What we know and do not know about women and kidney diseases: questions unanswered and answers unquestioned: reflection on World Kidney Day and International Women’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 the 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 equality in business, commerce and professional endeavours, while recognising that in many situations, equality 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 (Fig. 1). In this editorial, we focus on what we know 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 pre-eclampsia (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 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 reno-protective strategy to determine if progressive loss of kidney function can be attenuated.9-12 Specific systemic conditions, such as 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 haemodialysis 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 haemodialysis 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 versus 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 evaluate directly 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 fertilisation is becoming a leading cause in developed countries.12, 20-22 PE and hypertensive disorders of pregnancy occur in 3–10% of all pregnancies;2, 3, 18 in these disorders, the kidney is the main target of an unbalanced pro-angiogenic and anti-angiogenic 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 (Fig. 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 recognised in the development of PE. Newer definitions of PE recognise 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. There are long-term effects of PE on both maternal and foetal 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 co-exist.26, 27 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’.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 (CVD) 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 S1, Supporting information).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 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. Similarly, 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 Fertility 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 1970s, but in the new millennium this became an acknowledged real clinical possibility.8, 54, 55 More than 1000 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 towards counselling 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 rapamycin), the outcomes of pregnancy after kidney transplantation share 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 counselling is still forcibly based on personal experience or indirect evidence.61, 62 Assisted fertilisation 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 characterised by systemic inflammation leading to target organ dysfunction, including the kidneys. Sex differences in the incidence and severity of these diseases result from a complex interaction of hormonal, genetic and epigenetic factors (Table 1). 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 SLE is an autoimmune disease with multiple organ involvement, affecting approximately five 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 chromosome;66-68 another important aetiological explanation is the role of oestrogen in SLE. Oestrogen’s primary effects are mediated by transcription activity of the intracellular oestrogen 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-human leukocyte antigen 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 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 foeto-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 counselling 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 twofold higher in black and Hispanic women than in white women. In blacks, socioeconomic status was a determinant of pregnancy outcomes and a key contributor to adverse pregnancy outcomes.77, 78 RA also preferentially affects women (4:1 ratio to men) with the peak incidence at age 45–55, coinciding with the perimenopausal years. This suggests a possible association between oestrogen deficiency and disease onset. Female-to-male incidence ratio after the age of 60 years is approximately 1:1, potentially implicating changes in sex hormones in the development of RA, and a pattern of RA symptom improvement or even remission during pregnancy is well recognised.79-81 Renal involvement in RA is relatively common and multifactorial and is a predictor of mortality in RA patients. The risk of CKD is significantly higher in patients with RA than in the general population. The development of CKD may result from several ongoing processes, including specific renal involvement associated with RA (e.g. glomerulonephritis, interstitial nephritis), chronic inflammation, comorbidities and nephrotoxic anti-rheumatic drugs. The strong association between RA activity and AA amyloidosis increases morbidity and is the main cause of ESRD with RA and nephropathy. Importantly, some of the life-long and combined RA pharmacotherapy can lead to various renal side effects.82-84 SS predominantly affects women (female-to-male ratios ranging from 3:1 to 14:1), with the peak incidence in the fifth and sixth decades. Oestrogen may play a role in scleroderma pathogenesis through its stimulatory effect on transforming growth factor-beta 1 receptor and platelet-derived growth factor receptor.85 Vasculopathy is an important disease-related manifestation in SS, and the low oestrogenic state associated with menopause has been suggested to aggravate vascular manifestations in affected women.86 SS can also be complicated by several different forms of kidney disease, including scleroderma renal crisis, which represents a form of malignant hypertension with acute renal failure; or more commonly leading to progressive CKD, by hypertension and acute renal in patients with SS may be by interstitial 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 only 50% of patients receive and in and countries and even in parts of less than of ESRD are by The equality 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 was less than of that in in women million population no are for this study women significantly 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 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 haemodialysis higher in women and higher risk for In the use of which is associated with reduced and is lower among female than haemodialysis This may be due to several different including issues to of and This 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 represents the best form of in patients without data that women are less likely than men to be kidney patients, 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 Renal and reported a lower access to renal transplantation than Socioeconomic factors play 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. status and between may contribute to sex differences in transplantation because and income status is associated with which the for factors and education of women have been suggested as a contribution to sex 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 sex in access to kidney transplantation which at the of about kidney of women were more likely not to have with medical This result may that there is a for clinical and education for women, their and their Given the data with respect to pregnancy, autoimmune diseases, CKD, dialysis and transplantation, there are many In countries with maternal age and assisted there may be an increase in PE which may impact future if associated with adverse foetal The increase in in fertilisation 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 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 and reflux nephropathy, evidence is we risks of pregnancy with respect to current proteinuria on to dialysis in pregnancy are well established is the specific role of and In those with kidney the higher age at transplantation and reduced in women, there may be changes in attitudes towards pregnancy with less than kidney 60 this impact short- and long-term outcomes of and their babies is not pregnancies are very common in some parts of the world, and they are associated with low income and cultural The legal for assisted fertilisation and the of of the kidney function to the for for the role of sex hormones 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 association with other conditions more common in women. The incidence of kidney involvement in SLE during pregnancy and in those with PE has not been well The role of different and to for autoimmune diseases relative to sex has also not been well More to between conditions, the importance of sex hormones in inflammation, immune and vascular health, may lead to important and clinical women are more likely to be at differential does this impact both and risk for have we this well in the current with for CKD and to renal the that women have after donation by changes on as they are the risks of CKD and PE increased in the female kidney In the context of specific therapies for the or of CKD do we know if there are sex differences in to we at by vascular and immune biology is by sex hormones as described do we know the impact of various therapies by level or ratio of sex In low-middle income countries how does and impact women’s health, and what is the impact on CKD of predominance of 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 sex or the interaction of sex hormones and other are important to improve of the progression of kidney conditions, such as pregnancy as a state 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 diagnosis and 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 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 is not for the or of by the than be to the for the

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