Renal Insufficiency and Subsequent Death Resulting from Cardiovascular Disease in the United States

Study Population

Participants were selected by using a stratified, multistage, probability sampling design, with certain subpopulations being purposely oversampled. As described elsewhere (7), interview and examination data were collected for 14,407 NHANES II participants (age, 17 to 74 yr; response rate, 73%) between 1976 and 1980; of those, all 9250 participants of age 30 to 74 yr were included in the NHANES II Mortality Study. The analyses described here were limited to black subjects and white subjects, because of the small number of participants of other races (n = 153). Persons for whom any covariate information was missing were excluded from this study (n = 28). Additionally, participants with serum creatinine levels of ≥3.0 mg/dl were excluded because of the high probability that they had end-stage renal disease (n = 15). An additional 2989 participants were excluded from the creatinine analyses, primarily because of the loss of serum samples during shipping. Urinary protein measurements were not available for 305 otherwise eligible participants. After these exclusions, 8768 participants were included in the urinary protein analyses and 6534 in the estimated GFR analyses.

Baseline Measurements

Serum creatinine levels were measured by using a Jaffé reaction Smac Technicon device (Western Laboratories, Oakland, CA). Ames reagent strips were used to test for the presence of protein in urine samples.

In addition to demographic information, a history of heart attacks or strokes, recreational physical activity (much, moderate, or little or no activity), the highest grade of education completed, and current smoking status were assessed for each patient, on the basis of self-reported information. Two BP measurements were obtained by a specially trained physician, using a mercury sphygmomanometer. In addition, the body mass index and serum total cholesterol level were measured. Diabetes mellitus was defined as a self-reported history of the disorder or a fasting plasma glucose level of ≥126 mg/dl.

Mortality Assessments

Vital status as of December 31, 1992, was assessed for all NHANES II participants who were 30 to 74 yr of age (n = 9250) at the time of the baseline examinations, using the National Death Index and the Social Security Administration Death Master File, as described elsewhere (8). The sensitivity and specificity of outcome assessments using the National Death Index with the same variables but different matching criteria have been estimated to be 87 to 97% and 99% (9–12), respectively, whereas the sensitivity of matching to Social Security Administration data was only 70% (8). In addition to death from all causes, the following cause-specific mortality definitions (death codes from the 9th version of the International Classification of Diseases) were used in our analyses: cardiovascular disease (390 to 459), coronary disease (410 to 414), stroke (430 to 430.9, 436, 437.0, and 437.1), and congestive heart failure (428.0, 428.1, and 428.9).

Statistical Methods

Analyses of death from all causes, cardiovascular disease, heart disease, congestive heart failure, or stroke were conducted separately for estimated GFR and urinary protein levels, as measures of renal function, and used population-sampling weights developed for the NHANES II data set.

For analyses using dipstick urinary protein measurements, the experiences of participants with urinary protein levels of 30 to 299 mg/dl and ≥300 mg/dl were compared with those of their counterparts with urinary protein levels of <30 mg/dl. GFR was estimated by using the abbreviated equation developed at the Cleveland Clinic laboratory for the Modification of Diet in Renal Disease Study, as follows: GFR = 186.3 × (serum creatinine level)^−1.154 × age^−0.203 × (0.742 if female) × (1.21 if black) (13). GFR analyses were performed after categorization of participants using distribution cutoffs, i.e., >20th percentile (highest GFR), 5th to 20th percentile, or <5th percentile (lowest GFR). Estimated GFR is calculated for ml/min per 1.73 m².

Incidence rates and relative hazards were calculated on the basis of participant age rather than follow-up time (14). Because all-cause mortality rates were disproportionately high after age 85 yr and few participants contributed person-time experience in that age category, all analyses were truncated at that age. Crude cumulative mortality rates were calculated and cumulative mortality curves were plotted according to estimated GFR and urinary protein levels. Because the calculation of cumulative mortality rates is sensitive to small sample sizes, the assessment of cumulative mortality rates was limited to participants who were 50 to 85 yr of age during the follow-up period. Cox proportional-hazards regression analyses were used to determine the adjusted relative risks (and 95% confidence intervals) of death from all causes and the prespecified causes associated with estimated GFR and urinary protein levels, after adjustment for nonmodifiable factors (age, race, and gender) and additional adjustment for baseline systolic BP, cholesterol levels, diabetes mellitus, a history of major cardiovascular disease (myocardial infarction or stroke), body mass index, education, and physical inactivity. Updated measurements for potential confounders are not available for the NHANES II Mortality Study.

The consistency of the associations was assessed by using subgroup analysis and tests for interaction for each of the outcomes. Additionally, all analyses were replicated using elevated serum creatinine levels as the marker of renal function. These analyses were performed after categorization of the participants using the following gender-specific serum creatinine level distribution cutoffs: <80th percentile (lowest creatinine level), 80th to 95th percentile, or >95th percentile (highest creatinine level). All analyses were performed by using Stata version 6.0 (15) and Coxreg (a program developed by the National Cancer Institute for analysis of weighted time-to-event data).

Baseline Characteristics

Of the 8786 participants with urinary protein measurements, 196 and 62 exhibited levels of 30 to 299 and ≥300 mg/dl, respectively (Table 1). The 5 and 20% cutoffs for the estimated GFR distribution were 70 and 90 ml/min, respectively (Table 1). Mean age, systolic and diastolic BP, cholesterol levels, and body mass index all increased with progressively higher urinary protein levels and lower estimated GFR values. The proportion of the sample with diabetes mellitus or a history of cardiovascular disease was also higher with increasing urinary protein levels and decreasing estimated GFR values (P trend < 0.01). However, black subjects exhibited higher urinary protein and estimated GFR levels.

Urinary Protein Measurements

The 8768 NHANES II participants with baseline urinary protein measurements contributed 115,688 person-yr of follow-up data (Table 2). Graded positive associations were noted between higher baseline urinary protein levels and subsequent death as a result of all causes, cardiovascular disease, coronary disease, or congestive heart failure (Figure 1). After adjustment for age, race, and gender and additional adjustment for systolic BP, serum total cholesterol levels, body mass index, diabetes mellitus, a history of cardiovascular disease, physical inactivity, and the level of education, greater baseline urinary protein excretion was associated with increased mortality rates from all causes, cardiovascular disease, and congestive heart failure during the follow-up period (each P trend ≤ 0.03) (Table 2). In contrast, a higher baseline level of urinary protein excretion was significantly associated with increased heart disease-related mortality rates after adjustment for age, race, and gender but the relationship was not statistically significant after full adjustment (P trend = 0.29). A total of 194 stroke-related deaths were noted during follow-up monitoring; however, only two and four stroke-related deaths occurred among patients with urinary protein excretion levels of 30 to 299 and ≥300 mg/dl, respectively. Although urinary protein excretion of ≥300 mg/dl was associated with increased age-, race-, and gender-adjusted relative hazard (and 95% confidence interval) for stroke-related death [4.37 (1.11 to 17.1)], the association was decreased and was not statistically significant after full adjustment [1.80 (0.40 to 8.17)].

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Figure 1. Cumulative mortality curves for 8786 Second National Health and Nutrition Examination Survey (NHANES II) Mortality Study participants, on the basis of urinary protein category (no/trace, 30 to 299 mg/dl, or ≥300 mg/dl), for death resulting from all causes, cardiovascular disease, coronary disease, or congestive heart failure.

The presence of urinary protein (≥30 mg/dl) at the baseline examination was statistically significantly associated with an increased risk of death from all causes for each of the subgroups identified in Table 3, except for black subjects and subjects with histories of cardiovascular disease. With the exception of subjects with histories of cardiovascular disease, participants with baseline urinary protein levels of ≥30 mg/dl exhibited a higher risk of subsequent cardiovascular disease-related death; however, the 95% confidence interval included the null value for each of the subgroups except white subjects, female subjects, nonsmokers, and subjects without a history of cardiovascular disease (Table 3). The relative risk of coronary disease-related death was also greater for persons with baseline urinary protein levels of ≥30 mg/dl in all subgroups except subjects with histories of cardiovascular disease; however, the 95% confidence intervals included the null values for all of the subgroups except persons with diabetes mellitus and subjects with no history of cardiovascular disease. The relative risks of death from all causes, cardiovascular disease, or coronary disease associated with baseline urinary protein levels of ≥30 mg/dl were significantly lower among subjects with histories of cardiovascular disease, compared with those without (each P interaction < 0.02).

Estimated GFR

The 6453 NHANES II participants with baseline serum creatinine measurements contributed 84,025 person-yr of follow-up data to the estimated GFR analysis. Additionally, 1240 subjects died during the 12- to 16-yr follow-up period (797 died as a result of cardiovascular disease) (Table 4). After adjustment for age, race, and gender, all-cause mortality rates, cardiovascular disease-related mortality rates, and other cause-specific outcome rates were similar for subjects with estimated GFR of ≥90 ml/min and 70 to 89 ml/min but were higher for subjects with estimated GFR of <70 ml/min (Figure 2 and Table 4). Even after additional adjustment for systolic BP, serum total cholesterol levels, body mass index, diabetes mellitus, a history of cardiovascular disease, physical inactivity, and the level of education, patients with estimated GFR of <70 ml/min were at increased risk of all-cause-related, cardiovascular disease-related, and coronary disease-related death, compared with participants with estimated GFR of ≥90 ml/min. The corresponding relative hazards for congestive coronary failure-related death were >1, but the confidence limits included the null values. There were only 26 and 12 stroke-related deaths among patients with estimated GFR of 70 to 89 ml/min and <70 ml/min, respectively, and no statistically significant association with estimated GFR was noted (data not shown). Additionally, results obtained using serum creatinine levels were markedly similar to the associations detected using estimated GFR (data not shown).

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Figure 2. Cumulative mortality curves for 6354 NHANES II Mortality Study participants, with estimated GFR of <70 ml/min, 70 to 89 ml/min, or ≥90 ml/min, for death resulting from all causes, cardiovascular disease, coronary disease, or congestive heart failure.

Within all subgroups, subjects with estimated GFR of <70 ml/min were at increased risk of death from all causes, cardiovascular disease, or coronary disease, compared with participants with estimated GFR of ≥90 ml/min (Table 5). However, for all-cause-related death, the 95% confidence intervals included the null values for black subjects and subjects with histories of cardiovascular disease. For cardiovascular disease-related death, the confidence interval included the null value for black subjects. For coronary disease-related death, the confidence intervals included the null values for current smokers and subjects with chronic cardiovascular disease. The relative hazards of coronary disease-related death associated with estimated GFR of <70 ml/min were higher for black subjects, compared with white subjects (P interaction ≤ 0.001). Although differences in the relative hazards of all-cause-, cardiovascular disease-, and coronary disease-related death were observed between subjects with and without diabetes mellitus, tests for interaction did not indicate statistical significance (P interaction = 0.16, 0.20, and 0.07, respectively).