Few prospective studies have explored the association between renal function and risk for incident atrial fibrillation (AF) in apparently healthy populations. A total of 24,746 women participating in the Women’s Health Study who were free of cardiovascular disease and AF and provided blood samples at baseline were prospectively followed for incident AF from 1993 to 2010. AF events were confirmed by medical chart review. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine using the Chronic Kidney Disease Epidemiology (CKD-EPI) equation. Cox models were used to estimate hazard ratios and 95% confidence intervals (CIs) for incident AF across eGFR categories controlling for AF risk factors. During a median of 15.4 years of follow-up, 786 incident AF events occurred. The multivariate-adjusted hazard ratios for incident AF across eGFR categories (<60, 60 to 74.9, 75 to 89, and ≥90 ml/min/1.73 m 2 ) were 1.36 (95% CI 1.00 to 1.84), 0.90 (95% CI 0.71 to 1.14), 0.99 (95% CI 0.84 to 1.18) and 1.00, respectively, without evidence of a linear association (P for trend = 0.48). Similarly, there was no significant curvilinear association (quadratic p = 0.10) in multivariate analysis across categories. Compared to women with eGFRs ≥60 ml/min/1.73 m 2 , the 1,008 women with eGFRs <60 ml/min/1.73 m 2 had a multivariate-adjusted hazard ratio for AF of 1.39 (95% CI 1.04 to 1.86, p = 0.03). In conclusion, no significant linear or curvilinear relation was observed between incident AF and less severe impairment of renal function in this large prospective cohort of women. However, a significant elevation in AF risk was observed at a threshold eGFR of <60 ml/min/1.73 m 2 .
Several cross-sectional studies have found the prevalence of atrial fibrillation (AF) to be associated with decreasing glomerular filtration rate (GFR) and increasing cystatin C and urinary albumin levels. Among those with end-stage renal disease, the prevalence of AF is 3 to 15 times greater than in a general population. However, results from prospective studies involving more modest degrees of renal dysfunction have been conflicting, with positive associations observed in some but not all studies. In particular, there are few prospective data on the association between moderate renal dysfunction and incident AF in apparently healthy populations, in which confounding of the relation by established vascular disease would be expected to be lower. Therefore, we evaluated the association between kidney function as assessed by GFR and the subsequent development of incident AF in 24,746 women without previous cardiovascular disease.
Methods
All subjects were participants in the Women’s Health Study, a randomized, placebo-controlled trial evaluating the benefits and risks of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer. The study has previously been published. Briefly, a total of 39,876 United States female health professionals in 1993 who were aged ≥45 years and free of cardiovascular disease, cancer, and other major illnesses were randomly assigned to aspirin 100 mg every other day, vitamin E 600 IU every other day, both agents, or placebo. Randomized treatment ended on March 31, 2004, and women were invited to participate in continued observational follow-up with self-reported questionnaires regarding cardiovascular risk factors and lifestyle variables.
Blood samples were available for 28,345 women at the time of randomization. Of these women, 626 women with AF, 3 with cardiovascular disease, and 568 with missing values for important clinical characteristics at baseline were excluded. An additional 2,402 women who opted out of further observational follow-up were also excluded because self-reported AF cases within this group could not be reliably confirmed. Excluding these participants left 24,746 for the present analysis. The median follow-up period was 15.4 years (interquartile range 14.7 to 15.8). All participants provided written informed consent, and the institutional review board of Brigham and Women’s Hospital (Boston, Massachusetts) approved the study.
In a core laboratory certified by the National Heart, Lung, and Blood Institute and Centers for Disease Control and Prevention Lipid Standardization Program, all blood samples are collected in tubes containing ethylenediaminetetraacetic acid, stored in vapor-phase liquid nitrogen (−170°C), and analyzed for lipids and a panel of inflammatory markers. Creatinine was measured by a rate-blanked method based on the Jaffe reaction. Total cholesterol was assayed with reagents from Roche Diagnostics (Basel, Switzerland), and high-sensitivity C-reactive protein concentrations were measured with immunoturbidimetric assays on a Hitachi 917 analyzer (Roche Diagnostics, Indianapolis, Indiana) using reagents and calibrators from Denka Seiken (Tokyo, Japan).
The Chronic Kidney Disease Epidemiology (CKD-EPI) equation, which has been validated to perform better than the Modification of Diet in Renal Disease (MDRD) equation at higher GFRs, was used to calculate estimated GFR (eGFR). The CKD-EPI equation is eGFR = 141 × min(serum creatinine/0.7, 1) −0.32 × max(serum creatinine/0.7, 1) −1.209 × 0.993(age) × 1.018 (if female) × 1.159 (if black). As a secondary analysis, we used an abbreviated version of the MDRD equation to examine whether our results were substantially influenced by the equation used to calculate eGFR. The MDRD equation is eGFR = 186 × (serum creatinine) −1.154 × age −0.203 × 0.742 (if female) × 1.210 (if black). Using the 2 equations, participants were categorized on the basis of the classification of the National Kidney Foundation (eGFR <60, 60 to 74, 75 to 89, or ≥90 ml/min/1.73 m 2 ).
Women were asked to report diagnoses of incident AF at baseline, at 48 months, and then annually thereafter. Women enrolled in the continued observational follow-up who reported incident AF events on ≥1 yearly questionnaire were sent an additional questionnaire beginning on September 19, 2006, to confirm the episodes and collect additional information. Permission was obtained to review medical records, available electrocardiograms, rhythm strips, 24-hour electrocardiographic monitoring, and information on cardiac structure and function. For deceased participants reporting AF during the trial and observational period, family members were contacted to obtain consent for medical records. An end point committee of physicians reviewed medical records according to predefined criteria. An incident AF event was confirmed if there was electrocardiographic evidence of AF or if a medical report clearly indicated a personal history of AF. The earliest date in the medical records was set as the date of onset of AF. Only confirmed AF events are included in this analysis.
Baseline characteristics across eGFR categories were compared using Jonckheere-Terpstra tests for continuous variables and Mantel-Haenszel trend chi-square tests for categorical variables. For each woman, person-years of follow-up were calculated from the date of return of the baseline questionnaire to date of first end point, death, loss to follow-up, or March 16, 2010, whichever came first.
Cox proportional-hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for incident AF across eGFR categories, with the highest eGFR category (≥90 ml/min/1.73 m 2 ) serving as the reference category in all analyses. In a secondary analysis, eGFR was dichotomized at 60 ml/min/1.73 m 2 on the basis of GFR definition of chronic kidney disease. Model 1 adjusted for age and assigned treatment. Multivariate model 2 controlled for age (continuous), systolic blood pressure (10 mm Hg increments), antihypertensive treatment (yes or no), smoking (yes or no), diabetes (yes or no), body mass index (continuous), alcohol consumption (rarely or never, <1 drink/week, 1 to 6 drinks/week, or ≥1 drink/day), exercise (rarely or never, <1 time/week, 1 to 3 times/week, or ≥4 times/week), total cholesterol (continuous), high-sensitivity C-reactive protein concentration (continuous), and postmenopausal hormone use (never, past, or current). The proportionality assumption was tested by including an interaction term for eGFR categories with follow-up time in the Cox models, and no statistically significant violation was found. In addition, we checked for significant effect modification by adding indicator variables to the models and compared nested models using a likelihood ratio test.
Tests for linear trend across eGFR categories were performed by assigning the median value to each category and modeling this as a continuous variable in separate proportional-hazards models. To test for a curvilinear association, a quadratic term (the median value squared) was added to the above linear term in a separate model. Furthermore, a quadratic term (continuous squared) was added to the continuous variable of eGFR in a separate model. Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina). A 2-tailed p value <0.05 was considered to indicate statistical significance.
Results
The associations between baseline characteristics and eGFR categories are listed in Table 1 . There were significant differences for all baseline characteristics across the eGFR categories, except for body mass index, high-sensitivity C reactive protein, systolic blood pressure, diabetes, smoking, and alcohol consumption.
| Variable | GFR (ml/min/1.73 m 2 ) by CKD-EPI Equation | p Value ⁎ | |||
|---|---|---|---|---|---|
| ≥90 (n = 15,374) | 75–89 (n = 5,901) | 60–74 (n = 2,463) | <60 (n = 1,008) | ||
| Age (years) | 53.2 ± 6.0 | 56.4 ± 7.7 | 57.8 ± 8.0 | 58.1 ± 8.2 | <0.0001 |
| Total cholesterol concentration (mg/dl) | 203.7 ± 37.7 | 215.8 ± 38.2 | 229.6 ± 44.5 | 259.7 ± 58.9 | <0.0001 |
| Body mass index (kg/m 2 ) | 26.0 ± 5.1 | 25.6 ± 4.7 | 25.9 ± 4.8 | 25.8 ± 4.6 | 0.05 |
| C-reactive protein (mg/dl) | 2.0 (0.8–4.4) | 1.9 (0.8–4.2) | 2.1 (0.9–4.3) | 2.4 (1.0–5.0) | 0.05 |
| Systolic blood pressure (mm Hg) | 123.0 ± 13.3 | 124.0 ± 13.8 | 124.8 ± 13.7 | 125.5 ± 14.5 | 0.06 |
| Hypertension | 22.9% | 25.8% | 29.2% | 32.6% | <0.0001 |
| Antihypertensive treatment | 11.6% | 13.9% | 17.2% | 20.1% | <0.0001 |
| Diabetes mellitus | 2.4% | 2.1% | 2.4% | 2.4% | 0.73 |
| Physical activity | |||||
| Rarely/never | 37.1% | 35.8% | 37.8% | 36.1% | 0.003 |
| <1 time/week | 20.3% | 17.8% | 18.4% | 18.7% | |
| 1–3 times/week | 31.6% | 33.8% | 31.6% | 31.3% | |
| ≥4 times/week | 10.9% | 12.6% | 12.1% | 14.0% | |
| Smoking Status | |||||
| Never | 11.8% | 9.9% | 10.6% | 9.9% | 0.05 |
| Past | 36.2% | 37.7% | 36.5% | 38.4% | |
| Current | 52.0% | 52.4% | 52.9% | 51.7% | |
| Alcohol consumption | |||||
| Rarely/never | 43.9% | 42.2% | 44.2% | 43.3% | 0.16 |
| <1 drink/week | 13.6% | 13.0% | 12.6% | 13.4% | |
| 1–6 drinks/week | 32.4% | 33.4% | 32.9% | 33.3% | |
| ≥1 drink/day | 10.1% | 11.3% | 10.4% | 10.0% | |
| Postmenopausal hormone use | |||||
| Never | 50.2% | 46.8% | 45.5% | 44.6% | 0.0002 |
| Past | 7.2% | 9.9% | 11.5% | 11.6% | |
| Current | 42.6% | 43.3% | 43.1% | 43.8% | |
⁎ Based on Jonckheere-Terpstra tests for continuous variables and Mantel-Haenszel trend chi-square tests for categorical variables.
During a median follow-up period of 15.4 years, 786 women had ≥1 confirmed episode of incident AF. The age-adjusted incidence rates per 1,000 person-years across eGFR categories are listed in Table 2 . We did not find a significant linear association with incident AF across the full range of GFR categories in the age- or multivariate-adjusted models ( Table 2 ). Similarly, there was no association across eGFR categories and incident AF using the MDRD equation in the 2 models (data not shown). These results were not significantly altered when possible biologic intermediaries (systolic blood pressure, antihypertensive treatment, and high-sensitivity C-reactive protein) were excluded from the model (p for linear trend = 0.50). We also did not find any definitive evidence for a curvilinear relation between eGFR and AF in multivariate models using the medians across CKD-EPI categories (quadratic p = 0.10) or the continuous CKD-EPI variable for eGFR (quadratic p = 0.08).
| Variable | GFR (ml/min/1.73 m 2 ) by CKD-EPI Equation | p Value for Linear Trend ‡ | |||
|---|---|---|---|---|---|
| ≥90 (n = 15,374) | 75–89 (n = 5,901) | 60–74 (n = 2,463) | <60 (n = 1,008) | ||
| Number of events | 426 | 214 | 93 | 53 | |
| Age-adjusted incidence rate per 1,000 person-years | 2.15 | 2.21 | 2.01 | 2.61 | |
| Model 1 ⁎ | Referent | 0.94 (0.80–1.12) | 0.86 (0.68–1.08) | 1.22 (0.91–1.63) | 0.97 |
| Model 2 † | Referent | 0.99 (0.84–1.18) | 0.90 (0.71–1.14) | 1.36 (1.00–1.84) | 0.48 |
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