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

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 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 reno-protective 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 CKD [16]; 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 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 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.

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 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 (CVDs), 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].

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].

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 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 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 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 estrogen deficiency and disease onset. Female-to-male incidence ratio after age 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 recognized [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. 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 [85]. Vasculopathy is an important disease-related manifestation in SS, and the low estrogenic state associated with menopause has been suggested to aggravate vascular manifestations in affected women [86]. SS can also be complicated by a number of different forms of kidney disease, including scleroderma renal crisis, which represents a form of malignant hypertension with acute renal failure; or more commonly ischemic nephropathy leading to slowly progressive CKD, accompanied by hypertension and albuminuria [78]. Normotensive acute renal failure in patients with SS may be caused by interstitial nephritis or ANCA vasculitis, a separate entity in scleroderma with poor outcome [87‐89].

Although renal replacement therapy (RRT), including dialysis and transplantation is life-sustaining, not all patients receive RRT. The rate of ESRD treated by RRT differs greatly between countries and regions, and intricately depends on the economy of a country and health care system [90, 91]. Worldwide, only 50% of patients requiring RRT receive treatment [92], and in low and middle-income countries and regions, even less; in large parts of Sub-Saharan Africa, less than 2% of ESRD are treated by RRT [93]. The equality of access to RRT for women and girls is of particular concern because, in many societies, they are disadvantaged by discrimination rooted in sociocultural factors [94, 95].