NHANES III and NHANES 1999–2004 are cross-sectional nationally representative surveys of the noninstitutionalized civilian population of the U.S. Briefly, each survey employs a multistage stratified probability sample based on selection of counties, blocks, households, and persons within households. Mexican-Americans, non-Hispanic blacks, and older adults were oversampled in order to improve the estimate precision for these groups. Each NHANES consisted of an in-home interview and medical evaluation and a blood sample collection in a mobile examination center. In NHANES III and NHANES 1999–2004, 18,825 and 15,332 participants, respectively, completed the medical evaluation and study interview. Exclusions for the current study included those without serum creatinine measurements, estimated glomerular filtration rate (GFR)< 30 ml/min per 1.73 m2, and women pregnant at the examination, resulting in 15,502 and 12,453 participants from NHANES III and NHANES 1999–2004, respectively, available for analysis of stage 3 CKD. For the analysis of albuminuria, individuals missing urinary albumin or creatinine measurements and pregnant or menstruating women were excluded, resulting in valid data from 15,216 and 12,778 participants from NHANES III and NHANES 1999–2004, respectively.
Of relevance to the current analysis, variables collected during the in-home interview were age, race/ethnicity, sex, cigarette smoking, a history of diabetes, and pharmacologic treatment for hypertension, high cholesterol, or diabetes. Participants who reported having smoked ≥100 cigarettes during their lifetime were classified as current or former smokers if they answered affirmatively or negatively, respectively, to the question “Do you now smoke cigarettes?” A fixed stadiometer was used to measure height; a Toledo digital scale was used to measure weight with participants clothed in underwear, a disposable gown, and foam slippers. BMI was calculated as weight in kilograms divided by the square of height in meters; obesity was defined as BMI ≥30 kg/m2.
Three blood pressure measurements were obtained using a standard protocol (American Heart Association) during the evaluation. While three additional blood pressure measurements were taken during the NHANES III in-home interview, for comparability, the current analyses were limited to blood pressure measurements from the medical evaluation. Using the mean of all available blood pressure measurements, systolic and/or diastolic blood pressure ≥140 mmHg and/or ≥90 mmHg, respectively, or current use of blood pressure–lowering medication was used to define hypertension.
Laboratory measurements and exposure definitions
Blood samples were stored at −20°C. For lipid analyses, samples were shipped to the Lipoprotein Analytical Laboratory (Johns Hopkins University, Baltimore, MD). Total cholesterol was measured with the Hitachi 704 Analyzer; high cholesterol was defined as levels ≥240 mg/dl or concurrent pharmacologic lipid-lowering treatment.
Glucose was measured on previously frozen plasma at the University of Missouri at Columbia. Self-report of a prior diagnosis of diabetes with current use of an oral hypoglycemic agent or insulin was used to define diagnosed diabetes. For participants without diagnosed diabetes who attended a morning NHANES study visit after fasting 8 h or longer (n = 7,329 and 5,572 for NHANES III and NHANES 1999–2004, respectively), undiagnosed diabetes was defined as plasma glucose ≥126 mg/dl.
Serum creatinine was measured using the modified kinetic method of Jaffe (Hitachi 917 analyzer). Serum creatinine concentrations were calibrated to the assays used for the development of the modification of diet in renal disease (MDRD) equation (19). GFR was estimated with the simplified MDRD equation. Individuals with an estimated GFR (eGFR) of 30–59 ml/min per 1.73 m2 were considered to have stage 3 CKD.
Urine albumin and creatinine concentrations were measured in the same laboratory during both surveys. Urinary albumin was measured using a solid-phase fluorescence immunoassay; urinary creatinine was measured using modified kinetic method of Jaffe (Astra Analyzer; Beckman Coulter Synchron). Albuminuria was defined as a urinary albumin–to–urinary creatinine ratio ≥30 mg/g. The protocols for NHANES III and NHANES 1999–2004 were approved by the National Center for Health Statistics of the Centers for Disease Control and Prevention Institutional Review Board.
Characteristics of the populations with and without stage 3 CKD and with and without albuminuria were calculated for each time period. Characteristics included age, race/ethnicity, sex, mean levels of systolic and diastolic blood pressure, BMI, total cholesterol, glycated hemoglobin, use of blood pressure–and cholesterol-lowering medications, and prevalence of cigarette smoking, obesity, hypertension, high cholesterol, and diagnosed and undiagnosed diabetes. The statistical significance of differences in the means and prevalence estimates across the two surveys was determined using the Wald χ2 test. Test statistics were calculated as the difference in prevalence estimates divided by the standard error of the difference, calculated as the square root of the sum of each estimate's variance. The prevalence ratios (PRs) of stage 3 CKD and albuminuria associated with cigarette smoking, obesity, hypertension, high cholesterol, and diagnosed and undiagnosed diabetes were estimated for each time period, separately, using log-binomial regression models including adjustment for age, race, sex, hypertension, and self-reported diabetes. The statistical significance of changes in the PRs over time was calculated using two sample t tests (i.e., the difference in the β-coefficients from the regression models divided by the square root of the sum of their variance).
Sample weights that account for the complex survey design of NHANES, including unequal probabilities of selection, over-sampling, and nonresponse, were applied for all analyses using SUDAAN (Version 9.1; Research Triangle Institute, Research Triangle Park, NC). Standard errors were estimated using the Taylor series linearization method.