American Journal of Kidney Diseases

Sex Differences in Cardiovascular Outcomes in CKD: Findings From the CRIC Study

Published:April 12, 2021DOI:

      Rationale & Objective

      Cardiovascular events are less common in women than men in general populations; however, studies in chronic kidney disease (CKD) are less conclusive. We evaluated sex-related differences in cardiovascular events and death in adults with CKD.

      Study Design

      Prospective cohort study.

      Setting & Participants

      1,778 women and 2,161 men enrolled in the Chronic Renal Insufficiency Cohort (CRIC).


      Sex (women vs men).


      Atherosclerotic composite outcome (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, cardiovascular death, and all-cause death.

      Analytical Approach

      Cox proportional hazards regression.


      During a median follow-up period of 9.6 years, we observed 698 atherosclerotic events (women, 264; men, 434), 762 heart failure events (women, 331; men, 431), 435 cardiovascular deaths (women, 163; men, 274), and 1,158 deaths from any cause (women, 449; men, 709). In analyses adjusted for sociodemographic, clinical, and metabolic parameters, women had a lower risk of atherosclerotic events (HR, 0.71 [95% CI, 0.57-0.88]), heart failure (HR, 0.76 [95% CI, 0.62-0.93]), cardiovascular death (HR, 0.55 [95% CI, 0.42-0.72]), and death from any cause (HR, 0.58 [95% CI, 0.49-0.69]) compared with men. These associations remained statistically significant after adjusting for cardiac and inflammation biomarkers.


      Assessment of sex hormones, which may play a role in cardiovascular risk, was not included.


      In a large, diverse cohort of adults with CKD, compared with men, women had lower risks of cardiovascular events, cardiovascular mortality, and mortality from any cause. These differences were not explained by measured cardiovascular risk factors.

      Graphical abstract

      Index Words

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        • Go A.S.
        • Chertow G.M.
        • Fan D.
        • McCulloch C.E.
        • Hsu C.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N Engl J Med. 2004; 351: 1296-1305
        • Culleton B.F.
        • Larson M.G.
        • Wilson P.W.
        • Evans J.C.
        • Parfrey P.S.
        • Levy D.
        Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency.
        Kidney Int. 1999; 56: 2214-2219
        • Jousilahti P.
        • Vartiainen E.
        • Tuomilehto J.
        • Puska P.
        Sex, age, cardiovascular risk factors, and coronary heart disease: a prospective follow-up study of 14 786 middle-aged men and women in Finland.
        Circulation. 1999; 99: 1165-1172
        • Lerner D.J.
        • Kannel W.B.
        Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population.
        Am Heart J. 1986; 111: 383-390
        • Wingard D.L.
        • Suarez L.
        • Barrett-Connor E.
        The sex differential in mortality from all causes and ischemic heart disease.
        Am J Epidemiol. 1983; 117: 165-172
        • Rabi D.M.
        • Khan N.
        • Vallee M.
        • Hladunewich M.A.
        • Tobe S.W.
        • Pilote L.
        Reporting on sex-based analysis in clinical trials of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker efficacy.
        Can J Cardiol. 2008; 24: 491-496
        • Regitz-Zagrosek V.
        • Kararigas G.
        Mechanistic pathways of sex differences in cardiovascular disease.
        Physiol Rev. 2017; 97: 1-37
        • Mosca L.
        • Grundy S.M.
        • Judelson D.
        • et al.
        AHA/ACC scientific statement: consensus panel statement. Guide to preventive cardiology for women. American Heart Association/American College of Cardiology.
        J Am Coll Cardiol. 1999; 33: 1751-1755
        • Mosca L.
        • Appel L.J.
        • Benjamin E.J.
        • et al.
        Evidence-based guidelines for cardiovascular disease prevention in women.
        Circulation. 2004; 109: 672-693
        • Shah S.
        • Leonard A.C.
        • Meganathan K.
        • Christianson A.L.
        • Thakar C.V.
        Temporal trends in incident mortality in dialysis patients: focus on sex and racial disparities.
        Am J Nephrol. 2019; 49: 241-253
        • Navaneethan S.D.
        • Schold J.D.
        • Arrigain S.
        • Jolly S.E.
        • Nally J.V.
        Cause-specific deaths in non-dialysis-dependent CKD.
        J Am Soc Nephrol. 2015; 26: 2512-2520
        • Feldman H.I.
        • Appel L.J.
        • Chertow G.M.
        • et al.
        The Chronic Renal Insufficiency Cohort (CRIC) study: design and methods.
        J Am Soc Nephrol. 2003; 14: S148-153
        • Lash J.P.
        • Go A.S.
        • Appel L.J.
        • et al.
        Chronic Renal Insufficiency Cohort (CRIC) study: baseline characteristics and associations with kidney function.
        Clin J Am Soc Nephrol. 2009; 4: 1302-1311
        • Fischer M.J.
        • Go A.S.
        • Lora C.M.
        • et al.
        CKD in Hispanics: baseline characteristics from the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic-CRIC studies.
        Am J Kidney Dis. 2011; 58: 214-227
        • Pickering T.G.
        • Hall J.E.
        • Appel L.J.
        • et al.
        Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research.
        Circulation. 2005; 111: 697-716
        • Joffe M.
        • Hsu C.
        • Feldman H.I.
        • et al.
        Variability of creatinine measurements in clinical laboratories: results from the CRIC study.
        Am J Nephrol. 2010; 31: 426-434
        • Levey A.S.
        • Coresh J.
        • Greene T.
        • et al.
        Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values.
        Clin Chem. 2007; 53: 766-772
        • Anderson A.H.
        • Yang W.
        • Hsu C.
        • et al.
        Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) study.
        Am J Kidney Dis. 2012; 60: 250-261
        • Isakova T.
        • Xie H.
        • Yang W.
        • et al.
        Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.
        JAMA. 2011; 305: 2432-2439
        • Amdur R.L.
        • Feldman H.I.
        • Gupta J.
        • et al.
        Inflammation and Progression of CKD: the CRIC study.
        Clin J Am Soc Nephrol. 2016; 11: 1546-1556
        • Bansal N.
        • Hyre Anderson A.
        • Yang W.
        • et al.
        High-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and risk of incident heart failure in patients with CKD: the Chronic Renal Insufficiency Cohort (CRIC) study.
        J Am Soc Nephrol. 2015; 26: 946-956
        • Bansal N.
        • McCulloch C.E.
        • Lin F.
        • et al.
        Different components of blood pressure are associated with increased risk of atherosclerotic cardiovascular disease versus heart failure in advanced chronic kidney disease.
        Kidney Int. 2016; 90: 1348-1356
        • Amdur R.L.
        • Feldman H.I.
        • Dominic E.A.
        • et al.
        Use of measures of inflammation and kidney function for prediction of atherosclerotic vascular disease events and death in patients with CKD: findings from the CRIC study.
        Am J Kidney Dis. 2019; 73: 344-353
        • Lash J.P.
        • Ricardo A.C.
        • Roy J.
        • et al.
        Race/ethnicity and cardiovascular outcomes in adults with CKD: findings from the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic CRIC studies.
        Am J Kidney Dis. 2016; 68: 545-553
        • Mills K.T.
        • Chen J.
        • Yang W.
        • et al.
        Sodium excretion and the risk of cardiovascular disease in patients with chronic kidney disease.
        JAMA. 2016; 315: 2200-2210
        • Sandsmark D.K.
        • Messe S.R.
        • Zhang X.
        • et al.
        Proteinuria, but not eGFR, predicts stroke risk in chronic kidney disease: Chronic Renal Insufficiency Cohort Study.
        Stroke. 2015; 46: 2075-2080
        • Wang G.J.
        • Shaw P.A.
        • Townsend R.R.
        • et al.
        Sex differences in the incidence of peripheral artery disease in the Chronic Renal Insufficiency Cohort.
        Circ Cardiovasc Qual Outcomes. 2016; 9: S86-S93
        • Ho K.K.
        • Anderson K.M.
        • Kannel W.B.
        • Grossman W.
        • Levy D.
        Survival after the onset of congestive heart failure in Framingham Heart Study subjects.
        Circulation. 1993; 88: 107-115
        • Van der Laan M.J.
        • Polley E.C.
        • Hubbard A.E.
        Super Learner. U.C. Berkeley Division of Biostatistics Working Paper Series.
        (Working Paper 222, July 2007. Accessed July 11, 2018)
        • Kennedy C.
        Guide to SuperLearner.
        Comprehensive R Project Network, March 16, 2017 (Accessed December 16, 2020.)
        • Roca G.Q.
        • Redline S.
        • Claggett B.
        • et al.
        Sex-specific association of sleep apnea severity with subclinical myocardial injury, ventricular hypertrophy, and heart failure risk in a community-dwelling cohort: the Atherosclerosis Risk in Communities-Sleep Heart Health Study.
        Circulation. 2015; 132: 1329-1337
        • Kendrick J.
        • Chonchol M.
        Cardiovascular disease in CKD in 2013: reducing cardiovascular risk—light at the end of the tunnel.
        Nat Rev Nephrol. 2014; 10: 71-72
        • Menon V.
        • Gul A.
        • Sarnak M.J.
        Cardiovascular risk factors in chronic kidney disease.
        Kidney Int. 2005; 68: 1413-1418
        • Gold E.B.
        • Bromberger J.
        • Crawford S.
        • et al.
        Factors associated with age at natural menopause in a multiethnic sample of midlife women.
        Am J Epidemiol. 2001; 153: 865-874
        • Fine J.P.
        • Gray R.J.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509
        • Hsu J.Y.
        • Roy J.A.
        • Xie D.
        • et al.
        Statistical methods for cohort studies of CKD: survival analysis in the setting of competing risks.
        Clin J Am Soc Nephrol. 2017; 12: 1181-1189
        • Liu Y.
        • De A.
        Multiple imputation by fully conditional specification for dealing with missing data in a large epidemiologic study.
        Int J Stat Med Res. 2015; 4: 287-295
        • Rubin D.B.
        Multiple Imputation for Nonresponse in Surveys.
        John Wiley & Sons, 1987
        • Grambsch P.M.
        • Therneau T.M.
        Proportional hazards tests and diagnostics based on weighted residuals.
        Biometrika. 1994; 81: 515-526
        • Dubey R.K.
        • Jackson E.K.
        Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms.
        Am J Physiol Renal Physiol. 2001; 280: F365-388
        • Arnlöv J.
        • Pencina M.J.
        • Amin S.
        • et al.
        Endogenous sex hormones and cardiovascular disease incidence in men.
        Ann Intern Med. 2006; 145: 176-184
        • Zhao D.
        • Guallar E.
        • Ouyang P.
        • et al.
        Endogenous sex hormones and incident cardiovascular disease in post-menopausal women.
        J Am Coll Cardiol. 2018; 71: 2555-2566
        • Saran R.
        • Robinson B.
        • Abbott K.C.
        • et al.
        US Renal Data System 2018 annual data report: epidemiology of kidney disease in the United States.
        Am J Kidney Dis. 2019; 73: A7-A8
        • Dewan P.
        • Rørth R.
        • Jhund P.S.
        • et al.
        Differential impact of heart failure with reduced ejection fraction on men and women.
        J Am Coll Cardiol. 2019; 73: 29-40
        • O’Meara E.
        • Clayton T.
        • McEntegart M.B.
        • et al.
        Sex differences in clinical characteristics and prognosis in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program.
        Circulation. 2007; 115: 3111-3120
        • Tuegel C.
        • Bansal N.
        Heart failure in patients with kidney disease.
        Heart. 2017; 103: 1848-1853
        • GBD 2017 Causes of Death Collaborators
        Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.
        Lancet. 2018; 392: 1736-1788
        • Hecking M.
        • Bieber B.A.
        • Ethier J.
        • et al.
        Sex-specific differences in hemodialysis prevalence and practices and the male-to-female mortality rate: the Dialysis Outcomes and Practice Patterns Study (DOPPS).
        PLoS Med. 2014; 11e1001750
        • Piro M.
        • Della Bona R.
        • Abbate A.
        • Biasucci L.M.
        • Crea F.
        Sex-related differences in myocardial remodeling.
        J Am Coll Cardiol. 2010; 55: 1057-1065
        • Bairey Merz C.N.
        • Shaw L.J.
        • Reis S.E.
        • et al.
        Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease.
        J Am Coll Cardiol. 2006; 47: S21-29
        • O’Neil A.
        • Scovelle A.J.
        • Milner A.J.
        • Kavanagh A.
        Gender/sex as a social determinant of cardiovascular risk.
        Circulation. 2018; 137: 854-864