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American Journal of Kidney Diseases

Do Sex and Gender Matter in Kidney and Cardiovascular Disease?

      Related Articles, pp. 190 & 200
      Kidney disease is a global epidemic, and people living with chronic kidney disease (CKD) are among the highest risk groups for cardiovascular mortality. For this reason, improved understanding of the development and progression of CKD, as well as its cardiovascular complications, is urgently needed. Observational studies have demonstrated that while females have a higher prevalence of CKD overall, they may be protected from CKD progression compared to males,
      • Neugarten J.
      • Acharya A.
      • Silbiger S.R.
      Effect of gender on the progression of nondiabetic renal disease: a meta-analysis.
      although this may be limited to the premenopausal years.
      • Jafar T.H.
      • Schmid C.H.
      • Stark P.C.
      • et al.
      The rate of progression of renal disease may not be slower in women compared with men: a patient-level meta-analysis.
      Other reports suggest that neither female sex nor menopause are associated with either kidney benefit or risk.
      • Nitsch D.
      • Grams M.
      • Sang Y.
      • et al.
      Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis.
      The risk of cardiovascular mortality is higher in males overall, but occurs in females at an earlier stage of CKD.
      • Nitsch D.
      • Grams M.
      • Sang Y.
      • et al.
      Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis.
      With the advancement of precision medicine in nephrology, a critical question prevails: Do sex (biological attributes) and gender (sociocultural attributes) matter in kidney and cardiovascular disease?
      In this issue of AJKD, two studies aimed to examine this important question. First, Swartling et al
      • Swartling O.
      • Rydell H.
      • Stendahl M.
      • Segelmark M.
      • Lagerros Y.T.
      • Evans M.
      CKD progression and mortality among men and women: a nationwide study in Sweden.
      evaluated the association between sex and CKD progression, initiation of kidney replacement therapy (KRT), and mortality in an observational cohort study of over 25,000 incident patients with non–KRT-dependent CKD within the Swedish Renal Registry–CKD (SRR-CKD). The authors concluded that compared to women, men had an increased risk of CKD progression, as well as cardiovascular and all-cause mortality. In the other article, Toth-Manikowski et al
      • Toth-Manikowski S.M.
      • Yang W.
      • Appel L.
      • et al.
      on behalf of the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. Sex differences in cardiovascular outcomes in CKD: findings from the CRIC Study.
      explored sex differences in cardiovascular outcomes in almost 4,000 participants with mild-to-moderate CKD in a multicenter prospective observational study. The authors concluded that the risk of atherosclerotic events, incident heart failure, and cardiovascular and all-cause mortality was lower in women compared to men.
      Do the results of these two well-designed studies reflect sex (biological) differences between females and males in kidney and cardiovascular outcomes? Probably, although it is likely that gender also played an important role. In the first study,
      • Swartling O.
      • Rydell H.
      • Stendahl M.
      • Segelmark M.
      • Lagerros Y.T.
      • Evans M.
      CKD progression and mortality among men and women: a nationwide study in Sweden.
      the sex of the participants was derived from what had been manually inputted into the registry by individual nephrology clinic staff. In the second study,
      • Toth-Manikowski S.M.
      • Yang W.
      • Appel L.
      • et al.
      on behalf of the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. Sex differences in cardiovascular outcomes in CKD: findings from the CRIC Study.
      participant sex was self-identified. In both studies, it is possible that what was recorded was in actuality participant gender identity (man/woman), as opposed to sex (male/female), as sex and gender terms are often used interchangeably. As 0.4% to 1.3% of the population identify as transgender,
      • Winter S.
      • Diamond M.
      • Green J.
      • et al.
      Transgender people: health at the margins of society.
      this has the potential to confound the classification of participants into biological sex categories (male/female), though is unlikely to have significantly altered the study results. Previous reports demonstrate that independent of sex, gender identity and other measures of gender such as caregiving roles, domestic responsibilities, and socioeconomic position and power are associated with cardiovascular outcomes.
      • O’Neil A.
      • Scovelle A.J.
      • Milner A.J.
      • Kavanagh A.
      Gender/sex as a social determinant of cardiovascular risk.
      ,
      • Miller J.A.
      • Cherney D.Z.
      • Duncan J.A.
      • et al.
      Gender differences in the renal response to renin-angiotensin system blockade.
      To control for the potential effects of gender-related factors, Toth-Manikowski adjusted for important sociodemographic and lifestyle factors and determined that while cardiovascular risk was high in the overall cohort, women were at lower risk compared to men. Similarly, in a publicly funded health care system equally accessible to all (which may mitigate the effect of some gender variables on health), Swartling reported similar results. Taken together, the results of these studies suggest that female sex, independent of gender factors, is associated with improved mortality and cardiorenal risk in CKD.
      Previous studies have examined sex and gender differences in CKD progression, with conflicting results.
      • Neugarten J.
      • Acharya A.
      • Silbiger S.R.
      Effect of gender on the progression of nondiabetic renal disease: a meta-analysis.
      • Jafar T.H.
      • Schmid C.H.
      • Stark P.C.
      • et al.
      The rate of progression of renal disease may not be slower in women compared with men: a patient-level meta-analysis.
      • Nitsch D.
      • Grams M.
      • Sang Y.
      • et al.
      Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis.
      This likely at least partially relates to differences in definitions of outcomes; where some studies report loss of kidney function, others report KRT initiation as the primary outcome. Loss of kidney function likely represents a combination of both sex- and gender-related factors. From a biological perspective, males have increased activation and tissue responsiveness of the renal renin-angiotensin-aldosterone system,
      • Wang Q.
      • Xie D.
      • Xu X.
      • et al.
      Blood pressure and renal function decline: a 7-year prospective cohort study in middle-aged rural Chinese men and women.
      alongside an increased sensitivity to hypertension-related progression of CKD.
      • Ahmed S.B.
      • Fisher N.D.
      • Hollenberg N.K.
      Gender and the renal nitric oxide synthase system in healthy humans.
      Additionally, the male renal vasculature is increasingly dependent on nitric oxide with age compared to the female renal vasculature, suggesting that any kidney disease interfering with nitric oxide production may, over time, cause kidney damage to progress more quickly in males versus females.
      • Zhao J.V.
      • Schooling C.M.
      The role of testosterone in chronic kidney disease and kidney function in men and women: a bi-directional Mendelian randomization study in the UK Biobank.
      Animal studies demonstrate that increased testosterone plays a role in CKD progression; in humans, genetically predicted testosterone has been associated with reduced kidney function in men.
      • Crews D.C.
      • Kuczmarski M.F.
      • Miller 3rd, E.R.
      • Zonderman A.B.
      • Evans M.K.
      • Powe N.R.
      Dietary habits, poverty, and chronic kidney disease in an urban population.
      Gender factors may also contribute to the loss of kidney function. Adherence to a kidney-friendly diet,
      • Thompson A.E.
      • Anisimowicz Y.
      • Miedema B.
      • Hogg W.
      • Wodchis W.P.
      • Aubrey-Bassler K.
      The influence of gender and other patient characteristics on health care-seeking behaviour: a QUALICOPC study.
      as well as health-seeking behavior,
      • Hecking M.
      • Bieber B.A.
      • Ethier J.
      • et al.
      Sex-specific differences in hemodialysis prevalence and practices and the male-to-female mortality rate: the Dialysis Outcomes and Practice Patterns Study (DOPPS).
      is more common in women, which may also contribute to slower loss of kidney function in women compared to men.
      In contrast to loss of kidney function, which is considerably influenced by sex-related factors, the decision to initiate KRT has less of a biological basis and may be more reflective of gender factors. Men, particularly those with partners,
      • Antlanger M.
      • Noordzij M.
      • van de Luijtgaarden M.
      • et al.
      Sex differences in kidney replacement therapy initiation and maintenance.
      are more likely to choose to initiate KRT compared to women,
      • Chandna S.M.
      • Carpenter L.
      • Da Silva-Gane M.
      • Warwicker P.
      • Greenwood R.N.
      • Farrington K.
      Rate of decline of kidney function, modality choice, and survival in elderly patients with advanced kidney disease.
      who are more likely to opt for conservative care.
      • Slinin Y.
      • Guo H.
      • Li S.
      • et al.
      Provider and care characteristics associated with timing of dialysis initiation.
      Furthermore, women have been shown to initiate KRT at reduced kidney function compared to men.
      • Antlanger M.
      • Noordzij M.
      • van de Luijtgaarden M.
      • et al.
      Sex differences in kidney replacement therapy initiation and maintenance.
      Possibilities for this observation are that for the same level of estimated glomerular filtration rate (eGFR), women may be less likely than men to develop complications that trigger dialysis initiation, reflecting biological (ie, sex-based) differences. However, this may also reflect a personal choice of the person living with CKD or the timing of nephrology referral, as well as health care provider practice patterns regarding dialysis initiation.
      • Smilowitz N.R.
      • Mahajan A.M.
      • Roe M.T.
      • et al.
      Mortality of myocardial infarction by sex, age, and obstructive coronary artery disease status in the ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines).
      A strength of the nationwide study of referred CKD patients
      • Swartling O.
      • Rydell H.
      • Stendahl M.
      • Segelmark M.
      • Lagerros Y.T.
      • Evans M.
      CKD progression and mortality among men and women: a nationwide study in Sweden.
      is that CKD progression, eGFR slope, and KRT initiation were reported as outcomes, suggesting that both sex and gender play a role in the poorer outcomes observed in men, compared to women, with CKD.
      Similarly, cardiovascular mortality in CKD is likely linked to both sex and gender variables. In CKD, both albuminuria and reduced eGFR are independent risk factors for cardiovascular disease; however, the relationship curves between each variable and cardiovascular mortality are steeper in females as compared to males.
      • Nitsch D.
      • Grams M.
      • Sang Y.
      • et al.
      Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis.
      The pathophysiology of coronary heart disease differs by sex, where males in the general population are more likely to present with an obstructive coronary occlusion, while females are more likely to have nonobstructive coronary artery disease.
      • Vaccarino V.
      • Sullivan S.
      • Hammadah M.
      • et al.
      Mental stress-induced-myocardial ischemia in young patients with recent myocardial infarction: sex differences and mechanisms.
      Further, microvascular dysfunction as a result of mental stress is demonstrated much more frequently in women, who are at increased risk of mental stress–induced coronary events.
      • Bello A.K.
      • Stenvinkel P.
      • Lin M.
      • et al.
      Serum testosterone levels and clinical outcomes in male hemodialysis patients.
      Sex hormone physiology, which is disrupted in CKD, plays an important role in cardiorenal outcomes. Low testosterone, a common complication of CKD, is associated with increased cardiovascular risk in men in the general population and in men with CKD treated with dialysis,
      • Gagliano-Juca T.
      • Tang E.R.
      • Bhasin S.
      • et al.
      Effects of testosterone administration (and its 5-alpha-reduction) on parenchymal organ volumes in healthy young men: findings from a dose-response trial.
      though treatment with exogenous testosterone is not associated with change in kidney function in healthy men.
      • Ramesh S.
      • James M.T.
      • Holroyd-Leduc J.M.
      • et al.
      Estradiol and mortality in women with end-stage kidney disease.
      Furthermore, menopause and the subsequent reduction in estrogen levels are associated with increased cardiovascular risk in the general population, but in women with CKD treated with dialysis, no association is observed between estradiol levels and cardiovascular risk.
      • Ahmed S.B.
      • Culleton B.F.
      • Tonelli M.
      • et al.
      Oral estrogen therapy in postmenopausal women is associated with loss of kidney function.
      Conversely, although preclinical studies suggest a renoprotective role for estrogen, how estrogen may affect human kidney function is unclear. The use of oral estrogen as postmenopausal hormone therapy in older women is associated with more rapid loss of kidney function,
      • Kattah A.G.
      • Suarez M.L.G.
      • Milic N.
      • et al.
      Hormone therapy and urine protein excretion: a multiracial cohort study, systematic review, and meta-analysis.
      but other studies have suggested that postmenopausal estrogen therapy may decrease albuminuria risk.
      • Foy C.G.
      • Lovato L.C.
      • Vitolins M.Z.
      • et al.
      Gender, blood pressure, and cardiovascular and renal outcomes in adults with hypertension from the Systolic Blood Pressure Intervention Trial.
      While menopausal status was not ascertained in either study,
      • Swartling O.
      • Rydell H.
      • Stendahl M.
      • Segelmark M.
      • Lagerros Y.T.
      • Evans M.
      CKD progression and mortality among men and women: a nationwide study in Sweden.
      ,
      • Toth-Manikowski S.M.
      • Yang W.
      • Appel L.
      • et al.
      on behalf of the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. Sex differences in cardiovascular outcomes in CKD: findings from the CRIC Study.
      the authors stratified their results by the average age of menopause in their respective settings. Interestingly, their results did not change appreciably in older compared to younger women, suggesting that endogenous estrogen status does not play a role in the outcomes of interest. Toth-Manikowski et al reported that a minority of participants were using estrogen-containing compounds or testosterone therapy, so it is less likely that exogenous sex hormone use played a role in cardiovascular risk.
      Gender factors may also contribute to the increased cardiovascular risk demonstrated in men with CKD. Although men are more likely to be prescribed angiotensin-converting enzyme inhibitors and statins,
      • Pelletier R.
      • Khan N.A.
      • Cox J.
      • et al.
      for the GENESIS-PRAXY Investigators
      Sex Versus Gender-Related Characteristics: Which Predicts Outcome After Acute Coronary Syndrome in the Young?.
      men also have increased rates of behavioral cardiovascular risk factors, such as smoking and alcohol use, and are more likely to have less healthy dietary patterns, whereas women have increased adoption of primary cardiovascular prevention strategies.
      • Miller J.A.
      • Cherney D.Z.
      • Duncan J.A.
      • et al.
      Gender differences in the renal response to renin-angiotensin system blockade.
      The results of these 2 studies highlight that although there are important sex-related differences in risk, patients with CKD are at high risk of both CKD progression and cardiovascular disease. In this era of precision health, a patient-centered approach to CKD prevention and treatment is warranted to optimize outcomes. Studies demonstrating differences in CKD progression and cardiovascular risk in women and men should prompt the nephrology community to redesign our approach to research and care. Large, prospective studies incorporating both biological sex–based factors (such as genetics, sex hormones, physiology, and immunology) and measures of gender (such as identity, roles, relations, and institutionalized gender) are the first step in establishing differences in kidney and cardiovascular risk by sex and across genders, with the ultimate goal of improving health in all people living with CKD. So in response to the question – do sex and gender matter in kidney and cardiovascular disease? – the answer is yes, they do.

      Article Information

      Authors’ Full Names and Academic Degrees

      Sofia B. Ahmed, MD, MMSc, and Sandra M. Dumanski, MD, MSc.

      Support

      None.

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Peer Review

      Received April 5, 2021 in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form May 4, 2021.

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