Sex and the Risk of Atheromatous and Nonatheromatous Cardiovascular Disease in CKD: Findings From the CKD-REIN Cohort Study

Rationale & Objective

Sex differences in cardiovascular disease (CVD) are well established, but whether chronic kidney disease (CKD) modifies these risk differences and whether they differ between atheromatous CVD (ACVD) and nonatheromatous CVD (NACVD) is unknown. Assessing this interaction was the principal goal of this study.

Study Design

Prospective cohort study.

Setting & Participants

Adults enrolled in the CKD-REIN (CKD-Renal Epidemiology and Information Network) cohort, a nationally representative sample of 40 nephrology clinics in France, from 2013 to 2020.

Exposure

Sex.

Outcomes

Fatal and nonfatal composite ACVD events (ischemic coronary, cerebral, and peripheral artery disease) and composite NACVD events (heart failure, hemorrhagic stroke, and arrhythmias).

Analytical Approach

Multivariable cause-specific Cox proportional hazards models.

Results

1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs 69 y; mean estimated glomerular filtration rate [eGFR], 32 ± 12 vs 33 ± 12 mL/min/1.73 m²) were studied. During a median follow-up of 5.0 (IQR, 4.8-5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than in men, at 2.1 (95% CI, 1.6-2.5) versus 3.6 (3.2-4.0; P < 0.01), whereas the NACVD rate was not, at 5.7 (5.0-6.5) versus 6.4 (5.8-7.0; P = 0.55). NACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P < 0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted HR for women versus men was 0.42 (0.25-0.71) at 45 mL/min/1.73 m² and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62-1.63) at 16 mL/min/1.73 m². In contrast, the NACVD hazard did not differ between sexes across the eGFR range studied.

Limitations

Cardiovascular biomarkers and sex hormones were not assessed.

Conclusions

This study shows how the lower risk of ACVD among women versus men attenuates fully with kidney disease progression. The equal risk of NACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type.

Plain-Language Summary

Sex differences in the risks of atheromatous and nonatheromatous cardiovascular disease (CVD) are well established in the general population. If or how chronic kidney disease (CKD) might modify these risks is unknown. In this large cohort of 3,010 patients with CKD, women had a lower risk than men of atheromatous CVDs such as coronary artery disease or stroke when they were at an early stage of CKD. This advantage, partly due to women’s better cardiovascular risk profile, tended to attenuate as CKD progressed to kidney failure. In contrast, the risk of nonatheromatous CVDs such as heart failure for women with CKD appeared similar to that of men with CKD at all kidney function levels.