Advertisement

Sex and Gender Related Differences in Diabetic Kidney Disease

  • Vikas S. Sridhar
    Affiliations
    Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada

    Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta
    Search for articles by this author
  • Kevin Yau
    Affiliations
    Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada

    Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta

    Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta
    Search for articles by this author
  • Jamie L. Benham
    Affiliations
    Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta

    Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta
    Search for articles by this author
  • David J.T. Campbell
    Correspondence
    Address reprint requests to David Z.I. Cherney, MD, Division of Nephrology, Department of Medicine, University Health Network, 585 University Ave, 8N-845, Toronto, Ontario, M5G 2N2 Canada.
    Affiliations
    Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta

    Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta
    Search for articles by this author
  • David Z.I. Cherney
    Affiliations
    Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada

    Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta

    Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta
    Search for articles by this author

      Summary

      Diversity in sex and gender are important considerations in the pathogenesis, prognostication, research, and management of diabetic kidney disease (DKD). Sex and gender differences in the disease risk, disease-specific mechanisms, and outcomes in DKD may be attributed to biological differences between males and females at the cellular and tissue level, inconsistencies in the diagnostic and assessment tools used in chronic kidney disease and DKD, as well societal differences in the way men, women, and gender-diverse individuals self-manage and interact with health care systems. This review outlines key considerations related to the impact of sex on DKD, specifically elaborating on how they contribute to observed differences in disease epidemiology, pathogenesis, and treatment strategies. We also highlight the effect of gender on DKD progression and care.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Seminars in Nephrology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • World Health Organization
        Gender: definitions.
        2002
        • de Boer IH
        • Caramori ML
        • Chan JCN
        • et al.
        Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.
        Kidney Int. 2020; 98: 839-848https://doi.org/10.1016/j.kint.2020.06.024
        • Hyde JS
        • Bigler RS
        • Joel D
        • Tate CC
        • van Anders SM
        The future of sex and gender in psychology: five challenges to the gender binary.
        Am Psychol. 2019; 74: 171-193https://doi.org/10.1037/amp0000307
        • Piani F
        • Melena I
        • Tommerdahl KL
        • et al.
        Sex-related differences in diabetic kidney disease: a review on the mechanisms and potential therapeutic implications.
        J Diabetes Complications. 2021; 35107841https://doi.org/10.1016/j.jdiacomp.2020.107841
        • Mazure CM
        • Jones DP.
        Twenty years and still counting: including women as participants and studying sex and gender in biomedical research.
        BMC Womens Health. 2015; 15: 94https://doi.org/10.1186/s12905-015-0251-9
        • Laprise C
        • Cole K
        • Sridhar VS
        • et al.
        Sex and gender considerations in transplant research: a scoping review.
        Transplantation. Sep 2019; 103: e239-e247https://doi.org/10.1097/TP.0000000000002828
      1. Reutens AT. Epidemiology of diabetic kidney disease. 2022. (1557-9859 Electronic)

        • Li H
        • Lu W
        • Wang A
        • Jiang H
        • Lyu J.
        Changing epidemiology of chronic kidney disease as a result of type 2 diabetes mellitus from 1990 to 2017: estimates from Global Burden of Disease 2017.
        J Diabetes Investig. 2021; 12: 346-356https://doi.org/10.1111/jdi.13355
        • Piani F
        • Melena I
        • Tommerdahl KL
        • et al.
        Sex-related differences in diabetic kidney disease: a review on the mechanisms and potential therapeutic implications.
        J Diabetes Complications. 2021; 35107841https://doi.org/10.1016/j.jdiacomp.2020.107841
      2. Neugarten J, Acharya A, Silbiger SR. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. (1046-6673 print). 2022

        • Cobo G
        • Hecking M
        • Port Friedrich K
        • et al.
        Sex and gender differences in chronic kidney disease: progression to end-stage renal disease and haemodialysis.
        Clin Sci. 2016; 130: 1147-1163https://doi.org/10.1042/CS20160047
        • Neugarten J
        • Golestaneh L
        • Kolhe NV.
        Sex differences in acute kidney injury requiring dialysis.
        BMC Nephrol. 2018; 19: 131-131https://doi.org/10.1186/s12882-018-0937-y
        • 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: 2047-2053https://doi.org/10.1093/ndt/gfg317
        • Ahmed SB.
        Menopause and chronic kidney disease.
        Semin Nephrol. 2017; 37: 404-411https://doi.org/10.1016/j.semnephrol.2017.05.013
      3. De Cosmo S, Viazzi F, Pacilli A, et al. Predictors of chronic kidney disease in type 2 diabetes: a longitudinal study from the AMD Annals initiative. (1536-5964 (Electronic)). 2022

      4. Harjutsalo V, Maric C, Forsblom C, et al. Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes. (1432-0428 (Electronic)). 2022

      5. Möllsten A, Svensson M, Waernbaum I, et al. Cumulative risk, age at onset, and sex-specific differences for developing end-stage renal disease in young patients with type 1 diabetes: a nationwide population-based cohort study. (1939-327X (Electronic)). 2022

        • Schultz CJ
        • Konopelska-Bahu T
        • Dalton RN
        • et al.
        Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study.
        Oxford Regional Prospective Study Group. (0149-5992 (Print)), 2022
        • Bjornstad P
        • Cherney DZ.
        Renal hyperfiltration in adolescents with type 2 diabetes: physiology, sex differences, and implications for diabetic kidney disease.
        Curr Diabetes Rep. 2018; 18: 22https://doi.org/10.1007/s11892-018-0996-2
        • Bjornstad P
        • Cherney DZ
        • Snell-Bergeon JK
        • et al.
        Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with type 1 diabetes.
        Nephrol Dial Transplant. 2015; 30: 1706-1711https://doi.org/10.1093/ndt/gfv121
        • Lovshin JA
        • Skrtic M
        • Bjornstad P
        • et al.
        Hyperfiltration, urinary albumin excretion, and ambulatory blood pressure in adolescents with type 1 diabetes mellitus.
        Am J Physiol Renal Physiol. 2018; 314: F667-F674https://doi.org/10.1152/ajprenal.00400.2017
        • Ebert N
        • Shlipak MG.
        Cystatin C is ready for clinical use.
        Curr Opin Nephrol Hypertens. 2020; 29: 591-598
        • Inker LA
        • Eneanya ND
        • Coresh J
        • et al.
        New creatinine- and cystatin C–based equations to estimate GFR without race.
        N Engl J Med. 2021; 385: 1737-1749https://doi.org/10.1056/NEJMoa2102953
        • Delgado C
        • Baweja M
        • Crews DC
        • et al.
        A unifying approach for GFR estimation: recommendations of the NKF-ASN Task Force on reassessing the inclusion of race in diagnosing kidney disease.
        Am J Kidney Dis. 2022; 79: 268-288https://doi.org/10.1053/j.ajkd.2021.08.003
        • Huebschmann AG
        • Huxley RR
        • Kohrt WM
        • Zeitler P
        • Regensteiner JG
        • Reusch JEB.
        Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course.
        Diabetologia. 2019; 62: 1761-1772https://doi.org/10.1007/s00125-019-4939-5
      6. Cherney DZ, Montanari A. Gender, clamped hyperglycemia and arterial stiffness in patients with uncomplicated type 1 diabetes mellitus. (1525-6006 (Electronic)). 2022

        • Har R
        • Lai V
        • Cherney D.
        The effect of sex on endothelial function responses to clamped hyperglycemia in type 1 diabetes.
        Hypertens Res. 2014; 37: 220-224https://doi.org/10.1038/hr.2013.136
        • Russo G
        • Pintaudi B
        • Giorda C
        • et al.
        Age- and gender-related differences in LDL-cholesterol management in outpatients with type 2 diabetes mellitus.
        Int J Endocrinol. 2015; 2015957105https://doi.org/10.1155/2015/957105
        • Ferrara A
        • Mangione CM
        • Kim C
        • et al.
        Sex disparities in control and treatment of modifiable cardiovascular disease risk factors among patients with diabetes.
        Diabetes Care. 2008; 31: 69https://doi.org/10.2337/dc07-1244
        • Plows JF
        • Stanley JL
        • Baker PN
        • Reynolds CM
        • Vickers MH.
        The pathophysiology of gestational diabetes mellitus.
        Int J Mol Sci. 2018; 19: 3342https://doi.org/10.3390/ijms19113342
        • McIntyre HD
        • Catalano P
        • Zhang C
        • Desoye G
        • Mathiesen ER
        • Damm P.
        Gestational diabetes mellitus.
        Nat Rev Dis Primers. 2019; 5: 47https://doi.org/10.1038/s41572-019-0098-8
        • Bomback AS
        • Rekhtman Y
        • Whaley-Connell AT
        • et al.
        Gestational diabetes mellitus alone in the absence of subsequent diabetes is associated with microalbuminuria.
        Diabetes Care. 2010; 33: 2586https://doi.org/10.2337/dc10-1095
        • Shah BR
        • Feig DS
        • Herer E
        • et al.
        Increased risk for microvascular complications among women with gestational diabetes in the third trimester.
        Diabetes Res Clin Pract. 2021; 180109068https://doi.org/10.1016/j.diabres.2021.109068
        • Beharier O
        • Shoham-Vardi I
        • Pariente G
        • et al.
        Gestational diabetes mellitus is a significant risk factor for long-term maternal renal disease.
        J Clin Endocrinol Metab. 2015; 100: 1412-1416https://doi.org/10.1210/jc.2014-4474
        • Landon MB
        • Spong CY
        • Thom E
        • et al.
        A multicenter, randomized trial of treatment for mild gestational diabetes.
        N Engl J Med. 2009; 361: 1339-1348https://doi.org/10.1056/nejmoa0902430
        • Khalil R
        • Kim NR
        • Jardi F
        • et al .
        Sex steroids and the kidney: role in renal calcium and phosphate handling.
        Mol Cell Endocrinol. 2018; 465: 61-72https://doi.org/10.1016/j.mce.2017.11.011
        • Yanes LL
        • Sartori-Valinotti JC
        • Reckelhoff JF.
        Sex steroids and renal disease: lessons from animal studies.
        Hypertension. 2008; 51: 976-981https://doi.org/10.1161/hypertensionaha.107.105767
        • Irsik DL
        • Romero-Aleshire MJ
        • Chavez EM
        • et al.
        Renoprotective impact of estrogen receptor-alpha and its splice variants in female mice with type 1 diabetes.
        Am J Physiol Renal Physiol. 2018; 315: F512-F520https://doi.org/10.1152/ajprenal.00231.2017
        • Dixon A
        • Maric C.
        17beta-Estradiol attenuates diabetic kidney disease by regulating extracellular matrix and transforming growth factor-beta protein expression and signaling.
        Am J Physiol Renal Physiol. 2007; 293: F1678-F1690https://doi.org/10.1152/ajprenal.00079.2007
        • Catanuto P
        • Doublier S
        • Lupia E
        • et al.
        17 beta-estradiol and tamoxifen upregulate estrogen receptor beta expression and control podocyte signaling pathways in a model of type 2 diabetes.
        Kidney Int. 2009; 75: 1194-1201https://doi.org/10.1038/ki.2009.69
        • Wells CC
        • Riazi S
        • Mankhey RW
        • Bhatti F
        • Ecelbarger C
        • Maric C.
        Diabetic nephropathy is associated with decreasedcirculating estradiol levels and imbalance in the expression of renal estrogen receptors.
        Gend Med. 2005; 2: 227-237https://doi.org/10.1016/s1550-8579(05)80052-x
        • Szekacs B
        • Vajo Z
        • Varbiro S
        • et al.
        Postmenopausal hormone replacement improves proteinuria and impaired creatinine clearance in type 2 diabetes mellitus and hypertension.
        BJOG. 2000; 107: 1017-1021https://doi.org/10.1111/j.1471-0528.2000.tb10406.x
        • Agarwal M
        • Selvan V
        • Freedman BI
        • Liu Y
        • Wagenknecht LE.
        The relationship between albuminuria and hormone therapy in postmenopausal women.
        Am J Kidney Dis. 2005; 45: 1019-1025https://doi.org/10.1053/j.ajkd.2005.02.025
        • Hadjadj S
        • Gourdy P
        • Zaoui P
        • et al.
        Effect of raloxifene – a selective oestrogen receptor modulator – on kidney function in post-menopausal women with type 2 diabetes: results from a randomized, placebo-controlled pilot trial.
        Diabet Med. 2007; 24: 906-910https://doi.org/10.1111/j.1464-5491.2007.02165.x
        • Quinkler M
        • Meyer B
        • Bumke-Vogt C
        • et al.
        Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor.
        Eur J Endocrinol. 2002; 146: 789-799https://doi.org/10.1530/eje.0.1460789
        • Maric C
        • Forsblom C
        • Thorn L
        • Waden J
        • Groop PH
        FinnDiane Study Group. Association between testosterone, estradiol and sex hormone binding globulin levels in men with type 1 diabetes with nephropathy.
        Steroids. 2010; 75: 772-778https://doi.org/10.1016/j.steroids.2010.01.011
        • Nishad R
        • Mukhi D
        • Tahaseen SV
        • Mungamuri SK
        • Pasupulati AK.
        Growth hormone induces Notch1 signaling in podocytes and contributes to proteinuria in diabetic nephropathy.
        J Biol Chem. 2019; 294: 16109-16122https://doi.org/10.1074/jbc.RA119.008966
        • Birzniece V
        • McLean M
        • Reddy N
        • Ho KKY.
        Disparate effect of aromatization on the central regulation of GH secretion by estrogens in men and postmenopausal women.
        J Clin Endocrinol Metab. 2019; 104: 2978-2984https://doi.org/10.1210/jc.2019-00265
        • Salonia A
        • Lanzi R
        • Scavini M
        • et al.
        Sexual function and endocrine profile in fertile women with type 1 diabetes.
        Diabetes Care. 2006; 29: 312-316https://doi.org/10.2337/diacare.29.02.06.dc05-1067
        • Reckelhoff JF
        • Maric C.
        Sex and gender differences in cardiovascular-renal physiology and pathophysiology.
        Steroids. 2010; 75: 745-746https://doi.org/10.1016/j.steroids.2010.05.020
        • Geer EB
        • Shen W.
        Gender differences in insulin resistance, body composition, and energy balance.
        Gend Med. 2009; 6: 60-75https://doi.org/10.1016/j.genm.2009.02.002
        • Millstein RJ
        • Pyle LL
        • Bergman BC
        • et al.
        Sex-specific differences in insulin resistance in type 1 diabetes: the CACTI cohort.
        J Diabetes Complications. 2018; 32: 418-423https://doi.org/10.1016/j.jdiacomp.2018.01.002
        • Yeung EH
        • Zhang C
        • Mumford SL
        • et al.
        Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: the BioCycle Study.
        J Clin Endocrinol Metab. 2010; 95: 5435-5442https://doi.org/10.1210/jc.2010-0702
        • Bruns CM
        • Kemnitz JW.
        Sex hormones, insulin sensitivity, and diabetes mellitus.
        ILAR J. 2004; 45: 160-169https://doi.org/10.1093/ilar.45.2.160
        • Hesp AC
        • Schaub JA
        • Prasad PV
        • et al.
        The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?.
        Kidney Int. 2020; 98: 579-589https://doi.org/10.1016/j.kint.2020.02.041
        • Bjornstad P
        • Maahs DM
        • Cherney DZ
        • et al.
        Insulin sensitivity is an important determinant of renal health in adolescents with type 2 diabetes.
        Diabetes Care. 2014; 37: 3033-3039https://doi.org/10.2337/dc14-1331
        • White MC
        • Fleeman R
        • Arnold AC.
        Sex differences in the metabolic effects of the renin-angiotensin system.
        Biol Sex Differ. 2019; 10: 31https://doi.org/10.1186/s13293-019-0247-5
        • Miller JA
        • Cherney DZ
        • Duncan JA
        • et al.
        Gender differences in the renal response to renin-angiotensin system blockade.
        J Am Soc Nephrol. 2006; 17: 2554-2560https://doi.org/10.1681/asn.2005101095
        • Komukai K
        • Mochizuki S
        • Yoshimura M.
        Gender and the renin-angiotensin-aldosterone system.
        Fundam Clin Pharmacol. 2010; 24: 687-698https://doi.org/10.1111/j.1472-8206.2010.00854.x
        • Agrawal M
        • Spencer HJ
        • Faas FH.
        Method of LDL cholesterol measurement influences classification of LDL cholesterol treatment goals.
        J Investig Med. 2015; 58: 945-949https://doi.org/10.2310/JIM.0b013e3181fb7ca7
        • Liu H
        • Sridhar VS
        • Boulet J
        • et al.
        Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.
        Metabolism. 2021; 126154918https://doi.org/10.1016/j.metabol.2021.154918
        • Kafami M
        • Hosseini M
        • Niazmand S
        • Farrokhi E
        • Hajzadeh MA
        • Nazemi S.
        The effects of estradiol and testosterone on renal tissues oxidative after central injection of angiotensin II in female doca - salt treated rats.
        Horm Mol Biol Clin Investig. 2018; 37https://doi.org/10.1515/hmbci-2018-0044
        • Tonneijck L
        • Muskiet MH
        • Smits MM
        • et al.
        Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment.
        J Am Soc Nephrol. 2017; 28: 1023-1039https://doi.org/10.1681/ASN.2016060666
        • Bjornstad P
        • Nehus E
        • El Ghormli L
        • et al.
        Insulin sensitivity and diabetic kidney disease in children and adolescents with type 2 diabetes: an observational analysis of data from the TODAY clinical trial.
        Am J Kidney Dis. 2018; 71: 65-74https://doi.org/10.1053/j.ajkd.2017.07.015
        • Cherney DZ
        • Sochett EB
        • Miller JA.
        Gender differences in renal responses to hyperglycemia and angiotensin-converting enzyme inhibition in diabetes.
        Kidney Int. 2005; 68: 1722-1728https://doi.org/10.1111/j.1523-1755.2005.00588.x
        • Skrtic M
        • Lytvyn Y
        • Bjornstad P
        • et al.
        Influence of sex on hyperfiltration in patients with uncomplicated type 1 diabetes.
        Am J Physiol Renal Physiol. 2017; 312: F599-F606https://doi.org/10.1152/ajprenal.00357.2016
        • Slyvka Y
        • Malgor R
        • Inman SR
        • Ding J
        • Heh V
        • Nowak FV.
        Antioxidant diet and sex interact to regulate NOS isoform expression and glomerular mesangium proliferation in Zucker diabetic rat kidney.
        Acta Histochem. 2016; 118: 183-193https://doi.org/10.1016/j.acthis.2015.12.011
        • Cherney DZ
        • Scholey JW
        • Sochett EB.
        Sex differences in renal responses to hyperglycemia, L-arginine, and L-NMMA in humans with uncomplicated type 1 diabetes.
        Diabetes Care. 2013; 36: 1290-1296https://doi.org/10.2337/dc12-1305
        • Nair AV
        • Yanhong W
        • Paunescu TG
        • Bouley R
        • Brown D.
        Sex-dependent differences in water homeostasis in wild-type and V-ATPase B1-subunit deficient mice.
        PLoS One. 2019; 14e0219940https://doi.org/10.1371/journal.pone.0219940
        • Veiras LC
        • Girardi ACC
        • Curry J
        • et al.
        Sexual dimorphic pattern of renal transporters and electrolyte homeostasis.
        J Am Soc Nephrol. 2017; 28: 3504-3517https://doi.org/10.1681/ASN.2017030295
        • Sabolic I
        • Vrhovac I
        • Eror DB
        • et al.
        Expression of Na+-D-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences.
        Am J Physiol Cell Physiol. 2012; 302: C1174-C1188https://doi.org/10.1152/ajpcell.00450.2011
        • de Gasparo M
        • Levens NR.
        Pharmacology of angiotensin II receptors in the kidney.
        Kidney Int. 1994; 46: 1486-1491https://doi.org/10.1038/ki.1994.426
        • Gohar EY
        • Pollock DM.
        Sex-specific contributions of endothelin to hypertension.
        Curr Hypertens Rep. 2018; 20: 58https://doi.org/10.1007/s11906-018-0856-0
        • Matsumoto T
        • Kakami M
        • Kobayashi T
        • Kamata K.
        Gender differences in vascular reactivity to endothelin-1 (1-31) in mesenteric arteries from diabetic mice.
        Peptides. 2008; 29: 1338-1346https://doi.org/10.1016/j.peptides.2008.04.001
        • Achari AE
        • Jain SK.
        Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction.
        Int J Mol Sci. 2017; 18: 1321https://doi.org/10.3390/ijms18061321
        • Looker HC
        • Krakoff J
        • Funahashi T
        • et al.
        Adiponectin concentrations are influenced by renal function and diabetes duration in Pima Indians with type 2 diabetes.
        J Clin Endocrinol Metab. 2004; 89: 4010-4017https://doi.org/10.1210/jc.2003-031916
        • Lindsay RS
        • Funahashi T
        • Hanson RL
        • et al.
        Adiponectin and development of type 2 diabetes in the Pima Indian population.
        Lancet. 2002; 360: 57-58https://doi.org/10.1016/s0140-6736(02)09335-2
        • Laughlin GA
        • Barrett-Connor E
        • May S
        Sex-specific determinants of serum adiponectin in older adults: the role of endogenous sex hormones.
        Int J Obes (Lond). 2007; 31: 457-465https://doi.org/10.1038/sj.ijo.0803427
        • Kim Y
        • Park CW.
        Mechanisms of adiponectin action: implication of adiponectin receptor agonism in diabetic kidney disease.
        Int J Mol Sci. 2019; 20: 1782https://doi.org/10.3390/ijms20071782
        • O'Donoghue ML
        • Kato ET
        • Mosenzon O
        • et al.
        The efficacy and safety of dapagliflozin in women and men with type 2 diabetes mellitus.
        Diabetologia. 2021; 64: 1226-1234https://doi.org/10.1007/s00125-021-05399-2
        • Rådholm K
        • Zhou Z
        • Clemens K
        • Neal B
        • Woodward M.
        Effects of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes in women versus men.
        Diabetes Obes Metab. 2020; 22: 263-266https://doi.org/10.1111/dom.13876
        • Segerer H,
        • Wurm M
        • Grimsmann JM
        • et al.
        Diabetic ketoacidosis at manifestation of type 1 diabetes in childhood and adolescence—incidence and risk factors.
        Dtsch Arztebl Int. 2022; 118: 367-372https://doi.org/10.3238/arztebl.m2021.0133
        • Hampp C
        • Swain RS
        • Horgan C
        • et al.
        Use of sodium–glucose cotransporter 2 inhibitors in patients with type 1 diabetes and rates of diabetic ketoacidosis.
        Diabetes Care. 2020; 43: 90https://doi.org/10.2337/dc19-1481
        • Lega IC
        • Bronskill SE
        • Campitelli MA
        • et al.
        Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: a population-based study of older women and men with diabetes.
        Diabetes Obes Metab. 2019; 21: 2394-2404https://doi.org/10.1111/dom.13820
        • Bihan H
        • Ng WL
        • Magliano DJ
        • Shaw JE.
        Predictors of efficacy of GLP-1 agonists and DPP-4 inhibitors: a systematic review.
        Diabetes Res Clin Pract. 2016; 121: 27-34https://doi.org/10.1016/j.diabres.2016.08.011
        • Singh AK
        • Singh R.
        Gender difference in cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in type 2 diabetes: a systematic review and meta-analysis of cardio-vascular outcome trials.
        Diabetes Metab Syndr. 2020; 14: 181-187https://doi.org/10.1016/j.dsx.2020.02.012
        • Lachaux M
        • Barrera-Chimal J
        • Nicol L
        • et al.
        Short- and long-term administration of the non-steroidal mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome-related cardio-renal dysfunction.
        Diabetes Obes Metab. 2018; 20: 2399-2407https://doi.org/10.1111/dom.13393
        • Pitt B
        • Filippatos G
        • Agarwal R
        • et al.
        Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
        N Engl J Med. 2021; 385: 2252-2263https://doi.org/10.1056/nejmoa2110956
        • Bakris GL
        • Agarwal R
        • Anker SD
        • et al.
        Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
        N Engl J Med. 2020; 383: 2219-2229https://doi.org/10.1056/NEJMoa2025845
        • Heerspink HJL
        • Parving H-H
        • Andress DL
        • et al.
        Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.
        Lancet. 2019; 393: 1937-1947https://doi.org/10.1016/s0140-6736(19)30772-x
        • de Vries ST
        • Denig P
        • Ekhart C
        • Mol PGM
        • van Puijenbroek EP.
        Sex differences in adverse drug reactions of metformin: a longitudinal survey study.
        Drug Safety. 2020; 43: 489-495https://doi.org/10.1007/s40264-020-00913-8
        • Neugarten J
        • Golestaneh L
        Gender and the prevalence and progression of renal disease.
        Adv Chronic Kidney Dis. 2013; 20: 390-395
      7. White MC, Fleeman R, Arnold AA-O. Sex differences in the metabolic effects of the renin-angiotensin system. Biol Sex Differ. 2019;10(1):31.

        • Szekacs B
        • Vajo Z,
        • Varbiro S
        • et al.
        Postmenopausal hormone replacement improves proteinuria and impaired creatinine clearance in type 2 diabetes mellitus and hypertension.
        BJOG. 2000; 107: 1017-1021
        • Agarwal M
        • Selvan V
        • Freedman BI
        • et al
        The relationship between albuminuria and hormone therapy in postmenopausal women.
        Am J Kidney Dis. 2005; 45: 1019-1025
        • Lopaschuk GD
        • Verma S.
        Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review.
        JACC Basic Transl Sci. 2020; 5: 632-644https://doi.org/10.1016/j.jacbts.2020.02.004
        • Vallon V
        • Thomson SC.
        The tubular hypothesis of nephron filtration and diabetic kidney disease.
        Nat Rev Nephrol. 2020; 16: 317-336https://doi.org/10.1038/s41581-020-0256-y
        • Neal B
        • Perkovic V
        • Mahaffey KW
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657https://doi.org/10.1056/nejmoa1611925
        • Perkovic V
        • Jardine MJ
        • Neal B
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
        N Engl J Med. 2019; 380: 2295-2306https://doi.org/10.1056/nejmoa1811744
        • Zinman B
        • Wanner C
        • Lachin JM
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128https://doi.org/10.1056/nejmoa1504720
        • Wiviott SD
        • Raz I
        • Bonaca MP
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2018; 380: 347-357https://doi.org/10.1056/nejmoa1812389
        • Hammersen J
        • Tittel SR
        • Warncke K
        • et al.
        Previous diabetic ketoacidosis as a risk factor for recurrence in a large prospective contemporary pediatric cohort: results from the DPV initiative.
        Pediatr Diabetes. 2021; 22: 455-462
        • Ehrmann D
        • Kulzer B
        • Roos T
        • Haak T
        • Al-Khatib M
        • Hermanns N.
        Risk factors and prevention strategies for diabetic ketoacidosis in people with established type 1 diabetes.
        Lancet Diabetes Endocrinol. 2020; 8: 436-446https://doi.org/10.1016/S2213-8587(20)30042-5
        • Eberly LA
        • Yang L
        • Eneanya ND
        • et al.
        Association of race/ethnicity, gender, and socioeconomic status with sodium-glucose cotransporter 2 inhibitor use among patients with diabetes in the US.
        JAMA Network Open. 2021; 4: e216139https://doi.org/10.1001/jamanetworkopen.2021.6139
        • Quinn A
        • Campbell D
        • Au F
        • et al.
        Describing the uptake and patterns of SGLT2 inhibitor use among adults with type 2 diabetes in Alberta, Canada.
        Can J Diabetes. 2021; 45https://doi.org/10.1016/j.jcjd.2021.09.049
        • Agarwal R
        • Joseph A
        • Anker S
        • et al.
        Hyperkalemia risk with finerenone: results from the FIDELIO-DKD trial.
        J Am Soc Nephrol. 2022; 33: 225-223https://doi.org/10.1681/ASN.2021070942
        • Mauvais-Jarvis F
        • Berthold HK
        • Campesi I
        • et al.
        Sex- and gender-based pharmacological response to drugs.
        Pharmacol Rev. 2021; 73: 730https://doi.org/10.1124/pharmrev.120.000206
        • Maric-Bilkan C
        • Manigrasso MB.
        Sex differences in hypertension: contribution of the renin–angiotensin system.
        Gender Med. 2012; 9: 287-291https://doi.org/10.1016/j.genm.2012.06.005
        • Sandberg K
        • Ji H.
        Sex and the renin angiotensin system: implications for gender differences in the progression of kidney disease.
        Adv Ren Replace Ther. 2003; 10: 15-23https://doi.org/10.1053/jarr.2003.50006
        • Keane WF
        • Brenner BM, de Zeeuw D
        • et al.
        The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study.
        Kidney Int. 2003; 63: 1499-1507
        • Ruggenenti P
        • Perna A
        • Zoccali C
        • et al.
        Chronic proteinuric nephropathies. II. Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in relation to the ACE gene polymorphism. Gruppo Italiano di Studi Epidemologici in Nefrologia (Gisen).
        J Am Soc Nephrol. 2000; 11: 88-96https://doi.org/10.1681/ASN.V11188
        • Möllsten A
        • Toppe C
        • Eeg-Olofsson K
        • Lind T.
        Sex differences in treatment with ACE inhibitors and angiotensin receptor blockers in patients with type 1 diabetes.
        Diabetes Care. 2019; 42: e73https://doi.org/10.2337/dc18-2542
        • Radcliffe NJ
        • Seah J-M
        • Clarke M
        • MacIsaac RJ
        • Jerums G
        • Ekinci EI.
        Clinical predictive factors in diabetic kidney disease progression.
        J Diabetes Investig. 2017; 8 (doi:org/): 6-18https://doi.org/10.1111/jdi.12533
        • Lou Y
        • Qin P
        • Wang C
        • et al.
        Sex-specific association of serum uric acid level and change in hyperuricemia status with risk of type 2 diabetes mellitus: a large cohort study in China.
        J Diabetes Res. 2020; 20209637365https://doi.org/10.1155/2020/9637365
        • Chang P-Y
        • Chang Y-W
        • Lin Y-F
        • Fan H-C.
        Sex-specific association of uric acid and kidney function decline in Taiwan.
        J Pers Med. 2021; 11: 415https://doi.org/10.3390/jpm11050415
        • Badve SV
        • Pascoe EM
        • Tiku A
        • et al.
        Effects of allopurinol on the progression of chronic kidney disease.
        N Engl J Med. 2020; 382: 2504-2513https://doi.org/10.1056/NEJMoa1915833
        • Doria A
        • Galecki AT
        • Spino C
        • et al.
        Serum urate lowering with allopurinol and kidney function in type 1 diabetes.
        N Engl J Med. 2020; 382: 2493-2503https://doi.org/10.1056/NEJMoa1916624
        • Karl M
        • Berho M,
        • Pignac-Kobinger J
        • et al .
        Differential effects of continuous and intermittent 17beta-estradiol replacement and tamoxifen therapy on the prevention of glomerulosclerosis: modulation of the mesangial cell phenotype in vivo.
        Am J Pathol. 2006; 169: 351-361
        • Ahmed SB
        • Hovind P,
        • Parving H-H
        • et al.
        Oral contraceptives, angiotensin-dependent renal vasoconstriction, and risk of diabetic nephropathy.
        Diabetes Care. 2005; 28: 1988-1994
        • Monster TB
        • Janssen WM, de Jong PE
        • de Jong-van den Berg LT
        Oral contraceptive use and hormone replacement therapy are associated with microalbuminuria.
        Arch Intern Med. 2001; 161: 2000-2005
        • Tate CC
        • Youssef CP
        • Bettergarcia JN.
        Integrating the study of transgender spectrum and cisgender experiences of self-categorization from a personality perspective.
        Rev Gen Psychol. 2014; 18: 302-312https://doi.org/10.1037/gpr0000019
        • Nielsen MW
        • Stefanick ML
        • Peragine D
        • et al.
        Gender-related variables for health research.
        Biol Sex Differ. 2021; 12: 23https://doi.org/10.1186/s13293-021-00366-3
        • Dunkler D
        • Kohl M
        • Heinze G
        • et al.
        Modifiable lifestyle and social factors affect chronic kidney disease in high-risk individuals with type 2 diabetes mellitus.
        Kidney Int. 2015; 87: 784-791https://doi.org/10.1038/ki.2014.370
        • Ninomiya H
        • Katakami N
        • Matsuoka TA
        • et al.
        Association between poor psychosocial conditions and diabetic nephropathy in Japanese type 2 diabetes patients: a cross-sectional study.
        J Diabetes Investig. 2018; 9: 162-172https://doi.org/10.1111/jdi.12641
        • Ninomiya H
        • Katakami N
        • Takahara M
        • Matsuoka TA
        • Shimomura I.
        Psychosocial conditions and the progression of diabetic nephropathy in Japanese with type 2 diabetes mellitus.
        Diabetol Int. 2021; 12: 336-341https://doi.org/10.1007/s13340-020-00479-x
        • Brinkhues S
        • Dukers-Muijrers N
        • Hoebe C
        • et al.
        Social network characteristics are associated with type 2 diabetes complications: the Maastricht study.
        Diabetes Care. 2018; 41: 1654-1662https://doi.org/10.2337/dc17-2144
        • Williams AF
        • Manias E
        • Walker R.
        The role of irrational thought in medicine adherence: people with diabetic kidney disease.
        J Adv Nurs. 2009; 65: 2108-2117https://doi.org/10.1111/j.1365-2648.2009.05077.x
        • Roberti J
        • Cummings A
        • Myall M
        • et al.
        Work of being an adult patient with chronic kidney disease: a systematic review of qualitative studies.
        BMJ Open. 2018; 8e023507https://doi.org/10.1136/bmjopen-2018-023507
        • King N
        • Carroll C
        • Newton P
        • Dornan T.
        You can't cure it so you have to endure it": the experience of adaptation to diabetic renal disease.
        Qual Health Res. 2002; 12: 329-346https://doi.org/10.1177/104973202129119928
        • Fernandez-Fernandez B
        • Mahillo I
        • Sanchez-Rodriguez J
        • et al.
        Gender, albuminuria and chronic kidney disease progression in treated diabetic kidney disease.
        J Clin Med. 2020; 9: 1611https://doi.org/10.3390/jcm9061611
        • Duan J
        • Wang C
        • Liu D
        • et al.
        Prevalence and risk factors of chronic kidney disease and diabetic kidney disease in Chinese rural residents: a cross-sectional survey.
        Sci Rep. 2019; 9: 10408https://doi.org/10.1038/s41598-019-46857-7
        • Williams AF
        • Manias E
        • Walker R.
        Adherence to multiple, prescribed medications in diabetic kidney disease: a qualitative study of consumers' and health professionals' perspectives.
        Int J Nurs Stud. 2008; 45: 1742-1756https://doi.org/10.1016/j.ijnurstu.2008.07.002
        • Stuckey HL
        • Mullan-Jensen CB
        • Reach G
        • et al.
        Personal accounts of the negative and adaptive psychosocial experiences of people with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2) study.
        Diabetes Care. 2014; 37: 2466-2474https://doi.org/10.2337/dc13-2536
        • Joensen LE
        • Willaing I
        • Holt RI
        • Wens J
        • Skovlund S
        • Peyrot M.
        Household composition and psychological health: results of the Second Diabetes Attitudes, Wishes and Needs (DAWN2) study.
        J Diabetes Complications. 2017; 31: 340-346https://doi.org/10.1016/j.jdiacomp.2016.07.006
        • Stopford R
        • Winkley K
        • Ismail K.
        Social support and glycemic control in type 2 diabetes: a systematic review of observational studies.
        Patient Educ Couns. 2013; 93: 549-558https://doi.org/10.1016/j.pec.2013.08.016
        • Spencer-Bonilla G
        • Ponce OJ
        • Rodriguez-Gutierrez R
        • et al.
        A systematic review and meta-analysis of trials of social network interventions in type 2 diabetes.
        BMJ Open. 2017; 7e016506https://doi.org/10.1136/bmjopen-2017-016506
        • Kaplan RM
        • Hartwell SL.
        Differential effects of social support and social network on physiological and social outcomes in men and women with type II diabetes mellitus.
        Health Psychol. 1987; 6: 387-398https://doi.org/10.1037//0278-6133.6.5.387
        • Park H
        • Kim MT.
        Impact of social role strain, depression, social support and age on diabetes self-efficacy in Korean women with type 2 diabetes.
        J Cardiovasc Nurs. 2012; 27: 76-83https://doi.org/10.1097/JCN.0b013e318214d9d9
        • Karamanidou C
        • Weinman J
        • Horne R.
        A qualitative study of treatment burden among haemodialysis recipients.
        J Health Psychol. 2014; 19: 556-569https://doi.org/10.1177/1359105313475898
        • Saffer H
        • Dave D
        • Grossman M
        • Leung LA.
        Racial, ethnic, and gender differences in physical activity.
        J Hum Cap. 2013; 7: 378-410https://doi.org/10.1086/671200
        • Barrett JE
        • Plotnikoff RC
        • Courneya KS
        • Raine KD.
        Physical activity and type 2 diabetes: exploring the role of gender and income.
        Diabetes Educ. 2007; 33: 128-143https://doi.org/10.1177/0145721706297453
        • Nelson KM
        • Reiber G
        • Boyko EJ.
        Diet and exercise among adults with type 2 diabetes: findings from the Third National Health and Nutrition Examination Survey (NHANES III).
        Diabetes Care. 2002; 25: 1722-1728
        • Schofield HL
        • Herrman HE
        • Bloch S
        • Howe A
        • Singh B.
        A profile of Australian family caregivers: diversity of roles and circumstances.
        Aust N Z J Public Health. 1997; 21: 59-66https://doi.org/10.1111/j.1467-842x.1997.tb01655.x
        • Miller B
        • McFall S
        • Montgomery A.
        The impact of elder health, caregiver involvement, and global stress on two dimensions of caregiver burden.
        J Gerontol. 1991; 46: S9-19https://doi.org/10.1093/geronj/46.1.s9
        • Sharma N
        • Chakrabarti S
        • Grover S.
        Gender differences in caregiving among family - caregivers of people with mental illnesses.
        World J Psychiatry. 2016; 6: 7-17https://doi.org/10.5498/wjp.v6.i1.7
        • Li J
        • Huang B
        • Wang S
        • et al.
        [Effect of diabetic management modes on diabetic nephropathy: a prospective study].
        Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2019; 31: 1497-1500https://doi.org/10.3760/cma.j.issn.2095-4352.2019.12.012
        • Leung WY
        • So WY
        • Tong PC
        • Chan NN
        • Chan JC.
        Effects of structured care by a pharmacist-diabetes specialist team in patients with type 2 diabetic nephropathy.
        Am J Med. 2005; 118: 1414https://doi.org/10.1016/j.amjmed.2005.07.050
        • Carrero JJ
        • Hecking M
        • Ulasi I
        • Sola L
        • Thomas B.
        Chronic kidney disease, gender, and access to care: a global perspective.
        Semin Nephrol. 2017; 37: 296-308https://doi.org/10.1016/j.semnephrol.2017.02.009
        • Kramer HU
        • Ruter G
        • Schottker B
        • et al.
        Gender differences in healthcare utilization of patients with diabetes.
        Am J Manag Care. 2012; 18: 362-369
        • Hazel-Fernandez L
        • Li Y
        • Nero D
        • et al.
        Racial/ethnic and gender differences in severity of diabetes-related complications, health care resource use, and costs in a Medicare population.
        Popul Health Manag. 2015; 18: 115-122https://doi.org/10.1089/pop.2014.0038
        • Shalev V
        • Chodick G
        • Heymann AD
        • Kokia E.
        Gender differences in healthcare utilization and medical indicators among patients with diabetes.
        Public Health. 2005; 119: 45-49https://doi.org/10.1016/j.puhe.2004.03.004
        • Schectman JM
        • Schorling JB
        • Voss JD.
        Appointment adherence and disparities in outcomes among patients with diabetes.
        J Gen Intern Med. 2008; 23: 1685-1687https://doi.org/10.1007/s11606-008-0747-1
        • Bird CE
        • Fremont AM
        • Bierman AS
        • et al.
        Does quality of care for cardiovascular disease and diabetes differ by gender for enrollees in managed care plans?.
        Womens Health Issues. 2007; 17: 131-138https://doi.org/10.1016/j.whi.2007.03.001
        • Piette JD
        • Bibbins-Domingo K
        • Schillinger D.
        Health care discrimination, processes of care, and diabetes patients' health status.
        Patient Educ Couns. 2006; 60: 41-48https://doi.org/10.1016/j.pec.2004.12.001
        • Lutfey KE
        • Campbell SM
        • Renfrew MR
        • Marceau LD
        • Roland M
        • McKinlay JB.
        How are patient characteristics relevant for physicians' clinical decision making in diabetes? An analysis of qualitative results from a cross-national factorial experiment.
        Soc Sci Med. 2008; 67: 1391-1399https://doi.org/10.1016/j.socscimed.2008.07.005
        • Ahmed SB
        • Saad N
        • Dumanski SM.
        Gender and CKD: beyond the binary.
        Clin J Am Soc Nephrol. 2020; 16: 141-143https://doi.org/10.2215/CJN.03030320