renal Data System confirm a lower incidence of end-stage renal disease (ESRD) in women than in men12. This difference is often attributed to the protective effect of oestrogen, which is consistent with the increased risk of ESRD in older women, with a particularly steep increase in risk at the age of menopause. When the male:female ratio is evaluated across the lifetime, women aged ≥60 years are at a greater risk of ESRD than men12,13. (Fig. 1) Similar trends have been observed for hypertension and diabetes, which are major risk factors for renal disease. The prevalence of both conditions is higher in men than in women until the age of 60–65 years14,15, but then becomes higher in women, again suggesting loss of a protective effect of oestrogen at menopause. Consistent with these epidemiological findings, data from animal studies suggest that oestrogen protects against hypertensive kidney injury16 and diabetic nephropathy17. These data raise important questions as to the potential therapeutic role of oestrogen in renal disease. Future efforts should focus on developing compounds that mimic the protective effects of this hormone, but do not have adverse effects on reproductive tissues in men and women. Studies of coronary heart disease support a 'window-of-opportunity' approach whereby the initiation of hormone therapy before 60 years of age and/or within 10 years of menopause may reduce cardiovascular risk in women18. Similar timing of hormone therapy might also have renoprotective effects given the increased incidence of ESRD in postmenopausal women.
Ita P. Heilberg. Most kidney diseases can be asymptomatic in the early stages and therefore might not be detected until late in the disease course. Although CKD can result from primary kidney diseases and genetic nephropathies, diabetes (usually as a result of obesity) and hypertension are the leading causes of CKD in developed countries. The age-standardized global prevalence of adult overweight and obesity is higher in women than in men19. Similarly, a higher prevalence of CKD, regardless of age, has been reported in women20 despite faster progression to ESRD in men21. Moreover, AKI and CKD may manifest during pregnancy. Nevertheless, CKD is under-recognized in women, and self-reported awareness remains low22. Interestingly, diabetes and cardiovascular diseases (CVDs) were the most important causes of female death between the 2nd and 4th decade of life in less-developed countries, with even higher rates than those associated with pregnancy and childbirth23. As women represent nearly half of the global population, have key roles in society and in family life and make important, continuously increasing contributions to the work force, the maintenance of their kidney health deserves special attention.
Liz Lightstone. Women comprise just under 50% of the world's population, and maintaining their health is critical not only for themselves but also for their children, wider family and society in general. Women with kidney problems may have impaired fertility, miss multiple days of work and be less able to care for their children. Perhaps most importantly, their kidney disease may affect the health of future generations. Even CKD stage 1 is associated with an increased incidence of babies with growth restriction24, which has a global impact on the child's organs, including their kidneys. This impact is best illustrated by the example of the Tiwi Islanders: before the introduction of public health measures aimed at improving maternal health, nearly all children were born with reduced nephron numbers, which were associated with early onset of albuminuria, progressive CKD, hypertension and multiple other health risks25. The contribution of the adverse consequences of fetal growth restriction to the global epidemic of chronic non-communicable diseases mandates ensuring that all women, but particularly those with impaired kidney function, have safe and well-managed pregnancies to minimize fetal risks.
QWhat are the specific risks or key considerations for women in terms of kidney health?
G.E.A. Female anatomy and physiology may increase the risk of kidney injury and damage. UTIs are more frequent in women than in men, in part owing to the shorter urethra and its proximity to the anus6. HIV infection5 and complications of pregnancy, including pre-eclampsia, are risk factors for AKI and CKD. Pregnancy-related AKI accounts for 15–25% of AKI in low-income countries and is responsible for around 8% of maternal and fetal deaths7. Kidney damage occurs in 60% of patients with SLE, of whom around 90% are female3. Among patients with diabetes, the incidence of kidney disease is higher in women than in men, and among those with ESRD, diabetes is associated with increased mortality in women but not in men26. Another important consideration is menopause, which worsens the survival of women with ESRD8.
V.D.G. Pregnancy complications and adverse pregnancy outcomes might herald future risks for renal disease. Women with a history of pre-eclampsia have an increased risk of CKD later in life27 and up to a fivefold increased risk of ESRD28,29. American Heart Association guidelines have identified hypertension in pregnancy as a risk factor for future CVD30 and stroke31, but to date, no clinical guidelines have addressed the role of reproductive risks in future kidney health. A history of pregnancy outcomes and complications in women should be collected systematically, particularly because recurrent and severe pre-eclampsia further increase the risk of renal disease. Additional research is necessary and will require large databases to provide longitudinal data given the long latency (>20 years) between pregnancy complications and adverse renal outcomes.
I.P.H. Permanent loss of renal function can result from several diseases and clinical conditions (Box 1). For example, SLE and rheumatoid arthritis potentially lead to kidney dysfunction and disproportionately affect women compared with men. In addition, studies suggest that the incidence of urinary stone disease is increasing among women. In the USA, hospital discharges for women with renal calculi increased by 22% between 1997 and 200232.
Pregnancy is associated with an increased risk of AKI as well as with early manifestation or flares of SLE and other autoimmune diseases. Pre-eclampsia and gestational hypertension increase the lifetime risks of hypertension and CKD33, especially among living kidney donors34. In addition, diabetes, immunologic diseases, baseline hypertension, metabolic syndrome and obesity are risk factors for both pre-eclampsia and CKD, resulting in a vicious cycle.
Obesity is highly prevalent in women19, is associated with increased incidences of diabetes, hypertension and dyslipidaemia and contributes independently to the development of CKD (that is, obesity-related glomerulopathy) and to CKD progression. Importantly, CVD is both a cause and a consequence of CKD (Box 2), and the incidence of cardiovascular mortality at younger ages is increased among patients with all stages of CKD and in kidney transplant recipients35. CVD becomes more severe after menopause, and uraemia induces a derangement in bone and mineral homeostasis known as CKD–mineral and bone disorder (CKD–MBD), which worsens postmenopausal osteoporosis.
L.L. Women tend to be older and frailer than men at initiation of dialysis, are less likely to be waitlisted for renal transplantation and are much more likely to be kidney donors36. The reasons, assumptions and biases that underlie these differences need to be addressed.
UTIs are often trivialized or overlooked but, especially in children, can lead to renal scars, CKD and hypertension. Women with chronic pyelonephritis often have pregnancies that are complicated by recurrent UTIs, hypertension, pre-eclampsia and intrauterine growth restriction. In older women, UTIs often occur owing to menopausal changes in the urinary tract. however, these infections are often treated with antibiotics, that risk generating more resistant bacteria, rather than with topical oestrogen, which would address the underlying problem.
Lupus affects eight times as many women as men37, and the least-expensive effective treatment for lupus nephritis, cyclophosphamide, can impair fertility if the dose is not minimized and the ovaries are not protected38. This risk deters women from accepting treatment. A need exists for kidney disease therapies that do not impair fertility, are not teratogenic and are safe during pregnancy. As almost no studies directly address the latter requirement, older drugs with longer safety histories tend to be used during pregnancy.
Physicians must explain to their patients that kidney disease may affect pregnancy, ensure that medications are appropriate and provide advice on contraception and the timing of conception. Ideally, pre-pregnancy planning should be the norm for all women with kidney disease; however, the advice might differ considerably depending on the available resources39. A woman with fairly advanced CKD might consider going ahead with a high-risk pregnancy that could require neonatal intensive care for her baby and lead to faster progression to chronic dialysis for her if these facilities are available. In the absence of such facilities, the pregnancy might prove fatal for the baby and/or the mother; therefore, pregnancy avoidance should be advised, although this is a sad and challenging option.
QWhat are the key challenges and barriers to care for women with kidney diseases and how can they be overcome?
G.E.A. Limited access to care is a major challenge (Fig. 2). Women are under-represented in populations receiving RRT for ESRD worldwide8. They are also less likely to receive kidney grafts than men, although they outnumber men as kidney donors8. In general, women are disempowered — especially in low-income countries — by patriarchal societies that result in unequal power relationships between genders and limit the access of women and girls to education, family property and well-paying jobs40. In addition to limited employment possibilities, illiteracy restricts the ability of individuals to make informed health choices. The lack of autonomy in the context of scarce resources and expensive therapies renders dialysis and kidney transplantation inaccessible to most women in low-income countries. The lack of sex consideration in treatment targets is another key barrier to the optimal care of women with or at risk of kidney disease. For example, haemoglobin and Kt/V targets in haemodialysis do not take into account physiological sex differences in haemoglobin levels and total body water, thus leading to errors in calculations of erythropoietin requirements and in estimations of dialysis adequacy, respectively8.
V.D.G. Young women of reproductive age typically are seen by professionals in obstetrics and gynaecology for contraception and reproductive issues. Consequently, women aged <50 years often may not see internists or family practice specialists for routine medical care. Treatment of hypertension is suboptimal in this age group. A study evaluating the rates of hypertension diagnosis in women aged <50 years demonstrated that a diagnosis was made in less than one-third of these women41. Early recognition and treatment of hypertension — one of the leading causes of renal disease — require increased awareness and improved coordination between obstetricians and internal medicine specialists who care for premenopausal women.
Another challenge is the interpretation of test results in women. Clinical laboratories do not usually provide sex-specific normal values for markers of renal disease and renal function, with the exception of serum creatinine. However, for measurements of creatinine during pregnancy, normal values obtained from the general population are used, which commonly overestimate renal function in pregnant women. Glomerular filtration rate (GFR) increases during pregnancy, particularly during the second semester. Consequently, a creatinine value of 1.1 mg/dl (97.24 μmol/l), which would be considered normal for men and for most nonpregnant women, might indicate a substantial decrease in GFR in the setting of pregnancy42.
I.P.H. Girls with premature birth, low birth weight or high birth weight (for example, those born to mothers with diabetes) have increased risks of hypertension, young onset of diabetes, obesity and CVD, which predispose to CKD. Hypertension is under-recognized and is more often resistant to treatment in women than in men43, possibly owing to sex-related pharmacokinetic factors, such as lower weight, distribution volumes and renal drug clearance44. Pre-eclampsia and hypertensive disorders of pregnancy must be carefully managed to avoid maternal and fetal adverse kidney outcomes, the incidences of which are higher in low-to-middle-income countries than in high-income countries. Fighting the obesity epidemic among women is mandatory given the existence of related comorbidities that adversely affect the kidney. Proper diagnosis of CKD in all age groups, but particularly in elderly individuals, is required to identify the true prevalence of CKD among women.
In comparison to men, women have less access to dialysis, later initiation of dialysis and higher risks for hospitalization when on maintenance haemodialysis45. Women are also more likely to donate a kidney than men, but the number of female kidney transplant recipients is lower than that of male recipients, irrespective of age, in the USA, Canada, France, China, India and Brazil46,47. Whether these sex-specific differences in RRT and transplantation are the result of biological differences in kidney disease prevalence and progression or of socioeconomic and psychosocial factors is not yet clear.
L.L. Generally, women have greater opportunities for their kidney disease to be recognized than men as they tend to interact more frequently with health-care providers, at least in more affluent countries, for contraception, menstrual disorders, pregnancy and menopause. Each encounter should include blood pressure assessment and urine dipstick testing. However, haematuria and/or proteinuria are still too commonly attributed to UTIs, and hypertension is often assumed to be related to oral contraception or pregnancy and not driven by underlying kidney disease. In the UK, renal function is not part of antenatal screening; therefore, baseline kidney function is not known in pregnancy. Physicians often do not realize that a seemingly normal creatinine level in pregnancy may reflect substantial renal impairment; creatinine levels should decrease substantially in early pregnancy and not return to pre-pregnancy levels until late in the third trimester39. However, the key challenge is failing to follow up on abnormalities that are detected. Many women who present with advanced kidney disease report that they had proteinuria and hypertension in each of their pregnancies. Globally, having a chronic condition that might impair fertility, pregnancy and longevity carries a stigma; therefore, women may avoid diagnosis or may not have access to adequate care. Overcoming these barriers starts with the education of women and health-care professionals. Women must be empowered to ask for follow-up if abnormalities are detected, and health-care professionals must recognize when follow-up is warranted.
QWhat cost-effective policies and/or systems could be implemented to improve the kidney health of women and their offspring?
G.E.A. Awareness campaigns are needed to increase knowledge of the burden of kidney disease in women. Engaging governments, women's rights groups and communities is essential to highlight the vulnerability of women to kidney disease and their limited access to care. Women's rights groups need to go beyond reproductive health issues to advocate for equality in all aspects of health care, and government policies that promote gender equality should be encouraged. Safe motherhood through adequate nutrition, effective antenatal care and family planning, especially in regions where resources are scarce, will reduce the incidence of pregnancy-related kidney disease and improve outcomes for mothers and their offspring. Educational, economic and social empowerment of women has been shown to improve health determinants48. In particular, education and vocational training enables financial autonomy and increases the ability of individuals to make informed health-care choices. Gender considerations should be included in national kidney health policies and in the education, training and research initiatives of international kidney organizations. An example of such an initiative is the International Society of Nephrology Saving Young Lives programme, which provides affordable peritoneal dialysis for AKI. This programme has increased the access of women and children to RRT in low-income countries49.
V.D.G. Adverse cardiovascular and renal risk profiles have been reported in women who did not lose weight between 3 months and 12 months postpartum50, indicating a need for close follow-up and intervention, which has not yet been accepted in current practice. Gestational diabetes prompts follow-up for the development of diabetes after pregnancy, and similar strategies for frequent and long-term follow-up have been proposed for gestational hypertension30,31, but these are not commonly implemented.
Hypertension affects up to 8% of all pregnancies, and current guidelines advise the initiation of antihypertensive therapy for a systolic blood pressure (SBP) ≥160 mmHg and/or a diastolic blood pressure (DBP) ≥90 mmHg51. This conservative approach is based upon the assumption that such hypertension is of short duration (4–5 months) and therefore does not translate into substantial cardiovascular and renal risks, and on the concern that lowering blood pressure might decrease blood flow to the fetoplacental unit and ultimately compromise fetal growth. In 2000, a meta-analysis reported an association between treatment of hypertension in pregnancy and fetal growth restriction52. However, a 2015 clinical trial found that tight control of DBP does not pose a risk to the fetus or newborn and results in moderate benefit in preventing progression to severe hypertension in the mother compared with less-tight blood pressure control53. Notably, a SBP >160 mmHg is commonly considered to be a marker of severe pre-eclampsia and an indication for immediate delivery. Improved blood pressure control will not prevent pre-eclampsia, but it may enable the continuation of pregnancy, thus preventing premature birth and prematurity-related morbidity.
I.P.H. Improving kidney health in women is paramount to decrease the global burden of CKD and its consequences. As the risks of hypertension, young-onset diabetes, obesity and CVD can be transmitted to subsequent generations, promotion of healthy lifestyle and nutrition to reduce these risks must start early in life. Risk reduction should also include vaccination against infections that have been associated with AKI and CKD, such as hepatitis B and tuberculosis33. Risk factors for CKD (Box 1) should be identified, and risk-reduction strategies should be implemented before, during and after pregnancy.
After their childbearing years, women are generally advised to undergo a yearly consultation with their gynaecologist with the aim of preventing gynaecologic cancer, but more complete regular check-ups with general practitioners are unusual. A focus on education is important to increase the awareness of renal disease among women as well as among physicians who are involved in primary prevention of chronic diseases, including non-nephrology specialists such as cardiologists and endocrinologists, potentially enabling earlier nephrology referrals. The publication of gender-specific data on renal diseases and their treatment would help to achieve this goal.
Importantly, CKD is often overlooked in older women because serum creatinine level is affected by muscle mass. As women have less muscle mass than men and ageing reduces muscle mass, older women with CKD often have a serum creatinine level that is in the normal range for younger individuals, potentially resulting in a missed diagnosis22. Use of other surrogate markers of renal function, such as cystatin C54, might be more appropriate than serum creatinine for the assessment of kidney function in elderly women.
L.L. Early diagnosis of kidney disease is key to enable the initiation of appropriate treatment to prevent chronic damage and ultimately ESRD. For women with diseases that can affect the kidneys, blood pressure measurement (and control), urine dipstick and renal function assessment are mandated. CKD guidelines on referrals, investigations and blood pressure targets aim to ensure early treatment55. In addition, all women merit excellent antenatal care, at the very least assessment and treatment of hypertension, prompt diagnosis of pre-eclampsia56 and follow-up of antenatal kidney problems with nephrology referral as appropriate.
Education of women can enhance the health of whole communities (for example, through training to measure blood pressure, dip urine and administer antihypertensives). Very simple and inexpensive disease prevention strategies can rapidly transform the health of women, as evidenced by Wendy Hoy's seminal work with Aboriginal Australians in the Northern Territory25. Moreover, if women are taught to minimize their salt intake and are given safe antihypertensives and good contraceptive advice, they are likely to have healthier pregnancies that directly benefit the next generation. There is a need to define trimester-specific normal ranges of serum creatinine, and baseline serum creatinine levels in pregnancy should be evaluated in more affluent areas. Such a strategy might well be cost-effective, at least for those with UTIs, abnormal urine sediment, hypertension, diabetes or a family history of kidney disease.
QIs there adequate consideration of sex differences or of women in nephrology research? What key areas of research are needed to improve patient outcome for women with kidney disease?
G.E.A. No, I do not think enough attention has been given to women in nephrology research. Although the number of women participating in intervention studies in kidney health is increasing, sex-specific differences in kidney structure and in glomerular haemodynamics are often not considered when evaluating disease and treatment outcomes. The long-term effects of the changes in kidney structure and physiology that occur during pregnancy need to be evaluated, especially in multiparous women. The course of CKD in postmenopausal women, women with diabetes and women with pre-eclampsia also needs to be better characterized. Other areas that warrant research include early menopause and related reproductive issues in young women with CKD and sex-specific treatment targets in kidney disease. We also need to understand the reasons that underlie the low rates of kidney transplantation in women. Importantly, further research in the field should be inclusive of women from low-income countries, who bear the highest burden of kidney disease.
V.D.G. The role of sex-specific risk factors and their influence on clinical presentations and outcomes was initially recognized with respect to CVD. Consequently, enrolment of women in randomized controlled trials has improved over time, but is still low in comparison with the relative proportions of women who are affected by the specific diseases or conditions being investigated57. Although the role of sex-specific risk factors in the predisposition to, and progression of, renal disease is increasingly recognized, the relative proportion of female participants in clinical trials for hypertension and renal disease remains low. One notable example is the SPRINT trial58, which examined intensive versus standard blood pressure control (SBP <140 mmHg versus <120 mmHg) in nondiabetic patients with hypertension. The mean age of participants in this trial was 68 years. Although women represent at least 50% of all individuals with hypertension in this age group, only 36% of the SPRINT participants were female. This example underscores the need for ongoing efforts to reinforce National Institutes of Health policies regarding the inclusion of women in clinical trials and data analysis by sex.
I.P.H. Few studies have specifically assessed renal outcomes in women with CVD43. Although a meta-analysis reported faster progression of nondiabetic CKD (membranous and IgA nephropathies and autosomal dominant polycystic kidney disease) in men than in women, the available data did not enable assessment of whether the putative renoprotective effects of female gender were associated with premenopausal status, diet, blood pressure or lipid levels21. Female sex is generally under-represented in clinical research, including in phase III trials that should carefully monitor gender-related differences, adverse effects and co-medications, including hormone therapies.
Despite a later onset of hypertension in women than in men, the underlying molecular mechanisms remain unknown because females are under-represented in experimental animal studies. Although gonadal hormones might have a role, evidence suggests that the immunological mechanisms that underlie hypertension are sex-specific59.
UTIs are markedly prevalent in women. Those with chronic pyelonephritis and normal renal function or past UTI in childhood have a good prognosis, but outcomes are poor among those with bilateral or severe individual kidney damage. Despite this burden, only a limited number of long-term studies have investigated the course of chronic pyelonephritis in women.
Understanding of the role of sex hormone status in determining the bone mass of patients on dialysis or kidney transplant recipients is also lacking because fewer women than men have been included in studies of CKD–MBD60. Further clinical research should focus on female obesity, hypertension and pregnancy-related CKD, including nonproteinuric tubulointerstitial nephropathies, as well as bone diseases and CVD. Finally, the idea that breast and gynaecologic cancers are the leading cause of death among women needs to be reconsidered given the important contribution of chronic conditions that may compromise renal function.
L.L. Despite higher rates of CKD, women generally comprise <30% of the participants in CKD trials. This paucity is detrimental, as study results cannot normally be extrapolated to women, not least because those of childbearing age are often excluded. The exception is lupus nephritis, for which numerous studies have a majority of female participants. However, most eligible women decline to participate owing to risk-averse study designs that require undue postponement of pregnancy and involve intrusive contraceptive demands and a heavy burden of monitoring. This problem has an ethically worrying consequence; in an attempt to be global and to increase participation, investigators are going to countries where the trial drugs will not be affordable and where the standard of routine medical care may be inadequate. A patient-centred consensus is now emerging that the focus should be on reducing treatment-related toxicity and addressing key pathophysiological abnormalities61.
Many more long-term studies are needed as well as registries such as the UK Pregnancy and CKD Rare Disease Group62, which will provide 21st-century outcome data. Long-term follow-up of children is incredibly challenging owing to practical difficulties and ethical considerations relating to consent and monitoring. However, current pregnancy advice for women with kidney disease is based on short-term outcome measures — we need to know if there are adverse long-term effects on their children and, if so, how to prevent and treat them.
The global priority must be to identify key risk factors for CKD with the aim of preventing complications and ESRD, which is fatal for many women worldwide. However, a much more holistic view of kidney disease and women's health is needed. The psychological and economic effects of CKD in women are underestimated and understudied, but failure to address these aspects could be as detrimental to society and the economy as failure to diagnose the kidney disease in the first place.
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L.L. is grateful to have worked with and learned from thousands of women patients, as well as innumerable wise women colleagues near and far, all of whom have informed her answers.