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What we do and do not know about women and kidney diseases; questions unanswered and answers unquestioned:… Piccoli, Giorgina B; Alrukhaimi, Mona; Liu, Zhi-Hong; Zakharova, Elena; Levin, Adeera Mar 15, 2018

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EDITORIAL Open AccessWhat we do and do not know about womenand kidney diseases; questions unansweredand answers unquestioned: reflection onWorld Kidney Day and InternationalWoman’s DayGiorgina B. Piccoli1,2, Mona Alrukhaimi3, Zhi-Hong Liu4, Elena Zakharova5,6,7, Adeera Levin8* and On behalf of theWorld Kidney Day Steering CommitteeAbstractChronic Kidney Disease affects approximately 10% of the world’s adult population: it is within the top 20 causes ofdeath worldwide, and its impact on patients and their families can be devastating. World Kidney Day and InternationalWomen’s Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women’s health andspecifically their kidney health, on the community, and the next generations, as well as to strive to be more curious aboutthe 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 andtheir families. Gender differences continue to exist around the world in access to education, medical care, andparticipation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis ofkidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact futuregenerations with respect to kidney health. There are various autoimmune and other conditions that are more likely toimpact women with profound consequences for child bearing, and on the fetus. Women have different complicationson 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 whatwe might learn in the future to improve outcomes worldwide.Keywords: Women, Access to care, Kidney health, Acute and chronic kidney disease, InequitiesIntroductionChronic Kidney Disease (CKD) affects approximately10% of the world’s adult population: it is within the top20 causes of death worldwide [1], and its impact on pa-tients and their families can be devastating. WorldKidney Day and International Women’s Day in 2018 co-incide, thus offering an opportunity to reflect on the im-portance of women’ s health and specifically their kidneyhealth, on the community, and the next generations; aswell as to strive to be more curious about the uniqueaspects of kidney disease in women, so that we mayapply those learnings more broadly.Girls and women, who make up approximately 50% ofthe world’s population, are important contributors to soci-ety and their families. Besides childbearing, women are es-sential in childrearing and contribute to sustaining familyand community health. Women in the 21st century con-tinue to strive for equity in business, commerce, andprofessional endeavours, while recognizing that in manysituations, equity does not exist. In various locationsaround the world, access to education and medical care isnot equitable amongst men and women; women remainunder-represented in many clinical research studies, thus* Correspondence: alevin@providencehealth.bc.ca8Department of Medicine, Division of Nephrology, University of BritishColumbia, Vancouver, BC, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Piccoli et al. BMC Nephrology  (2018) 19:66 https://doi.org/10.1186/s12882-018-0864-ylimiting the evidence base on which to make recommen-dations to ensure best outcomes (Fig. 1).In this editorial, we focus on what we do and do notknow about women’s kidney health and kidney disease,and what we might learn in the future to improve out-comes for all.Kidney Health and Women’s Health: a case foroptimizing outcomes for present and futuregenerationsWhat we know and do not knowPregnancy is a unique challenge and is a major cause ofacute 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 earlystages [6, 7]. The risks increase with CKD progressionthus posing potentially challenging ethical issues aroundconception and maintaining of pregnancies [6–8]. We doknow that PE increases the probability of hypertensionand CKD in later years, but we have not evaluated a sur-veillance or reno-protective strategy to determine if pro-gressive loss of kidney function can be attenuated [9–12].Specific systemic conditions like Systemic LupusErythematosus (SLE), Rheumatoid Arthritis (RA), andSystemic Scleroderma (SS), are more likely to affectwomen than men. We do not know the relative contri-bution of these acute and chronic conditions on progres-sion to end-stage renal disease (ESRD) in women.In CKD cohorts, the prevalence in women is alwaysless than in men, and they have slower progression toESRD [13–15]. We do not know why and how much ofthis is due to differences in identification of kidneyimpairment, different access to care, or true differencein disease severity and prevalence.Women with CKD have a higher cardiovascular riskthan women without CKD [16]; but their risk is stilllower than that of men with similar degrees of kidneyimpairment. In hemodialysis cohorts, there are differ-ences in vascular access types in women versus men,which may be due to biological or systemic factors. Insome locations there is differential use of peritoneal andhemodialysis in women and men.Women are more likely to donate kidneys for trans-plantation than to receive them. We do not know if thisis because of the differential incidence of CKD in menvs women, cultural factors, or other reasons.There remain gender differences in access to care indifferent regions of the world, and we do not have datato directly evaluate the extent of these differences, in thepoorest parts of the world in particular.Pregnancy, preeclampsia, pregnancy-inducedhypertensive disorders, and fetal health.The importance of women’s health to presentand future kidney healthWhat we knowPE is the principal cause of AKI and maternal death, par-ticularly in developing countries [2, 17]. Pregnancy is themost 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 leadto pregnancy-related AKI. Causes vary in different regions.Septic abortion after an illegal procedure is the leadingcause of early AKI in countries where legal abortions arenot available, while PE after assisted fertilization is becom-ing a leading cause in developed countries [12, 20–22].Fig. 1 Sex differences throughout the continuum of CKD care. SLE = Systemic Lupus Erythematosus; RA = Rheumatoid Arthritis; SS = Systemic Scleroderma;AKI = acute kidney injury; CKD= chronic kidney disease; AI = autoimmune; AVF = arteriovenous fistula; HD= hemodialysis; KT = kidney transplantPiccoli et al. BMC Nephrology  (2018) 19:66 Page 2 of 11PE and hypertensive disorders of pregnancy occur in3-10% of all pregnancies [2, 3, 18]; in these disorders thekidney is the main target of an unbalanced pro-angiogenic and anti-angiogenic derangement, leading tohypertension, proteinuria, and widespread endothelialdamage. The incidence of PE, higher in low-middle in-come countries (possibly reflecting undiagnosed predis-posing diseases), peaks at the extremes of reproductiveage for reasons mentioned above [12, 20–22].The relationship between kidney and placenta is biuni-vocal, and the presence of CKD is a risk factor for PEand hypertensive disorders of pregnancy (Fig. 2). BesidesCKD, other conditions cited as risk factors for PE(diabetes, immunologic diseases, baseline hypertension,obesity, and metabolic syndrome), are also risk factorsfor CKD. Given that even minor alterations of kidneyfunction are present in many of these disorders, theimportance of kidney function is indirectly recognized inthe development of PE. Newer definitions of PErecognize differences between “placental” and “maternal”causes of PE, based on novel angiogenic-antiangiogenicmarkers [23, 24], which may be important for manage-ment during and after pregnancy.There are long term effects of PE on both maternaland fetal health, but this remains an area of activeresearch with many unknowns.PE is a risk factor for the future development of CKDand ESRD in the mother [3–5]. The reasons are not fullyunderstood; podocyte loss is a hallmark of PE, suggest-ing permanent glomerular damage [25]. Endotheliosis,associated with PE, but also found in normalpregnancies, may herald glomerulosclerosis; tubular andvascular damage may co-exist [26, 27].Besides maternal risks, PE is associated with intrauter-ine and perinatal death, preterm delivery, and restrictedintrauterine growth; the latter two are linked to “smallbabies” [2, 3, 5]. Small babies and preterm babies havehighly increased risks of neurological deficits and post-natal complications, especially sepsis [28–32]. The risksmay be higher in low-income countries, since survivaland deficit-free survival depend on the provision of post-natal intensive care [20, 21]. In the long term, smallbabies are at risk for the development of diabetes, meta-bolic syndrome, cardiovascular diseases (CVDs), andCKD in adulthood [33–37]. Since kidney development iscompleted in the last phases of pregnancy, delayed, in-sufficient kidney growth, resulting in low nephron num-ber is probably the basis of the increased risk of CKDand hypertension in small for gestational age, and pre-term babies [33–37].Pregnancy in chronic kidney disease, dialysis,and transplantationWhat we knowChronic kidney diseaseCKD is a risk factor for adverse pregnancy outcomes fromits early stages (Table 1) [6, 38, 39]. The risks increasefrom CKD stage 1 to CKD stage 5, and may be higher inglomerular nephropathies, autoimmune diseases, and dia-betic nephropathy [6, 7, 38–41]. Results of pregnancy afterkidney donation suggest that reduction of kidney paren-chyma may be associated with a higher risk of PE andhypertensive disorders of pregnancy [42, 43].Fig. 2 Pregnancy and kidney function: complex interactions between 2 organs, the kidney and placenta. PE = preeclampsia; AKI = acute kidneyinjury; CKD = chronic kidney diseasePiccoli et al. BMC Nephrology  (2018) 19:66 Page 3 of 11Hypertension and proteinuria at baseline are import-ant modulators of pregnancy-related risks; among therisks, we know that malformations are not increasedwith respect to the overall population (out of the contextof inherited diseases, such as reflux nephropathy, poly-cystic kidney disease, or congenital anomalies of thekidney and urinary tract), maternal death is unusual (inhighly resourced countries), while the incidence of pre-term delivery and of small for gestational age babies, in-trinsically linked, is increased in stage 1 CKD patients,and rises with the worsening of kidney function.Likewise, the effect of pregnancy on CKD progression isnot fully understood because of different study designs,obstetric policies, and duration of follow-up. Overall,short- and long- term decrease in kidney function isunusual in early CKD, but the risk increases as CKD se-verity increases [6, 7, 38–41, 44–48].Pregnancy is a potential occasion for the initial diagno-sis of CKD. In poorly or unevenly resourced countries,advanced CKD may be discovered only during preg-nancy. The implications of dialysis initiation may presentimportant clinical and ethical issues; in highly resourcedcountries with established prenatal care, the diagnosis ofearlier stages of CKD may lead to more intensive therapyand surveillance [49–51].Dialysis and transplantationFertility is reduced in ESRD; Australian and Europeandata suggest a 1:10 ratio from general population totransplantation and from transplantation to dialysisTable 1 Adverse pregnancy outcomes in patients with chronic kidney disease and in their offspringTerm Definition Main IssuesMaternal death Death in pregnancy or within1 week-1 month postpartumToo rare to be quantified, at least in highly resourced settings, where cases are in thesetting of severe flares of immunologic diseases (SLE in primis). Still an issue in AKI; and inlow resourced countries; not quantified in low-resourced countries, where it merges withdialysis need.CKD progression Decrease in GFR, rise in sCr, shiftto a higher CKD stageDifferently assessed and estimated; may be linked to obstetric policy (anticipating deliveryin the case of worsening of the kidney function); between 20% and 80% in advanced CKD.Probably not increased in early CKD stages.Immunologic flaresand neonatal SLEFlares of immunologic diseasesin pregnancyOnce thought to be increased in pregnancy, in particular in SLE, are probably a risk inpatients who start pregnancy with an active disease, or with a recent flare-up. Definition ofa “safe” zone is not uniformly agreed; in quiescent, well controlled diseases do not appearto be increased with respect to non-pregnant, carefully-matched controls.TransplantrejectionAcute rejection in pregnancy Similar to SLE, rejection episodes are not increased with respect to matched controls;may be an issue in unplanned pregnancies, in unstable patients.Abortion Fetal loss, before 21- 24 gestationalweeksMay be increased in CKD, 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 infant, after21-24 gestational weeksProbably not increased in early CKD, maybe an issue in dialysis patients; when not linkedto extreme prematurity, may specifically linked to SLE, immunologic diseases and diabeticnephropathy.Perinatal death Death within 1 week –1 month form deliveryUsually a result of extreme prematurity, which bears a risk of respiratory distress, neonatalsepsis, cerebral hemorrhage.Small, very smallbabyA baby weighting< 2500- 1500 g at birthHas to be analyzed with respect to gestational age.Preterm, earlyextremely pretermDelivery before 37 – 34or 28 completed gestational weeksIncrease in risk of preterm and early preterm delivery across CKD stages;extremely preterm may be an important issue in undiagnosed or late referred CKD and PE-AKI.SGA (IUGR) < 5th or <10th centilefor gestational ageStrictly and inversely related to pre-term delivery; SGA and IUGR are probably related to riskfor hypertension, metabolic syndrome and CKD in adulthood.Malformations Any kind of malformations Malformations are not increased in CKD patients not treated by teratogen drugs (MMF,mTor inhibitors, ACEi, ARBS); exception: diabetic nephropathy (attributed to diabetes);hereditary diseases, such as PKD, reflux nephropathy, CAKUT may be evident at birth.Hereditary kidneydiseasesAny kind of CKD Several forms of CKD recognize a hereditary pattern or predisposition; besides PKD, refluxand CAKUT, Alport’s disease, IgA, kidney tubular disorders and mitochondrial diseases havea genetic background, usually evident in adulthood and not always clearly elucidated.CKD -hypertensionHigher risk of hypertensionand CKD in adulthoodLate maturation of nephrons results in a lower nephron number in preterm babies; the risksare probably higher in SGA-IUGR babies than in pre-term babies adequate for gestational age.Other long-termissuesDevelopmental disorders Mainly due to prematurity, cerebral hemorrhage or neonatal sepsis, are not specific of CKD,but are a threat in all preterm babies.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 mechanistictarget of rapamycin, ACEi angiotensin-converting-enzyme inhibitor, ARBS angiotensin II receptor blockers, PKD polycystic kidney disease, CAKUT congenital anomalies ofthe kidney and urinary tract, IgA immunoglobulin APiccoli et al. BMC Nephrology  (2018) 19:66 Page 4 of 11(1:100 probability as compared to the general popula-tion) [52, 53]. The first sporadic cases of successful preg-nancy on dialysis were described in the 70s, but in thenew millennium this became an acknowledged real clin-ical possibility [8, 54, 55].More than 1000 pregnancies have been reported in dialy-sis patients [55]. The most important advance has been thedemonstration of a strong relationship between the inten-sity (frequency and duration) of the dialysis sessions andpositive pregnancy results: thus, intensifying dialysis up todaily, is the current standard of care [8, 54]. Changing atti-tudes towards counselling women with advanced CKD maybe impacted, with the knowledge of positive outcomes ondialysis for women and their offspring.Fertility is partly restored after kidney transplantation[56–60]. However, even in an ideal situation (normal kid-ney function, no hypertension or proteinuria, at least2 years after transplantation, without recent rejection epi-sodes), the risk of complications is higher in women withtransplanted kidneys than in the general population. How-ever, if teratogen drugs are avoided (mycophenolic acidand rapamycine), the outcomes of pregnancy after kidneytransplantation shares the same risk factors as CKD(kidney function, hypertension, and proteinuria) [59].Experience with pregnancy in patients with a reducedrenal function or failing kidney graft is limited and coun-seling is still forcedly based on personal experience orindirect evidence [61, 62]. Assisted fertilization tech-niques are increasingly popular in some settings, butdedicated studies in CKD patients are few; multiplepregnancies may bear an added risk in CKD patients,with both native and transplanted kidneys.Autoimmune diseases, women, and kidney diseaseWhat we knowAutoimmune diseases such as SLE, RA, and SS preferen-tially affect women and are characterized by systemic in-flammation leading to target organ dysfunction,including kidneys. Sex differences in the incidence andseverity of these diseases result from a complex inter-action of hormonal, genetic, and epigenetic factors(Table 2). The public health burden of autoimmune dis-eases, which collectively represent a leading cause ofmorbidity and mortality among women throughoutadulthood, is substantial [63–65].SLE is an autoimmune disease with multiple organ in-volvement, affecting approximately five million peopleworldwide; 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 ofthese differences has been explored: one explanation isthe number of X chromosomes and genetic variants onthe X chromosome [66–68]; another importantetiological explanation is the role of estrogen in SLE.Estrogen’s primary effects are mediated by transcriptionactivity of the intracellular estrogen receptors, whoseprofile is altered in T-cells from female SLE patients [69,70]. Cathepsin S protein has recently been identified as apotential cause of lupus, triggering the immune systemto attack healthy cells, particularly in females [71].Numerous non-HLA genetic markers may predisposeindividuals of European, Hispanic, and Afro-Americanancestry to lupus [72]. Susceptibility to SLE during preg-nancy is also multifactorial; one factor being upregula-tion of IFN-α. Elevated IFN-α, expressed by theplacenta, plays a pathogenic role in SLE, contributingboth to the success of placental reproduction and to in-creased susceptibility to SLE [73]. Regulatory T-cells(which may be the key to cell modulating feto-maternaltolerance) have abnormalities of structure and function,and may contribute to pregnancy pathology in womenwith SLE and to challenges of managing them duringpregnancy [74]. SLE affects kidneys in about 50% of pa-tients, including glomerular, interstitial, and vascular le-sions. Lupus nephritis is a major risk factor for overallmorbidity and mortality in SLE, and despite potent ther-apies still leads to significant impairment of kidneyfunction for many patients [75]. Kidney disease is a crit-ical concern in counseling women with lupus consider-ing pregnancy, with previous kidney involvement andlower C4 levels conferring high risk of active nephritisoccurring in pregnancy [76]. Socioeconomic disparitiesare also linked to the health of patients with lupus.Poverty is associated with an increased long-term levelof accumulated disease-associated damage and a 1.67-times increased likelihood of experiencing a clinicallymeaningful increase in damage. Frequency of adversepregnancy outcomes in women with lupus is twofoldhigher in black and Hispanic women than in whitewomen. In blacks, socioeconomic status was a determin-ant of pregnancy outcomes and a key contributor to ad-verse pregnancy outcomes [77, 78].RA also preferentially affects women (4:1 ratio tomen) with the peak incidence at age 45-55, coincidingwith the perimenopausal years. This suggests a possibleTable 2 Sex differences in the incidence and severity ofautoimmune diseasesSLE RA SSPeak Incidence ReproductiveagePerimenopausal After50-60 yearsFemale/MaleRatioPeak 15:1 Peak 4:1 Peak 14:1Total 9:1 After60 years 1:1Total 3:1Influence ofEstrogenHigh levels Negative Positive ?Low levels ? Negative NegativeSLE Systemic Lupus Erythematosus, RA Rheumatoid Arthritis, SS Systemic SclerodermaPiccoli et al. BMC Nephrology  (2018) 19:66 Page 5 of 11association between estrogen deficiency and disease on-set. Female-to-male incidence ratio after age 60 years isapproximately 1:1, potentially implicating changes in sexhormones in the development of RA, and a pattern ofRA symptom improvement or even remission duringpregnancy is well recognized [79–81]. Renal involvementin RA is relatively common and multifactorial and is apredictor of mortality in RA patients. The risk of CKD issignificantly higher in patients with RA than in the gen-eral population. The development of CKD may resultfrom several ongoing processes, including specific renalinvolvement associated with RA (e.g., glomeruloneph-ritis, interstitial nephritis), chronic inflammation, comor-bidities, and nephrotoxic anti-rheumatic drugs. Thestrong association between RA activity and AA amyloid-osis increases morbidity and is the main cause of ESRDwith RA and nephropathy. Importantly, some of the life-long and combined RA pharmacotherapy can lead tovarious renal side effects [82–84].SS predominantly affects women (female-to-male ra-tios ranging from 3:1 to 14:1), with the peak incidence inthe fifth and sixth decades. Estrogen may play a role inscleroderma pathogenesis through its stimulatory effecton transforming growth factor-beta 1 receptor andplatelet-derived growth factor receptor [85]. Vasculopa-thy is an important disease-related manifestation in SS,and the low estrogenic state associated with menopausehas been suggested to aggravate vascular manifestationsin affected women [86]. SS can also be complicated by anumber of different forms of kidney disease, includingscleroderma renal crisis, which represents a form of ma-lignant hypertension with acute renal failure; or morecommonly ischemic nephropathy leading to slowly pro-gressive CKD, accompanied by hypertension and albu-minuria [78]. Normotensive acute renal failure inpatients with SS may be caused by interstitial nephritisor ANCA vasculitis, a separate entity in sclerodermawith poor outcome [87–89].Women, chronic kidney disease, and access to renalreplacement therapiesWhat we knowAlthough renal replacement therapy (RRT), includingdialysis and transplantation is life-sustaining, not all pa-tients receive RRT. The rate of ESRD treated by RRTdiffers greatly between countries and regions, and intri-cately depends on the economy of a country and healthcare system [90, 91]. Worldwide, only 50% of patientsrequiring RRT receive treatment [92], and in low andmiddle-income countries and regions, even less; in largeparts of Sub-Saharan Africa, less than 2% of ESRD aretreated by RRT [93]. The equality of access to RRT forwomen and girls is of particular concern because, inmany societies, they are disadvantaged by discriminationrooted in sociocultural factors [94, 95].Sex differences in access to dialysisAt least 2.284 million people may have died prematurelydue to lack of access to RRT with treatment gaps beingmuch larger in low-income countries, with conservativeestimates in Asia and Africa of 1.907 million and432,000 people not receiving RRT. By 2030, the esti-mated number of RRT should be more than double to5.439 million (3.899–7.640 million), with the mostgrowth in Asia (0.968 million to a projected 2.162 mil-lion [1.71–3.14 million]) [92]. These numbers are de-rived from an extensive systematic review.There are few data to compare the gender differencefor the treatment gaps. Studies in Africa show that menwere more likely to receive RRT than women [96, 97]. InJapan, the incidence of treated ESRD in females was lessthan half of that in males (3287 in males vs. 1764women per million population treated) [91]: no explana-tions are given for this finding. One US study reportswomen having significantly higher odds ratio of 1.70 forlate initiation of dialysis compared to men [98]. Aware-ness levels of previous kidney disease in women werereported much lower than in men (2.9% ± 1.6% inwomen vs. 17.9% ± 5.9% in men), which may contributeto later initiation of RRT [99].Mortality rates are similar in men and women on dia-lysis, but the incident rates of some dialysis-associatedcomplications and morbidity are higher in women. A USreport of hospitalizations in 111,653 patients undergoingmaintenance hemodialysis describes higherhospitalization rates in women, and higher risk for 30-day readmissions [100].In addition, the prevalent use of arteriovenous fistula,which is associated with reduced mortality, complication,and costs, is lower among female than male hemodialysispatients [101]. This may be due to a number of differentfactors, including anatomical/surgical issues relating tovessel size, timing of referral, and attitudinal differences.This has not been systematically studied.Dialysis dose, which is evaluated by Kt/V may result inunder-dialysis in women who have an average smallervolume of urea distribution or total body water thanmen [102]. Women receiving dialysis have also beenreported to have worse clinical parameters includinganemia, nutrition, and quality of life [103]. Reasons arenot certain.Sex differences in access to kidney transplantationTransplantation represents the best form of RRT inpatients without contraindications. Worldwide data de-scribes that women are less likely than men to be kidneytransplant recipients, either from a cadaveric or livingPiccoli et al. BMC Nephrology  (2018) 19:66 Page 6 of 11donor, but are more likely to serve as living donors forkidney transplantation [104]. Data from different coun-tries, including the US, France, China, and India, con-firm differential kidney transplant rates (lower in womenthan men), less likelihood of women being registered onnational transplant waiting lists, and longer time fromdialysis initiation to listing. Mothers are more likely tobe donors, as are female spouses [91, 105–108]. Sex in-equality also exists in the pediatric population. A surveyfrom 35 countries participating in the European Societyfor Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry,reported girls had a lower access to renal transplantationthan boys [109].Socioeconomic factors undoubtedly play a role in theinequality of transplantation between sexes, especially inthe low and middle-income countries and regions.Generally, men provide the major income for their fam-ily which may discourage them to donate kidneys.Different employment status and incomes between gen-ders may contribute to sex differences in transplantationbecause employment and income status is usually asso-ciated with better healthcare insurance which cover thecosts for transplantation. Psychosocial factors and edu-cation of women have been suggested as a contributionto sex disparity. US data found black women were lesslikely to want living donor kidney transplantation com-pared with men, despite being twice as likely as men toreceive unsolicited offers for kidneys. They were also lesslikely to have been evaluated for a kidney transplant[110]. Other reports describe disparities in age and sexin access to kidney transplantation which originate atthe time of pre-referral discussions about kidney trans-plantation; irrespective of age, women were more likelynot to have had discussions with medical professionals.This result may imply that there is a need for better clin-ical guidelines and education for women, their socialnetwork, and their providers [111].Present and future: what we do not knowGiven the data presented above with respect to pregnancy,AKI, autoimmune diseases, CKD, dialysis and transplant-ation, there are many unanswered questions. In high in-come countries with increasing maternal age and assistedfertilization, there may be an increase in PE which mayimpact future generations if associated with adverse fetaloutcomes. The increase in in-vitro fertilization techniquesfor those of advanced maternal age may lead to multiplepregnancies, which may predispose to PE, intrauterinegrowth restriction, or both. Will this lead to an increase inCKD and CVD for women in the future?Due to the high heterogeneity of CKD, we do notknow if and how pregnancy outcomes are modulated bythe different nephropathies, as besides the most com-mon ones such as IgA or lupus nephropathy, diabeticnephropathy, and reflux nephropathy, evidence is scant[44, 45, 112–114]. How should we define preconceptionrisks of pregnancy with respect to current proteinuriacut offs? Indications on when to start dialysis in preg-nancy are not well established, nor is the specific role offrequency and duration. In those with kidney trans-plants, given the changing expanded donor policies,higher age at transplantation, and reduced fertility inolder women, there may be changes in attitudes towardspregnancy with less than optimal kidney function [56,60]. How this will impact short and long-term outcomesof mothers and their babies is not clear.Teen pregnancies are very common in some parts ofthe world, and are often associated with low income andcultural levels. The uneven legal rules for assistedfertilization and the lack of systematic assessment of thekidney function point to the need for further research.Despite elegant demonstrations for the role of sexhormones in vascular health and immunoregulation, thestriking predominance in females of SLE, RA, and SS re-mains unexplained relative to other systemic diseasessuch as ANCA vasculitis and hemolytic-uremic syn-drome. Note that thrombotic thrombocytopenic purpurahas a higher incidence in women, though this is likelydue to the association with other conditions morecommon in women. The incidence of kidney involve-ment in SLE during pregnancy and similarities/differ-ences in those with PE have not been well studied. Therole of different medications and responses to medica-tions for autoimmune diseases relative to sex has alsonot been well studied.More attention to similarities between conditions, theimportance of sex hormones in inflammation, immune-modulation, and vascular health, may lead to importantinsights and clinical breakthroughs over time. If womenare more likely to be living donors, at differential ages,does this impact both CVD risk, and risk for ESKD: havewe studied this well enough, in the current era, withmodern diagnostic criteria for CKD and sophisticatedtools to understand renal reserve? Are the additional ex-posures that women have after living donation com-pounded by hormonal changes on vasculature as theyage? And are the risks of CKD and PE increased in theyounger female kidney living donor?In the context of specific therapies for the treatmentor delay of CKD progression, do we know if there aresex differences in therapeutic responses to ACEi/ARB?Should we look at dose finding/adjustments by sex? Ifvascular and immune biology is impacted by sex hor-mones as described earlier, do we know the impact ofvarious therapies by level or ratio of sex hormones? Inlow-middle income countries how does changingPiccoli et al. BMC Nephrology  (2018) 19:66 Page 7 of 11economic and social cultures impact women’s health,and what is the nutritional impact on CKD of increasingpredominance of obesity, diabetes, and hypertension?SummaryWomen have unique risks for kidney diseases: kidneydiseases, as well as issues related to access to care, havea profound impact on both the current and next genera-tions. Advocating for improved access to care forwomen is critical to maintain the health of families,communities, and populations.Focused studies on the unique contribution of sex hor-mones, or the interaction of sex hormones and otherphysiology, is important to improve our understandingof the progression of kidney diseases. Immunologicalconditions such as pregnancy (viewed as a state of toler-ance to non-self ) as well as SLE and other autoimmuneand systemic conditions common in women, better stud-ied may also lead to breakthroughs in understandingand care paradigms.There is a clear need for higher awareness, timely diagno-sis, and proper follow up of CKD in pregnancy. In turn,pregnancy may also be a valuable occasion for early diagno-sis of CKD, allowing planning of therapeutic interventions.On this occasion, World Kidney Day and theInternational Women’s Day 2018 are commemorated onthe same day, offering us the opportunity to highlightthe importance of women’s health and particularly theirkidney health. On its 13th anniversary, World KidneyDay promotes affordable and equitable access to healtheducation, healthcare, and prevention for all women andgirls in the world.The coinciding of World Kidney Day and InternationalWomen’s Day offers an opportunity to develop and de-fine best practices and future research agendas, andultimately, to optimize the outcomes of all people livingwith or at risk for kidney disease.AcknowledgementsMembers 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.DisclosureAll authors have contributed to the manuscript equally. None of the authorshave direct conflicts of interest with this paper and material contained herein;full disclosures are listed in the individual authors’ Conflict of Interest forms.Authors’ contributionsAll authors contributed equally to the conception, preparation, and editingof the manuscript. All authors read and approved the final manuscript.Competing interestsAt the time of publication, Giorgina B Piccoli is a Section Editor at BMCNephrology. All other authors confirm that they have no competinginterests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Clinical and Biological Sciences, University of Torino, Torino,Italy. 2Nephrology, Centre Hospitalier Le Mans, Le Mans, France. 3Departmentof Medicine, Dubai Medical College, Dubai, United Arab Emirates. 4NationalClinical Research Center of Kidney Diseases, Jinling Hospital, NanjingUniversity School of Medicine, Nanjing, China. 5Nephrology, Moscow CityHospital n.a. S.P. Botkin, Moscow, Russian Federation. 6Nephrology, MoscowState University of Medicine and Dentistry, Moscow, Russian Federation.7Nephrology, Russian Medical Academy of Continuous ProfessionalEducation, Moscow, Russian Federation. 8Department of Medicine, Divisionof Nephrology, University of British Columbia, Vancouver, BC, Canada.Received: 5 March 2018 Accepted: 5 March 2018References1. 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