Advertisement

Sex, Gender, and Cardiovascular Disease in Chronic Kidney Disease

  • Tae Won Yi
    Affiliations
    The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia

    Clinician Investigator Program, University of British Columbia, Vancouver, Canada

    Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada
    Search for articles by this author
  • Adeera Levin
    Correspondence
    Address reprint requests to Adeera Levin, MD, BC Renal, Provincial Health Services Authority, 1081 Burrard St, Suite 601, Vancouver, British Columbia, V6Z1Y6 Canada.
    Affiliations
    Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada

    BC Renal, Provincial Health Services Authority, Vancouver, British Columbia, Canada
    Search for articles by this author

      Summary

      This review on sex, gender, and cardiovascular diseases in chronic kidney disease attempts to summarize what we know and what we do not know about the effects of sex and gender on cardiovascular disease in chronic kidney disease. We discuss and define the terminology of sex and gender, and the underlying physiology for differences observed. We explore how sex and gender affect specific cardiovascular diseases such as coronary artery disease, congestive heart failure, arrhythmias, cardiovascular mortality, and pre-eclampsia. We conclude with a review of recent randomized controlled trials and highlight the pharmacokinetic and pharmacodynamic differences in both sexes.

      Keywords

      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

      1. U.S. Renal Data System: USRDS annual report 2020. Accessed November 16, 2021. https://adr.usrds.org

        • Jankowski J
        • Floege J
        • Fliser D
        • Böhm M
        • Marx N.
        Cardiovascular disease in chronic kidney disease.
        Circulation. 2021; 143: 1157-1172
        • London GM.
        The clinical epidemiology of cardiovascular diseases in chronic kidney disease: cardiovascular disease in chronic renal failure: pathophysiologic aspects.
        Semin Dial. 2003; 16: 85-94
        • Levey AS
        • Beto JA
        • Coronado BE
        • et al.
        Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease.
        Am J Kidney Dis. 1998; 32: 853-906
        • Sarnak MJ.
        Cardiovascular complications in chronic kidney disease.
        Am J Kidney Dis. 2003; 41: 11-17
        • Perkovic V
        • Jardine MJ
        • Neal B
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
        N Engl J Med. 2019; 380: 2295-2306
        • Heerspink HJL
        • Stefánsson BV
        • Correa-Rotter R
        • et al.
        Dapagliflozin in patients with chronic kidney disease.
        N Engl J Med. 2020; 383: 1436-1446
        • 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: 2219-2229
      2. Health Canada. Health portfolio sex and gender-based analysis policy. 2017. Accessed February 11, 2022.https://www.canada.ca/en/health-canada/corporate/transparency/corporate-management-reporting/heath-portfolio-sex-gender-based-analysis-policy.html

        • Woodward M.
        Cardiovascular disease and the female disadvantage.
        Int J Environ Res Public Health. 2019; 16: E1165
        • Ahmed SB
        • Dumanski SM.
        Do sex and gender matter in kidney and cardiovascular disease?.
        Am J Kidney Dis. 2021; 78: 177-179
        • Pelletier R
        • Khan NA
        • Cox J
        • et al.
        Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young?.
        J Am Coll Cardiol. 2016; 67: 127-135
        • O'Neil A
        • Scovelle AJ
        • Milner AJ
        • Kavanagh A.
        Gender/sex as a social determinant of cardiovascular risk.
        Circulation. 2018; 137: 854-864
        • Carrero JJ
        • Hecking M
        • Chesnaye NC
        • Jager KJ.
        Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
        Nat Rev Nephrol. 2018; 14: 151-164
        • Seng JJB
        • Tan JY
        • Yeam CT
        • Htay H
        • Foo WYM.
        Factors affecting medication adherence among pre-dialysis chronic kidney disease patients: a systematic review and meta-analysis of literature.
        Int Urol Nephrol. 2020; 52: 903-916
        • Mosca L
        • Barrett-Connor E
        • Wenger NK.
        Sex/gender differences in cardiovascular disease prevention what a difference a decade makes.
        Circulation. 2011; 124: 2145-2154
        • Peters SAE
        • Muntner P
        • Woodward M.
        Sex differences in the prevalence of, and trends in, cardiovascular risk factors, treatment, and control in the United States, 2001 to 2016.
        Circulation. 2019; 139: 1025-1035
        • Birkeland KI
        • Bodegard J
        • Norhammar A
        • et al.
        How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study.
        Diabetes Obes Metab. 2019; 21: 968-974
        • Zhao M
        • Woodward M
        • Vaartjes I
        • et al.
        Sex differences in cardiovascular medication prescription in primary care: a systematic review and meta-analysis.
        J Am Heart Assoc. 2020; 9e014742
        • Shaw C
        • Nitsch D
        • Steenkamp R
        • et al.
        Inpatient coronary angiography and revascularisation following non-ST-elevation acute coronary syndrome in patients with renal impairment: a cohort study using the Myocardial Ischaemia National Audit Project.
        PLoS One. 2014; 9: e99925
        • Weiner DE
        • Tighiouart H
        • Elsayed EF
        • et al.
        The Framingham Predictive Instrument in chronic kidney disease.
        J Am Coll Cardiol. 2007; 50: 217-224
        • Barrett-Connor E.
        Sex differences in coronary heart disease.
        Circulation. 1997; 95: 252-264
        • El Khoudary SR
        • Aggarwal B
        • Beckie TM
        • et al.
        Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association.
        Circulation. 2020; 142: e506-e532
        • Ahmed SB
        • Ramesh S.
        Sex hormones in women with kidney disease.
        Nephrol Dial Transplant. 2016; 31: 1787-1795
        • Kattah AG
        • Smith CY
        • Rocca LG
        • Grossardt BR
        • Garovic VD
        • Rocca WA.
        CKD in patients with bilateral oophorectomy.
        Clin J Am Soc Nephrol. 2018; 13: 1649-1658
        • Gallagher PE
        • Li P
        • Lenhart JR
        • Chappell MC
        • Brosnihan KB.
        Estrogen regulation of angiotensin-converting enzyme mRNA.
        Hypertension. 1999; 33: 323-328
        • Dubey RK
        • Oparil S
        • Imthurn B
        • Jackson EK.
        Sex hormones and hypertension.
        Cardiovasc Res. 2002; 53: 688-708
        • Ramesh S
        • James MT
        • Holroyd-Leduc JM
        • et al.
        Estradiol and mortality in women with end-stage kidney disease.
        Nephrol Dial Transplant. 2020; 35: 1965-1972
        • Dousdampanis P
        • Trigka K
        • Fourtounas C
        • Bargman JM.
        Role of testosterone in the pathogenesis, progression, prognosis and comorbidity of men with chronic kidney disease.
        Ther Apher Dial. 2014; 18: 220-230
        • Carrero JJ
        • Qureshi AR
        • Parini P
        • et al.
        Low serum testosterone increases mortality risk among male dialysis patients.
        J Am Soc Nephrol. 2009; 20: 613-620
        • Sarnak MJ
        • Amann K
        • Bangalore S
        • et al.
        Chronic kidney disease and coronary artery disease.
        J Am Coll Cardiol. 2019; 74: 1823-1838
        • Go AS
        • Chertow GM
        • Fan D
        • McCulloch CE
        • Hsu C.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N Engl J Med. 2004; 351: 1296-1305
      3. Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis in prolonged maintenance hemodialysis. 2010. Accessed November 21, 2021. https://www.nejm.org/doi/10.1056/NEJM197403282901301

        • Sarnak MJ
        • Amann K
        • Bangalore S
        • et al.
        Chronic kidney disease and coronary artery disease: JACC state-of-the-art review.
        J Am Coll Cardiol. 2019; 74: 1823-1838
        • Tamis-Holland JE
        • Jneid H
        • Reynolds HR
        • et al.
        Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association.
        Circulation. 2019; 139: e891-e908
        • Zalewska-Adamiec M
        • Malyszko J
        • Grodzka E
        • Kuzma L
        • Dobrzycki S
        • Bachorzewska-Gajewska H.
        The outcome of patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) and impaired kidney function: a 3-year observational study.
        Int Urol Nephrol. 2021; 53: 2557-2566
        • Engelbertz C
        • Pinnschmidt HO
        • Freisinger E
        • et al.
        Sex-specific differences and long-term outcome of patients with coronary artery disease and chronic kidney disease: the Coronary Artery Disease and Renal Failure (CAD-REF) Registry.
        Clin Res Cardiol. 2021; 110: 1625-1636
        • Zhang Q-L
        • Rothenbacher D.
        Prevalence of chronic kidney disease in population-based studies: systematic review.
        BMC Public Health. 2008; 8: 117
        • Virani SS
        • Alonso A
        • Aparicio HJ
        • et al.
        Heart disease and stroke statistics—2021 update.
        Circulation. 2021; 143: e254-e743
        • Muntner P
        • He J
        • Astor BC
        • Folsom AR
        • Coresh J.
        Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the Atherosclerosis Risk in Communities Study.
        J Am Soc Nephrol. 2005; 16: 529-538
        • Jung C-Y
        • Heo GY
        • Park JT
        • et al.
        Sex disparities and adverse cardiovascular and kidney outcomes in patients with chronic kidney disease: results from the KNOW-CKD.
        Clin Res Cardiol. 2021; 110: 1116-1127
        • Toth-Manikowski SM
        • Yang W
        • Appel L
        • et al.
        Sex differences in cardiovascular outcomes in CKD: findings from the CRIC study.
        Am J Kidney Dis. 2021; 78: 200-209.e1
        • Edmonston DL
        • Pun PH.
        Coronary artery disease in chronic kidney disease: highlights from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
        Kidney Int. 2020; 97: 642-644
        • Di Lullo L
        • House A
        • Gorini A
        • Santoboni A
        • Russo D
        • Ronco C.
        Chronic kidney disease and cardiovascular complications.
        Heart Fail Rev. 2015; 20: 259-272
        • House AA
        • Wanner C
        • Sarnak MJ
        • et al.
        Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
        Kidney Int. 2019; 95: 1304-1317
        • Lullo LD
        • Gorini A
        • Russo D
        • Santoboni A
        • Ronco C.
        Left ventricular hypertrophy in chronic kidney disease patients: from pathophysiology to treatment.
        Cardiorenal Med. 2015; 5: 254-266
        • Glassock RJ
        • Pecoits-Filho R
        • Barberato SH.
        Left ventricular mass in chronic kidney disease and ESRD.
        Clin J Am Soc Nephrol. 2009; 4: S79-S91
        • Levin A.
        The clinical epidemiology of cardiovascular diseases in chronic kidney disease: clinical epidemiology of cardiovascular disease in chronic kidney disease prior to dialysis.
        Semin Dial. 2003; 16: 101-105
        • Löfman I
        • Szummer K
        • Dahlström U
        • Jernberg T
        • Lund LH.
        Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction.
        Eur J Heart Fail. 2017; 19: 1606-1614
        • Gori M
        • Senni M
        • Gupta DK
        • et al.
        Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction.
        Eur Heart J. 2014; 35: 3442-3451
        • Damman K
        • Valente MAE
        • Voors AA
        • O'Connor CM
        • van Veldhuisen DJ
        • Hillege HL
        Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis.
        Eur Heart J. 2014; 35: 455-469
        • Ehdaie A
        • Cingolani E
        • Shehata M
        • Wang X
        • Curtis AB
        • Chugh SS.
        Sex differences in cardiac arrhythmias.
        Circ Arrhythm Electrophysiol. 2018; 11 (e005680)
        • Tadros R
        • Ton A-T
        • Fiset C
        • Nattel S.
        Sex differences in cardiac electrophysiology and clinical arrhythmias: epidemiology, therapeutics, and mechanisms.
        Can J Cardiol. 2014; 30: 783-792
        • Ruff CT
        • Giugliano RP
        • Braunwald E
        • et al.
        Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
        Lancet. 2014; 383: 955-962
        • Humphries KH
        • Kerr CR
        • Connolly SJ
        • et al.
        New-onset atrial fibrillation.
        Circulation. 2001; 103: 2365-2370
        • Lip GYH
        • Rushton-Smith SK
        • Goldhaber SZ
        • et al.
        Does sex affect anticoagulant use for stroke prevention in nonvalvular atrial fibrillation?.
        Circ Cardiovasc Qual Outcomes. 2015; 8: S12-S20
        • Linde C
        • Bongiorni MG
        • Birgersdotter-Green U
        • et al.
        Sex differences in cardiac arrhythmia: a consensus document of the European Heart Rhythm Association, endorsed by the Heart Rhythm Society and Asia Pacific Heart Rhythm Society.
        Europace. 2018; 20 (1565-1565ao)
        • Bonato FOB
        • Lemos MM
        • Cassiolato JL
        • Canziani MEF.
        Prevalence of ventricular arrhythmia and its associated factors in nondialyzed chronic kidney disease patients.
        PLoS One. 2013; 8 (e66036)
        • Bansal N
        • Fan D
        • Hsu C
        • Ordonez JD
        • Marcus GM
        • Go AS.
        Incident atrial fibrillation and risk of end-stage renal disease in adults with chronic kidney disease.
        Circulation. 2013; 127: 569-574
        • McManus DD
        • Saczynski JS
        • Ward JA
        • et al.
        The relationship between atrial fibrillation and chronic kidney disease : epidemiologic and pathophysiologic considerations for a dual epidemic.
        J Atr Fibrillation. 2012; 5: 442
        • Soliman EZ
        • Prineas RJ
        • Go AS
        • et al.
        Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC).
        Am Heart J. 2010; 159: 1102-1107
        • Baber U
        • Howard VJ
        • Halperin JL
        • et al.
        Association of chronic kidney disease with atrial fibrillation among adults in the United States.
        Circ Arrhythm Electrophysiol. 2011; 4: 26-32
        • Gregg LP
        • Hedayati SS.
        Management of traditional cardiovascular risk factors in CKD: what are the data?.
        Am J Kidney Dis. 2018; 72: 728-744
        • Shajahan S
        • Amin J
        • Phillips JK
        • Hildreth CM.
        Relationship between sex and cardiovascular mortality in chronic kidney disease: a systematic review and meta-analysis.
        PLoS One. 2021; 16 (e0254554)
        • Swartling O
        • Rydell H
        • Stendahl M
        • Segelmark M
        • Lagerros YT
        • Evans M.
        CKD progression and mortality among men and women: a nationwide study in Sweden.
        Am J Kidney Dis. 2021; 78: 190-199.e1
        • Meisinger C
        • Döring A
        • Löwel H
        • Study Group KORA
        Chronic kidney disease and risk of incident myocardial infarction and all-cause and cardiovascular disease mortality in middle-aged men and women from the general population.
        Eur Heart J. 2006; 27: 1245-1250
        • Navaneethan SD
        • Schold JD
        • Walther CP
        • et al.
        HDL-cholesterol and causes of death in chronic kidney disease.
        J Clin Lipidol. 2018; 12: 1061-1071.e7
        • Chen S-C
        • Teh M
        • Huang J-C
        • et al.
        Increased aortic arch calcification and cardiomegaly is associated with rapid renal progression and increased cardiovascular mortality in chronic kidney disease.
        Sci Rep. 2019; 9: 5354
        • Lee W-H
        • Hsu P-C
        • Chu C-Y
        • et al.
        Upstroke time as a novel predictor of mortality in patients with chronic kidney disease.
        Diagnostics (Basel). 2020; 10: 422
        • Şimşek MA
        • Değertekin M
        • Türer Cabbar A
        • et al.
        NT-proBNP level in stage 3-4 chronic kidney disease and mortality in long-term follow-up: HAPPY study subgroup analysis.
        Turk Kardiyol Dern Ars. 2020; 48: 454-460
      4. Gestational Hypertension and Preeclampsia. Accessed November 30, 2021.https://www.acog.org/en/clinical/clinical-guidance/practice-bulletin/articles/2020/06/gestational-hypertension-and-preeclampsia

        • Wiles K
        • Chappell LC
        • Lightstone L
        • Bramham K.
        Updates in diagnosis and management of preeclampsia in women with CKD.
        Clin J Am Soc Nephrol. 2020; 15: 1371-1380
        • Garovic VD
        • White W
        • Vaughan L
        • et al.
        Incidence and long-term outcomes of hypertensive disorders of pregnancy.
        J Am Coll Cardiol. 2020; 75: 2323-2334
        • Honigberg MC
        • Zekavat SM
        • Aragam K
        • et al.
        Long-term cardiovascular risk in women with hypertension during pregnancy.
        J Am Coll Cardiol. 2019; 74: 2743-2754
        • Bellamy L
        • Casas J-P
        • Hingorani AD
        • Williams DJ.
        Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
        BMJ. 2007; 335: 974
      5. Kattah AG, Garovic VD. Chapter 9 - preeclampsia: cardiovascular and renal risks during and after pregnancy. In: LaMarca B, Alexander BT, eds. Sex Differences in Cardiovascular Physiology and Pathophysiology. Academic Press; 2019:137-147. Accessed December 3, 2021. https://www.sciencedirect.com/science/article/pii/B9780128131978000099

        • Stillman IE
        • Karumanchi SA.
        The glomerular injury of preeclampsia.
        J Am Soc Nephrol. 2007; 18: 2281-2284
        • Ferreira RC
        • Fragoso MBT
        • dos Santos Tenório MC
        • et al.
        Pre-eclampsia is associated with later kidney chronic disease and end-stage renal disease: systematic review and meta-analysis of observational studies.
        Pregnancy Hypertens. 2020; 22: 71-85
        • Piccoli GB
        • Alrukhaimi M
        • Liu Z-H
        • et al.
        Women and kidney diseases: questions unanswered and answers unquestioned.
        Kidney Int Rep. 2018; 3: 225-235
        • Garg AX
        • Nevis IF
        • McArthur E
        • et al.
        Gestational hypertension and preeclampsia in living kidney donors.
        N Engl J Med. 2015; 372: 124-133
        • Mjøen G
        • Hallan S
        • Hartmann A
        • et al.
        Long-term risks for kidney donors.
        Kidney Int. 2014; 86: 162-167
        • Garg AX
        • Meirambayeva A
        • Huang A
        • et al.
        Cardiovascular disease in kidney donors: matched cohort study.
        BMJ. 2012; 344 (e1203)
        • Zinman B
        • Wanner C
        • Lachin JM
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2228
        • Wanner C
        • Inzucchi SE
        • Lachin JM
        • et al.
        Empagliflozin and progression of kidney disease in type 2 diabetes.
        N Engl J Med. 2016; 375: 323-334
        • Zinman B
        • Inzucchi SE
        • Wanner C
        • et al.
        Empagliflozin in women with type 2 diabetes and cardiovascular disease – an analysis of EMPA-REG OUTCOME®.
        Diabetologia. 2018; 61: 1522-1527
        • Maas AHEM
        • Appelman YEA
        Gender differences in coronary heart disease.
        Neth Heart J. 2010; 18: 598-602
        • Johansson I
        • Dahlström U
        • Edner M
        • Näsman P
        • Rydén L
        • Norhammar A.
        Risk factors, treatment and prognosis in men and women with heart failure with and without diabetes.
        Heart. 2015; 101: 1139-1148
        • Neal B
        • Perkovic V
        • Mahaffey KW
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Perkovic V
        • de Zeeuw D
        • Mahaffey KW
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.
        Lancet Diabetes Endocrinol. 2018; 6: 691-704
        • Yi TW
        • Smyth B
        • Kang A
        • et al.
        129-LB: kidney and cardiovascular effects of canagliflozin according to age and sex in the CREDENCE trial.
        Diabetes. 2021; 70 (Accessed December 2, 2021.)
        • Pitt B
        • Filippatos G
        • Agarwal R
        • et al.
        Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
        N Engl J Med. 2021; (Accessed December 2, 2021)
        • Tamargo J
        • Rosano G
        • Walther T
        • et al.
        Gender differences in the effects of cardiovascular drugs.
        Eur Heart J Cardiovasc Pharmacother. 2017; 3: 163-182
        • Soldin O
        • Mattison D.
        Sex differences in pharmacokinetics and pharmacodynamics.
        Clin Pharmacokinet. 2009; 48: 143-157
        • Clemens KK
        • Woodward M
        • Neal B
        • Zinman B.
        Sex disparities in cardiovascular outcome trials of populations with diabetes: a systematic review and meta-analysis.
        Diabetes Care. 2020; 43: 1157-1163