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Women and Kidney Disease: Reflections on World Kidney Day 2018.

Chronic kidney disease (CKD) affects approximately 10% of the world's adult population; it is within the top 20 causes of death worldwide (GBD 2015 Disease and Injury Incidence and Prevalence Collaboration, 2016), and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide on March 8, thus offering an opportunity to reflect on the importance of women' s health, and specifically, their kidney health, on the community and future generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so we may apply those learnings more broadly.

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

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

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?

Summary

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.

References

Ethier, J., Mendelssohn, D., Elder, S J., Hasegawa, T., Akizawa, T., & Akiba, T., ... Pisono, R.L. (2008). Vascular access use and outcomes: an international perspective from the dialysis outcomes and practice patterns study. Nephrology Dialysis Transplantation, 23(10), 3219-3226. doi:10.1093/ ndt/gfn261

GBD 2015 Disease and Injury Incidence and Prevalence Collaborative. (2016). Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. The Lancet, 388(10053), 1545-1602. doi:10. 1016/s0140-6736(16)31678-6

Goemaere, S., Ackerman, C., Goethals, K., De Keyser, F., Van der Straeten, C., Verbruggen, G., ... Veys, E.M. (1990). Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition. The Journal of Rheumatology, 17(12), 1620-1622.

Jindal, R.M., Ryan, JJ., Sajjad, I., Murthy, M.H., & Baines, L.S. (2005). Kidney transplantation and gender disparity. American Journal of Nephrology, 25(5), 474-483. doi: 10.1159/000087920

Kim, SJ., Schatzle, S., Ahmed, S.S., Haap, W., Jang, S., & Gregersen, P., ... Diamond, B. (2017). Increased cathepsin S in Prdm1-/- dendritic cells alters the TFH cell repertoire and contributes to lupus. Nature Immunobgy, 18(9), 1016-1024. doi:10.1038/ni.3793

Liu, Y., Ma, X., Zheng, J., Liu, X., & Yan, T. (2017). Pregnancy outcomes in patients with acute kidney injury during pregnancy: a systematic review and meta-analysis. BMC Pregnancy and Childbirth, 17(1), 235. doi: 10. 1186/s12884-017-1402-9

Liyanage, T., Ninomiya, T., Jha, V., Neal, B., Patrice, H., Okpechi, I., ... Perkovic, V. (2015). Worldwide access to treatment for end-stage kidney disease: A systematic review. The Lancet, 385(9981), 1975-1982. doi:10.1016/s0140-6736(14) 61601-9

Luyckx, V.A., Bertram, J.F., Brenner, B.M., Fall, C., Hoy, W.E., Ozanne, S.E., & Vikse, B.E. (2013). Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. The Lancet, 382(9888), 273-283. doi:10. 1016/s0140-6736(13)60311-6

Mol, B.WJ., Roberts, C.T., Thangaratinam, S., Magee, L.A., de Groot, C.J.M., & Hofmeyr, GJ. (2016). Preeclampsia. The Lancet, 387(10022), 999-1011. doi:10.1016/s0140-6736(15)00070-7

Nitsch, D., Grams, M., Sang, Y., Black, C., Cirillo, M., Djurdjev, O., . Hemmelgam, B.R. (2013). Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: A meta-analysis. BMJ, 346, f324-f324. doi:10.1136/bmj.f324

Ortona, E., Pierdominici, M., Maselli, A., Veroni, C., Aloisi, F., & Shoenfeld, Y. (2016). Sex-based differences in autoimmune diseases. Annali dell' Istituto Superiore di Sanita, 52(2), 205-212. doi: 10.4415/ANN_16_02_12

Piccoli, G.B., Cabiddu, G., Attini, R., Vigotti, F.N., Maxia, S., & Lepori, N., ... Todros, T. (2015). Risk of adverse pregnancy outcomes in women with CKD. Journal of The American Society of Nephrology, 26(8), 2011-2022. doi:10.1681/asn.2014050459

Pierdominici, M., & Ortona, E. (2013). Estrogen impact on autoimmunity onset and progression: The paradigm of systemic lupus erythematosus. International Trends in Immunity, 1(2), 24-34.

Salter, M.L., McAdams-Demarco, M.A., Law, A., Kamil, R.J., Meoni, L.A., Jaar, B.G., ...Segev, D.L. (2014). Age and sex disparities in discussions about kidney transplantation in adults undergoing dialysis. Journal of The American Geriatrics Society, 62(5), 843-849. doi: 10.1111/jgs.12801

Webster, P., Lightstone, L., McKay, D.B., & Josephson, M.A. (2017). Pregnancy in chronic kidney disease and kidney transplantation. Kidney International, 91(5), 1047-1056. doi:10.1016/ j.kint.2016.10.045

Giorgina B. Piccoli

Mona Alrukhaimi

Zhi-Hong Liu

Elena Zakharova

Adeera Levin

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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