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Gender and the Prevalence and Progression of Renal Disease
Gender and the Prevalence and Progression of Renal Disease Joel Neugarten and Ladan Golestaneh In most experimental models of CKD, male animals progress more rapidly than females. Modulation of the hormonal milieu can replicate the effects of gender on the course of kidney disease. These observations suggest that sex hormones per se may be important determinants of the greater susceptibility of males to progressive kidney injury. The predominance of data in humans suggests that the course of nondiabetic kidney disease is more aggressive in men than women. Male gender is arguably also a risk factor for progression of diabetic nephropathy. Sex hormones directly or indirectly affect many cellular processes by modulating the synthesis of various cytokines, growth factors, and vasoactive agents. In particular, estrogen acts in a receptordependent mechanism to regulate genes involved in extracellular matrix metabolism. Estrogen has profound effects on transforming growth factor-b signal transduction and on the renin-angiotensin system. These effects may contribute to alterations in kidney hemodynamics and affect kidney disease progression. Selective estrogen receptor modulators, agents that mimic many of the beneficial effects of estrogen without reproducing estrogen’s deleterious effects on reproductive tissue, ameliorate the course of kidney disease in animal models and in postmenopausal women. Q 2013 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Gender, Sex, CKD, Estrogen, Testosterone
Gender and Nondiabetic CKD The mechanisms underlying the gender disparity observed in the incidence, prevalence, and progression rate of kidney disease has not been fully elucidated. In most experimental models of kidney disease, male animals show accelerated progression.1 Hormonal manipulations replicate the effects of gender on the course of experimental kidney disease, suggesting that female sex hormones may slow progression of kidney disease whereas male hormones may accelerate progression.1 These observations also suggest that sex hormones per se, rather than genetically determined structural differences, determine the greater susceptibility of the male kidney to progressive kidney injury. Unlike experimental models, studies describing the relationship between gender and kidney disease progression in humans have yielded conflicting data. To further evaluate these discrepant data, we performed a metaanalysis involving 11,345 patients from 68 studies to determine the effect of gender on the progression of nondiabetic kidney disease.2 In men with autosomal dominant polycystic kidney disease, immunoglobulin A (IgA) nephropathy, membranous nephropathy, or CKD of unspecified etiology, progression was more rapid than in women. The Modification of Diet in Renal Disease Study also found that the rate of deterioration of glomerular filtration rate (GFR) was slower in younger women as compared From Montefiore Medical Center/Renal Division, Albert Einstein College of Medicine, Bronx, NY. The authors declare no relevant financial disclosures. Address correspondence to Joel Neugarten, MD, Albert Einstein College of Medicine, Montefiore Medical Center/Renal Division, 111 E. 210 Street, Bronx, NY, 10467. E-mail: [email protected] Ó 2013 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.05.004
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with men, but this difference was no longer significant after adjusting for differences in blood pressure, urinary protein excretion, and high-density lipoprotein levels.3 Another meta-analysis analyzed 11 randomized studies evaluating the effect of angiotensin converting enzyme inhibitors on the progression of nondiabetic kidney disease.4 The authors concluded that women have a worse kidney prognosis than men after correction for differences in systolic blood pressure and urinary protein excretion. However, most of the female participants in these studies were postmenopausal, which may explain the different findings in the two meta-analyses. Cattran and coworkers5 reported a reduced rate of decline in kidney function and/or increased kidney survival in younger women with membranous nephropathy or focal and segmental glomerulosclerosis as compared with men. A beneficial effect of female sex persisted, even after correction for the fact that blood pressure and proteinuria were lower in women. In contrast, this study found no effect of sex on the progression of IgA nephropathy. The Ramapril (Sanofi-Aventis, Paris, France) Efficacy in Nephropathy Study, a multicenter, randomized, doubleblind, placebo-controlled trial to determine whether Ramapril therapy affects the rate of progression of chronic nondiabetic, proteinuric kidney disease, found that the rate of decline of GFR was faster in women compared with men in the placebo arm, whereas in the Ramapriltreated arm, progression was slower and reduction in proteinuria was greater in women.6 Angiotensin converting enzyme (ACE) inhibitor therapy was uniformly renoprotective in women, regardless of ACE polymorphism, but in men it was renoprotective only in those with the DD genotype.6 The authors concluded that men with chronic proteinuric kidney disease are at increased risk of progression because their lesser response to ACE inhibitor therapy. More recent population-based, observational studies
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disparity in ESRD incidence rates has also been reported from the United States, Europe, and Japan, including sevfrom Japan.17 It is unlikely that the slightly lower eGFR eral mass screening studies, have identified male sex as 7-12 Despite certain at which men initiate renal replacement therapy can aca predictor of poor kidney outcome. methodological limitations, these studies are consistent count for this sexual disparity in incidence rates. with observations in experimental animals showing The age- and race-adjusted prevalence of ESRD is also a faster rate of progression of kidney disease in men. greater in men than in women.14 Likewise, the prevalence of most primary, immune-mediated glomerular diseases On the other hand, other studies have concluded that is greater in males than females.1 Among patients with there is no difference in the rate of kidney disease proidiopathic membranous nephropathy, IgA nephropathy, gression between men and women, or that women progand minimal change disease in children, males outnumress to kidney failure at a faster rate than do men. Niche ber females by 2-3 to 1.1 Because most studies show and colleagues13 performed a meta-analysis using pooled individual participant data from 46 cohorts. The authors that male animals exhibit reduced immune responsivefound that lower estimated glomerular filtration rate ness and that administration of exogenous testosterone (eGFR) and greater albuminuria were each associated is immunosuppressive, the mechanisms responsible for with all-cause mortality and cardiovascular mortality this sexual disparity remains to be elucidated. and that the risk was higher for men than women. However, the slope of the risk relationship was steeper in Gender and Diabetic CKD women. Lower eGFR and higher albumin-to-creatinine ratio were associated with increased risk of developing The effect of gender on the progression of diabetic nephropathy merits separate consideration. Inconsistent ESRD, but the risk was similar between men and women. data with respect to sexual Results did not change when dimorphism in the develsubjects less than 50 years of opment and progression of age were compared with CLINICAL SUMMARY nephropathy in type I diathose greater than 65 years In experimental models of kidney disease, male animals of age. Despite the size of betics may reflect differprogress more rapidly than females. this meta-analysis, interpreences among studies in the tation is confounded by comage of onset of diabetes Although data are conflicting, men have a worse kidney prognosis than do women. and the length of followpeting mortality. Men are up. A later age at onset of more likely to die a nonrenal It is likely that direct effects of sex hormones rather than type I diabetes has been asdeath. This sexual disparity structural differences between the sexes are responsible for sexual dimorphism in kidney disease progression. sociated with sex-related reduces the number of men differences in ESRD risk at risk for progression to Selective estrogen receptor modulators ameliorate the ESRD. These factors limit only after follow-up pecourse of kidney disease in animal models and in postmenopausal women. the validity of conclusions riods of 25 to 40 years.18,19 Numerous crossabout the role of sex in kidsectional and longitudinal ney disease progression destudies in persons with type I diabetes show a greater rived from studies in which ESRD is the sole outcome prevalence of micro- and macroalbuminuria in men vs measure. women or an increased risk of developing microalbumiIn contrast to the analysis reported by Niche,13 ESRD registry data convincingly establish a role for male gender nuria and progressing to macroalbuminuria. In in accelerating kidney disease progression. Although the particular, a large study from Germany of 27,805 type I prevalence of Stage 3 to 5 CKD is equivalent or greater diabetics reported that male sex was associated with the in women than men, the incidence of ESRD is greater in development of microalbuminuria.20 In addition, several studies suggest that males with type I diabetic nephropamen than in women. National Health and Nutrition Examthy have significantly higher rates of decline in GFR than ination Survey data indicate that the prevalence of an women.1 However, other studies report no gender-related eGFR less than 60 mL/min per 1.73 m2 is 7.7% in women vs 5.6% in men, and the prevalence of an albumin-todifferences in the rate of progression of nephropathy in creatinine ratio greater than 30 mg/g creatinine is 10.2% type I diabetics.1 The Collaborative Captopril (Bristol14 in women vs 8.6% in men. In contrast, the incident rate Myers Squibb, New York, NY) Study Group performed of reported ESRD in the United States in 2010, per million a prospective, double-blind, randomized, placebopopulation adjusted for age and race, is 60% greater in controlled trial of the effect of Captopril on the progression of nephropathy in type I diabetes and reported no effect of men compared with women.14 The United Kingdom Renal Registry and the European Renal Associationgender on kidney disease progression.21 There are limited and even less consistent data reEuropean Dialysis and Transplant Association Registry garding the contribution of gender to the rate of progresalso report ESRD incidence rates that are more than 60% sion of nephropathy in type II diabetes.22 Numerous greater in men than women.15,16 A similar sexual
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cross-sectional and longitudinal studies of type II diabetics show a greater prevalence of albuminuria in males and an increased risk for developing microalbuminuria as well as an increased risk of progression.22,23 In contrast, numerous other cross-sectional and longitudinal studies have found no influence of sex on the prevalence, incidence, or progression of nephropathy in type II diabetics. In the placebo arm of the Reduction of Endpoints in NIIDM with the angiotensin II Antagonist Losartan (Merck & Co., Summit, NJ) study, a multicenter, double-blind, randomized, placebocontrolled trial of the effect of Losartan on the progression of type II diabetes mellitus, male sex was protective by univariate but not multivariate analysis.24 Most female subjects were postmenopausal, and at baseline women had significantly greater proteinuria and a lower eGFR than men, confounding interpretation of these data. The Collaborative Study Group performed a multicenter, doubleblind, randomized, placebo-controlled trial of the effects of Irbesartan (Sanofi-Aventis, Paris, France) on the progression of nephropathy in type II diabetics.25 The investigators found that albuminuria progressed more rapidly in women, and that women benefited less from Irbesartan therapy than did men. However, most female subjects in this trial were again postmenopausal. In contrast, ESRD registry data suggest a more aggressive course of diabetic nephropathy in men. The incident rate of reported diabetic ESRD in the United States in 2010, per million population of individuals with diabetes mellitus, adjusted for age and race, is 24% greater in men than in women.26 Unadjusted United Kingdom Renal Registry data indicate an 80% greater incidence rate for ESRD in diabetic men than in diabetic women.17 Similar data have been reported from Germany.27
Factors Contributing to Gender-Related Differences in Kidney Disease Progression Numerous mechanisms have been suggested to explain the protective effect of female gender on the progression of kidney diseases. These include differences between the sexes in kidney structure, systemic and kidney hemodynamics, diet, lipid metabolism, and blood pressure. Sex hormones also affect numerous cellular processes including mesangial cell proliferation and matrix accumulation, either directly or indirectly by regulating the synthesis and release of cytokines, vasoactive agents, and growth factors.
Direct Effects of Sex Hormones on Cellular Biology Transforming Growth Factor-b and Mesangial Matrix Accumulation Transforming growth factor-b (TGF-b) simulates type IV collagen gene transcription by increasing the quantity of free Sp1 available to transactivate the collagen IV pro-
moter via a mechanism dependent on activation of protein kinase CK2.28 Estradiol reverses TGF-b-stimulated type IV collagen gene transcription by preventing TGFb-induced activation of CK2.28 Estrogen also reverses TGF-b-induced mesangial cell apoptosis by preventing TGF-b-induced upregulation of CK2 activity and p53 phosphorylation.29 In transfected human embryonic kidney cells exposed to estrogen, a complex forms among estrogen receptor a, Smad2/Smad3, and the ubiquitin ligase Smurf.30 This action increases ubiquitization and degradation of these Smad proteins and explains the finding that estrogen decreases the expression of total and phosphorylated Smad2/3 in kidneys from ovariectomized diabetic rats.30,31 Estradiol also suppresses mesangial cell type I collagen gene transcription and protein synthesis via a mitogen-activated protein kinase/AP 1-mediated mechanism, stimulates mesangial cell metalloproteinase 2 activity via a mitogen-activated/AP 2-mediated mechanism, and stimulates metalloproteinase 9 activity.1,32,33 These actions shift the balance of matrix metabolism away from matrix accumulation and glomerulosclerosis. Alb/TGF- b mice overexpress TGF-b and develop proteinuria and progressive kidney injury. Estradiol, by preventing CK2 activation, reverses the injurious effects of TGF-b and ameliorates kidney injury in this model.34 Nitric Oxide Nitric oxide (NO) contributes to the development and progression of kidney injury in numerous experimental models. In cultured glomerular and vascular endothelial cells, physiological concentrations of estrogen cause a rapid release of NO via estrogen receptor a.35 The promoter region of the endothelial nitric oxide synthase (eNOS) gene contains an estrogen responsive element, which may mediate estrogen-induced upregulation of eNOS mRNA and protein levels.35 Estrogen also causes release of intracellular calcium and increases local synthesis of prostaglandin E2 and prostacyclin, which in turn upregulates eNOS activity.35 Female rats express higher levels of eNOS than males, an effect that is reversed by ovariectomy.35 Although chronic NO inhibition in rats induces systolic hypertension in both sexes, only male rats develop proteinuria, which is prevented by orchiectomy.35 Aging male rats are more dependent on NO than aging females, which may contribute to greater age-dependent kidney damage in males.35 Renin-Angiotensin System Sex hormones have profound effects on the reninangiotensin system (RAS) at multiple levels. Estrogen downregulates the expression of renin, ACE, and angiotensin II (AII), but it upregulates the expression of angiotensinogen.36 The tissue response to AII may also be downregulated in women. Estrogen increases
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angiotensin type 2 (AT-2) receptor density in the renal medulla and decreases angiotensin type 1 (AT-1) receptor density in the kidney and in vascular smooth muscle.36 Downregulation of AT-1 receptor density antagonizes sodium retention and vasoconstriction.36 Enhanced AT-2 receptor expression stimulates bradykinin synthesis, which in turn stimulates NO release and upregulates prostaglandin E2 expression.36 In contrast, testosterone activates the RAS.36 Kidney angiotensinogen mRNA levels are higher in adult male rats compared with females, an effect that is reversed by orchiectomy and restored by testosterone administration.36 Prorenin and renin levels and plasma renin activity are higher in men than in women.36 In cultured mesangial cells, dihydrotestosterone upregulates the expression of AT-1 receptors.36 Consistent with sex hormone-related alterations in receptor density and modulation of counter-regulatory vasoactive hormones, the effect of infused AII on kidney hemodynamics also differs between the sexes.37 It is clear that interactions between sex hormones and the RAS may contribute to gender dimorphism in kidney disease progression. Endothelin Endothelin is a potent vasoconstrictor that enhances kidney sodium reabsorption, promotes oxidative stress, and contributes to increased blood pressure.38 Estradiol inhibits not only the synthesis of endothelin but also inhibits its vasoconstrictor and inflammatory effects.38 Men have higher endothelin-1 levels than women, and levels decline in estrogen-treated men. In women, levels increase after menopause. Because AII stimulates endothelin synthesis, the ability of estrogen to decrease AII levels may contribute to a reduction in endothelin levels.37,38 Kidney Hemodynamics In humans, GFR in men and women is similar when corrected for body surface area.1 In addition, neither testosterone nor estrogen has direct effects on GFR or kidney blood flow.1 Despite these data, there is evidence to suggest that glomerular hemodynamic responses to vasoactive agents may differ in men vs women.37,39,40 Men respond to an infusion of AII by maintaining their GFR at the expense of an increased filtration fraction, suggesting an increased glomerular capillary pressure.37 In contrast, women showed a decrease in GFR and effective renal plasma flow without change in filtration fraction, suggesting no increase in glomerular capillary pressure. This gender dimorphism may contribute to renoprotection in females by blunting elevations in glomerular capillary pressure in the face of kidney injury, resulting in reduced glomerular hemodynamic stress. During clamped hyperglycemia in normoalbuminuric, normotensive adolescents with type I diabetes mellitus,
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males did not exhibit any change in kidney hemodynamics whereas females showed a decrease in effective renal plasma flow and increases in kidney vascular resistance and filtration fraction, suggesting an increase in glomerular capillary pressure.39 It was suggested that these gender-related differences may explain the lack of a consistent protective effect of female gender on the course of nephropathy in type I diabetes. Reactive Oxygen Species Enhanced generation of reactive oxygen species (ROS) has been shown to contribute to kidney injury in experimental models of kidney disease. In numerous animal models of kidney injury, estrogen blunts upregulation of nicotinamide adenosine dinucleotide phosphate oxidase activity, which in turn suppresses the generation of superoxide anion, the major ROS produced by the kidney.41 In contrast, testosterone increases oxidative stress either directly or indirectly. Testosterone inhibits various antioxidant enzymes and amplifies the generation of ROS in response to kidney insults. Reversal of kidney injury by estrogen and exaggeration of injury by testosterone in experimental models of hypertension is mediated by the ability of sex hormones to modulate ROS generation.41 Apoptosis In vitro, testosterone induces apoptosis in podocytes via an androgen-receptor-dependent mechanism independent of TGF-b signaling.42 Testosterone also promotes apoptosis in human proximal tubular cells by stimulating the c-Jun amino terminal kinase signal transduction pathway, which in turn activates a Fas/Fas ligand-dependent apoptotic pathway in association with increased expression of Bax and caspase 3, reduced Bcl2 expression, and poly(ADP-ribose)polymerase (PARP)-1 cleavage.43 In vitro, estrogen protects podocytes from apoptosis induced by testosterone, TGF-b, tumor necrosis factora, and puromycin aminonucloside.42 This protective effect may be mediated by activation of the phosphoinisotide 3-kinase/protein kinase B (PI3K/AKT) signal transduction cascade, by reduced generation of ROS, or by reduced activation of the extracellular signalregulated kinase (ERK) signaling cascade. Estrogen also antagonizes TGF-b-induced mesangial cell apoptosis by inhibiting activation of CK2, which in turn inhibits phosphorylation of p53.29
Environmental Factors Excessive caloric intake or high dietary intake of protein, phosphorus, or sodium promotes the development and progression of kidney disease in numerous experimental models, whereas dietary restriction slows progression. Protein loading increases GFR and glomerular transcapillary hydraulic pressure difference, which, if sustained,
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will ultimately be detrimental to the kidney. Men generally consume more calories and protein than women. Consistent with these observations, in the Modification of Diet in Renal Disease Study, women showed a lesser benefit from dietary protein restriction than did men. It is not known whether greater occupational exposure to industrial nephrotoxins such as lead and hydrocarbons contributes to the excess risk of ESRD in men. The resistance of female rats to the development of nephropathy after chronic inhalation of petroleum products suggests the possibility of gender-related differences in susceptibility to these agents. Although smoking is been shown to interact with estrogen deficiency to promote kidney injury in an experimental model, this observation has not been confirmed in humans.
Hypertension The overall prevalence of hypertension and the incidence of uncontrolled hypertension are higher among men than women.35 There is no difference in systemic blood pressure between prepubescent boys and girls, and it is only after puberty that boys exhibit higher blood pressure than girls.35 Blood pressure increases with age in men and women, but the rate of rise in blood pressure is steeper in women beginning in their 60s such that after the 7th decade, women have higher systolic blood pressures and pulse pressures than men.35 Progression of cardiovascular and kidney disease related to hypertension may also be more rapid in men.
Selective Estrogen Receptor Modulators Selective estrogen receptor modulators are agents that mimic many of the beneficial effects of estrogen on bone and vascular tissue without reproducing estrogens deleterious effects on reproductive tissue. Selective estrogen receptor modulators inhibit mesangial cell matrix synthesis and ameliorate kidney injury in numerous experimental models of kidney disease. A recent post hoc analysis of the Multiple Outcomes of Raloxifene Evaluation study, a multicenter, randomized, double-blind trial of Raloxifene vs placebo on the risk of fractures in postmenopausal women, found that women in the group that received Raloxifene had a slower yearly rate of increase in creatinine and a significantly slower yearly rate of decline in eGFR over 3 years of follow-up.44
References 1. Silbiger S, Neugarten J. The impact of gender on the progression of chronic renal disease. Am J Kidney Dis. 1995;25(4):515-533. 2. 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(2):319-329. 3. Coggins CH, Lewis JB, Caggiula AW, Castaldo LS, Klahr S, Wang SR. Differences between women and men with chronic renal disease. Nephrol Dial Transplant. 1998;13(6):1430-1437.
4. 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(10):2047-2053. 5. Cattran DC, Reich HN, Beanlands HJ, et al, Genes, Gender and Glomerulonephritis Group. The impact of sex in primary glomerulonephritis. Nephrol Dial Transplant. 2008;23(7):2247-2253. 6. Ruggenenti P, Perna A, Zoccalli C, et al, ‘‘Gruppo Italiano di Studi Epidemologici in Nefrologia’’ (GISEN). Chronic proteinuric nephropathies. II. Outcomes and response to treatment in a prospective cohort of 352 patients: differences between men and women in relation to the ACE gene polymorphism. J Am Soc Nephrol. 2000;11(1):88-96. 7. Evans M, Fryzek JP, Elinder CG, et al. The natural history of chronic renal failure: results from an unselected population-based inception cohort in Sweden. Am J Kidney Dis. 2005;46(5):863-870. 8. Eriksen BO, Ingebretsen OC. The progression of chronic kidney disease: a 10 year population-based study of the effects of gender and age. Kidney Int. 2006;69(2):375-382. 9. Hallan SI, Ritz E, Lyndersen S, Romundstad S, Kvenild K, Orth SR. Combining GFR and albuminuria to classify CKD improves prediction of ESRD. J Am Soc Nephrol. 2009;20(5):1069-1077. 10. Iseki K, Iseki C, Ikemiya Y, Fukiyama K. Risk of developing endstage renal disease in a cohort of mass screening. Kidney Int. 1996;49(3):800-805. 11. Haroun MK, Jarr BG, Hoffman SC, Comstock GW, Klag MJ, Coresh J. Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland. J Am Soc Nephrol. 2003;14(11):2934-2941. 12. Babayev R, Whaley-Connell A, Kshirsagar A, et al. Association of race and body mass index with ESRD and mortality in CKD stages 3-4: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis. 2013;61(3):404-412. 13. Nitsch D, Grams M, Sang Y, et al, Chronic Kidney Disease Prognosis Consortium. Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a metaanalysis. BMJ. 2013;346:f324. 14. U.S. Renal Data System. USRDS 2012 annual data report: atlas of chronic kidney disease and end stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2012. 15. Gilg J, Castledine C, Fogarty D. UK Renal Registry 14th annual report: Chapter 1 UK RRT incidence in 2010: National and centrespecific analyses. Nephrol Clin Pract. 2012;120(suppl 1):c1-c27. 16. ERA-EDA Registry Annual Report. Available at: www.espn-reg. org. Accessed May 15, 2013. 17. Iseki K, Nakai S, Shinzato T, Nagura Y, Akiba T, Patient Registration Committee of the Japanese Society for Dialysis Therapy. Increasing gender difference in the incidence of chronic dialysis therapy in Japan. Ther Apher Dial. 2005;9(5):407-411. 18. Harjutsalo V, Maric C, Forsblom C, Thorn L, Waden J, Groop PH, FinnDiane Study Group. Sex related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes. Diabetologia. 2011;54(8):1992-1999. 19. Orchard TJ, Dorman JS, Maser RE, et al. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes. 1990;39(9):1116-1124. 20. Raile K, Galler A, Hoffer S, et al. Diabetic nephropathy in 27,805 children, adolescents, and adults with type 1 diabetes. Effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex. Diabetes Care. 2007;30(10):2523-2528. 21. Breyer JA, Bain RP, Evans JK, et al. Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. Kidney Int. 1996;50(5):1651-1658. 22. Maric C, Sullivan S. Estrogens and the diabetic kidney. Gend Med. 2008;5(suppl A):S103-S113. 23. Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R. Main risk factors for nephropathy in type 2 diabetes mellitus are plasma
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cholesterol levels, mean blood pressure and hyperglycemia. Arch Intern Med. 1998;158(9):998-1004. Keane WF, Brenner BM, de Zueeuw D, et al, RENAAL Study investigators. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL Study. Kidney Int. 2003;63(4):1499-1507. Lewis EJ, Hunsicker LG, Clarke WR, et al, Collaborative Group. Renoprotective effect of the angiotensin-receptor antagonist Irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860. Centers for Disease Control and Prevention. Age-adjusted incidence of end-stage renal disease related to diabetes mellitus (ESRD-DM) per 100,000 diabetic population, by race, ethnicity, and sex, United States, 1980–2008. Available at: www.cdc.gov/ diabetes/statistics/esrd/fig5.htm. Accessed May 15, 2013. Icks A, Haastert B, Genz J, et al. Incidence of renal replacement therapy (RRT) in the diabetic population in a German region, 2002-2008. Nephrol Dial Transplant. 2011;26(1):264-269. Zdunek M, Silbiger S, Lei J, Neugarten J. Protein kinase CK2 mediates TGF-b1-stimulated type IV collagen gene transcription and its reversal by estradiol. Kidney Int. 2001;60(6):2097-2108. Negulescu O, Bognar I, Lei J, Devarajan P, Silbiger S, Neugarten J. Estradiol reverses TGF-b1-induced mesangial cell apoptosis by a casein kinase 2-dependent mechanism. Kidney Int. 2002;62(6): 1989-1998. Ito I, Hanyu A, Wayama M, et al. Estrogen inhibits transforming growth factor eta signaling by promoting Smad 2/3 degradation. J Biol Chem. 2010;285(19):14747-14755. Dixon A, Maric C. 17b-Estradiol attenuates diabetic kidney disease by regulating extracellular matrix and transforming growth factor-beta protein expression and signaling. Am J Physiol. 2007; 293(5):F1678-F1690. Neugarten J, Medve I, Lei J, Siliger SR. Estradiol suppresses mesangial cell type I collagen synthesis via activation of the MAP kinase cascade. Am J Physiol. 1999;277(6 Pt 2):F875-F881.
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33. Guccione M, Silbiger S, Lei J, Neugarten J. Estradiol upregulates mesangial cell MMP-2 activity via the transcription factor AP-2. Am J Physiol. 2002;282(1):F164-F169. 34. Blush J, Lei J, Ju W, Silbiger S, Pullman J, Neugarten J. Estradiol reverses renal injury in Alb/TGF-b1 transgenic mice. Kidney Int. 2004;66(6):2148-2154. 35. Neugarten J, Silbiger SR, Golestaneh L. Gender and kidney disease. In: Brenner BM, ed. Brenner and Rector’s The Kidney. 9th ed. Amsterdam, The Netherlands: Elsevier; 2008:674-680. 36. Kang AK, Miller JA. Effects of gender on the renin-angiotensin system, blood pressure, and renal function. Curr Hypertens Rep. 2002;4(2):143-151. 37. Miller JA, Abacta LA, Cattran DC. Impact of gender on renal response to angiotensin II. Kidney Int. 1999;55(1):278-285. 38. Tostes RC, Rortes ZB, Callera GE, et al. Endothelin, sex and hypertension. Clin Sci (Lond). 2008;114(2):85-97. 39. Cherney DZI, Sochett EB, Miller JA. Gender differences in renal response to hyperglycemia and angiotensin-converting enzyme inhibition in diabetes. Kidney Int. 2005;68(4):1722-1728. 40. Cherney DZI, Scholey JW, Nasrallah R, et al. Renal hemodynamic effect of cyclooxygenase 2 inhibition in young men and women with uncomplicated type1 diabetes mellitus. Am J Physiol. 2008; 294(6):F1336-F1341. 41. Neugarten J. Estrogen and oxidative stress. Gend Med. 2007;4(1): 31-32. 42. Doublier S, Lupia E, Catanuto P, et al. Testosterone and 17 betaestradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice. Kidney Int. 2011;79(4):404-413. 43. Verzola D, Villagio B, Procopio V, et al. Androgen-mediated apoptosis of kidney tubule cells: role of c-Jun amino terminal kinase. Biochem Biophys Res Commun. 2009;387(3):531-536. 44. Melamed ML, Blackwell T, Neugarten J, et al. Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post-hoc analysis. Kidney Int. 2011;79(2):241-249.
Gender and Nondiabetic CKD The mechanisms underlying the gender disparity observed in the incidence, prevalence, and progression rate of kidney disease has not been fully elucidated. In most experimental models of kidney disease, male animals show accelerated progression.1 Hormonal manipulations replicate the effects of gender on the course of experimental kidney disease, suggesting that female sex hormones may slow progression of kidney disease whereas male hormones may accelerate progression.1 These observations also suggest that sex hormones per se, rather than genetically determined structural differences, determine the greater susceptibility of the male kidney to progressive kidney injury. Unlike experimental models, studies describing the relationship between gender and kidney disease progression in humans have yielded conflicting data. To further evaluate these discrepant data, we performed a metaanalysis involving 11,345 patients from 68 studies to determine the effect of gender on the progression of nondiabetic kidney disease.2 In men with autosomal dominant polycystic kidney disease, immunoglobulin A (IgA) nephropathy, membranous nephropathy, or CKD of unspecified etiology, progression was more rapid than in women. The Modification of Diet in Renal Disease Study also found that the rate of deterioration of glomerular filtration rate (GFR) was slower in younger women as compared From Montefiore Medical Center/Renal Division, Albert Einstein College of Medicine, Bronx, NY. The authors declare no relevant financial disclosures. Address correspondence to Joel Neugarten, MD, Albert Einstein College of Medicine, Montefiore Medical Center/Renal Division, 111 E. 210 Street, Bronx, NY, 10467. E-mail: [email protected] Ó 2013 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.05.004
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with men, but this difference was no longer significant after adjusting for differences in blood pressure, urinary protein excretion, and high-density lipoprotein levels.3 Another meta-analysis analyzed 11 randomized studies evaluating the effect of angiotensin converting enzyme inhibitors on the progression of nondiabetic kidney disease.4 The authors concluded that women have a worse kidney prognosis than men after correction for differences in systolic blood pressure and urinary protein excretion. However, most of the female participants in these studies were postmenopausal, which may explain the different findings in the two meta-analyses. Cattran and coworkers5 reported a reduced rate of decline in kidney function and/or increased kidney survival in younger women with membranous nephropathy or focal and segmental glomerulosclerosis as compared with men. A beneficial effect of female sex persisted, even after correction for the fact that blood pressure and proteinuria were lower in women. In contrast, this study found no effect of sex on the progression of IgA nephropathy. The Ramapril (Sanofi-Aventis, Paris, France) Efficacy in Nephropathy Study, a multicenter, randomized, doubleblind, placebo-controlled trial to determine whether Ramapril therapy affects the rate of progression of chronic nondiabetic, proteinuric kidney disease, found that the rate of decline of GFR was faster in women compared with men in the placebo arm, whereas in the Ramapriltreated arm, progression was slower and reduction in proteinuria was greater in women.6 Angiotensin converting enzyme (ACE) inhibitor therapy was uniformly renoprotective in women, regardless of ACE polymorphism, but in men it was renoprotective only in those with the DD genotype.6 The authors concluded that men with chronic proteinuric kidney disease are at increased risk of progression because their lesser response to ACE inhibitor therapy. More recent population-based, observational studies
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disparity in ESRD incidence rates has also been reported from the United States, Europe, and Japan, including sevfrom Japan.17 It is unlikely that the slightly lower eGFR eral mass screening studies, have identified male sex as 7-12 Despite certain at which men initiate renal replacement therapy can aca predictor of poor kidney outcome. methodological limitations, these studies are consistent count for this sexual disparity in incidence rates. with observations in experimental animals showing The age- and race-adjusted prevalence of ESRD is also a faster rate of progression of kidney disease in men. greater in men than in women.14 Likewise, the prevalence of most primary, immune-mediated glomerular diseases On the other hand, other studies have concluded that is greater in males than females.1 Among patients with there is no difference in the rate of kidney disease proidiopathic membranous nephropathy, IgA nephropathy, gression between men and women, or that women progand minimal change disease in children, males outnumress to kidney failure at a faster rate than do men. Niche ber females by 2-3 to 1.1 Because most studies show and colleagues13 performed a meta-analysis using pooled individual participant data from 46 cohorts. The authors that male animals exhibit reduced immune responsivefound that lower estimated glomerular filtration rate ness and that administration of exogenous testosterone (eGFR) and greater albuminuria were each associated is immunosuppressive, the mechanisms responsible for with all-cause mortality and cardiovascular mortality this sexual disparity remains to be elucidated. and that the risk was higher for men than women. However, the slope of the risk relationship was steeper in Gender and Diabetic CKD women. Lower eGFR and higher albumin-to-creatinine ratio were associated with increased risk of developing The effect of gender on the progression of diabetic nephropathy merits separate consideration. Inconsistent ESRD, but the risk was similar between men and women. data with respect to sexual Results did not change when dimorphism in the develsubjects less than 50 years of opment and progression of age were compared with CLINICAL SUMMARY nephropathy in type I diathose greater than 65 years In experimental models of kidney disease, male animals of age. Despite the size of betics may reflect differprogress more rapidly than females. this meta-analysis, interpreences among studies in the tation is confounded by comage of onset of diabetes Although data are conflicting, men have a worse kidney prognosis than do women. and the length of followpeting mortality. Men are up. A later age at onset of more likely to die a nonrenal It is likely that direct effects of sex hormones rather than type I diabetes has been asdeath. This sexual disparity structural differences between the sexes are responsible for sexual dimorphism in kidney disease progression. sociated with sex-related reduces the number of men differences in ESRD risk at risk for progression to Selective estrogen receptor modulators ameliorate the ESRD. These factors limit only after follow-up pecourse of kidney disease in animal models and in postmenopausal women. the validity of conclusions riods of 25 to 40 years.18,19 Numerous crossabout the role of sex in kidsectional and longitudinal ney disease progression destudies in persons with type I diabetes show a greater rived from studies in which ESRD is the sole outcome prevalence of micro- and macroalbuminuria in men vs measure. women or an increased risk of developing microalbumiIn contrast to the analysis reported by Niche,13 ESRD registry data convincingly establish a role for male gender nuria and progressing to macroalbuminuria. In in accelerating kidney disease progression. Although the particular, a large study from Germany of 27,805 type I prevalence of Stage 3 to 5 CKD is equivalent or greater diabetics reported that male sex was associated with the in women than men, the incidence of ESRD is greater in development of microalbuminuria.20 In addition, several studies suggest that males with type I diabetic nephropamen than in women. National Health and Nutrition Examthy have significantly higher rates of decline in GFR than ination Survey data indicate that the prevalence of an women.1 However, other studies report no gender-related eGFR less than 60 mL/min per 1.73 m2 is 7.7% in women vs 5.6% in men, and the prevalence of an albumin-todifferences in the rate of progression of nephropathy in creatinine ratio greater than 30 mg/g creatinine is 10.2% type I diabetics.1 The Collaborative Captopril (Bristol14 in women vs 8.6% in men. In contrast, the incident rate Myers Squibb, New York, NY) Study Group performed of reported ESRD in the United States in 2010, per million a prospective, double-blind, randomized, placebopopulation adjusted for age and race, is 60% greater in controlled trial of the effect of Captopril on the progression of nephropathy in type I diabetes and reported no effect of men compared with women.14 The United Kingdom Renal Registry and the European Renal Associationgender on kidney disease progression.21 There are limited and even less consistent data reEuropean Dialysis and Transplant Association Registry garding the contribution of gender to the rate of progresalso report ESRD incidence rates that are more than 60% sion of nephropathy in type II diabetes.22 Numerous greater in men than women.15,16 A similar sexual
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cross-sectional and longitudinal studies of type II diabetics show a greater prevalence of albuminuria in males and an increased risk for developing microalbuminuria as well as an increased risk of progression.22,23 In contrast, numerous other cross-sectional and longitudinal studies have found no influence of sex on the prevalence, incidence, or progression of nephropathy in type II diabetics. In the placebo arm of the Reduction of Endpoints in NIIDM with the angiotensin II Antagonist Losartan (Merck & Co., Summit, NJ) study, a multicenter, double-blind, randomized, placebocontrolled trial of the effect of Losartan on the progression of type II diabetes mellitus, male sex was protective by univariate but not multivariate analysis.24 Most female subjects were postmenopausal, and at baseline women had significantly greater proteinuria and a lower eGFR than men, confounding interpretation of these data. The Collaborative Study Group performed a multicenter, doubleblind, randomized, placebo-controlled trial of the effects of Irbesartan (Sanofi-Aventis, Paris, France) on the progression of nephropathy in type II diabetics.25 The investigators found that albuminuria progressed more rapidly in women, and that women benefited less from Irbesartan therapy than did men. However, most female subjects in this trial were again postmenopausal. In contrast, ESRD registry data suggest a more aggressive course of diabetic nephropathy in men. The incident rate of reported diabetic ESRD in the United States in 2010, per million population of individuals with diabetes mellitus, adjusted for age and race, is 24% greater in men than in women.26 Unadjusted United Kingdom Renal Registry data indicate an 80% greater incidence rate for ESRD in diabetic men than in diabetic women.17 Similar data have been reported from Germany.27
Factors Contributing to Gender-Related Differences in Kidney Disease Progression Numerous mechanisms have been suggested to explain the protective effect of female gender on the progression of kidney diseases. These include differences between the sexes in kidney structure, systemic and kidney hemodynamics, diet, lipid metabolism, and blood pressure. Sex hormones also affect numerous cellular processes including mesangial cell proliferation and matrix accumulation, either directly or indirectly by regulating the synthesis and release of cytokines, vasoactive agents, and growth factors.
Direct Effects of Sex Hormones on Cellular Biology Transforming Growth Factor-b and Mesangial Matrix Accumulation Transforming growth factor-b (TGF-b) simulates type IV collagen gene transcription by increasing the quantity of free Sp1 available to transactivate the collagen IV pro-
moter via a mechanism dependent on activation of protein kinase CK2.28 Estradiol reverses TGF-b-stimulated type IV collagen gene transcription by preventing TGFb-induced activation of CK2.28 Estrogen also reverses TGF-b-induced mesangial cell apoptosis by preventing TGF-b-induced upregulation of CK2 activity and p53 phosphorylation.29 In transfected human embryonic kidney cells exposed to estrogen, a complex forms among estrogen receptor a, Smad2/Smad3, and the ubiquitin ligase Smurf.30 This action increases ubiquitization and degradation of these Smad proteins and explains the finding that estrogen decreases the expression of total and phosphorylated Smad2/3 in kidneys from ovariectomized diabetic rats.30,31 Estradiol also suppresses mesangial cell type I collagen gene transcription and protein synthesis via a mitogen-activated protein kinase/AP 1-mediated mechanism, stimulates mesangial cell metalloproteinase 2 activity via a mitogen-activated/AP 2-mediated mechanism, and stimulates metalloproteinase 9 activity.1,32,33 These actions shift the balance of matrix metabolism away from matrix accumulation and glomerulosclerosis. Alb/TGF- b mice overexpress TGF-b and develop proteinuria and progressive kidney injury. Estradiol, by preventing CK2 activation, reverses the injurious effects of TGF-b and ameliorates kidney injury in this model.34 Nitric Oxide Nitric oxide (NO) contributes to the development and progression of kidney injury in numerous experimental models. In cultured glomerular and vascular endothelial cells, physiological concentrations of estrogen cause a rapid release of NO via estrogen receptor a.35 The promoter region of the endothelial nitric oxide synthase (eNOS) gene contains an estrogen responsive element, which may mediate estrogen-induced upregulation of eNOS mRNA and protein levels.35 Estrogen also causes release of intracellular calcium and increases local synthesis of prostaglandin E2 and prostacyclin, which in turn upregulates eNOS activity.35 Female rats express higher levels of eNOS than males, an effect that is reversed by ovariectomy.35 Although chronic NO inhibition in rats induces systolic hypertension in both sexes, only male rats develop proteinuria, which is prevented by orchiectomy.35 Aging male rats are more dependent on NO than aging females, which may contribute to greater age-dependent kidney damage in males.35 Renin-Angiotensin System Sex hormones have profound effects on the reninangiotensin system (RAS) at multiple levels. Estrogen downregulates the expression of renin, ACE, and angiotensin II (AII), but it upregulates the expression of angiotensinogen.36 The tissue response to AII may also be downregulated in women. Estrogen increases
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angiotensin type 2 (AT-2) receptor density in the renal medulla and decreases angiotensin type 1 (AT-1) receptor density in the kidney and in vascular smooth muscle.36 Downregulation of AT-1 receptor density antagonizes sodium retention and vasoconstriction.36 Enhanced AT-2 receptor expression stimulates bradykinin synthesis, which in turn stimulates NO release and upregulates prostaglandin E2 expression.36 In contrast, testosterone activates the RAS.36 Kidney angiotensinogen mRNA levels are higher in adult male rats compared with females, an effect that is reversed by orchiectomy and restored by testosterone administration.36 Prorenin and renin levels and plasma renin activity are higher in men than in women.36 In cultured mesangial cells, dihydrotestosterone upregulates the expression of AT-1 receptors.36 Consistent with sex hormone-related alterations in receptor density and modulation of counter-regulatory vasoactive hormones, the effect of infused AII on kidney hemodynamics also differs between the sexes.37 It is clear that interactions between sex hormones and the RAS may contribute to gender dimorphism in kidney disease progression. Endothelin Endothelin is a potent vasoconstrictor that enhances kidney sodium reabsorption, promotes oxidative stress, and contributes to increased blood pressure.38 Estradiol inhibits not only the synthesis of endothelin but also inhibits its vasoconstrictor and inflammatory effects.38 Men have higher endothelin-1 levels than women, and levels decline in estrogen-treated men. In women, levels increase after menopause. Because AII stimulates endothelin synthesis, the ability of estrogen to decrease AII levels may contribute to a reduction in endothelin levels.37,38 Kidney Hemodynamics In humans, GFR in men and women is similar when corrected for body surface area.1 In addition, neither testosterone nor estrogen has direct effects on GFR or kidney blood flow.1 Despite these data, there is evidence to suggest that glomerular hemodynamic responses to vasoactive agents may differ in men vs women.37,39,40 Men respond to an infusion of AII by maintaining their GFR at the expense of an increased filtration fraction, suggesting an increased glomerular capillary pressure.37 In contrast, women showed a decrease in GFR and effective renal plasma flow without change in filtration fraction, suggesting no increase in glomerular capillary pressure. This gender dimorphism may contribute to renoprotection in females by blunting elevations in glomerular capillary pressure in the face of kidney injury, resulting in reduced glomerular hemodynamic stress. During clamped hyperglycemia in normoalbuminuric, normotensive adolescents with type I diabetes mellitus,
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males did not exhibit any change in kidney hemodynamics whereas females showed a decrease in effective renal plasma flow and increases in kidney vascular resistance and filtration fraction, suggesting an increase in glomerular capillary pressure.39 It was suggested that these gender-related differences may explain the lack of a consistent protective effect of female gender on the course of nephropathy in type I diabetes. Reactive Oxygen Species Enhanced generation of reactive oxygen species (ROS) has been shown to contribute to kidney injury in experimental models of kidney disease. In numerous animal models of kidney injury, estrogen blunts upregulation of nicotinamide adenosine dinucleotide phosphate oxidase activity, which in turn suppresses the generation of superoxide anion, the major ROS produced by the kidney.41 In contrast, testosterone increases oxidative stress either directly or indirectly. Testosterone inhibits various antioxidant enzymes and amplifies the generation of ROS in response to kidney insults. Reversal of kidney injury by estrogen and exaggeration of injury by testosterone in experimental models of hypertension is mediated by the ability of sex hormones to modulate ROS generation.41 Apoptosis In vitro, testosterone induces apoptosis in podocytes via an androgen-receptor-dependent mechanism independent of TGF-b signaling.42 Testosterone also promotes apoptosis in human proximal tubular cells by stimulating the c-Jun amino terminal kinase signal transduction pathway, which in turn activates a Fas/Fas ligand-dependent apoptotic pathway in association with increased expression of Bax and caspase 3, reduced Bcl2 expression, and poly(ADP-ribose)polymerase (PARP)-1 cleavage.43 In vitro, estrogen protects podocytes from apoptosis induced by testosterone, TGF-b, tumor necrosis factora, and puromycin aminonucloside.42 This protective effect may be mediated by activation of the phosphoinisotide 3-kinase/protein kinase B (PI3K/AKT) signal transduction cascade, by reduced generation of ROS, or by reduced activation of the extracellular signalregulated kinase (ERK) signaling cascade. Estrogen also antagonizes TGF-b-induced mesangial cell apoptosis by inhibiting activation of CK2, which in turn inhibits phosphorylation of p53.29
Environmental Factors Excessive caloric intake or high dietary intake of protein, phosphorus, or sodium promotes the development and progression of kidney disease in numerous experimental models, whereas dietary restriction slows progression. Protein loading increases GFR and glomerular transcapillary hydraulic pressure difference, which, if sustained,
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will ultimately be detrimental to the kidney. Men generally consume more calories and protein than women. Consistent with these observations, in the Modification of Diet in Renal Disease Study, women showed a lesser benefit from dietary protein restriction than did men. It is not known whether greater occupational exposure to industrial nephrotoxins such as lead and hydrocarbons contributes to the excess risk of ESRD in men. The resistance of female rats to the development of nephropathy after chronic inhalation of petroleum products suggests the possibility of gender-related differences in susceptibility to these agents. Although smoking is been shown to interact with estrogen deficiency to promote kidney injury in an experimental model, this observation has not been confirmed in humans.
Hypertension The overall prevalence of hypertension and the incidence of uncontrolled hypertension are higher among men than women.35 There is no difference in systemic blood pressure between prepubescent boys and girls, and it is only after puberty that boys exhibit higher blood pressure than girls.35 Blood pressure increases with age in men and women, but the rate of rise in blood pressure is steeper in women beginning in their 60s such that after the 7th decade, women have higher systolic blood pressures and pulse pressures than men.35 Progression of cardiovascular and kidney disease related to hypertension may also be more rapid in men.
Selective Estrogen Receptor Modulators Selective estrogen receptor modulators are agents that mimic many of the beneficial effects of estrogen on bone and vascular tissue without reproducing estrogens deleterious effects on reproductive tissue. Selective estrogen receptor modulators inhibit mesangial cell matrix synthesis and ameliorate kidney injury in numerous experimental models of kidney disease. A recent post hoc analysis of the Multiple Outcomes of Raloxifene Evaluation study, a multicenter, randomized, double-blind trial of Raloxifene vs placebo on the risk of fractures in postmenopausal women, found that women in the group that received Raloxifene had a slower yearly rate of increase in creatinine and a significantly slower yearly rate of decline in eGFR over 3 years of follow-up.44
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33. Guccione M, Silbiger S, Lei J, Neugarten J. Estradiol upregulates mesangial cell MMP-2 activity via the transcription factor AP-2. Am J Physiol. 2002;282(1):F164-F169. 34. Blush J, Lei J, Ju W, Silbiger S, Pullman J, Neugarten J. Estradiol reverses renal injury in Alb/TGF-b1 transgenic mice. Kidney Int. 2004;66(6):2148-2154. 35. Neugarten J, Silbiger SR, Golestaneh L. Gender and kidney disease. In: Brenner BM, ed. Brenner and Rector’s The Kidney. 9th ed. Amsterdam, The Netherlands: Elsevier; 2008:674-680. 36. Kang AK, Miller JA. Effects of gender on the renin-angiotensin system, blood pressure, and renal function. Curr Hypertens Rep. 2002;4(2):143-151. 37. Miller JA, Abacta LA, Cattran DC. Impact of gender on renal response to angiotensin II. Kidney Int. 1999;55(1):278-285. 38. Tostes RC, Rortes ZB, Callera GE, et al. Endothelin, sex and hypertension. Clin Sci (Lond). 2008;114(2):85-97. 39. Cherney DZI, Sochett EB, Miller JA. Gender differences in renal response to hyperglycemia and angiotensin-converting enzyme inhibition in diabetes. Kidney Int. 2005;68(4):1722-1728. 40. Cherney DZI, Scholey JW, Nasrallah R, et al. Renal hemodynamic effect of cyclooxygenase 2 inhibition in young men and women with uncomplicated type1 diabetes mellitus. Am J Physiol. 2008; 294(6):F1336-F1341. 41. Neugarten J. Estrogen and oxidative stress. Gend Med. 2007;4(1): 31-32. 42. Doublier S, Lupia E, Catanuto P, et al. Testosterone and 17 betaestradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice. Kidney Int. 2011;79(4):404-413. 43. Verzola D, Villagio B, Procopio V, et al. Androgen-mediated apoptosis of kidney tubule cells: role of c-Jun amino terminal kinase. Biochem Biophys Res Commun. 2009;387(3):531-536. 44. Melamed ML, Blackwell T, Neugarten J, et al. Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post-hoc analysis. Kidney Int. 2011;79(2):241-249.