Women and Kidney Disease: Reflections on World Kidney Day 2018.
Girls and women, who comprise approximately 50% of the world's population, are important contributors to society and their families. In addition to childbearing, women contribute to sustaining family and community health. Women in the 21st century continue to strive for equity in business, commerce, and professional endeavours, while recognizing that in many situations, equity does not exist. In various locations around the world, access to education and medical care is not equitable among men and women; women remain under-represented in many clinical research studies, thus limiting the evidence base on which to make recommendations to ensure best outcomes (see Figure 1). In this article, we focus on what we do and do not know about women's kidney health and kidney disease, and what we might learn in the future to improve outcomes for all.
What We Know and Do Not Know
Pregnancy is a unique challenge and a major cause of acute kidney injury (AKI) in women of childbearing age (Liu, Ma, Zheng, Liu, & Yan, 2017). AKI and pre-eclampsia (PE) may lead to subsequent CKD, but quantification of this risk is not known (Mol et al., 2016). PE and hypertensive disorders of pregnancy occur in 3% to 10% of all pregnancies. PE is a risk factor for the future development of CKD and end stage renal disease (ESRD) in the mother, and it is the principal cause of AKI and maternal death in developing countries. The presence of any degree of CKD has a negative effect on pregnancy, and given the increase in risk of CKD progression postpartum, raises challenging ethical issues around conception and maintenance of pregnancies (Piccoli et al., 2015). Global differences in causes of AKI during pregnancy reflect socioeconomic and cultural issues. Septic abortion after an illegal procedure is the leading cause of early AKI in countries where legal abortions are not available, while PE after assisted fertilization is becoming a leading cause in developed countries. (See Table 1 for adverse effects of pregnancy, and Figure 2 for relationship between pregnancy and kidney disease.)
Besides maternal risks, PE is associated with intrauterine and perinatal death, preterm delivery, and restricted intrauterine growth; the latter two are linked to "small babies" (Mol et al., 2016). In the long term, babies are small for gestational age, and preterm babies are at risk for developing diabetes, metabolic syndrome, cardiovascular diseases (CVDs), and CKD in adulthood (Luyckx et al., 2013). The increased risk of CKD is probably due to a low nephron number, leading to hyperfiltration, hypertension, and reduced resilience after AKI episodes.
Long-term effects of PE on both maternal and fetal health remain an area of active research with many unknowns. Although PE increases the probability of hypertension and CKD in later years, we have not evaluated a surveillance or reno-protective strategy to determine if progressive loss of kidney function can be attenuated (Liu et al., 2017). Despite the risk for CKD in small-for-term children, there are no systematic screening programs for them, either.
Autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren's syndrome (SS), preferentially affect women and are characterized by systemic inflammation leading to target organ dysfunction, including kidneys. Sex differences in the incidence and severity of these diseases result from a complex interaction of hormonal, genetic, and epigenetic factors (see Table 2). The public health burden of autoimmune diseases is substantial and is a leading cause of morbidity and mortality among women throughout adulthood (Ortona et al., 2016)
SLE is an autoimmune disease that affects approximately 5 million people worldwide. It affects women (9:1 female to male ratio) and individuals of non-European ancestry disproportionately. The highest female predominance (up to 15:1) is in peak reproductive years. The biology of these differences has been explored extensively and include the number of X chromosomes and genetic variants on the X chromosome; the role of estrogen, whose primary effects are mediated by transcription activity of the intracellular estrogen receptors (Pierdominici & Ortona, 2013); and the role of Cathespin S protein as potential causes of lupus, triggering the immune system to attack healthy cells (Kim et al., 2017). In addition, numerous non-HLA genetic markers may predispose individuals of European, Hispanic, and Afro-American ancestry to lupus.
RA also affects women preferentially (4:1 ratio to men); peak incidence is at age 45 to 55 years, coincident with perimenopause. Possible association between estrogen deficiency and disease onset is further corroborated by noting the change in female-to-male incidence ratio after age 60 years (1:1). Further, RA symptom improvement or remission during pregnancy is well-recognized (Goemaere et al., 1990). Renal involvement in RA is relatively common, multifactorial, and a predictor of mortality in patients with RA.
SS predominantly affects women (female-to-male ratios range from 3:1 to 14:1); peak incidence is in the 5th and 6th decades. Estrogen may play a role in scleroderma pathogenesis through its stimulatory effect on transforming growth factor-beta 1 receptor and platelet-derived growth factor receptor (Ortona et al., 2016).
Renal Replacement Therapies
In CKD cohorts, the prevalence in women is always less than in men, and they have slower progression to ESRD (Nitsch et al., 2013). The equality of access to renal replacement therapy (RRT) for women and girls is of concern because in many societies, they are disadvantaged by discrimination rooted in sociocultural factors. There is a paucity of information about sex differences in RRT (Liyanage et al., 2015). In Africa, men were more likely to receive RRT than women; in Japan, the incidence of treated ESRD in females is less than half of that in males (3,287 in males vs. 1,764 women per million ESRD); in the United States, women have significantly higher likelihood of late initiation of dialysis compared to men. Awareness of previous kidney disease was much lower in women than in men, which may contribute to this later RRT start, and higher hospitalization rates in women on dialysis and higher risk for 30-day readmissions than men have been reported.
Women with CKD have a higher cardiovascular risk than women without CKD, but their risk is still lower than that of men with similar degrees of kidney impairment. In hemodialysis cohorts, there are differences in vascular access types in women versus men (Ethier et al., 2008), which may be due to biological or systemic factors. In some locations, there is differential use of peritoneal and hemodialysis in women and men.
We do not know why and how much of this is due to differences in identification of kidney impairment, different access to care, or true difference in disease severity and prevalence. Women are more likely to donate kidneys for transplantation than to receive them. Data from different countries (United States, France, China, and India) confirm differential kidney transplant rates (lower in women than men), less likelihood of women being registered on transplant waiting lists, and longer time from dialysis initiation to listing. Mothers are more likely to be donors, as are female spouses (Jindal, Ryan, Sajjad, Murthy, & Baines, 2005).
Psychosocial factors and education may also contribute to disparities. Several reports find disparities in age and sex in access to kidney transplantation, starting at the time of pre-referral discussions. Irrespective of age, women were more likely not to have had discussions with medical professionals (Salter et al., 2014). There are sex differences in access to care in different regions of the world, and we do not have data to directly evaluate the extent of these differences, especially in the poorest parts of the world.
Present and Future: What We Do Not Know
Given data presented here with respect to pregnancy, AKI, autoimmune diseases, CKD, dialysis, and transplantation, there are many unanswered questions. In high-income countries with increasing maternal age and assisted fertilization, there may be an increase in PE that may impact future generations if associated with adverse fetal outcomes. The increase in in-vitro fertilization techniques for those of advanced maternal age may lead to multiple pregnancies, which may predispose to PE or intrauterine growth restriction, or both. Will this lead to an increase in CKD and CVD for women and impact their offspring in the future? Due to the high heterogeneity of CKD and scant evidence, we do not know if and how pregnancy outcomes are modulated by the different nephropathies.
How should we define preconception risks of pregnancy with respect to current proteinuria cut offs? Indications on when to start dialysis in pregnancy are not well-established, nor is the specific role of frequency and duration. In patients with kidney transplants, given the changing expanded donor policies, higher age at transplantation, and reduced fertility in older women, there may be changes in attitudes toward pregnancy with less-than-optimal kidney function (Webster, Lightstone, McKay, & Josephson, 2017). How this will impact short- and long-term outcomes of mothers and their babies is unclear.
Teen pregnancies are common in some parts of the world, and are often associated with low income and cultural levels. The uneven legal rules for assisted fertilization and the lack of systematic assessment of the kidney function point to the need for further research.
Despite elegant demonstrations for the role of sex hormones in vascular health and immunoregulation, the striking predominance of SLE, RA, and SS in females remains unexplained relative to other systemic diseases, such as antineutrophil cytoplasmic antibodies (ANCA), associated vasculitis, and hemolytic-uremic syndrome. The incidence of kidney involvement in SLE during pregnancy and similarities/differences in those with PE have not been well studied. The role of different medications and responses to medications for autoimmune diseases relative to sex has also not been well-studied.
More attention to similarities between conditions, the importance of sex hormones in inflammation, immune-modulation, and vascular health may lead to important insights and clinical breakthroughs over time. If women are more likely to be living donors at differential ages, does this impact both CVD and ESRD risk? Have we studied this well enough in the current era, with modern diagnostic criteria for CKD and sophisticated tools, to understand renal reserve? Are additional exposures that women have after living donation compounded by hormonal changes on vasculature as they age? Are risks of CKD and PE increased in the younger female kidney living donor?
In the context of specific therapies for the treatment or delay of CKD progression, do we know if there are sex differences in therapeutic responses to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)? Should we look at dose finding/adjustments by sex? If vascular and immune biology is impacted by sex hormones, do we know the impact of various therapies by level or ratio of sex hormones? In low to middle-income countries, how does changing economic and social cultures impact women's health, and what is the nutritional impact on CKD of increasing predominance of obesity, diabetes, and hypertension?
Women have unique risks for kidney diseases. Kidney diseases and issues related to access to care have a profound impact on both the current and next generations. Advocating for improved access to care for women is critical to maintain the health of families, communities, and populations.
Focused studies on the unique contribution of sex hormones or the interaction of sex hormones and other physiology are important to improve our understanding of the progression of kidney diseases. Learning more about immunological conditions, such as pregnancy (viewed as a state of tolerance to non-self), as well as SLE and other autoimmune and systemic conditions common in women, may also lead to breakthroughs in understanding and care paradigms.
There is a clear need for higher awareness, timely diagnosis, and proper follow up of CKD in pregnancy. In turn, pregnancy may also be a valuable occasion for early diagnosis of CKD, allowing planning of therapeutic interventions.
World Kidney Day and International Women's Day 2018 are commemorated on the same day, providing an opportunity to highlight the importance of women's health, and particularly, their kidney health. On its 13th anniversary, World Kidney Day promotes affordable and equitable access to health education, health care, and prevention for all women and girls in the world. The coinciding of World Kidney Day and International Women's Day offers an opportunity to develop and define best practices and future research agendas, and ultimately, to optimize outcomes of present and future generations living with or at risk for kidney disease.
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Giorgina B. Piccoli
Picolli, G.B., Alrukhaimi, M., Liu, Z.H., Zakharova, E., & Levin, A. (2018). Women and kidney disease: Reflections on World Kidney Day 2018. Nephrology Nursing Journal, 45(1), 65-70.
Giorgina B. Piccoli, MD, is a Researcher in Nephrology, Department of Clinical and Biological Sciences, University of Torino, Italy, and the head of a Nephrology Unit, Nephrology, Centre Hospitalier Le Mans, Le Mans, France.
Mona Alrukhaimi, B.Sc., MBBCh, MRCP (UK), FRCP, FRCPE, is a Professor of Medicine, Department of Medicine, Dubai Medical College, Dubai, United Arab Emirates.
Zhi-Hong Liu, MD, is a Professor of Medicine, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Elena Zakharova, MD, PhD, is Head of the Nephrology Unit, Nephrology, Moscow City Hospital n.a. S.P. Botkin, Moscow, Russian Federation; an Associate Professor of Nephrology and a Chair, Nephrology, Moscow State University of Medicine and Dentistry, Moscow, Russian Federation; and an Associate Professor of Nephrology and Dialysis Chair, Nephrology, Russian Medical Academy of Continuous Professional Education, Moscow, Russian Federation.
Adeera Levin, MD, FRCPC, CM, is a Professor of Medicine, Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
Authors' Note: Authors listed are on behalf of the World Kidney Day Steering Committee. All authors contributed equally to the conception, preparation, and editing of the article. Members of the World Kidney Day Steering Committee are: Philip Kam Tao Li, Guillermo Garcia- Garcia, Mohammed Benghanem- Gharbi, Kamyar Kalantar-Zadeh, Charles Kernahan, Latha Kumaraswami, Giorgina Barbara Piccoli, Gamal Saadi, Louise Fox, Elena Zakharova, and Sharon Andreoli.
Editor's Note: This article is being published simultaneously in numerous peer-reviewed scientific journals around the world.
Statement of Disclosure: The authors reported no actual or potential conflict of interest in relation to this continuing nursing education activity.
Note: The Learning Outcome, additional statements of disclosure, and instructions for CNE evaluation can be found on page 71.
Caption: Figure 1 Sex Differences Throughout the Continuum of CKD Care
Caption: Figure 2 Pregnancy and Kidney Function: Complex Interactions Between 2 Organs--The Kidney and Placenta
Table 1 Adverse Pregnancy Outcomes in Patients with Chronic Kidney Disease and in Their Offspring Term Definition Main Issues Maternal death Death in pregnancy or Too rare to be within 1-week to 1-month quantified, at least in postpartum. highly resourced settings, where cases are in the setting of severe flares of immunologic diseases (SLE in primis). Still an issue in AKI and in low-resourced countries; not quantified in low-resourced countries, where it merges with dialysis need. CKD progression Decrease in GFR, rise in Differently assessed and sCr, shift to a higher estimated; may be linked CKD stage. to obstetric policy (anticipating delivery in the case of worsening of the kidney function); between 20% and 80% in advanced CKD. Probably not increased in early CKD stages. Immunologic Flares of immunologic Once thought to be flares and diseases in pregnancy. increased in pregnancy. neonatal SLE In particular, in SLE, are probably a risk in patients who start pregnancy with an active disease or with a recent flare up. Definition of a "safe" zone is not uniformly agreed; in quiescent, well controlled diseases do not appear to be increased with respect to non-pregnant, carefully-- matched controls. Transplant Acute rejection in Similar to SLE, rejection rejection pregnancy. episodes are not increased with respect to matched controls; may be an issue in unplanned pregnancies in unstable patients. Abortion Fetal loss, before 21 to May be increased in CKD, 24 gestational weeks. but data are scant. An issue in immunologic diseases (eventually, but not exclusively linked to the presence of LLAC) and in diabetic nephropathy. Stillbirth Delivery of a nonviable Probably not increased in infant, after 21 to 24 early CKD, may be an gestational weeks . issue in patients on dialysis; when not linked to extreme prematurity, may specifically linked to SLE, immunologic diseases and diabetic nephropathy. Perinatal death Death within 1 week to 1 Usually a result of month from delivery. extreme prematurity, which bears a risk of respiratory distress, neonatal sepsis, and cerebral hemorrhage. Small, very A baby weighting less Has to be analyzed with small baby than 2,500 to 1,500 g at respect to gestational birth. age. Preterm, early Delivery before 37 to 34 Increase in risk of extremely or 28 completed preterm and early preterm preterm gestational weeks. delivery across CKD stages; extremely preterm may be an important issue in undiagnosed or late referred CKD and PE-AKI. SGA (IUGR) Less than 5th or less Strictly and inversely than 10th centile for related to pre-term gestational age. delivery; SGA and IUGR are probably related to risk for hypertension, metabolic syndrome and CKD in adulthood. Malformations Any kind of Malformations are not malformations. increased in patients with CKD not treated by teratogen drugs (MMF, mTor inhibitors, ACEi, ARBS); exceptions are diabetic nephropathy (attributed to diabetes); hereditary diseases, such as PKD, reflux nephropathy. CAKUT may be evident at birth. Hereditary Any kind of CKD. Several forms of CKD kidney diseases recognize a hereditary pattern or predisposition; besides PKD, reflux and CAKUT, Alport's disease, IgA, kidney tubular disorders, and mitochondrial diseases have a genetic background, usually evident in adulthood and not always clearly elucidated. CKD-- Higher risk of Late maturation of hypertension hypertension and CKD in nephrons results in a adulthood. lower nephron number in preterm babies; risks are probably higher in SGA- IUGR babies than in preterm babies adequate for gestational age. Other long- Developmental disorders. Mainly due to term issues prematurity, cerebral hemorrhage, or neonatal sepsis; are not specific of CKD, but are a threat in all preterm babies. Notes: SLE = systemic lupus erythematosus; AKI = acute kidney injury; GFR = glomerular filtration rate; sCR = serum creatinine; CKD = chronic kidney disease; LLAC = Lupus-like anticoagulant; PE-AKI = preeclampsia acute kidney injury; SGA = small for gestational age; IUGR = intrauterine growth restriction; MMF = mycophenolate mofetil; mTor = mechanistic target of rapamycin; ACEi = angiotensin-converting-enzyme inhibitor; ARBS = angiotensin II receptor blockers; PKD = polycystic kidney disease; CAKUT = congenital anomalies of the kidney and urinary tract; IgA = immunoglobulin A. Table 2 Sex Differences in the Incidence and Severity of Autoimmune Diseases SLE RA Reproductive Peak incidence age Perimenopausal Female/male ratio Peak 15:1 Peak 4:1 Total 9:1 After 60 years 1:1 Influence High levels Negative Positive of estrogen Low levels ? Negative SS Peak incidence After 50-60 years Female/male ratio Peak 14:1 Total 3:1 Influence High levels ? of estrogen Low levels Negative Notes: SLE = systemic lupus erythematosus; RA = rheumatoid arthritis; SS = systemic scleroderma.
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|Author:||Piccoli, Giorgina B.; Alrukhaimi, Mona; Liu, Zhi-Hong; Zakharova, Elena; Levin, Adeera|
|Publication:||Nephrology Nursing Journal|
|Date:||Jan 1, 2018|
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