What We Do and Do Not Know About Women and Kidney Diseases; Questions Unanswered and Answers Unquestioned: Reflection on World Kidney Day and International Woman’s Day

Chronic kidney disease (CKD) affects approximately 10% of the world’s adult population: it is within the top 20 causes of death worldwide,1 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, on 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 approximately 50% of the world’s population, are important contributors to society and their families. Besides childbearing, women are essential in childrearing and contribute to sustaining family and community health. Women in the 21st century continue to strive for equity in business, commerce, and professional endeavors, 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 underrepresented in many clinical research studies, thus limiting the evidence base on which to make recommendations to ensure best outcomes (Figure 1). Sex differences throughout the continuum of CKD care. Abbreviations: AI, autoimmune; AKI, acute kidney injury; AVF, arteriovenous fistula; CKD, chronic kidney disease; HD, hemodialysis; KT, kidney transplant; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, systemic scleroderma. In this editorial, 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. Pregnancy is a unique challenge and is a major cause of acute kidney injury (AKI) in women of childbearing age; AKI and preeclampsia (PE) may lead to subsequent CKD, but the entity of the risk is not completely known.2–5 CKD has a negative effect on pregnancy even at very early stages.6,7 The risks increase with CKD progression thus posing potentially challenging ethical issues around conception and maintaining of pregnancies.6–8 We do know that PE increases the probability of hypertension and CKD in later years, but we have not evaluated a surveillance or renoprotective strategy to determine if progressive loss of kidney function can be attenuated.9–12 Specific systemic conditions like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic scleroderma (SS) are more likely to affect women than men. We do not know the relative contribution of these acute and chronic conditions on progression to end-stage renal disease (ESRD) in women. In CKD cohorts, the prevalence in women is always less than in men, and they have slower progression to ESRD.13–15 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 with CKD have a higher cardiovascular risk than women without CKD16; 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, which may be due to biological or systemic factors. In some locations there is differential use of peritoneal and hemodialysis in women and men. Women are more likely to donate kidneys for transplantation than to receive them. We do not know if this is because of the differential incidence of CKD in men vs. women, cultural factors, or other reasons. There remain gender 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, in the poorest parts of the world in particular. PE is the principal cause of AKI and maternal death, particularly in developing countries.2,17 Pregnancy is the most common cause of AKI in women of childbearing age.10,18,19 Several diseases and conditions, besides PE, hypertensive disorders of pregnancy, and CKD, can lead to pregnancy-related AKI. Causes vary in different regions. 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.12,20–22 PE and hypertensive disorders of pregnancy occur in 3–10% of all pregnancies2,3,18; in these disorders, the kidney is the main target of an unbalanced proangiogenic and antiangiogenic derangement, leading to hypertension, proteinuria, and widespread endothelial damage. The incidence of PE, higher in low-middle income countries (possibly reflecting undiagnosed predisposing diseases), peaks at the extremes of reproductive age for reasons mentioned above.12,20–22 The relationship between kidney and placenta is biunivocal, and the presence of CKD is a risk factor for PE and hypertensive disorders of pregnancy (Figure 2). Besides CKD, other conditions cited as risk factors for PE (diabetes, immunologic diseases, baseline hypertension, obesity, and metabolic syndrome), are also risk factors for CKD. Given that even minor alterations of kidney function are present in many of these disorders, the importance of kidney function is indirectly recognized in the development of PE. Newer definitions of PE recognize differences between “placental” and “maternal” causes of PE, based on novel angiogenic-antiangiogenic markers,23,24 which may be important for management during and after pregnancy. Pregnancy and kidney function: complex interactions between 2 organs, the kidney and placenta. Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; PE, preeclampsia. There are long-term effects of PE on both maternal and fetal health, but this remains an area of active research with many unknowns. PE is a risk factor for the future development of CKD and ESRD in the mother.3–5 The reasons are not fully understood; podocyte loss is a hallmark of PE, suggesting permanent glomerular damage.25 Endotheliosis, associated with PE, but also found in normal pregnancies, may herald glomerulosclerosis; tubular and vascular damage may coexist.26,27 Besides maternal risks, PE is associated with intrauterine and perinatal death, preterm delivery, and restricted intrauterine growth; the latter 2 are linked to “small babies”.2,3,5 Small babies and preterm babies have highly increased risks of neurological deficits and postnatal complications, especially sepsis.28–32 The risks may be higher in low-income countries, since survival and deficit-free survival depend on the provision of postnatal intensive care.20,21 In the long term, small babies are at risk for the development of diabetes, metabolic syndrome, cardiovascular diseases, and CKD in adulthood.33–37 Since kidney development is completed in the last phases of pregnancy, delayed, insufficient kidney growth, resulting in low nephron number is probably the basis of the increased risk of CKD and hypertension in small for gestational age, and preterm babies.33–37 CKD is a risk factor for adverse pregnancy outcomes from its early stages (Table 1).6,38,39 The risks increase from CKD stage 1 to CKD stage 5, and may be higher in glomerular nephropathies, autoimmune diseases, and diabetic nephropathy.6,7,38–41 Results of pregnancy after kidney donation suggest that reduction of kidney parenchyma may be associated with a higher risk of PE and hypertensive disorders of pregnancy.42,43 Adverse pregnancy outcomes in patients with chronic kidney disease and in their offspring Abbreviations: ACEi, angiotensin-converting-enzyme inhibitor; AKI, acute kidney injury; ARBs, angiotensin II receptor blockers; CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; GFR, glomerular filtration rate; IgA, immunoglobulin A; IUGR, intrauterine growth restriction; LLAC, Lupus-like anticoagulant; MMF, mycophenolate mofetil; mTor, mechanistic target of rapamycin; PE-AKI, preeclampsia acute kidney injury; PKD, polycystic kidney disease; sCR, serum creatinine; SGA, small for gestational age; SLE, systemic lupus erythematosus. Adverse pregnancy outcomes in patients with chronic kidney disease and in their offspring Abbreviations: ACEi, angiotensin-converting-enzyme inhibitor; AKI, acute kidney injury; ARBs, angiotensin II receptor blockers; CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; GFR, glomerular filtration rate; IgA, immunoglobulin A; IUGR, intrauterine growth restriction; LLAC, Lupus-like anticoagulant; MMF, mycophenolate mofetil; mTor, mechanistic target of rapamycin; PE-AKI, preeclampsia acute kidney injury; PKD, polycystic kidney disease; sCR, serum creatinine; SGA, small for gestational age; SLE, systemic lupus erythematosus. Hypertension and proteinuria at baseline are important modulators of pregnancy-related risks; among the risks, we know that malformations are not increased with respect to the overall population (out of the context of inherited diseases, such as reflux nephropathy, polycystic kidney disease, or congenital anomalies of the kidney and urinary tract), maternal death is unusual (in highly resourced countries), while the incidence of preterm delivery and of small for gestational age babies, intrinsically linked, is increased in stage 1 CKD patients, and rises with the worsening of kidney function. Likewise, the effect of pregnancy on CKD progression is not fully understood because of different study designs, obstetric policies, and duration of follow-up. Overall, short- and long-term decrease in kidney function is unusual in early CKD, but the risk increases as CKD severity increases.6,7,38–41,44–48 Pregnancy is a potential occasion for the initial diagnosis of CKD. In poorly or unevenly resourced countries, advanced CKD may be discovered only during pregnancy. The implications of dialysis initiation may present important clinical and ethical issues; in highly resourced countries with established prenatal care, the diagnosis of earlier stages of CKD may lead to more intensive therapy and surveillance.49–51 Ferti lity is reduced in ESRD; Australian and European data suggest a 1:10 ratio from general population to transplantation and from transplantation to dialysis (1:100 probability as compared to the general population).52,53 The first sporadic cases of successful pregnancy on dialysis were described in the 70s, but in the new millennium this became an acknowledged real clinical possibility.8,54,55 More than 1,000 pregnancies have been reported in dialysis patients.55 The most important advance has been the demonstration of a strong relationship between the intensity (frequency and duration) of the dialysis sessions and positive pregnancy results: thus, intensifying dialysis up to daily, is the current standard of care.8,54 Changing attitudes toward counseling women with advanced CKD may be impacted, with the knowledge of positive outcomes on dialysis for women and their offspring. Fertility is partly restored after kidney transplantation.56–60 However, even in an ideal situation (normal kidney function, no hypertension or proteinuria, at least 2 years after transplantation, without recent rejection episodes), the risk of complications is higher in women with transplanted kidneys than in the general population. However, if teratogen drugs are avoided (mycophenolic acid and rapamycine), the outcomes of pregnancy after kidney transplantation shares the same risk factors as CKD (kidney function, hypertension, and proteinuria).59 Experience with pregnancy in patients with a reduced renal function or failing kidney graft is limited and counseling is still forcedly based on personal experience or indirect evidence.61,62 Assisted fertilization techniques are increasingly popular in some settings, but dedicated studies in CKD patients are few; multiple pregnancies may bear an added risk in CKD patients, with both native and transplanted kidneys. Autoimmune diseases such as SLE, RA, and 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 (Table 2). The public health burden of autoimmune diseases, which collectively represent a leading cause of morbidity and mortality among women throughout adulthood, is substantial.63–65 Sex differences in the incidence and severity of autoimmune diseases Abbreviations: RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, systemic scleroderma. Sex differences in the incidence and severity of autoimmune diseases Abbreviations: RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, systemic scleroderma. SLE is an autoimmune disease with multiple organ involvement, affecting approximately 5 million people worldwide; disproportionately predominant in women (9:1 female-to-male ratio) and individuals of non-European ancestry. The highest female predominance (up to 15:1) is in peak reproductive years. The biology of these differences has been explored: one explanation is the number of X chromosomes and genetic variants on the X chromosome66–68; another important etiological explanation is the role of estrogen in SLE. Estrogen’s primary effects are mediated by transcription activity of the intracellular estrogen receptors, whose profile is altered in T-cells from female SLE patients.69,70 Cathepsin S protein has recently been identified as a potential cause of lupus, triggering the immune system to attack healthy cells, particularly in females.71 Numerous non-HLA genetic markers may predispose individuals of European, Hispanic, and Afro-American ancestry to lupus.72 Susceptibility to SLE during pregnancy is also multifactorial; one factor being upregulation of interferon (IFN)-α. Elevated IFN-α, expressed by the placenta, plays a pathogenic role in SLE, contributing both to the success of placental reproduction and to increased susceptibility to SLE.73 Regulatory T-cells (which may be the key to cell modulating feto-maternal tolerance) have abnormalities of structure and function, and may contribute to pregnancy pathology in women with SLE and to challenges of managing them during pregnancy.74 SLE affects kidneys in about 50% of patients, including glomerular, interstitial, and vascular lesions. Lupus nephritis is a major risk factor for overall morbidity and mortality in SLE, and despite potent therapies still leads to significant impairment of kidney function for many patients.75 Kidney disease is a critical concern in counseling women with lupus considering pregnancy, with previous kidney involvement and lower C4 levels conferring high risk of active nephritis occurring in pregnancy.76 Socioeconomic disparities are also linked to the health of patients with lupus. Poverty is associated with an increased long-term level of accumulated disease-associated damage and a 1.67-times increased likelihood of experiencing a clinically meaningful increase in damage. Frequency of adverse pregnancy outcomes in women with lupus is 2-fold higher in Black and Hispanic women than in White women. In Blacks, socioeconomic a of pregnancy outcomes and a key to adverse pregnancy also preferentially affects women ratio to with the peak incidence at age with the years. a between estrogen and disease incidence ratio after age years is approximately potentially in in the development of RA, and a of or even during pregnancy is well involvement in is common and and is a of mortality in The risk of CKD is higher in patients with than in the general population. The development of CKD may result from including renal involvement associated with chronic and The strong between activity and increases morbidity and is the main cause of ESRD with and some of the and can lead to various renal SS affects women from to with the peak incidence in the and may a role in scleroderma its effect on growth 1 receptor and growth factor is an important in SS, and the low associated with has been to vascular in SS can also be by a number of different of kidney disease, including scleroderma renal which a of hypertension with acute renal or more leading to progressive CKD, by hypertension and acute renal in patients with SS may be by nephritis or a entity in scleroderma with renal therapy including dialysis and transplantation is not all patients receive The of ESRD by between countries and and on the of a and health care only 50% of patients receive and in and countries and even in parts of less than of ESRD are by The of access to for women and is of concern in many they are by in least million people may have due to of access to with being much in low-income countries, with in and of million and people not the number of be more than to million with the most growth in million to a million are from an There are data to the gender difference for the in that men were more likely to receive than In the incidence of ESRD in less than of that in in vs. women million population no are for this study women higher ratio of for initiation of dialysis compared to levels of previous kidney disease in women were reported much lower than in men in women vs. in which may contribute to later initiation of are similar in men and women on but the of some complications and morbidity are higher in women. of in patients hemodialysis higher in women, and higher risk for In the use of arteriovenous which is associated with reduced and is lower among female than hemodialysis may be due to a number of different factors, including issues to of and has not been which is evaluated by may result in in women who have an of or than Women dialysis have also been reported to have clinical including and of are not the best of in patients without data that women are less likely than men to be kidney from a or but are more likely to as for kidney from different countries, including the and differential kidney in women than less likelihood of women being on and from dialysis initiation to are more likely to be as are female Sex also in the population. from countries in the European for and reported a lower access to renal transplantation than Socioeconomic factors a role in the of transplantation between especially in the and countries and regions. men the major income for their family which may them to donate kidneys. and between may contribute to differences in transplantation because and income is associated with health care which the for factors and education of women have been as a contribution to data found Black women were less likely to kidney transplantation compared with men, despite being as likely as men to receive for kidneys. were also less likely to have been evaluated for a kidney disparities in age and in access to kidney transplantation which at the of about kidney of age, women were more likely not to have with medical result may that there is a for clinical and education for women, their and their Given the data with respect to pregnancy, AKI, autoimmune diseases, CKD, and transplantation, there are many In high income countries with maternal age and assisted there may be an increase in PE which may impact future if associated with adverse fetal The increase in fertilization techniques for those of advanced maternal age may lead to multiple pregnancies, which may predispose to PE, intrauterine growth or this lead to an increase in CKD and cardiovascular disease for women in the to the high of CKD, we do not know if and how pregnancy outcomes are by the different nephropathies, as besides the most common such as or lupus nephropathy, diabetic nephropathy, and reflux nephropathy, evidence is we risks of pregnancy with respect to current proteinuria on to dialysis in pregnancy are not well established is the role of and In those with kidney the policies, higher age at transplantation, and reduced in women, there may be in attitudes toward pregnancy with less than kidney this impact short- and long-term outcomes of and their babies is not pregnancies are very common in some parts of the world and are associated with low income and cultural The legal for assisted fertilization and the of of the kidney function to the for for the role of in vascular health and the predominance in of SLE, RA, and SS remains relative to other systemic diseases such as and that has a higher incidence in women, this is likely due to the with other conditions more common in women. The incidence of kidney involvement in SLE during pregnancy and in those with PE have not been well The role of different and to for autoimmune diseases relative to has also not been well More to between conditions, the importance of in and vascular health, may lead to important and clinical women are more likely to be at differential does this impact both cardiovascular disease and risk for have we this well in the current with for CKD and to renal the that women have after donation by on as they are the risks of CKD and PE increased in the female kidney In the context of therapies for the or of CKD do we know if there are differences in to angiotensin-converting-enzyme II receptor we at by vascular and immune biology is by as described do we know the impact of various therapies by level or ratio of In income countries, how does and impact women’s health, and what is the impact on CKD of predominance of obesity, diabetes, and Women have unique risks for kidney kidney diseases, as well as issues to access to care, have a impact on both the current and next for access to care for women is critical to the health of and studies on the unique contribution of or the interaction of and other is important to improve of the progression of kidney conditions such as pregnancy as a of to as well as SLE and other autoimmune and systemic conditions common in women, may also lead to in and care There is a for higher and up of CKD in pregnancy. In pregnancy may also be a occasion for early diagnosis of CKD, of this World Kidney Day and the International Women’s Day 2018 are on the same offering the opportunity to the importance of women’s health and particularly their kidney health. its World Kidney Day and equitable access to health health care, and for all women and in the The of World Kidney Day and International Women’s Day an opportunity to and best and future research and to the outcomes of all people with or at risk for kidney The no of have to the

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