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Sex hormones and their influence on chronic kidney disease

Valdivielso, José Manuela; Jacobs-Cachá, Conxitab; Soler, María Joséb,c

Current Opinion in Nephrology and Hypertension: January 2019 - Volume 28 - Issue 1 - p 1–9
doi: 10.1097/MNH.0000000000000463
HORMONES, AUTACOIDS, NEUROTRANSMITTERS AND GROWTH FACTORS: Edited by Mark Cooper and Merlin Thomas

Purpose of review The majority of end-stage renal disease including dialysis and kidney transplant patients are men. In contrast, the incidence of chronic kidney disease (CKD) is higher in women compared with men. In this review, we dissect the sex hormone levels and its effects on experimental models and patients with CKD.

Recent findings Sex hormones are clearly involved in CKD progression to end-stage renal disease (ESRD). A significant reduction in lipid peroxidation as a mechanism of renoprotection has been observed in kidneys of streptozotocin (STZ)-diabetic ovariectomized rats after estradiol administration. Furthermore, a G-protein-coupled estrogen receptor inhibits podocyte oxidative stress maintaining the integrity of the mitochondrial membrane. Sex hormone depletion has been shown to modulate RAS system and protect against kidney injury in the male STZ-diabetic model. In human primary proximal tubular epithelial cells, a proteomic study showed that dihydrotestosterone dysregulated metabolic, suggesting that the deleterious effect of androgens within the kidney maybe related to altered energy metabolism in renal tubules.

Summary Male gender is associated with worse CKD progression and this fact may be ascribed to sex hormone. Although male hormones exert a deleterious effect in terms of increasing oxidative stress, activating RAS system, and worsening fibrosis within the damaged kidney, female hormones exert a renoprotective effect.

aUnit for Detection and Treatment of Atherothrombotic Diseases, Experimental Nephrology Laboratory, Arnau de Vilanova University Hospital, Biomedical Research Institute of Lleida, Spanish Research Network for Renal Diseases (RedInRen. ISCIII), Lleida

bNephrology Research Group, Vall d’Hebron Research Institute (VHIR)

cNephrology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain

Correspondence to María José Soler, Romeo, Servicio de Nefrología, Hospital General Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Tel: +34 934 89 30 00; e-mail: mjsoler01@gmail.com

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INTRODUCTION

There is a clear sexual dimorphism in the incidence and prevalence of end-stage chronic kidney disease (ESRD) [1,2]. Registry data indicate that the incidence of ESRD is significantly lower in women compared with men across all age groups and has been maintained over the years [1,3]. Surprisingly, the registry data also demonstrates that the incidence of chronic kidney disease (CKD) is significantly higher in women compared with men [1]. The sex imbalance between CKD and ESRD patients has been classically related to faster CKD progression in men. In agreement with this thinking, ESRD progression has been reported to be slower in women affected by nondiabetic renal disease on the basis of studies involving human patients or animals with IgA or membranous nephropathy, hypertensive nephropathy, polycystic kidney disease, and others [4–6]. In contrast, Jafar et al. [7], in a meta-analysis of 11 randomized trials that used angiotensin-converting enzyme inhibitors in patients with CKD found that the rate of renal disease progression might not be slower among women and in fact might even be faster among women than in men. This contradictory result and the nonagreement between the previous mentioned studies may be ascribed to different factors such as the patients included in the study. In the last study, the majority of included women were postmenopausal, whereas in the previous studies were not the case [8]. As reviewed by Carrero et al. [8], data from population-based studies, that are a mirror of the population as a whole, reinforce the idea that men experience faster renal function decline than women. An interesting study by van den Brand et al. [9] also focused on the effect of age and sex in lifetime risk of renal replacement therapy (RRT) using data from The European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) registry. Lifetime risk of RRT was defined as the cumulative incidence of RRT up to age 90 years. This study demonstrated that lifetime risk of RRT is lower in women compared with men of the same age [9]. In United States Renal Data System (USRDS) 2017 data, there was a slightly lower incidence of transplantation as a percentage of RRT modalities in women than in men [1,10▪]. As fewer women than men start dialysis programs, the finding that a smaller number of women than men receive deceased donor kidneys seems to be logical (Fig. 1). These results again reinforce the protective effects of estrogens (in premenopausal women) versus of the deleterious effects of testosterone on kidney function. This review will focus on the clinical and experimental evidence that postulates an important role for sex hormones in the incidence and progression of CKD, the effect of sex hormones and its receptors, specifically estrogens and androgen effects on diabetic and nondiabetic experimental nephropathy, and the imbalance of sex hormones in patients with CKD.

FIGURE 1

FIGURE 1

Box 1

Box 1

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Sex hormones and its receptors

Sex steroid hormones are essential for the correct development and function of the reproductive system but they are also involved in other physiological and pathological processes. Estrogens and progestins have a significant role in the regulation of skeletal homeostasis [11,12], the central nervous [13], and cardiovascular system [14] among others, and androgens exert an anabolic function in several tissues (bone, muscle, and red blood cells). In the pathological context, estrogens and progestins are responsible for hormone-dependent carcinomas [15] and androgens have a role in benign and malignant prostatic hyperplasia [16].

Cholesterol is the precursor of all sex hormones. Cholesterol is first converted into pregnenolone, the direct precursor of progesterone and also, through a series of enzymatic reactions, of estrogens and androgens. A complex metabolic pathway mediates the transformation of pregnenolone into dehydroepiandrosterone (DHEA). DHEA is converted into testosterone in the Leydig cells and afterward into dihydrotestosterone (DHT) in extragonadal tissues. In the ovaries but also in other extragonadal tissues, DHEA can be aromatized to estrone and 17-β-estradiol, the most active estrogen isoform. Estrone and estradiol can be transformed to estriol, a third isoform of estrogens, in the liver and in the placenta of pregnant women [17].

Sex hormones act via specific receptors in the target tissues that can be located in both the cytoplasm and the plasma membrane of the cell, thus transcription-dependent and independent pathways can be activated. The first and the most studied signaling pathway of sex hormones is the transcription-dependent pathway that is mediated by the cytoplasmic estrogen receptors, androgen receptors (AR), and progesterone receptors. There are two isoforms for each sex hormone receptor: estrogen receptors: estrogen receptor-α and estrogen receptor-β [18]; ARs: AR-A and AR-B [19]; and progesterone receptors: progesterone receptor-A and progesterone receptor-B [20]. These isoforms are selectively expressed on the target tissues and have differential affinity to their ligands so they can promote specific responses. Normally, sex steroids circulate in blood stabilized by the sex hormone-binding globulin (SHBG) or by albumin, but they can also be found in a free form (around 5% of the total depending on the sex hormone and the sex) that diffuses through the plasma membrane to the cytoplasm in which the specific receptors are found. Once the hormone binds to the receptor, dimerization happens (in a homo or heterodimeric way) and a conformational change promotes the coupling of regulator proteins to the hormone–receptor complex. The whole complex translocates into the nucleus in which it binds with specific sequences of DNA (sex steroid response elements) promoting or repressing gene expression [21,22]. The activation of this kind of signaling pathway leads to late effects that can even take several days; however, it is well known that sex hormone can induce fast responses (from seconds to 10 min). These early responses cannot be ascribed to the transcription-dependent pathway [21,23]. It has been described that the previously mentioned sex hormone receptors and other forms such as the G-protein-coupled estrogen receptor (GPER), the G protein-coupled receptor family C group 6 member A (GPRC6A) (for androgens), and the SHBG receptor can be found on the plasma membrane. These receptors can be activated directly by the sex hormone or by the sex hormone–SHBG complex, induce several nongenomic signaling mechanisms mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), proto-oncogene tyrosine-protein kinase (c-Src), protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) among others, and subsequently modulate the activity of transcription factors (Fig. 2) [19,23]. Finally, estrogen-related receptors have been described. These receptors are named ‘orphan’ as these kinds of transcription factors are constitutively activated without the need of estrogen binding and modulated by estrogen-dependent gene expression [24].

FIGURE 2

FIGURE 2

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Estrogen and androgen in experimental diabetic nephropathy

In a model of type 1 diabetes, STZ-induced 6-week-old Sprague–Dawley rats, de Alencar Franco Costa et al. [25] demonstrated that 12 weeks of T1DM led to significantly higher albuminuria and SBP in diabetic males compared with females. In addition, diabetic males, but not females, showed increased renal collagen I and fibronectin mRNA levels compared with controls. Furthermore, when exploring the renin-angiotensin system (RAS), renal angiotensinogen (AOGEN) mRNA levels were significantly increased by diabetes in males but not in females. Interestingly, this increase in AOGEN was strongly correlated with albuminuria. In this study, AR blockade by flutamide attenuated diabetes-induced albuminuria but not renal fibrosis or AOGEN expression. In concordance with these findings, we also demonstrated that the modulation of the renin–angiotensin system by angiotensin converting enzyme 2 (ACE2) deletion in STZ-diabetic mice is sex-dependent. Thus, we simultaneously studied the influence of ACE2 deficiency and gonadectomy (GDX) on hypertension and kidney damage in STZ-diabetic male mice. GDX angiotensin converting enzyme 2 knockout (ACE2KO) diabetic mice showed lower blood pressure (BP) values and decreased nephropathy compared to male ACE2KO diabetic mice. These animals exhibited modulation of circulating and renal RAS favoring the ‘pro-Ang (1–7)’ axis [26]. In addition, histological evidence of renal protection, namely, a reduction in mesangial expansion and attenuation of glomerular hypertrophy, attenuation of podocyte loss, and reduction in interstitial fibrosis and collagen deposition in the GDX ACE2KO mice were also found. These two studies that decrease male sex hormones by either chemical or surgical castration contribute to the knowledge of sex differences in RAS in DN [26]. Later on, we also studied the effect of angiotensin II (ANGII) infusion on DN progression in both male and female diabetic mice with or without ACE2 deficiency [27▪]. We demonstrated that Ace2 deletion accentuates diabetes and ANGII-induced alterations in a sex-dependent manner and these differences could be ascribed to a different imbalance of the RAS. Thus, a sex dimorphism was clearly observed between ACE2, DN, and angiotensin II (ANGII)-related hypertension. In diabetic wild-type (WT) animals, ANGII infusion markedly increased albuminuria, glomerular filtration rate, and mesangial expansion in males but not in females. Of note, ACE2 deficiency accentuated ANGII-induced hypertension and albuminuria in diabetic females, whereas in males, ACE2 deficiency accentuated glomerular lesions such as glomerular hypertrophy, mesangial expansion, and podocyte depletion. At the molecular level, ANGII induced a greater down-regulation of renal angiotensin converting enzyme (ACE) in ACE2KO diabetic males, suggesting a sex-specific ANGII-mediated cross-talk between the two ACEs [27▪]. These studies reinforce the hypothesis that sex-hormone differences in diabetes can in part be ascribed to differences in the intrarenal RAS balance.

Although few studies have directly examined the effects of estrogens in diabetic nephropathy, numerous reports indicate that 17β-estradiol modulates cellular processes in the kidney that are involved in the pathophysiology of DN [28]. In an experimental model of type 2 diabetes, Otsuka–Long–Evans–Tokushima–Fatty (OLETF) strain, Tomiyoshi et al. [30] found that castration attenuated proteinuria, glomerular sclerosis, mesangial expansion, and glomerular basement membrane (GBM) thickening, whereas estrogen treatment did not attenuate proteinuria or glomerular sclerosis despite having the ability to attenuate mesangial expansion and GBM thickening. These findings suggest that apart from the mechanisms involved in the development of DN, other mechanisms such as growth hormone (GH), age, and blood pressure (BP) may contribute to progression of glomerulosclerosis in the estrogen-treated OLETF rats [29,30]. Whitney et al. [31] demonstrated that GH administration worsened renal injury in diabetes in a sex-specific manner (GH significantly increased glomerulosclerosis and tubulointerstitial fibrosis by 30 and 25% in male rats, but not in female rats) and was associated with an increase in pro-inflammatory mediators. In contrast with the previous study in estrogen-treated OLETF rats, Mankhey et al. [32] in a model of type 1 diabetes, the STZ-diabetic rat, replacement with E2 for 12 weeks exerted a renoprotective effect, by reducing albuminuria, improving creatinine clearance, attenuating glomerulosclerosis, and renal fibrosis in terms of tubulointerstitial fibrosis, and reducing transforming growth factor beta (TGF-β) protein expression. Another study confirmed that diabetes is associated with mild glomerulosclerosis and tubulointerstitial fibrosis and that these changes are attenuated with E2 supplementation. Supplementation with E2 early on from the onset of diabetes both decreases extracellular matrix (ECM) synthesis and increases ECM degradation, thus having a dual renoprotective role relating to ECM metabolism. The major regulators of ECM degradation in the kidney are MMP-2 and MMP-9. Mankhey et al. [33] demonstrated that E2 supplementation increased the expression and activity of both matrix metalloproteinase (MMP)-2 and MMP-9 in the diabetic kidney. In addition, both Tissue Inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2 protein expression are upregulated in DN and E2 supplementation reduced TIMP protein expression, thus providing further evidence that E2 is not only renoprotective by reducing ECM synthesis but also by increasing ECM degradation [33]. In concordance, in the db/db mouse, a model of type 2 diabetes, E2, and raloxifene, another elective estrogen receptor modulator reduces fibronectin expression in the diabetic kidney.

In the STZ-diabetic ovariectomized rats, E2 and E2+ α-tocopherol administration may strengthen the antioxidant defense system by reducing lipid peroxidation, as a mechanism of DN protection [34]. Interestingly, recent in-vitro studies of podocytes, demonstrated that icariin (which is a GPER 1 agonist) inhibits podocyte oxidative stress, reduces reactive oxygen species production, and protects the integrity of the mitochondrial membrane. Icariin may also attenuate high glucose-induced podocyte apoptosis by inhibiting reactive oxygen species production and inducing the mitochondrial translocation of B-cell lymphoma 2 (Bcl-2) via a GPER-dependent pathway. By evaluating this, the important role of GPER and Bcl-2 mitochondrial translocation in icariin-inhibited apoptosis was demonstrated [35▪▪]. Further studies are needed to prove that icariin can selectively inhibit apoptosis and provide sex-specific kidney protection in DN.

In STZ-diabetic castrated male rats, a low dose of DHT attenuated, whereas a high dose accentuated the severity of several hallmarks of kidney disease such as albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis [36]. These observations suggested that DHT may play an important role in the pathophysiology of diabetic renal disease, but that its effects are dose dependent and may be related to its action at higher doses on the estrogen receptor [37]. The deleterious effects of androgens have also been studied in podocytes, in which testosterone induced an increase in the percentage of terminal transferase-mediated dUTP nick end labeling (TUNEL)-positive cells in ovariectomized B6 mice. In addition, testosterone also induced podocyte apoptosis in vitro by AR activation, but independent of the TGF-β1 signaling pathway. In this sense, testosterone administration was associated with podocyte damage and augmented apoptosis both in vivo and in vitro [38]. Clotet et al. [39▪▪] have recently performed a proteomic study with stable isotope labeling with amino acids in an indirect spike-in fashion to accurately quantify the proteome in DHT and 17β-estradiol-treated human primary proximal tubular epithelial cells. That study demonstrated that DHT alone led to dysregulated metabolic processes that are also altered in the diabetic kidney. These processes, including glucose metabolism, the hexosamine biosynthetic pathway, and fatty acid β-oxidation, are associated with diabetes and CKD. Sex-specific regulation by DHT of glucose-6-phosphate isomerase, mitochondrial trifunctional protein subunit α, and glucosamine-6-phosphate-N-acetyltransferase 1 was demonstrated in vitro and in vivo, suggesting that the detrimental effects of androgens in diabetic DN may be, at least in part, mediated by altered energy metabolism within the tubular cell. In addition, they also demonstrated sexual dimorphism in renal nitrotyrosine levels in the diabetic kidney [39▪▪].

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Estrogen and androgen in experimental nondiabetic kidney disease

Premenopausal women had lower CKD progression than males of the same age. This difference is not observed in postmenopausal women [6]. Although there are data in conflict with this view [7] and the differences may not only be related to the effect of the sex steroids on the kidney but also by different habits among the sexes [8]; it is mostly thought that estrogens have a protective role and/or testosterone, by contrast, damages the kidney [40]. In this sense, studies using animal models of natural aging support the idea that estrogens slow progression of CKD as male rats developed kidney impairment faster than their female littermates [41,42]. In several rat models of kidney injury like experimental polycystic disease [43], aging Dahl salt sensitive rats [44], or kidney damage due to ischemia–reperfusion injury [45] or adenine treatment [46], estrogens retard the progression of apoptosis and fibrotic processes in the kidney. Testosterone seems to have the opposite action [46,47]. The estrogen protective effect is not only related to a direct action on the kidney but also to its protective role in the cardiovascular system. dos Santos et al. [48] elegantly review the effect of sex hormones on different aspects of the cardiovascular system. Estrogens have a positive effect on myocardial contractility and also on the vasculature promoting nitric oxide synthesis and release. Nitric oxide is a potent vasodilator and its deficiency leads to endothelial dysfunction and, consequently, to the progression of CKD. In rat models, nitric oxide production is better preserved in female animals as a result of estrogen activity than in male littermates [49]. Recently, Fanelli et al. [50] showed using a rat model of chronic nitric oxide inhibition that female animals showed less histological damage and fibrosis in the kidney but curiously higher BP than male under the same conditions. This experimental model avoids the effect of the estrogens on the nitrous oxide systems (NOS) as a potent inhibitor of NOS enzyme is used, N-(ω)-nitro-L-arginine methyl ester. The fact is that in this model, female animals showed less kidney damage than male littermates demonstrating again the direct protective effect of estrogens on the kidney. Surprisingly, long-term treatment with N-(ω)-nitro-L-arginine methyl ester leads to a feedback loop that produces an inverse effect on NOS, that is activation of the enzyme [51]. As the enzyme can be reactivated by a feedback mechanism, estrogens can have an impact on nitric oxide synthesis and contribute to renoprotective mechanism of estrogens in this model as well.

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Sex hormone levels in chronic kidney disease

The prevalence of sexual dysfunction and infertility are very common in CKD patients, both in men and in women, and is caused by abnormalities in multiple areas of reproductive physiology [52]. Thus, the levels of sex hormones in CKD patients have been extensively reported, at least in men. Testosterone deficiency is common in CKD patients, both in early stages and in dialysis [53,54]. Furthermore, the CKD stage is inversely associated with the levels of free testosterone [55]. In addition, an increase in testosterone has also been reported after renal transplantation, and this increase is dependent on the time after receiving the graft [56,57]. The mechanisms for the decreased testosterone levels in men have not been completely elucidated, but an increase in prolactin clearance [58] and the inhibition of luteinizing hormone effects in Leydig cells [59] seem to be involved.

In women, the cyclic nature of hormonal control of the reproductive system complicates its study. Infertility is common in women with early stages of CKD, but the precise mechanisms have not been adequately explored. However, it is suggested that in women on dialysis, the lack of stimulation of luteinizing hormone by estradiol (and not a deficiency of estradiol levels per se) could be the cause of the lack of ovulation and the abnormal menstruation and dysfunctional uterine bleeding reported in women on dialysis [52]. After successful transplantation, fertility is restored in a high percentage of women [60].

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Effects of sexual hormone changes in chronic kidney disease patients

Apart from the expected effects of the changes in sexual hormones on fertility and sexual activity, several other related complications have been reported in CKD patients. Thus, lower testosterone levels have been associated with depression [61] and impaired cognition level [62], two common complications of CKD patients [63]. Furthermore, testosterone deficiency could cause anemia, and a reduced response to erythropoietin stimulating agents [64], as testosterone stimulates erythroid progenitor cells [65]. In addition, lower testosterone levels are independently associated with lower muscle mass [66]. However, the effect of testosterone administration on muscle mass in CKD patients has yielded negative results [67], although the results of this trial showed no increase in circulating testosterone levels after the treatment. Lower levels of testosterone have been also reported to be an independent predictor of increased mortality in all CKD stages [55]. The cause of this increase mortality is not clear, but low testosterone levels have been associated with many comorbidities of CKD patients like atherosclerosis, metabolic syndrome, cardiovascular disease, and systemic inflammation [68,69]. Conversely, comorbid conditions frequently found in CKD, like diabetes, hypertension, or obesity, can also have an effect decreasing testosterone levels [70].

A serious consequence of CKD is the increase in bone abnormalities. Testosterone also plays a role in bone mineral density by increasing osteoblastic activity and reducing osteoclastic activity [71], and with a meta-analysis determining a positive effect of testosterone supplementation in bone health [72]. However, the data in CKD patients are reduced to one report showing that free testosterone levels are associated with bone mineral density in male kidney-transplanted patients [73▪▪]. In women on dialysis, higher estradiol levels have been also associated with a better bone mineral density [74].

The role of sex hormones in the incidence and progression of CKD is still a matter of debate. Although a recent article reviewing population-based studies showed a higher prevalence of women affected by CKD [8], specific CKD cohorts display the opposite result [75–77]. In any case, this discrepancy seems to be only in early stages of CKD, as the incidence of RRT has been reported to be lower in women, at least in Europe [3,10▪]. Indeed, the normal decline of glomerular filtration rate (GFR) with age is lower in females than in males [78] and the progression rate of CKD follows the same pattern [6,79]. Furthermore, a peak in the prevalence of ESRD is observed in women aged between 40 and 50, when the activity of female sexual hormones begins to decline [80].

Therefore, it seems that sex hormones could be playing a role in protecting women from progression of CKD. Indeed, several potential deleterious effects of testosterone have been described in experimental animals. Thus, testosterone induces apoptosis of podocytes [38] and proximal tubular cells [81], whereas estrogens antagonize TGF-β induced apoptosis in podocytes [38] and mesangial cells [82]. Estrogens have also shown protective effects in potentially kidney-damaging pathways like collagen synthesis [82], nitric oxide production [83], the renin–angiotensin system [84], the formation of free radical species [85], and the synthesis of endothelin [86] (Fig. 3).

FIGURE 3

FIGURE 3

Data about the effect of estrogen treatment on CKD progression are scarce. A very early report in 1955 showed remission of the symptoms of three patients with severe nephrotic syndrome after treatment with estrogens [87]. Nowadays, we have better therapeutic options with the availability of selective estrogen receptor modulators. A recent post-hoc analysis of the Multiple Outcomes of Raloxifene Evaluation study has shown that women receiving raloxifene showed a lower rate of decline in renal function over 3 years [88]. Furthermore, in a recent meta-analysis, the use of hormone replacement therapy was associated with lower odds of albuminuria [89].

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CONCLUSION

In summary, male gender is associated with faster CKD progression to ESRD when compared to females. Sex hormones and its receptors play a critical role in the progression of the damaged kidney through different pathophysiological pathways such as the RAS system, oxidative stress, and fibrosis. Strategies aimed to enhance female sex hormones and decrease male sex hormones may exert a future positive effect on the damaged kidney.

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Acknowledgements

None.

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Financial support and sponsorship

This work was supported by the Fondo de Investigación Sanitaria-Feder, ISCIII, and REDINREN, Spain.

The authors are current recipients of research grants from the Fondo de Investigación Sanitaria-Feder, ISCIII, PI14/00557, PI17/00257, and REDINREN, RD16/0009/0013.

J.M.V. is currently receiving a research grant from Fondo de Investigación Sanitaria-Feder, ISCIII, (RETIC RD16/0009/0011, PI15/00960); M.J.S. has received honoraria from Novo Nordisk. M.J.S. is currently receiving a grant (PI17/00257) from Fondo de Investigación Sanitaria-Feder, ISCIII, and (RD16/0009/0013) from Fondo de Investigación Sanitaria-Feder.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

3. Kramer A, Pippias M, Noordzij M, et al. The European Renal Association—European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015: a summary. Clin Kidney J 2018; 11:108–122.
4. Shin H-Y, Kang H-T. Recent trends in the prevalence of chronic kidney disease in Korean adults: Korean National Health and Nutrition Examination Survey from 1998 to 2013. J Nephrol 2016; 29:799–807.
5. Juutilainen A, Kastarinen H, Antikainen R, et al. Trends in estimated kidney function: the FINRISK surveys. Eur J Epidemiol 2012; 27:305–313.
6. Neugarten J, Acharya A, Silbiger SR. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. J Am Soc Nephrol 2000; 11:319–329.
7. Jafar TH, Schmid CH, Stark PC, et al. The rate of progression of renal disease may not be slower in women compared with men: a patient-level meta-analysis. Nephrol Dial Transplant 2003; 18:2047–2053.
8. Carrero JJ, Hecking M, Chesnaye NC, Jager KJ. Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. Nat Rev Nephrol 2018; 14:151–164.
9. van den Brand JA, Pippias M, Stel VS, et al. Lifetime risk of renal replacement therapy in Europe: a population-based study using data from the ERA-EDTA Registry. Nephrol Dial Transplant 2017; 32:348–355.
10▪. Fernandez-Prado R, Fernandez-Fernandez B, Ortiz A. Women and renal replacement therapy in Europe: lower incidence, equal access to transplantation, longer survival than men. Clin Kidney J 2018; 11:1–6.

This article summarizes the incidence of renal replacement in women and access to renal replacement therapy in Europe.

11. Narla RR, Ott SM. Bones and the sex hormones. Kidney Int 2018; 94:239–242.
12. Kenkre J, Bassett J. The bone remodelling cycle. Ann Clin Biochem 2018; 55:308–327.
13. Del Río JP, Alliende MI, Molina N, et al. Steroid hormones and their action in women's brains: the importance of hormonal balance. Front Publ Health 2018; 6:141.
14. Boese AC, Kim SC, Yin K-J, et al. Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol 2017; 313:H524–H545.
15. Diep CH, Daniel AR, Mauro LJ, et al. Progesterone action in breast, uterine, and ovarian cancers. J Mol Endocrinol 2015; 54:R31–R53.
16. Xu X, Chen X, Hu H, et al. Current opinion on the role of testosterone in the development of prostate cancer: a dynamic model. BMC Cancer 2015; 15:806.
17. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011; 32:81–151.
18. Yaşar P, Ayaz G, User SD, et al. Molecular mechanism of estrogen–estrogen receptor signaling. Reprod Med Biol 2017; 16:4–20.
19. Davey RA, Grossmann M. Androgen receptor structure, function and biology: from bench to bedside. Clin Biochem Rev 2016; 37:3–15.
20. Jacobsen BM, Horwitz KB. Progesterone receptors, their isoforms and progesterone regulated transcription. Mol Cell Endocrinol 2012; 357:18–29.
21. Contrò V, Basile JR, Proia P. Sex steroid hormone receptors, their ligands, and nuclear and nonnuclear pathways. AIMS Mol Sci 2015; 2:294–310.
22. Boese AC, Kim SC, Yin K-J, et al. Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol 2017; 313:524–545.
23. Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J. The many faces of estrogen signaling. Biochem Med 2014; 24:329–342.
24. Saito K, Cui H. Emerging roles of estrogen-related receptors in the brain: potential interactions with estrogen signaling. Int J Mol Sci 2018; 19:1091.
25. de Alencar Franco Costa D, Todiras M, Campos LA, et al. Sex-dependent differences in renal angiotensinogen as an early marker of diabetic nephropathy. Acta Physiol (Oxford, Engl) 2015; 213:740–746.
26. Clotet S, Soler MJ, Rebull M, et al. Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin–angiotensin system. J Hypertens 2016; 34:1752–1765.
27▪. Clotet-Freixas S, Soler MJ, Palau V, et al. Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy. Laboratory Investigation 2018; 98:1237–1249.

This article clearly demonstrates the important effect of sex hormones in experimental diabetic nephropathy. Although male diabetic mice showed alterations in terms of worsening glomerular lesions, female diabetic mice had worse tubular lesions. These gender-related different patterns were associated with differences in the RAS.

28. Maric C, Sullivan S. Estrogens and the diabetic kidney. Gend Med 2008; 5:S103–S113.
29. Chua S Jr, Liu SM, Li Q, et al. Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB− Lepr (db)) and obese (DBA− Lep (ob)) mice. Diabetologia 2002; 45:976–990.
30. Tomiyoshi Y, Sakemi T, Aoki S, Miyazono M. Different effects of castration and estrogen administration on glomerular injury in spontaneously hyperglycemic Otsuka–Long–Evans–Tokushima–Fatty (OLETF) rats. Nephron 2002; 92:860–867.
31. Whitney JL, Bilkan CM, Sandberg K, et al. Growth hormone exacerbates diabetic renal damage in male but not female rats. Biol Sex Differ 2013; 4:12.
32. Mankhey RW, Bhatti F, Maric C. 17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy. Am J Physiol Ren Physiol 2005; 288:F399–405.
33. Mankhey RW, Wells CC, Bhatti F, Maric C. 17β-Estradiol supplementation reduces tubulointerstitial fibrosis by increasing MMP activity in the diabetic kidney. Am J Physiol Regul Integr Comparat Physiol 2007; 292:R769–R777.
34. Ulas M, Cay M. 17β-Estradiol and vitamin E modulates oxidative stress-induced kidney toxicity in diabetic ovariectomized rat. Biological Trace Elem Res 2011; 144:821–831.
35▪▪. Qiao C, Ye W, Li S, et al. Icariin modulates mitochondrial function and apoptosis in high glucose-induced glomerular podocytes through G-protein-coupled estrogen receptors. Mol Cell Endocrinol 2018; 473:146–155.

This article demonstrates the beneficial effect of estrogen receptor activation within glomerular podocytes.

36. Xu Q, Prabhu A, Xu S, et al. Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney. Am J Physiol Ren Physiol 2009; 297:F307–F315.
37. Karamouzis MV, Papavassiliou KA, Adamopoulos C, Papavassiliou AG. Targeting androgen/estrogen receptors crosstalk in cancer. Trends Cancer 2016; 2:35–48.
38. Doublier S, Lupia E, Catanuto P, et al. Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice. Kidney Int 2011; 79:404–413.
39▪▪. Clotet S, Soler MJ, Riera M, et al. Stable isotope labeling with amino acids (SILAC)-based proteomics of primary human kidney cells reveals a novel link between male sex hormones and impaired energy metabolism in diabetic kidney disease. Mol Cell Proteom 2017; 16:368–385.

This article is the first to show by using spike-in stable isotope labeling with amino acids quantitative proteomic approach between two different renal cell lines that male sex hormones induce perturbations in the metabolism of the tubular cell that may ultimately lead to impaired oxidative stress and hypertrophy in the kidney.

40. Dousdampanis P, Trigka K, Fourtounas C, Bargman JM. Role of testosterone in the pathogenesis, progression, prognosis and comorbidity of men with chronic kidney disease. Therap Apher Dial 2014; 18:220–230.
41. Hajdu A, Rona G. The protective effect of estrogens against spontaneous pancratic islet and renal changes in aging male rats. Experientia 1971; 27:956–957.
42. Silbiger SR, Neugarten J. The impact of gender on the progression of chronic renal disease. Am J Kidney Dis 1995; 25:515–533.
43. Stringer KD, Komers R, Osman SA, et al. Gender hormones and the progression of experimental polycystic kidney disease. Kidney Int 2005; 68:1729–1739.
44. Maric C, Sandberg K, Hinojosa-Laborde C. Glomerulosclerosis and tubulointerstitial fibrosis are attenuated with 17-estradiol in the aging Dahl salt sensitive rat. J Am Soc Nephrol 2004; 15:1546–1556.
45. Hutchens MP, Fujiyoshi T, Komers R, et al. Estrogen protects renal endothelial barrier function from ischemia–reperfusion in vitro and in vivo. Am J Physiol Ren Physiol 2012; 303:F377–F385.
46. Diwan V, Small D, Kauter K, et al. Gender differences in adenine-induced chronic kidney disease and cardiovascular complications in rats. Am J Physiol Renal Physiol 2014; 307:F1169–F1178.
47. Metcalfe PD, Leslie JA, Campbell MT, et al. Testosterone exacerbates obstructive renal injury by stimulating TNF-α production and increasing proapoptotic and profibrotic signaling. Am J Physiol Endocrinol Metab 2008; 294:E435–E443.
48. dos Santos RL, da Silva FB, Ribeiro RF, Stefanon I. Sex hormones in the cardiovascular system. Horm Mol Biol Clin Invest 2014; 18:89–103.
49. Baylis C. Sexual dimorphism in the aging kidney: differences in the nitric oxide system. Nat Rev Nephrol 2009; 5:384–396.
50. Fanelli C, Dellê H, Cavaglieri RC, et al. Gender differences in the progression of experimental chronic kidney disease induced by chronic nitric oxide inhibition. BioMed Res Int 2017; 2017:2159739.
51. Kopincová J, Púzserová A, Bernátová I. L-NAME in the cardiovascular system—nitric oxide synthase activator? Pharmacol Rep 2012; 64:511–520.
52. Holley JL, Schmidt RJ. Changes in fertility and hormone replacement therapy in kidney disease. Adv Chronic Kidney Dis 2013; 20:240–245.
53. Dhindsa S, Reddy A, Karam JS, et al. Prevalence of subnormal testosterone concentrations in men with type 2 diabetes and chronic kidney disease. Eur J Endocrinol 2015; 173:359–366.
54. Hylander B, Lehtihet M. Testosterone and gonadotropins but not SHBG vary with CKD stages in young and middle aged men. Basic Clin Androl 2015; 25:9.
55. Grossmann M, Hoermann R, Ng Tang Fui M, et al. Sex steroids levels in chronic kidney disease and kidney transplant recipients: associations with disease severity and prediction of mortality. Clin Endocrinol 2015; 82:767–775.
56. Park MG, Koo HS, Lee B. Characteristics of testosterone deficiency syndrome in men with chronic kidney disease and male renal transplant recipients: a cross-sectional study. Transpl Proc 2013; 45:2970–2974.
57. Saha MT, Saha HH, Niskanen LK, et al. Time course of serum prolactin and sex hormones following successful renal transplantation. Nephron 2002; 92:735–737.
58. Schmidt A, Luger A, Hörl WH. Sexual hormone abnormalities in male patients with renal failure. Nephrol Dial Transplant 2002; 17:368–371.
59. Dunkel L, Raivio T, Laine J, Holmberg C. Circulating luteinizing hormone receptor inhibitor(s) in boys with chronic renal failure. Kidney Int 1997; 51:777–784.
60. Phocas I, Sarandakou A, Kassanos D, et al. Hormonal and ultrasound characteristics of menstrual function during chronic hemodialysis and after successful renal transplantation. Int J Gynaecol Obstetr 1992; 37:19–28.
61. Giltay EJ, Tishova YA, Mskhalaya GJ, et al. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J Sex Med 2010; 7:2572–2582.
62. Muller M, Aleman A, Grobbee DE, et al. Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level? Neurology 2005; 64:866–871.
63. McQuillan R, Jassal SV. Neuropsychiatric complications of chronic kidney disease. Nat Rev Nephrol 2010; 6:471–479.
64. Carrero JJ, Bárány P, Yilmaz MI, et al. Testosterone deficiency is a cause of anaemia and reduced responsiveness to erythropoiesis-stimulating agents in men with chronic kidney disease. Nephrol Dial Transplant 2012; 27:709–715.
65. Mirand EA, Gordon AS, Wenig J. Mechanism of testosterone action in erythropoiesis. Nature 1965; 206:270–272.
66. Cigarrán S, Pousa M, Castro MJ, et al. Endogenous testosterone, muscle strength, and fat-free mass in men with chronic kidney disease. J Ren Nutr 2013; 23:e89–95.
67. Brockenbrough AT, Dittrich MO, Page ST, et al. Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. Am J Kidney Dis 2006; 47:251–262.
68. Shiraki N, Nakashima A, Doi S, et al. Low serum testosterone is associated with atherosclerosis in postmenopausal women undergoing hemodialysis. Clin Exp Nephrol 2014; 18:499–506.
69. Karakitsos D, Patrianakos AP, De Groot E, et al. Androgen deficiency and endothelial dysfunction in men with end-stage kidney disease receiving maintenance hemodialysis. Am J Nephrol 2006; 26:536–543.
70. Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care 2010; 33:1186–1192.
71. van den Beld AW, de Jong FH, Grobbee DE, et al. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 2000; 85:3276–3282.
72. Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol 2005; 63:280–293.
73▪▪. Jørgensen HS, Winther S, Bøttcher M, et al. Bioavailable testosterone is positively associated with bone mineral density in male kidney transplantation candidates. Kidney Int Rep 2018; 3:661–670.

This article demonstrates that increased endogenous levels of sex hormones are associated with greater BMD in male CKD patients. Alterations in the gonadal axis may contribute to bone fragility in advanced CKD patients.

74. Sugiya N, Nakashima A, Takasugi N, et al. Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life. Osteoporos Int 2011; 22:1573–1579.
75. Matsushita K, Ballew SH, Astor BC, et al. Cohort profile: the chronic kidney disease prognosis consortium. Int J Epidemiol 2013; 42:1660–1668.
76. Arroyo D, Betriu A, Martinez-Alonso M, et al. Investigators from the NEFRONA StudyObservational multicenter study to evaluate the prevalence and prognosis of subclinical atheromatosis in a Spanish chronic kidney disease cohort: baseline data from the NEFRONA study. BMC Nephrol 2014; 15:168.
77. Villain C, Metzger M, Combe C, et al. Prevalence of atheromatous and nonatheromatous cardiovascular disease by age in chronic kidney disease. Nephrol Dial Transplant 2018; doi:10.1093/ndt/gfy277. [Epub ahead of print].
78. Berg UB. Differences in decline in GFR with age between males and females. Reference data on clearances of inulin and PAH in potential kidney donors. Nephrol Dial Transplant 2006; 21:2577–2582.
79. Coggins CH, Breyer Lewis J, Caggiula AW, et al. Differences between women and men with chronic renal disease. Nephrol Dial Transplant 1998; 13:1430–1437.
80. Kummer S, von Gersdorff G, Kemper MJ, Oh J. The influence of gender and sexual hormones on incidence and outcome of chronic kidney disease. Pediatr Nephrol (Berlin, Germany) 2012; 27:1213–1219.
81. Verzola D, Gandolfo MT, Salvatore F, et al. Testosterone promotes apoptotic damage in human renal tubular cells. Kidney Int 2004; 65:1252–1261.
82. Negulescu O, Bognar I, Lei J, et al. Estradiol reverses TGF-beta1-induced mesangial cell apoptosis by a casein kinase 2-dependent mechanism. Kidney Int 2002; 62:1989–1998.
83. Duckles SP, Miller VM. Hormonal modulation of endothelial NO production. Pflugers Arch 2010; 459:841–851.
84. Komukai K, Mochizuki S, Yoshimura M. Gender and the renin–angiotensin–aldosterone system. Fundam Clin Pharmacol 2010; 24:687–698.
85. Neugarten J. Estrogen and oxidative stress. Gend Med 2007; 4:31–32.
86. Tostes RC, Fortes ZB, Callera GE, et al. Endothelin, sex and hypertension. Clin Sci (London) 2008; 114:85–97.
87. Nitsch W, Thein K. Therapy of the nephrotic syndrome with estradiol. Therap Gegenw 1955; 94:364–366.
88. Melamed ML, Blackwell T, Neugarten J, et al. Raloxifene, a selective estrogen receptor modulator, is renoprotective: a posthoc analysis. Kidney Int 2011; 79:241–249.
89. Kattah AG, Suarez ML, Milic N, et al. Hormone therapy and urine protein excretion: a multiracial cohort study, systematic review, and meta-analysis. Menopause (New York, NY) 2018; 25:625–634.
Keywords:

androgens; chronic kidney disease; estrogens; sex hormones; sexual dimorphism

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