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Sex disparities and adverse cardiovascular and kidney outcomes in patients with chronic kidney disease: results from the KNOW-CKD



Longitudinal studies of the association between sex and adverse clinical outcomes in patients with chronic kidney disease (CKD) are scarce. We assessed whether major outcomes may differ by sex among CKD patients.


We analyzed a total of 1780 participants with non-dialysis CKD G1-5 from the KoreaN cohort study for Outcome in patients with Chronic Kidney Disease (KNOW-CKD). The primary outcome was a composite of non-fatal cardiovascular events or all-cause mortality. Secondary outcomes included fatal and non-fatal cardiovascular events, all-cause mortality, and a composite kidney outcome of ≥ 50% decline in estimated glomerular filtration rate from baseline or the onset of end-stage kidney disease.


There were 1088 (61%) men and 692 (39%) women in the study cohort. The proportion of smokers was significantly higher in men (24% vs. 3%). During 8430 person-years of follow-up, 201 primary outcome events occurred: 144 (13%) in men and 57 (8%) in women, with corresponding incidence rates of 2.9 and 1.7 per 100 person-years, respectively. In multivariable Cox models, men were associated with a 1.58-fold (95% CI 1.06–2.35) higher risk of composite outcome. Propensity score matching analysis revealed similar findings (HR 1.81; 95% CI 1.14–2.91). Risk of all-cause mortality was significantly higher in men of the matched cohort. However, there was no difference in the risk of CKD progression. In the subgroup with coronary artery calcium (CAC) measurements, men had a higher likelihood of CAC progression.


In Korean CKD patients, men were more likely to experience adverse cardiovascular events and death than women.

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Availability of data and material

The data that support the findings of this study are available from the corresponding author (SHH) upon reasonable request.


  1. 1.

    GBD (2019) Demographic Collaborators (2020) Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950–2019: a comprehensive demographic analysis for the global burden of disease study 2019. Lancet 396:1160–1203

    Google Scholar 

  2. 2.

    Regitz-Zagrosek V, Kararigas G (2017) Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev 97:1–37

    PubMed  Google Scholar 

  3. 3.

    Metcalfe PD, Leslie JA, Campbell MT, Meldrum DR, Hile KL, Meldrum KK (2008) Testosterone exacerbates obstructive renal injury by stimulating TNF-alpha production and increasing proapoptotic and profibrotic signaling. Am J Physiol Endocrinol Metab 294:E435–E443

    CAS  PubMed  Google Scholar 

  4. 4.

    Mauvais-Jarvis F, Merz NB, Barnes PJ et al (2020) Sex and gender: modifiers of health, disease, and medicine. Lancet 396:565–582

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Millett ERC, Peters SAE, Woodward M (2018) Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants. BMJ 363:1–11

    Google Scholar 

  6. 6.

    Huebschmann AG, Huxley RR, Kohrt WM, Zeitler P, Regensteiner JG, Reusch JEB (2019) Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course. Diabetologia 62:1761–1772

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Garawi F, Devries K, Thorogood N, Uauy R (2014) Global differences between women and men in the prevalence of obesity: is there an association with gender inequality? Eur J Clin Nutr 68:1101–1106

    CAS  PubMed  Google Scholar 

  8. 8.

    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics. CA Cancer J Clin 67:7–30

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Vaccarezza M, Papa V, Milani D et al (2020) Sex/gender-specific imbalance in CVD: could physical activity help to improve clinical outcome targeting CVD molecular mechanisms in women? Int J Mol Sci 21:1–16

    Google Scholar 

  10. 10.

    Nitsch D, Grams M, Sang Y et al (2013) Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis. BMJ 346:1–14

    Google Scholar 

  11. 11.

    Carrero JJ, Hecking M, Chesnaye NC, Jager KJ (2018) Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. Nat Rev Nephrol 14:151–164

    PubMed  Google Scholar 

  12. 12.

    Seppi T, Prajczer S, Dörler MM et al (2016) Sex differences in renal proximal tubular cell homeostasis. J Am Soc Nephrol 27:3051–3062

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kim C, Ricardo AC, Boyko EJ et al (2019) Sex hormones and measures of kidney function in the diabetes prevention program outcomes study. J Clin Endocrinol Metab 104:1171–1180

    PubMed  Google Scholar 

  14. 14.

    Elliot SJ, Karl M, Berho M et al (2003) Estrogen deficiency accelerates progression of glomerulosclerosis in susceptible mice. Am J Pathol 162:1441–1448

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Doublier S, Lupia E, Catanuto P et al (2011) Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice. Kidney Int 79:404–413

    CAS  PubMed  Google Scholar 

  16. 16.

    Neugarten J, Acharya A, Silbiger SR (2000) Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. J Am Soc Nephrol 11:319–329

    PubMed  Google Scholar 

  17. 17.

    Jafar TH, Schmid CH, Start PC et al (2003) The rate of progression of renal disease may not be slower in women compared with men: a patient-level meta-analysis. Nephrol Dial Transplant 18:2047–2053

    PubMed  Google Scholar 

  18. 18.

    Ricardo AC, Yang W, Sha D et al (2019) Sex-related disparities in CKD progression. J Am Soc Nephrol 30:137–146

    CAS  PubMed  Google Scholar 

  19. 19.

    Minutolo R, Gabbai FB, Chiodini P et al (2020) Sex differences in the progression of CKD among older patients: pooled analysis of 4 cohort studies. Am J Kidney Dis 75:30–38

    CAS  PubMed  Google Scholar 

  20. 20.

    Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group (2017) KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 7:1–59

    Google Scholar 

  21. 21.

    Levey AS, Stevens LA, Schmid CH et al (2009) CKD-EPI (chronic kidney disease epidemiology collaboration): a new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Oh KH, Park SK, Park HC et al (2014) KNOW-CKD (KoreaN cohort study for outcome in patients with chronic kidney disease): design and methods. BMC Nephrol 15:80

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Neves PO, Andrade J, Monção H (2017) Coronary artery calcium score: current status. Radiol Bras 50:182–189

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R (1990) Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15:827–832

    CAS  PubMed  Google Scholar 

  25. 25.

    Chen J, Budoff MJ, Reilly MP et al (2017) Coronary artery calcification and risk of cardiovascular disease and death among patients with chronic kidney disease. JAMA Cardiol 2:635–643

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Parikh NI, Hwang SJ, Larson MG, Meigs JB, Levy D, Fox CS (2006) Cardiovascular disease risk factors in chronic kidney disease. Arch Intern Med 166:1884–1891

    PubMed  Google Scholar 

  27. 27.

    Eriksen BO, Ingebretsen OC (2006) The progression of chronic kidney disease: a 10 year population-based study of the effects of gender and age. Kidney Int 69:375–382

    CAS  PubMed  Google Scholar 

  28. 28.

    Carrero JJ, de Jager DJ, Verduijn M et al (2011) Cardiovascular and noncardiovascular mortality among men and women starting dialysis. Clin J Am Soc Nephrol 6:1722–1730

    PubMed  Google Scholar 

  29. 29.

    Bild DE, Detrano R, Peterson D et al (2005) Ethnic differences in coronary calcification: the multi-ethnic study of atherosclerosis (MESA). Circulation 111:1313–1320

    PubMed  Google Scholar 

  30. 30.

    Schmermund A, Möhlenkamp S, Stang A et al (2002) Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in health middle-aged subjects: rationale and design of the Heinz Nixdorf RECALL study. risk factors, evaluation of coronary calcium and lifestyle. Am Heart J 144:212–218

    PubMed  Google Scholar 

  31. 31.

    Vliegenthart R, Oudkerk M, Hofman A et al (2005) Coronary calcification improves cardiovascular risk prediction in the elderly. Circulation 112:572–577

    PubMed  Google Scholar 

  32. 32.

    Yano Y, O’Donnell CJ, Kuller L et al (2017) Association of coronary artery calcium score vs age with cardiovascular risk in older adults: an analysis of pooled population-base studies. JAMA Cardiol 2:986–894

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Zhao M, Woodward M, Vaartjes I et al (2020) Sex differences in cardiovascular medication prescription in primary care: a systematic review and meta-analysis. J Am Heart Assoc 9:e014742

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Tamargo J, Rosano G, Walther T et al (2017) Gender differences in the effects of cardiovascular drugs. Eur Heart J Cardiovasc Pharmacother 3:163–182

    CAS  PubMed  Google Scholar 

  35. 35.

    Miller JA, Anacta L, Cattran DC (1999) Impact of gender on the renal response to angiotensin II. Kidney Int 55:278–285

    CAS  PubMed  Google Scholar 

  36. 36.

    Ruggenenti P, Perna A, Zoccali C et al (2000) 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. J Am Soc Nephrol 11:88–96

    CAS  PubMed  Google Scholar 

  37. 37.

    Karp I, Chen SF, Pilote L (2007) Sex differences in the effectiveness of statins after myocardial infarction. CMAJ 176:333–338

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Garg R, Yusuf S (1995) Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative group on ACE inhibitor trials. JAMA 273:1450–1456

    CAS  PubMed  Google Scholar 

  39. 39.

    Kotecha D, Manzano L, Krum H et al (2016) Beta-blockers in heart failure collaborative group. Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. BMJ 353:i18

    Google Scholar 

  40. 40.

    Cholesterol Treatment Tiralists’ (CTT) Collaboration, Fulcher J, O’connel R, Voysey M, et al. (2015) Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 385:1397–1405

    Google Scholar 

  41. 41.

    Jamal A, King BA, Neff LJ, Whitmill J, Dabb SD, Graffunder CM (2016) Current cigarette smoking among Adults—United States, 2005–2015. MMWR Morb Mortal Wkly Rep 65:1205–1211

    PubMed  Google Scholar 

  42. 42.

    Peters SAE, Huxley RR, Woodward M (2014) Do smoking habits differ between women and men in contemporary Western populations? Evidence from half a million people in the UK Biobank study. BMJ Open 4:1–8

    Google Scholar 

  43. 43.

    Gunter R, Szeto E, Jeong SH, Suh S, Waters AJ (2020) Cigarette smoking in south korea: a narrative review. Korean J Fam Med 41:3–13

    PubMed  Google Scholar 

  44. 44.

    Mons U, Müezzinler A, Gellert C et al (2015) Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium. BMJ 350:h1551

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Coresh J, Byrd-Holt D, Astor BC et al (2005) Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000. J Am Soc Nephrol 16:180–188

    PubMed  Google Scholar 

  46. 46.

    Piccoli GB, Alrukhaimi M, Liu ZH, Zakharova E, Levin A (2018) What we do and do not know about women and kidney diseases; questions unanswered and answers unquestioned: reflection on World Kidney Day and International Women’s Day. BMC Nephrol 19:1–18

    Google Scholar 

  47. 47.

    Xue JL, Eggers PW, Agodoa LY, Foley RN, Collins AJ (2007) Longitudinal study of racial and ethnic differences in developing end-stage renal disease among aged medicare beneficiaries. J Am Soc Nephrol 18:1299–1306

    PubMed  Google Scholar 

  48. 48.

    Kausz AT, Obrador GT, Arora P, Ruthazer R, Levey AS, Pereira BJ (2000) Late initiation of dialysis among women and ethnic minorities in the United States. J Am Soc Nephrol 11:2351–2357

    PubMed  Google Scholar 

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This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (2011E3300300, 2012E3301100, 2013E3301600, 2013E3301601, 2013E3301602, 2016E3300200, and 2019E320101).

Author information




C-YJ, GYH, and SHH contributed to the conception of the study. TIC, EWK, T-HY, JL, SWK, YKO, JYJ, K-HO, CA, and SHH contributed to data collection. C-YJ, GYH, HL, and SHH contributed to data analysis and interpretation. C-YJ and SHH drafted the manuscript. C-YJ, GYH, JTP, YSJ, HWK, HL, TIC, EWK, T-HY, S-WK, JL, SWK, YKO, JYJ, K-HO, CA, and SHH revised the manuscript for important intellectual content. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Seung Hyeok Han.

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Conflict of interest

The authors declare no conflicts of interest with respect to this manuscript.

Ethical approval

The study was conducted in accordance with the principles of the Declaration of Helsinki, and approved by the institutional review boards of participating institutions.

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Jung, CY., Heo, G.Y., Park, J.T. et al. Sex disparities and adverse cardiovascular and kidney outcomes in patients with chronic kidney disease: results from the KNOW-CKD. Clin Res Cardiol 110, 1116–1127 (2021).

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  • Sex
  • Disparities
  • Cardiovascular events
  • Mortality
  • Chronic kidney disease