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Continue Cancel. Article Menu. Giuffrida, A. Edoardo Gembillo, G. Cucinotta, D. Squadrito, G. Santoro, D. Russo, G. Giandalia, A. Need Help? Support Find support for a specific problem in the support section of our website. Get Support.
Feedback Please let us know what you think of our products and services. Give Feedback. Get Information. Open Access Review. Alfio Edoardo Giuffrida. Guido Gembillo. Domenico Cucinotta. Giovanni Squadrito. Domenico Santoro. Giuseppina T. Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far.
Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a ificant role in explaining these differences.
Additionally, the impact of sex chromosomes as well as the influence of gene—sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. Keywords: gender; sex; diabetic kidney disease; estrogens; gene polymorphisms gender ; sex ; diabetic kidney disease ; estrogens ; gene polymorphisms.
DKD is diagnosed according to the presence of albuminuria, reduced estimated glomerular filtration rate eGFRor both [ 2 ]. In the last few decades, research on DKD has witnessed enormous activity, a revolution encompassing epidemiology, diagnosis, clinical manifestations, risk factors and treatment options [ 3 ]. These advances have been highlighted in a t document of the Italian Diabetes Society SID and the Italian Society of Nephrology SINproviding an extensive review of the available evidence as well as updated treatment recommendations [ 5 ].
Considering sex- and gender-specific aspects is one of the first and simpler step toward personalized and patient-centered care also in the management of DM and its complications. Gender medicine analyzes the differences between men and women in human physiology, pathophysiology, and the clinical features of diseases, specifically evaluating the impact of sex as a biological and functional marker, and that of gender, which refers to a complex interrelation and integration of sex with psychological, social, ethnical and cultural behavior.
Despite over 20 years of gender medicine and the insistent recommendations of scientific societies and research institutions [ 6 ], sex-based differences in biology, genetics, biomedical and clinical aspects of major diseases, including DM and its complications, are still poorly explored so far, a gap that may impair the efficacy of our diagnostic and therapeutic efforts, ultimately exposing patients to unwanted outcomes [ 7 ].
In this review, we explored potential sex- and gender-based differences in DKD prevalence and evolution, risk factors, clinical manifestations and treatment options, including the role of hormonal and genetic factors. Gender-related differences have been reported in non-diabetic chronic kidney disease CKD [ 8 ]. Overall, CKD seems to have a higher prevalence in women than in men [ 91011 ]. However, a review including a large of studies found 38 studies reporting a higher CKD prevalence in women and 13 among men [ 12 ].
On the contrary, the risk of progression to ESRD appears to be higher among males [ 1314 ]. Accordingly, a large meta-analysis confirmed a more rapid decline in men than in women with non-diabetic CKD [ 16 ]. Women live longer than men and age and post-menopausal status appear to modify the association between sex and nondiabetic kidney disease [ 17 ]; in this regard, Jafar et al. How CKD is defined may also play a relevant role in determining the effect of gender on CKD incidence and progression risk. In cohorts of DM subjects, several large epidemiological studies have explored sex differences in the prevalence of DKD and its phenotypes, specifically evaluating low eGFR, micro- or macroalbuminuria or both Table 1.
Studies performing a separate gender analysis varied in de, sample size, type of diabetes, length of follow-up, and how DKD was reported, as shown in Table 1 [ 13202122232425262728293031323334353637383940414243444546474849505152535455565758 ] and in two recently published reviews [ 5960 ].
The pooled adjusted risk ratio of DKD was 3. In T2DM patients, the prevalence of both eGFR and albuminuria increases with age, with male sex also positively associated with albuminuria rise and negatively with eGFR impairment in older subjects [ 64 ]. Although the prevalence of microalbuminuria was higher among men with T2DM, women presented a greater risk of advanced renal dysfunction and higher prevalence of common DKD risk factors, with these differences being most evident amongst older subjects. Male gender also appears to be an independent risk factor for DKD incidence, especially when the albuminuric phenotype is taken into.
A prospective observational study of T2DM patients followed for a median period of 5. Moreover, an association between sex and incident DKD was also found in patients with diabetes and normal renal function at baseline, followed-up for almost 10 years [ 65 ]. Although the available information is still not conclusive, the overall epidemiological data indicate that the risk of developing DKD is higher in DM men, who also have a higher risk of DKD progression.
However, when DKD specific phenotypes are taken intoDM men are at higher risk of developing the albuminuric phenotype, while women are at higher risk of eGFR impairment, and of developing ESRD, especially at older ages. These differences seem to apply to both type of diabetes, with important implications for the diagnosis and management of DKD in the clinical practice.
The reasons behind these reported sex and gender-disparities in DKD are still largely unknown, but hormonal or genetic differences, as well as differences in the prevalence or impact of major risk factors seem to play a relevant role. Sex hormones play an important role in the pathophysiology of diabetes and its complications, especially in DM women, who seem to lose the protective effects of estrogens on the cardiovascular bed, even before menopause. In the last few decades, the pleiotropic effects of estrogens beyond those on the reproductive system have been objects of intense research [ 747576 ], including their potential role in DKD Figure 1.
The activity of estrogens is closely related to the presence of specific receptors that are ubiquitously localized, with particular reference to the vascular district and endothelial cells [ 77 ]. These pathways lead to decreased apoptosis processes, cellular growth, differentiation, and inflammation [ 8182 ].
The former has especially predominant anti-inflammatory effects on the liver [ 90 ]. Moreover, E2 seems to attenuate glomerulosclerosis and tubulointerstitial fibrosis [ 96 ]. In animal models estrogens seem to counter fibrosis and apoptosis in the kidney [ 97 ], while testosterone promotes pro-inflammatory, pro-apoptotic and pro-fibrotic processes [ 9899]. These findings are partially in contrast with evidence from human studies showing an association of oral contraceptives and estrogen replacement therapy with an increased risk of microalbuminuria and kidney function decline . Estrogens may exert their effects even through another receptor, associated with protein G, the G protein-coupled estrogen receptor 1 GPER-1which explains their rapid non-genomic effects [ ].
This is a membrane receptor encoded by the GPER gene located at chromosome 7p Some studies have also evidenced a predominant expression of GPER-1 in renal tubular cells , and therapy with GPER-1 agonist in female mice with salt-sensitive disease has been reported to improve glomerular function and hypertrophy and to reduce proteinuria [ ], thus suggesting a key role of this receptor in kidney disorders and, probably, in DKD. This hypothesis is further supported by data coming from the sustained use of icarine, a GPER-1 activator.
This metabolite seems to improve the nephropathy of T1DM mice, through GPER mediated pdependent Keap1 degradation and Nrf2 activation, also attenuating mesangial expansion [ ]. GPER is implicated in different pathways by several receptors such as serotonin 1A receptor [,]. The experimental data on estrogen supplementations in murine models of diabetes also seem to confirm the role of female hormones in renal protection. Thus, Wells et al. Supplementation with E2 restored this rate, supporting the hypothesis of nephroprotection exerted by estrogens in DM [ ].
Furthermore, in diabetic mice, estrogen pellet implantation was able to inhibit glomerulosclerosis, collagen IV deposition and albuminuria, even in animals with an advanced stage of renal injury, suggesting the efficacy of E2 treatment in the reduction of DKD progression [ ].
On the other hand, the inhibition of estradiol synthesis using the anastrozole, an aromatase inhibitor, partially attenuated renal injury in male streptozotocin-induced diabetic rats [ ]. Both the levels of E2 and the androgen-to-E2 ratio seem to be crucial factors for progression of renal injury in diabetic subjects; estrogenic activity is modulated by androgens, probably through the accessibility of ER to E2. In humans, DKD is associated with an increase in estrogen concentration and a decrease in testosterone levels in male patients [ ], but not in women .
The potential beneficial effect of hormonal replacement therapy HRT on DKD has also been explored, with some studies supporting the efficacy of estrogenic therapy in improving insulin sensitivity, plasma lipid levels and creatinine clearance in postmenopausal diabetic women [, ].
Maric et al. Oral therapy with selective estrogen receptor modulators showed similar benefits. Additionally, a provisional regimen with raloxifene, a selective estrogen receptor modulator, reduced albuminuria levels in post-menopausal women with T2DM [ ]. Furthermore, improvements of important kidney outcomes, including a reduction in the progression of the albumin—creatinine ratio in post-menopausal T2DM women [ ] has been reported in a randomized trial with raloxifen.
Accordingly, the oral combination therapy with estradiol and norgestrel improved eGFR and proteinuria in T2DM postmenopausal women with hypertension, and this nephroprotective action was not related to the modification of conventional risk factors such as blood pressure and lipids [ ]. Vitamin D could also exert a synergetic action with estrogens in renal protection and diabetes control [ ].
Thus, vitamin D acts as a real steroid hormone and its level is influenced by estrogen status [ ]. It exerts a modulating action at both tubular [ ] and glomerular level [ ], with peculiar protective action in DKD [ ].
Moreover, pre- and post-menopausal DM women with an adequate vitamin D status seem to have a better glycemic control [ ]. Estrogens interfere with vitamin D immunomodulatory activities [ ] and, in turn, vitamin D down-regulates aromatase action, with a reduction of the adverse events linked to peripheral estrogen overexpression [ ]. Combined therapy with vitamin D supplementations and sex steroids seems to protect endothelium integrity, contrasting the cardiovascular damage that contributes to CKD and DKD progression .
Multiple mechanisms behind the reno-protective effects of oral estrogen supplementation in DM women have been reported. Chronic hyperglycemia le to an increase of reactive oxygen species ROSand an impairment of nitric oxide NO secretion [ ]. Additionally, the polyol pathways are involved in the DKD genesis [ ] Another pathway of glycemic damage is represented by the accumulation of Advanced Glycation End Products AGEswhich are derived from nonenzymatic glycosylation of product proteins or lipids .
E2 therapy can interfere with these pathways at different levels. The increased activity of nitric oxide synthase at the glomerular level may be another effect of estrogens in the kidney, improving vascular permeability and glomerular function [ ]. Beyond the role of estrogens, progesterone also seems to play an important role in kidney protection.Licata sex singles text
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