Chronic kidney disease affects 10% of the world’s adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women’s Day in 2018 coincide, thus offering an opportunity to reﬂect on the importance of women’s health, and speciﬁcally their kidney health, to the community and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women, so that we may apply those learnings more broadly. Girls and women, who make up 50% of the world’s population, are important contributors to society as a whole and to their families. Gender differences continue to exist around the world in access to education, medical care and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, and also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for child bearing, and for the fetus. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health and kidney disease, and what we might learn in the future to improve outcomes worldwide. Received: November 20, 2017. Editorial decision: November 20, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/7/4794876 by Ed 'DeepDyve' Gillespie user on 16 March 2018 8| G.B. Piccoli et al. Key words: access to care, acute and chronic kidney disease, inequities, kidney health, women this risk is not known. PE is a risk factor for the future develop- Introduction ment of CKD and end-stage renal disease (ESRD) in the mother , Chronic kidney disease (CKD) affects 10% of the world’s adult and is the principal cause of AKI and maternal death in develop- population: it is within the top 20 causes of death worldwide , ing countries . Furthermore, PE is linked to ‘small babies’, who and its impact on patients and their families can be devastating. are at risk for developing diabetes,metabolic syndrome,cardio- World Kidney Day and International Women’s Day in 2018 coin- vascular diseases (CVDs) and CKD in adulthood . cide, thus offering an opportunity to reflect on the importance The presence of any degree of CKD has a negative effect on of women’s health, and specifically their kidney health, to the pregnancy, and given the increase in risk of CKD progression community and the next generations, as well as to strive to be postpartum, it raises challenging ethical issues around concep- more curious about the unique aspects of kidney disease in tion and maintenance of pregnancies. Table 1 describes the var- women, so that we may apply those learnings more broadly. ious potential adverse effects of pregnancy on kidney health. Girls and women, who make up 50% of the world’s popula- tion, are important contributors to society as a whole and to Autoimmune diseases their families. Besides childbearing, women are essential in childrearing and contribute to sustaining family and commun- Autoimmune diseases such as systemic lupus erythematosus ity health. Women in the 21st century continue to strive for (SLE), rheumatoid arthritis (RA) and systemic scleroderma (SS) preferentially affect women and are characterized by systemic equity in business, commerce and professional endeavors, while recognizing that in many situations, equity does not exist. inflammation leading to target organ dysfunction, including In various locations around the world, access to education and kidneys. Sex differences in the incidence and severity of these diseases result from a complex interaction of hormonal, genetic medical care is not equitable amongst men and women; women remain underrepresented in many clinical research studies, and epigenetic factors (Table 2). The public health burden of autoimmune diseases is substantial, as a leading cause of mor- thus limiting the evidence based on which to make recommen- bidity and mortality among women throughout adulthood [6–8]. dations to ensure best outcomes (Figure 1). In this editorial, we focus on what we do and do not know about women’s kidney health and kidney disease, and what we Renal replacement therapies (RRTs) might learn in the future to improve outcomes for all. In CKD cohorts, the prevalence in women is always lower than in men, and they have slower progression to ESRD . Women What we know and do not know with CKD have a higher cardiovascular risk than women with- out CKD . Pregnancy Access to RRT in general is inequitable around the world Pregnancy is a unique challenge and a major cause of acute kid- . The equality of access to RRT for women and girls is of con- neyinjury(AKI) in womenofchildbearingage . AKI and pree- cern because, in many societies, they are disadvantaged by dis- clampsia (PE) may lead to subsequent CKD, but quantification of crimination rooted in sociocultural factors. There is a paucity of Fig. 1. Sex differences throughout the continuum of CKD care. AI, autoimmune; AVF, arteriovenous ﬁstula; HD, hemodialysis; KT, kidney transplant. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/7/4794876 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Women and kidney disease | 9 Table 1. Adverse pregnancy outcomes in patients with CKD and in their offspring Term Definition Main issues Maternal death Death in pregnancy or Too rare to be quantiﬁed, at least in highly resourced settings, where within 1 week–1 month cases are in the setting of severe ﬂares of immunologic diseases postpartum (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 sCr, Differently assessed and estimated; may be linked to obstetric policy shift to a higher CKD (anticipating delivery in the case of worsening of the kidney func- stage tion); between 20 and 80% in advanced CKD. Probably not increased in early CKD stages. Immunologic ﬂares Flares of immunologic Once thought to be increased in pregnancy, in particular in SLE, are and neonatal SLE diseases in pregnancy probably a risk in patients who start pregnancy with an active dis- ease, or with a recent ﬂare-up. Deﬁnition of a ‘safe’ zone is not uni- formly agreed; in quiescent, well-controlled diseases do not appear to be increased with respect to nonpregnant, carefully matched controls. Transplant rejection Acute rejection in Similar to SLE, rejection episodes are not increased with respect to pregnancy matched controls; may be an issue in unplanned pregnancies, in unstable patients. Abortion Fetal loss, before 21–24 May be increased in CKD, but data are scant. An issue in immunologic gestational weeks diseases (eventually, but not exclusively linked to the presence of LLAC) and in diabetic nephropathy. Stillbirth Delivery of a nonviable Probably not increased in early CKD, maybe an issue in dialysis infant, after 21–24 patients; when not linked to extreme prematurity, may speciﬁcally gestational weeks linked to SLE, immunologic diseases and diabetic nephropathy. Perinatal death Death within 1 week–1 Usually a result of extreme prematurity, which bears a risk of respira- month from delivery tory distress, neonatal sepsis and cerebral hemorrhage. Small, very small baby A baby weighing <2500– Has as to be analyzed with respect to gestational age. 1500 g at birth Preterm, early Delivery before 37–34 or 28 Increase in risk of preterm and early preterm delivery across CKD extremely preterm completed gestational stages; extremely preterm may be an important issue in undiag- weeks nosed or late-referred CKD and PE-AKI. SGA (IUGR) <5th or<10th centile for Strictly and inversely related to preterm delivery; SGA and IUGR are gestational age probably related to risk for hypertension, metabolic syndrome and CKD in adulthood. Malformations Any kind of malformations Malformations are not increased in CKD patients not treated by terato- gen drugs (MMF, mTor inhibitors, ACEi, ARB); exception: diabetic nephropathy (attributed to diabetes); hereditary diseases, such as PKD, reﬂux nephropathy, CAKUT may be evident at birth. Hereditary kidney diseases Any kind of CKD Several forms of CKD 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—hypertension Higher risk of hypertension Late maturation of nephrons results in a lower nephron number in and CKD in adulthood preterm babies; the risks are probably higher in SGA–IUGR babies than in preterm babies adequate for gestational age. Other long-term issues Developmental disorders Mainly due to prematurity, cerebral hemorrhage or neonatal sepsis, are not speciﬁc of CKD, but are a threat in all preterm babies. GFR, glomerular ﬁltration rate; sCR, serum creatinine; 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; ARB, angioten- sin 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 SS Peak incidence Reproductive age Perimenopausal After 50–60 years Female/male ratio Peak 15: 1 Peak 4: 1 Peak 14: 1 Total 9: 1 After 60 years 1: 1 Total 3: 1 Inﬂuence of estrogen High levels Negative Positive Unknown Low levels Unknown Negative Negative Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/7/4794876 by Ed 'DeepDyve' Gillespie user on 16 March 2018 10 | G.B. Piccoli et al. information about sex differences in RRT, but in multiple coun- income countries, how do changing economic and social cul- tries, men are reported to be more likely than women to receive tures impact women’s health, and what is the nutritional dialysis [11, 12]. impact on CKD of increasing predominance of obesity, diabetes Women are more likely to donate kidneys for transplanta- and hypertension? tion than to receive them, as reported from multiple countries; they are less likely to be registered on transplant waiting lists, Summary and wait longer from dialysis initiation to listing. Mothers are more likely to be donors, as are female spouses [13, 14]. 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 Present and future: what we do not know access to care for women is critical to maintain the health of Pregnancy, AKI, autoimmune diseases, CKD, dialysis and trans- families, communities and populations. There is a clear need plantation present specific challenges for women, for which for higher awareness, timely diagnosis and proper follow-up of many unanswered questions persist. CKD in pregnancy. In high-income countries with increasing maternal age and Focused studies on the unique contribution of sex hor- assisted fertilization, there maybe an increase in PE, which may mones, or the interaction of sex hormones and other physiol- impact future generations if associated with adverse fetal out- ogy, is important to improve our understanding of the comes. The increase in in vitro fertilization techniques for those progression of kidney diseases. Immunological conditions such of advanced maternal age may lead to multiple pregnancies, as pregnancy (viewed as a state of tolerance to non-self) as well which may predispose to PE, intrauterine growth restriction or as SLE and other autoimmune and systemic conditions com- both. Will this lead to an increase in CKD and CVD for women, mon in women, when better studied may also lead to break- and impact their offspring, in the future? throughs in understanding and care paradigms. How should we define preconception risks of pregnancy with World Kidney Day and the International Women’s Day 2018 respect to current proteinuria cutoffs? Indications on when to are commemorated on the same day, an opportunity to high- start dialysis in pregnancy are not well established, nor is there a light the importance of women’s health and particularly their specificity of frequency and duration. In those with kidney trans- kidney health. On its 13th anniversary, World Kidney Day pro- plants, given the changing expanded donor policies, higher age at motes affordable and equitable access to health education, transplantation and reduced fertility in older women, there may be changes in attitudes toward pregnancy with less than optimal healthcare and prevention of kidney diseases for all women and kidney function . How this will impact short- and long-term girls in the world. outcomes of mothers and their babies is not clear. Teen pregnancies are very common in some parts of the Acknowledgements world, and are often associated with low income and cultural *Members of the World Kidney Day Steering Committee are: levels. The impact of uneven legal rules for assisted fertilization and the lack of systematic assessment of kidney function Philip Kam Tao Li, Guillermo Garcia-Garcia, Mohammed require more research. Benghanem-Gharbi, Kamyar Kalantar-Zadeh, Charles Despite elegant demonstrations for the role of sex hormones Kernahan, Latha Kumaraswami, Giorgina Barbara Piccoli, in vascular health and immunoregulation, the striking predomi- Gamal Saadi, Louise Fox, Elena Zakharova and Sharon nance in females of SLE, RA and SS remains unexplained rela- Andreoli. tive to other systemic diseases such as anti-neutrophil cytoplasmic antibody (ANCA) vasculitis and hemolytic-uremic Authors’ contributions syndrome. The incidence of kidney involvement in SLE during pregnancy and similarities/differences in those with PE have All authors have contributed to the conception, preparation not been well studied. The role of different medications and and editing of the manuscript. responses to medications for autoimmune diseases relative to sex has also not been well studied. Attention to similarities between conditions, the importance Conflict of interest statement of sex hormones in inflammation, immune modulation and vas- None declared. Full disclosures are listed in the individual cular health may lead to important insights and clinical break- authors’ conﬂict of interest forms. throughs over time. If women are more likely to be living donors, at differential ages, does this impact both CVD risk and risk for ESKD: have we studied this well enough, in the current era, with References modern diagnostic criteria for CKD and sophisticated tools to 1. GBD 2015 Disease and Injury Incidence and Prevalence understand renal reserve? Are the additional exposures that Collaborators. Global, regional, and national incidence, prev- women have after living donation compounded by hormonal alence, and years lived with disability for 310 diseases and changes on vasculature as they age? And are the risks of CKD injuries, 1990–2015: a systematic analysis for the Global and PE increased in the younger female kidney living donor? Burden of Disease Study 2015. Lancet 2016; 388: 1545–1602 In the context of specific therapies for the treatment or delay 2. Liu Y, Ma X, Zheng J et al. Pregnancy outcomes in patients of CKD progression, do we know if there are sex differences in with acute kidney injury during pregnancy: a systematic therapeutic responses to angiotensin-converting enzyme inhib- review and meta-analysis. BMC Pregnancy Childbirth 2017; 17: itor/angiotensin II receptor blocker? Should we look at dose finding/adjustments by sex? If vascular and immune biology is 235 3. Mol BWJ, Roberts CT, Thangaratinam S et al. Pre-eclampsia. impacted by sex hormones, do we know the impact of various therapies by level or ratio of sex hormones? In low–middle Lancet 2016; 387: 999–1011. 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Clinical Kidney Journal – Oxford University Press
Published: Feb 1, 2018
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