Among a large, diverse cohort of adults with CKD, we found that incident AF was independently associated with a 67% higher relative rate of subsequent ESRD, even after adjustment for a broad set of potential confounders. Furthermore, this association was consistent among all age, gender, racial and baseline eGFR subgroups. While previous literature has shown that CKD is associated with a high incidence and prevalence of AF,4–8
our novel results support that AF may contribute to an accelerated progression of CKD to ESRD independent of other known risk factors.
We found that the incidence of documented AF was high among patients with CKD, which supports and extends results from previous studies. For example, within the Atherosclerosis Risk in Community (ARIC) Study, during 10 years of follow-up, there was a graded, increased risk of incident AF with lower baseline eGFR or higher level of albuminuria, even after adjustment for other risk factors.4
In contrast, a study of patients with CKD with prevalent AF found that the graded association between lower eGFR and prevalent AF was no longer significant after adjustment for age, sex, race/ethnicity and study center.8
Previous studies have reported that AF is associated with worse long-term clinical outcomes in patients with ESRD.2
For example, among >17,000 dialysis patients enrolled in the international Dialysis Outcomes and Practice Patterns Study (DOPPS), AF at study enrollment was associated with higher rates of stroke (adjusted hazard ratio 1.28, 95% CI: 1.01–1.63) and death (adjusted hazard ratio 1.16, 95% CI: 1.08–1.25).3
Within the nationally representative U.S. Renal Data System between 1989 and 2006, the adjusted 1-year risk of death was 45% higher in dialysis patients with AF compared with those who did not have documented AF.1
In our study based on a large, diverse community-based cohort of adults with CKD, we found a higher mortality rate among those who developed incident AF. Even taking this into account, we demonstrated that incident AF was independently linked to a higher rate of ESRD, which is associated with tremendous morbidity and mortality. To our knowledge, there are no previously published studies that have evaluated the relation between incident AF and adverse renal events. In addition, we found relatively similar associations between incident AF and risk of ESRD in various patient subgroups (), including those without
a high burden of cardiovascular risk factors (e.g., younger age, female gender, higher eGFR level). While we focused on ESRD as a definitive clinical outcome, it is possible that AF may also be associated with the development and progression of CKD at earlier stages.
Several possible mechanisms may contribute to how AF could increase the risk of ESRD. AF promotes systemic inflammation,22–26
which has been strongly associated with progression of ESRD in patients with CKD.27, 28
Given that AF can also induce fibrosis within the myocardium,29
it is possible that this same fibrosis process is activated within the kidney as well, perhaps through a systemic pro-fibrotic tendency (although there is not definitive evidence for this mechanism). AF also contributes to decline of left ventricular systolic and diastolic function over time,30, 31
which may promote progression of CKD through altered hemodynamics,31, 32
venous congestion and activation of the renin-angiotensin-aldosterone system.33, 34
It is also possible that AF may be prothrombotic, leading to renal micro-infarcts, similar to silent cerebral infarcts that have been noted in patients with AF.35
It is possible that some of the medications used to treat AF may contribute to decline in renal function (e.g., diuretics).
Our study had several strengths. We examined a very large and diverse sample of well-characterized community-based adults across the spectrum of CKD, with outcomes through 2010. We were able to capture documented incident AF in both the inpatient and outpatient setting through validated diagnosis codes in health plan automated databases. We also had serial calibrated outpatient serum creatinine measurements available on entry into the study cohort to confirm the presence and severity of CKD. Our primary endpoint was ESRD requiring dialysis or renal transplant which was comprehensively captured, and we did not depend on outcomes based only on changes in estimated glomerular filtration rate which could be susceptible to ascertainment bias within a clinical practice population. Our study also had several limitations. As systematically timed measures of eGFR were not available in this cohort of CKD patients treated in a “real world” clinical practice setting, we were unable to evaluate intermediate outcomes such as the specific rate of decline of eGFR. We were not able to quantify accurately the severity of proteinuria as only urine dipstick results were available. We were also unable to determine the exact mechanisms explaining the association between AF and ESRD. We cannot completely rule out residual confounding, although we were able to statistically adjust for a wide range of potential explanatory factors, including differential exposure to relevant medications, blood pressure and hemoglobin level. We conducted our study among health plan members within a large integrated health care delivery system in northern California, so our findings may not be completely generalizable to other health care settings or to uninsured patients.
In conclusion, incident AF is associated with 67% higher relative rate of ESRD among patients with CKD, independent of known clinical risk factors and medical therapies. Further study is needed to delineate the contributing factors leading to the development of AF in the setting of CKD and potentially modifiable pathways through which AF leads to a higher risk of progression to ESRD.