Epidemiology and Outcomes

Reduced Kidney Function as a Risk Factor for Incident Heart Failure: The Atherosclerosis Risk in Communities (ARIC) Study

Anna Kottgen, Stuart D. Russell, Laura R. Loehr, Ciprian M. Crainiceanu, Wayne D. Rosamond, Patricia P. Chang, Lloyd E. Chambless and Josef Coresh
JASN April 2007, 18 (4) 1307-1315; DOI: https://doi.org/10.1681/ASN.2006101159

Abstract

Reduced kidney function is a risk factor for cardiovascular morbidity and mortality, and both heart failure (HF) and kidney failure incidences are increasing. This study therefore sought to determine the effect of decreased kidney function on HF incidence in a population-based study of middle-aged adults. From 1987 through 2002, 14,857 participants of the Atherosclerosis Risk in Communities (ARIC) study who were free of prevalent HF at baseline were followed for incident HF hospitalization or death (International Classification of Diseases, Ninth Revision/10th Revision 428/I50). Estimated GFR (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation, and kidney function was categorized as normal (eGFR ≥90 ml/min per 1.73 m2; n = 7143), mildly reduced (eGFR 60 to 89 ml/min per 1.73 m2; n = 7311), and moderately/severely reduced (eGFR <60 ml/min per 1.73 m2; n = 403). Cox proportional hazards models were used to control for demographic and cardiovascular risk factors; analyses were stratified by the presence of coronary heart disease at baseline. During a mean follow-up of 13.2 yr, 1193 participants developed HF. The incidence of HF was three-fold higher for individuals with eGFR <60 ml/min per 1.73 m2 compared to the reference group with eGFR ≥90 ml/min per 1.73 m2 (18 versus 6 per 1000 person-years). The overall adjusted relative hazard of developing HF was 1.94 (1.49 to 2.53) for individuals with eGFR <60 ml/min per 1.73 m2 compared to the reference group and was significantly increased for individuals with and without prevalent coronary heart disease at baseline. A substantially greater decline in kidney function occurred in individuals concomitant with HF hospitalization/death compared to those who did not develop HF. In summary, middle-aged adults with moderately/severely reduced kidney function are at high risk for developing HF.

Reduced kidney function has been established as a risk factor for cardiovascular disease (CVD) in several recent studies, both in populations at high risk for CVD and in the general population (1–7). Moderately reduced kidney function is very common, affecting an estimated 8.3 million US adults (8). Specifically, reduced kidney function has been proposed as a risk factor for deterioration of prevalent heart failure (HF) as well as a risk factor for incident HF (9–15). However, most previous studies were restricted to subgroups such as elderly individuals (9–11,13), predominantly white individuals (16), or individuals with preexisting coronary heart disease (CHD) (12). These individuals might be at increased risk for incident HF as a result of advanced age or comorbidities. Therefore, we sought to determine the role of impaired kidney function as a risk factor for incident HF in a large, population-based, biracial study of middle-aged US adults, the Atherosclerosis Risk in Communities (ARIC) Study. We hypothesized that individuals with reduced kidney function are at increased risk for incident HF and sought to estimate both the absolute risk and the adjusted relative risk.

Chronic kidney disease (CKD) and HF often occur together (1,14,17,18), but relatively few studies have data on the decline in kidney function in relation to incident HF. A recent study of individuals with left ventricular systolic dysfunction reported significantly higher mortality for those with a more rapid compared to those with a slower decline in kidney function (19). Using data from multiple ARIC study visits, we also investigated the changes in kidney function in the years before and after the first HF hospitalization.

Finally, previous studies did not account for the impact of measurement error and biologic variability in serum creatinine on the association between reduced kidney function and incident HF. Therefore, it is useful to use models that take into account variability in estimated kidney function that is assessed using a creatinine-based estimating equation, a procedure that is feasible in a large population-based study but subject to sizable measurement error as a result of both biologic and measurement variation (20).

Materials and Methods

Study Population and Design

The ARIC Study is a community-based prospective cohort to investigate the etiology of atherosclerosis (21). From 1987 to 1989, 15,792 male and female volunteers aged 45 to 64 were recruited by probability sampling from four US communities (Forsyth County, NC; suburban Minneapolis, MN; Washington County, MD; and Jackson, MS). The baseline visit (visit 1) included at-home interviews, laboratory measurements, and clinic examinations. The study participants returned for additional visits in 1990 to 1992 (visit 2), 1993 to 1995 (visit 3), and 1996 to 1998 (visit 4). Details of the enrollment process and study procedures are fully described elsewhere (21).

Baseline Variables and Data Collection

The study participants provided information on demographic, socioeconomic, health behavior, risk factor control, and medical history variables to a trained interviewer at the baseline visit. Resting, seated systolic (SBP) and diastolic blood pressure (DBP) measurements were recorded by certified technicians using a random-zero sphygmomanometer, and the average of the second and third readings was used. Body mass index was calculated as measured weight (kg)/height (m2). Medication use was self-reported and verified by the inspection of medication bottles. For laboratory measurements, fasting blood samples were drawn, centrifuged, frozen, and shipped to ARIC study laboratories for analysis (22). Measurement of serum glucose, albumin, and plasma LDL and HDL followed standard ARIC protocols (23,24). Ultrasound examinations to assess the presence of carotid atherosclerosis have been described previously (25). Serum creatinine was measured using a modified kinetic Jaffe reaction from serum samples at visits 1 and 2 and plasma samples at visit 4 (24). Kidney function was then assessed by calculation of the estimated GFR (eGFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation (26): eGFR (ml/min per 1.73 m2) = 186.3*(serum creatinine in mg/dl−1.154)*(age−0.203)*(0.742 if female)*(1.21 if black). For obtaining more valid estimates from this formula, creatinine values were standardized across ARIC study visits, and creatinine values from all ARIC visits were calibrated using regression to the Cleveland Clinic laboratory, where the MDRD equation was developed, by subtraction of 0.24 mg/dl from visits 1 and 2 and addition of 0.18 mg/dl to visit 4 (2,27).

Assessment of HF

Study participants with evidence of prevalent HF (n = 752) at baseline were excluded from analyses. Prevalent HF was defined as the reported current intake of HF medication at visit 1 (n = 83) or evidence of manifest HF as defined by the Gothenburg criteria stage 3 (n = 669), which require the presence of specific cardiac and pulmonary symptoms as well as medical treatment of HF (28,29).

Incident HF was defined as the first HF hospitalization or HF coded as the underlying cause of death and was identified through review of local hospital discharge lists that showed HF in any position and county death certificates. Hospitalizations were coded as heart failure (428) using the International Classification of Diseases Code, Ninth Revision (ICD-9), and deaths were coded as HF (428 and I50) using the ICD-9 and ICD-10. All cohort hospitalizations and deaths that occurred before January 1, 2003, were included.

Statistical Analyses

Analyses were limited to 14,857 participants, excluding those with prevalent HF (n = 752) and those who were missing information that was needed to calculate eGFR (race, n = 47; baseline serum creatinine, n = 136). Current smoking (yes, no), completed years of education (<12, 12 to 16, >16), and evidence of atherosclerosis of the common carotid arteries on ultrasound examination (shadowing or plaque on either side, none) were categorized. Use of antihypertensive medication at baseline included the use of α, β, and calcium channel blockers, angiotensin-converting enzyme inhibitors, diuretics, or a combination thereof. SBP (mmHg) and age (years) were analyzed continuously. Prevalent diabetes was defined as a fasting serum glucose level ≥126 mg/dl, nonfasting glucose level ≥200 mg/dl, report of a physician diagnosis of diabetes, or current use of diabetes medication. Prevalent CHD was based on evidence of previous myocardial infarction by electrocardiogram at visit 1, history of physician-diagnosed myocardial infarction, and previous coronary reperfusion procedure (bypass, angioplasty). Anemia was defined as present for hemoglobin values <13.5 g/dl in men and <12 g/dl in women. Kidney function was categorized using national guidelines (30) as normal (eGFR ≥90 ml/min per 1.73 m2), mildly decreased (eGFR 60 to 89 ml/min per 1.73 m2), and moderately or severely (eGFR <60 ml/min per 1.73 m2). The last category includes individuals with moderately (eGFR 30 to 59 ml/min per 1.73 m2) and severely (eGFR <30 ml/min per 1.73 m2) decreased kidney function, because only 25 individuals had severely decreased kidney function at baseline. eGFR as a measure of kidney function was also modeled continuously and was explored for deviations from linearity using linear spline models. To account for measurement error in eGFR, these analyses were repeated using the simulation extrapolation (SIMEX) methodology (31).

Analyses were conducted using Stata version 9.2 software (32). Demographic and health characteristics by eGFR and HF status were compared using χ2 tests, t tests, and ANOVA as applicable. HF incidence rates and 95% confidence intervals (CI) were calculated using time-to-event methods. The proportion of individuals who remained free of incident HF at any time during follow-up was calculated using the Kaplan-Meier method. For all survival analyses, the follow-up time was defined as the period from entry into the study (visit 1) to the first HF hospitalization, death from HF, or up to the time an individual left the study. Individuals who were free of HF by January 1, 2003, were subject to administrative censoring. Relative hazards (RH) of incident HF in those with a reduced compared with those with a normal level of kidney function were calculated using Cox proportional hazards models. Extended models that subsequently adjusted for covariates as well as for interactions between covariates were compared with nested models using likelihood ratio tests. The proportionality assumption of all Cox models was assessed by inspection of the complementary log(−log[survival function]) curves. Changes in eGFR between study visits were plotted using an Epanechnikov kernel density estimator for smoothing (33), and the proportion of individuals with a decline of eGFR ≥25% (34) between study visits was assessed by HF status.

Results

Of the 14,857 participants who were available for analysis, 7143 (48.1%) had an eGFR of ≥90 ml/min per 1.73 m2 at visit 1, 7311 (49.2%) had an eGFR of 60 to 89 ml/min per 1.73 m2, and 403 (2.7%) had an eGFR of <60 ml/min per 1.73 m2. Participants were followed for an average (SD) of 13.2 (3.0) years. Of the total study population, 45.6% were male, 25.9% were black, and the mean age (SD) was 54.1 (5.8) years at baseline. During the course of follow-up, 2079 (14.0%) study participants died.

Baseline Characteristics

The mean baseline eGFR (SD) of the total study population was 93.2 (20.7) ml/min per 1.73 m2. The baseline characteristics of participants in each of the three eGFR categories are presented in Table 1. In general, the prevalence of cardiovascular risk factors except for male gender and smoking was significantly higher with reduced kidney function.

View this table:
Table 1.

Baseline characteristics of study population (n = 14,857) by eGFR category (ml/min per 1.73 m2)a

Baseline characteristics of participants by HF status are compared in Table 2. Because the presence of CHD at baseline was significantly related to both main exposure and outcome, analyses were conducted to stratify the group of individuals who developed HF by the presence of CHD at baseline. A total of 180 (15.5%) individuals who developed HF had evidence of CHD at baseline, and these individuals differed significantly with respect to several cardiovascular risk factors from those who developed HF without prevalent CHD at baseline (Table 2).

View this table:
Table 2.

Baseline characteristics of individuals who developed HF versus those who did not develop HFa

Incidence of HF

During the course of follow-up, 1193 study participants developed HF. Of these, 1187 (99.5%) were identified through a hospitalization. The overall incidence rate of HF was 6.1 per 1000 person-years. Crude and age-adjusted incidence rates of HF are presented in Table 3; the reduction of age-adjusted HF incidence rates compared to crude HF incidence rates in the categories of reduced kidney function reflects the higher proportion of older individuals with reduced kidney function. Crude and age-adjusted incidence rates of HF were significantly higher in individuals with baseline eGFR <60 ml/min per 1.73 m2 as compared with those with eGFR ≥90 ml/min per 1.73 m2. Again, analyses were stratified by presence of CHD at baseline, yielding crude HF incidence rates in those with prevalent CHD at baseline that were up to fives times as high as in those without prevalent CHD (Table 3).

View this table:
Table 3.

Incidence rates of HF in the ARIC cohort by baseline eGFRa

Survival Analyses

Figure 1 shows the cumulative incidence of HF during the course of follow-up by category of eGFR and presence (Figure 1a) or absence (Figure 1b) of CHD at baseline. A higher proportion of individuals with eGFR <60 ml/min per 1.73 m2 developed incident HF as compared to individuals in either of the other two categories of renal function. The difference between the cumulative incidence curves was highly significant (logrank test P < 0.001 for no CHD, 0.01 for CHD at baseline). After 13 yr of follow-up, 19.0% of individuals with eGFR <60 ml/min per 1.73 m2 and no baseline CHD experienced an HF hospitalization/HF death, compared to 51.1% with baseline CHD (Figure 1, a and b).

Figure 1.
Figure 1.

Cumulative incidence of heart failure (HF) stratified by category of estimated GFR (eGFR) and presence of coronary heart disease (CHD) at baseline in 14,824 Atherosclerosis Risk in Communities (ARIC) Study participants. Cumulative incidence curves for CHD-negative individuals (a) in the eGFR categories of 90 and 60 to 89 ml/min per 1.73 m2 are virtually indistinguishable.

Analyses using Cox proportional hazards models yielded crude RH of incident HF of 1.05 (95% CI 0.93 to 1.18) for individuals with eGFR of 60 to 89 ml/min per 1.73 m2 and 3.24 (95% CI 2.56 to 4.09) for those with eGFR <60 ml/min per 1.73 m2 compared to those with eGFR ≥90 ml/min per 1.73 m2. Models that subsequently adjusted for baseline demographic factors and traditional and nontraditional CVD risk factors attenuated the RH: the fully adjusted model (adjusted for age, gender, race, level of education, SBP, use of antihypertensive medication, smoking, diabetes, body mass index, CHD at baseline, LDL and HDL cholesterol, serum albumin, anemia, and carotid atherosclerosis) yielded RH of 1.10 (95% CI 0.97 to 1.26, eGFR 60 to 89 ml/min per 1.73 m2) and 1.94 (95% CI 1.49 to 2.53, eGFR <60 ml/min per 1.73 m2; Table 4), and fit the data significantly better than a model that adjusted for demographics and traditional CVD risk factors only (likelihood ratio test P < 0.001). The significantly increased RH of incident HF in individuals with eGFR <60 ml/min per 1.73 m2 compared to those with eGFR ≥90 ml/min per 1.73 m2 was observed in individuals with and without CHD at baseline (Table 4). Moreover, the significant findings comparing individuals with eGFR <60 ml/min per 1.73 m2 to those with eGFR ≥90 ml/min per 1.73 m2 and using the fully adjusted model held when individuals who were free of prevalent CHD and remained free of incident CHD up to and at the incidence of HF were evaluated (RH 2.12; 95% CI 1.48 to 3.02; n = 13,146). Finally, the association of reduced kidney function with HF incidence remained similar when SBP and the intake of antihypertensive medication were incorporated as time-varying covariates into the fully adjusted Cox model (eGFR 60 to 89 ml/min per 1.73 m2: RH 1.11 [95% CI 0.97 to 1.26]; eGFR <60 ml/min per 1.73 m2: RH 2.06 [95% CI 1.59 to 2.69] compared with eGFR <60 ml/min per 1.73 m2 for all individuals, n = 13,711).

View this table:
Table 4.

Adjusted relative hazard (95% CI) of HF by category of eGFRa

eGFR was also modeled continuously using a piece-wise linear spline model with and without accounting for measurement error in eGFR (SD of eGFR measurement error 8.8; reliability coefficient 0.82). Models that incorporated as many as five spline terms were explored. Figure 2 shows this model as well as a model that retains the only statistically significant knot at 90 ml/min per 1.73 m2. Below an eGFR of 90 ml/min per 1.73 m2, the RH of incident HF was 1.21 (95% CI 1.14 to 1.29) per 10 ml/min per 1.73 m2 lower eGFR, whereas it was 0.94 (95% CI 0.91 to 0.99) per 10 ml lower eGFR for eGFR values ≥90 ml/min per 1.73 m2 (P interaction = 0.008). The increase in RH of HF was not significantly different in individuals with eGFR <60 ml/min per 1.73 m2 compared with those with eGFR of 60 to 89 ml/min per 1.73 m2 (P interaction = 0.145). Accounting for measurement error in eGFR led to a 33% higher RH of incident HF below an eGFR of 90 ml/min per 1.73 m2: The RH of HF was 1.28 (95% CI 1.19 to 1.37) per 10 ml/min per 1.73 m2 lower eGFR.

Figure 2.
Figure 2.

Relative hazard (RH) of incident HF across the range of continuous GFR values before and after accounting for measurement error in eGFR. eGFR is modeled using linear spline models with one knot (at 90 ml/min per 1.73 m2; solid lines) and five knots (at 60, 75, 90, 105, and 120 ml/min per 1.73 m2; dashed lines). Estimates are shown before (black) and after (gray) accounting for measurement error. Tick marks along the x axis indicate eGFR values for individual participants.

A significant interaction of race and eGFR was present: Using the fully adjusted model and individuals with eGFR ≥90 ml/min per 1.73 m2 as the reference category, the RH of HF in individuals with eGFR of 60 to 89 ml/min per 1.73 m2 was significantly higher in black compared to white individuals (1.57 [95% CI 1.25 to 1.98] versus 0.94 [95% CI 0.81 to 1.10]). In individuals with eGFR <60 ml/min per 1.73 m2, the RH of HF was higher, although not statistically significant, in black compared to white individuals (2.40 [95% CI 1.57 to 3.67] versus 1.69 [95% CI 1.21 to 2.36]). There was no significant interaction between reduced eGFR and diabetes status at baseline or between reduced eGFR and hypertension status at baseline (hypertension defined as SBP ≥140 mmHg, DBP ≥90 mmHg, or the current intake of antihypertensive medication). Significant interactions between age in 5-yr intervals and both diabetes and CHD did not alter the association of reduced kidney function and incident HF.

To address the temporality of a decline in kidney function and the first HF hospitalization/HF death, we compared the percentage change in eGFR between the study visits of those who developed the study outcome between visits 2 and 4 (on average 3 and 9 yr after baseline) and of those who did not develop HF by visit 4. A ≥25% eGFR decline between visits 1 and 2 was present to a similar extent in those who experienced the first HF hospitalization/HF death between visits 2 and 4 and those who did not (7.8% versus 8.6%). However, a ≥25% eGFR decline in the time interval between visits 2 and 4 was present to a much greater degree in individuals who experienced the first HF hospitalization/HF death during that time interval compared to those who did not (25.7% versus 6.6%; P < 0.001; Figure 3). Therefore, a high rate of decline in kidney function several years before HF hospitalization is not a very strong risk factor for HF incidence, whereas the first HF hospitalization is strongly associated with having a substantial decrement in kidney function detected at a visit that on average was approximately 2 yr after the hospitalization.

Figure 3.
Figure 3.

Percentage change in eGFR between study visits 2 and 4 in individuals who developed HF between visits 2 and 4 (black) versus those who did not develop HF by visit 4 (gray). Percentages in boxes refer to the proportion of individuals with an eGFR decline of ≥25% (25.7% of those who developed HF and 6.6% of those who did not develop HF between visits 2 and 4). Vertical lines represent the mean percentage change in eGFR between study visits 2 and 4 in those who developed (black) and did not develop (gray) HF.

Discussion

In this analysis of the ARIC Study as a prospective, community-based, biracial sample of middle-aged adults, reduced kidney function was an independent risk factor for incident HF hospitalization or HF death. This finding is in agreement with most previously published studies (9,10,12,13,15). The two studies that found no significant association between reduced eGFR and incident HF after adjustment for cardiovascular risk factors used serum creatinine instead of a GFR estimating equation as a measure of kidney function (16,35).

National guidelines define normal kidney function as eGFR ≥90 ml/min per 1.73 m2. Our analyses of eGFR as a continuous variable show that the higher risk for HF starts below this threshold, and the risk increases further as eGFR is <60 ml/min per 1.73 m2. At baseline, 3.0% of our study population had moderately or severely reduced kidney function (eGFR <60 ml/min per 1.73 m2) and would therefore be classified as having CKD stage 3 or higher following national guidelines (30). This proportion is in agreement with numbers reported for the general US population as represented in the Third and Fourth National Health and Nutrition Examination Surveys (NHANES III/IV) (8,36). After exclusion of 4.8% of the total study population because of prevalent HF, these 3% were reduced by 10%, confirming the observation from previous studies that CKD is overrepresented in individuals with prevalent HF (17,18,37). That almost half of our study population had an eGFR of 60 to 89 ml/min per 1.73 m2 at baseline corresponding to mildly reduced kidney function is in agreement with estimates from the population-based data of NHANES III for this age range (8). Therefore, HF risk relates to estimates of kidney function in a large proportion of the population with the caveat that GFR estimates in this mildly decreased range are substantially less reliable and are strongly influenced by the source population (20). In addition, our observation that 8.0% of our study population experienced incident HF hospitalization/HF death during the course of follow-up corresponds well to data from other large US prospective studies of community-dwelling individuals of comparable age (38,39).

The study population's baseline distribution of characteristics by outcome (HF) is consistent with the most common cause of HF. Considering that CHD is the underlying cause for up to 70% of HF cases in the United States (38–40), one would expect to observe a statistically significantly higher proportion of individuals who develop HF with risk factors for CHD. Because CHD is also associated with CKD (2,4,5,7,41), we stratified our analyses by the presence of this important potential confounder at baseline. Still, the fully adjusted RH of incident HF in individuals without CHD at baseline and eGFR <60 ml/min per 1.73 m2 compared to those with eGFR ≥90 ml/min per 1.73 m2 was substantial at 1.83 (95% CI 1.37 to 2.45; Table 4). The fully adjusted model included adjustment for two other important potential confounders, SBP and diabetes, as well as for baseline anemia and serum albumin. Because BP elevations, anemia, and lower serum albumin are known consequences of reduced kidney function, adjusting for them to some extent overadjusts the true association between reduced kidney function and incident HF. However, evidence exists that the effect of anemia and low serum albumin as a result of albuminuria, inflammation, and malnutrition are associated with increased cardiovascular risk beyond simply being measures of reduced kidney function (42–45).

Many patients with HF have impaired kidney function (14,19). Our study supports this observation, because the proportion of individuals with eGFR <60 ml/min per 1.73 m2 was approximately three times greater in individuals who were excluded because of prevalent HF than in individuals who were classified as free of HF at baseline (7.7% versus 2.7%). This observation can result from two causal pathways: Reduced eGFR leading to HF, or HF leading to reduced eGFR. Our observation that reduced eGFR is an independent risk factor for incident HF hospitalization/HF death is consistent with the hypothesis that reduced kidney function contributes to mechanisms that lead to incident HF. Volume overload and renin-angiotensin-aldosterone system–mediated increase in BP and cardiac remodeling (46) are known consequences of CKD, which likely contribute to this direction of the observed association between reduced eGFR and incident HF. CKD-related abnormalities in nitric oxide balance, coagulation/fibrinolysis, homocysteine, inflammation, and lipids may contribute as well. Moreover, excess comorbidities, lesser use of beneficial therapies, and excess toxicities from conventional therapies are important to consider as reasons for elevated cardiovascular risk in CKD in addition to the vascular pathobiology of CKD (42). Prevalent HF that leads to worsening kidney function (17,18) can plausibly be explained by decreased renal perfusion as a result of reduced cardiac output as well as neurohumoral mechanisms. The observation that reduced renal function occurred concomitantly with our study outcome could also be due either to subclinical HF or to a common underlying cause, such as CVD first manifesting itself in the kidneys.

The inability to account for the effect of subclinical HF on worsening kidney function over the entire length of follow-up is a limitation of our findings. Of the exclusions for prevalent HF, 89% were based on the Gothenburg criteria, which are reported to have high specificity (96%; SD 0.8) but only moderate sensitivity (41%; SD 4.2) for diagnosis of HF in the community (47). We therefore might have failed to exclude some individuals with prevalent HF. However, the number of middle-aged individuals who had HF and were missed by our exclusion criteria is likely to be small given the low prevalence of HF in this middle-aged, community-based population. Additional sensitivity analyses that were conducted to address this issue showed that exclusion of events that occurred in the first 3 and the first 6 yr of follow-up did not alter our results.

Other limitations of our study are related to the lack of chart abstraction of HF events by an adjudication committee and to the estimation of GFR using the MDRD Study equation. We therefore conducted sensitivity analyses to address the possibility that acute renal failure was misclassified as HF, excluding from our analyses 126 individuals with ICD-9 codes 584.00 to 584.99 for acute renal failure; our significant results remained unchanged. Whereas estimates that incorporate serum creatinine are valid at lower eGFR levels, they are less precise at higher eGFR levels (20,48). Also, the indirect calibration of the ARIC serum creatinine values to the Cleveland Clinic laboratory where the MDRD equation was developed may have resulted in some inaccuracy of the eGFR. However, this would have been true at all creatinine levels, producing a relatively small effect on the association of eGFR with HF. The existence of only one measurement of serum creatinine per study visit leaves potential for misclassification of eGFR category. As a result, because of regression dilution bias, the RH that we observed in the category of lowest eGFR may have underestimated the association observed without error, and estimates that we present in Figure 3 correcting for measurement error may be more appropriate. Moreover, we cannot exclude the possibility that individuals have changed exposure category after the last measurement of serum creatinine at visit 4 but before their developing HF. Finally, although we adjusted for a large number of traditional and nontraditional CVD risk factors, we cannot rule out residual confounding by unmeasured factors.

Our study has several advantages, including a large, prospective, community-based setting that represents an age group that is at risk for development of kidney dysfunction as well as HF. Furthermore, the ARIC study population is biracial, and RH of HF that were derived from our study should therefore be more generalizable to the middle-aged US population. In addition, the repeated visits of ARIC study participants allowed for investigation of the temporality of change in eGFR in relation to our study outcome. Moreover, we could account not only for prevalent CHD at baseline but also for incident CHD up to the HF event in our analyses. Finally, we were able to account for the effect of measurement error in eGFR.

Conclusion

Moderately and severely reduced kidney function as defined by national guidelines is an independent risk factor for incident HF hospitalization or HF death in a population-based sample of middle-aged individuals. eGFR as an important risk marker should be calculated not only by nephrologists but also by cardiologists and could then help in risk stratification and management of patients who are at risk for HF.

Disclosures

None.

Acknowledgments

The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022.

We thank the staff and participants of the ARIC study for their important contributions, and Kathryn Carson for assistance with data preparation.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

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Reduced Kidney Function as a Risk Factor for Incident Heart Failure: The Atherosclerosis Risk in Communities (ARIC) Study
Anna Kottgen, Stuart D. Russell, Laura R. Loehr, Ciprian M. Crainiceanu, Wayne D. Rosamond, Patricia P. Chang, Lloyd E. Chambless, Josef Coresh
JASN Apr 2007, 18 (4) 1307-1315; DOI: 10.1681/ASN.2006101159
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