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Albuminuria Within the “Normal” Range and Risk of Cardiovascular Disease and Death in American Indians: The Strong Heart Study
Albuminuria Within the “Normal” Range and Risk of Cardiovascular Disease and Death in American Indians: The Strong Heart Study Jiaqiong Xu, PhD, William C. Knowler, MD, DrPH, Richard B. Devereux, MD, Jeunliang Yeh, PhD, Jason G. Umans, MD, PhD, Momotaz Begum, MBBS, MPH, Richard R. Fabsitz, PhD, and Elisa T. Lee, PhD Background: “Normal” albuminuria has been defined as urinary albumin-creatinine ratio (UACR) less than 30 mg/g (3.4 mg/mmol). Whether higher UACR within this range independently predicts cardiovascular disease (CVD) and CVD death is uncertain. Methods: A total of 3,000 participants aged 45 to 74 years with a UACR less than 30 mg/g and free of CVD at the baseline examination of the Strong Heart Study (SHS) were evaluated. Survival time was calculated from the baseline examination to the first nonfatal CVD, fatal CVD, or December 31, 2002. Results: During follow-up (average, 10.4 years), 383 incident nonfatal CVD and 145 fatal CVD cases were ascertained. After adjustment for conventional CVD risk factors, participants with a UACR in the third (UACR ⱖ 5.4 to ⬍10.2 mg/g [ⱖ0.6 to ⬍1.1 mg/mmol] in men, ⱖ7.6 to ⬍12.9 mg/g [ⱖ0.9 to ⬍1.4 mg/mmol] in women) and the fourth (UACR ⱖ10.2 to ⬍30 mg/g in men, ⱖ12.9 to ⬍30 mg/g in women) quartiles had 41% and 72% greater risks of all CVD events and 118% and 199% greater risks of CVD mortality than those in the lowest quartile (UACR ⬍ 2.7 mg/g [⬍0.3 mg/mmol] in men, ⬍4.3 mg/g [⬍0.5 mg/mmol] in women), respectively. In subgroup analysis, these associations were more pronounced in persons with diabetes. Conclusion: In the SHS cohort of middle-aged to elderly American Indians, albuminuria levels less than the traditional cutoff value predict CVD. Our findings agree with a growing number of studies questioning the concept that UACR less than 30 mg/g is normal. Am J Kidney Dis 49:208-216. © 2007 by the National Kidney Foundation, Inc. INDEX WORDS: Albuminuria; urinary albumin-creatinine; cardiovascular disease; death.
U
rinary albumin excretion rate, often measured by using urinary albumin-creatinine ratio (UACR) in a single urine sample, has a well-documented association with mortality rates and incidence of cardiovascular disease (CVD). Abnormal UACR levels (ie, microalbuminuria or macroalbuminuria, conventionally defined as UACR ⱖ 30 to ⬍300 mg/g [ⱖ3.4 to ⬍34 mg/mmol] or ⱖ300 mg/g, respectively) were associated with greater risk than “normal” albuminuria (UACR ⬍ 30 mg/g).1-9 This finding also
was reported recently in the Strong Heart Study (SHS), in which CVD mortality rates in persons with diabetes with microalbuminuria and macroalbuminuria were 1.5 and 3.7 times greater than those with normal UACR, respectively.10 Several studies also showed that incidence rates of all CVD events or of CVD death can be predicted by UACR values within the normal range of less than 30 mg/g. For example, among subjects with normal albuminuria in the Framingham Study, the incidence of CVD was greater in
From the Center for American Indian Health Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ; Cornell University Medical Center, New York, NY; Penn Med Lab, MedStar Research Institute, Washington, DC; and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Received July 25, 2006; accepted in revised form October 19, 2006. Originally published online as doi:10.1053/j.ajkd.2006.10.017 on December 26, 2006. Support: This study was supported by cooperative agreement grants U01-HL-41642, U01-HL-41652, and UL01-HL-
41654 from the National Heart, Lung, and Blood Institute and, in part, by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Potential conflicts of interest: None. Address reprint requests to Jiaqiong Xu, Center for American Indian Health Research, University of Oklahoma Health Sciences Center, College of Public Health, 801 NE 13th St, Rm 112, Oklahoma City, OK 73190. E-mail: susan-xu@ ouhsc.edu © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/4902-0006$32.00/0 doi:10.1053/j.ajkd.2006.10.017
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American Journal of Kidney Diseases, Vol 49, No 2 (February), 2007: pp 208-216
Normal Albuminuria and Cardiovascular Disease
those with a UACR greater than median value than in those with a UACR less than median value.11 In the Heart Outcomes Prevention Evaluation (HOPE) clinical trial, the incidence of cardiovascular events was associated positively with baseline UACR over a normal range of less than 18 mg/g.4 Other studies found cardiovascular end points to be predictable by UACR variation within the normal range9,12,13 or by urine albumin concentration not corrected for creatinine concentration.8 The SHS, a longitudinal population-based study of CVD and its risk factors in men and women aged 45 to 74 years from 13 AmericanIndian communities in central Arizona, Oklahoma, and North and South Dakota,14 showed that CVD was the leading cause of death.15 Because of the high prevalence of diabetes in the SHS, it is important to explore whether variations in albuminuria within the conventional normal range also predict increased risks of all CVD events and CVD death in the presence and absence of diabetes. The information will extend our understanding of what constitutes prognostically normal urinary albumin excretion in individuals without diabetes and in the increasing segment of the population with diabetes. The purpose of this study is to evaluate associations of albuminuria within the traditional normal range with risk of CVD events and CVD death. METHODS Detailed information about the SHS design, survey methods, and laboratory techniques was reported previously.14,15 Briefly, the SHS cohort comprises 4,549 American Indians aged 45 to 74 years at baseline examination (1989 to 1991). Survivors of the entire cohort were reexamined in 1993 to 1995 and 1998 to 1999. Examinations included a personal interview with each participant to obtain demographic data, personal medical history, health habits, and family history of CVD and diabetes; a physical examination including a 12-lead resting electrocardiogram; and a fasting blood sample for various laboratory measurements, including plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, highdensity lipoprotein (HDL) cholesterol, glucose, and creatinine. A random morning urine sample was collected for measurements of creatinine and albumin. Urine creatinine was measured by means of the picric acid method,16 while urine albumin was measured by using a sensitive nephelometric technique.17 Thirty-six urine samples with albumin concentrations less than 0.20 g/dL (⬍2 g/L), the lowest detection limit of the assay, were considered to have values of 0.19 g/dL (1.9 g/L).
209 Height and weight were measured with the participant in light clothing with shoes removed. Body mass index (BMI) was calculated as weight in kilograms/height in m2. Systolic (SBP) and diastolic arterial blood pressures (BPs) were measured 3 times while participants were sitting, and the mean of the last 2 measurements was used to estimate blood pressure. Hypertension is defined as SBP of 140 mm Hg or greater, diastolic BP of 90 mm Hg or greater, or use of antihypertensive medication. Diabetes is defined by American Diabetes Association criteria,18 ie, use of antidiabetic medication or fasting glucose level of 126 mg/dL or greater (ⱖ7.0 mmol/L). Cigarette and alcohol consumption were determined by questionnaire. For this report, the follow-up period is from the baseline examination to December 31, 2002. All CVD events comprised the first nonfatal CVD or fatal CVD that occurred during the follow-up period. Nonfatal CVD included definite myocardial infarction, definite coronary heart disease, and nonfatal stroke. Fatal CVD is defined as death from fatal myocardial infarction, sudden death caused by coronary heart disease, other fatal coronary heart disease, fatal stroke, and other fatal CVD. Criteria and definitions used were described previously.15,19 CVD events that occurred during follow-up were ascertained by annual mortality and morbidity surveillance and at the second and third examinations. Medical records were abstracted and CVD deaths and events were confirmed by mortality and morbidity review committees, as previously reported.14,15,19 Mortality and morbidity follow-up were 99.8% and 99.2% complete, respectively. The Indian Health Service, Institutional Review Boards, and participating tribes approved the study. Informed consent was obtained from all participants. Of 4,549 participants, 4,249 were free of CVD (definite myocardial infarction, coronary heart disease, and stroke) and had a UACR measured at the baseline SHS examination. Among these participants, 3,000 (71%) had normal UACR, 806 (19%) had microalbuminuria, and 443 (10%) had macroalbuminuria. Because microalbuminuria and macroalbuminuria are established independent risk factors for CVD in the SHS,10,15 participants with a UACR of 30 mg/g or greater at the baseline examination were excluded from the main analyses, but were shown separately for comparison. The final subsample consisted of 3,000 participants with a UACR less than 30 mg/g without CVD at the baseline SHS examination. Because urinary albumin and creatinine levels vary with plasma albumin level, creatinine level, and muscle mass, which, in turn, vary by sex, we used sex-specific quartiles of UACR.20 Crude incidence rates of all CVD events, nonfatal CVD, and fatal CVD were computed by quartiles of albuminuria and expressed as cases per 1,000 person-years. Personyears were based on length of follow-up, calculated as number of years from the baseline examination to the first event or censoring. The significance of trends with higher quartiles of UACR was evaluated by using the Mantel trend statistic, modified for person-time denominators.21 Crude incidence rates for all CVD events, nonfatal CVD, and fatal CVD also were calculated for participants with microalbuminuria or macroalbuminuria in the entire cohort. Survival data were analyzed by using statistical methods for censored failure times.22 Cox proportional hazards models were used to examine associations between baseline
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sex-specific quartiles of UACR and all CVD events, nonfatal CVD, and fatal CVD. Variables entered in models included age, sex, study center (Arizona, Oklahoma, North/ South Dakota), presence of diabetes, HDL and LDL cholesterol levels, BMI, SBP, use of antihypertensive medication, plasma creatinine level, smoking and alcohol drinking status, and, for individuals with diabetes, diabetes duration and treatment (insulin alone, insulin with oral hypoglycemic agents, or oral hypoglycemic alone) also were included. Interactions between quartiles of UACR and all covariates were not statistically significant. Tests for trend modeled the median of each quartile-defined category of UACR as a continuous variable in the Cox proportional hazards models. The proportionality assumption of Cox models was assessed by including time-dependent interactions of each covariate with survival time in the model. There was no evidence of violation of this assumption for any covariate. Furthermore, we repeated analyses by modeling log2-transformed UACR as a continuous variable. Analyses were performed using SAS, version 9.00 (SAS Institute, Cary, NC). Statistical significance is defined as 2-tailed P less than 0.05 for all tests.
RESULTS
Table 1 lists baseline characteristics by sexspecific UACR quartiles. There were significant positive relations between UACR and age, BMI,
SBP, diastolic BP, fasting glucose level, and prevalences of diabetes and hypertension. LDL and total cholesterol levels, plasma creatinine level, and prevalence of current smoking were related negatively to UACR. There was no significant relationship between UACR and HDL cholesterol level or prevalences of current alcohol use or use of antihypertensive medication. Average follow-up was 10.4 ⫾ 3.4 (SD) years. During follow-up (31,075 person-years), 495 incident CVD events (91, 110, 128, and 166 events in quartiles 1 to 4 of UACR) were ascertained, as were 383 incident nonfatal CVD (78, 90, 101, and 114 in ascending quartiles of UACR) and 145 CVD deaths (17, 25, 41, and 62 by quartile of UACR). Figure 1 shows crude incidence rates of all CVD events, nonfatal CVD, and fatal CVD by UACR quartiles. Incidence rates of all events increased significantly with ascending quartiles of UACR within the normal range of UACR less than 30 mg/g. As a reference, crude incidence rates of CVD events for persons with microalbuminuria and macroalbuminuria also are shown in Fig 1.
Table 1. Baseline Characteristics by Sex-Specific UACR Quartiles Within the Normal Range for All Participants Sex-Specific UACR quartiles*
Variable
Q1 (n ⫽ 751)
Q2 (n ⫽ 750)
Q3 (n ⫽ 751)
Q4 (n ⫽ 748)
P for Trend
Men Age (y) BMI (kg/m2) SBP (mm Hg) Diastolic BP (mm Hg) Fasting glucose (mg/dL) HDL (mg/dL) LDL (mg/dL) Total cholesterol (mg/dL) Plasma creatinine (mg/dL) Diabetes† Hypertension‡ Antihypertensive drug use Current smoking§ Current drinking储
304 (40.5) 54.7 ⫾ 7.5 30.7 ⫾ 5.9 121.3 ⫾ 16.1 75.0 ⫾ 10.0 113.1 ⫾ 31.2 46.1 ⫾ 12.6 121.2 ⫾ 32.2 193.3 ⫾ 35.8 0.90 ⫾ 0.16 146 (19.7) 204 (27.2) 131 (17.4) 295 (39.4) 339 (45.3)
304 (40.5) 55.3 ⫾ 7.7 29.9 ⫾ 6.0 121.4 ⫾ 15.8 75.2 ⫾ 9.2 117.5 ⫾ 44.8 47.0 ⫾ 14.2 120.9 ⫾ 33.3 193.4 ⫾ 37.2 0.89 ⫾ 0.16 148 (20.1) 189 (25.3) 113 (15.1) 291 (38.8) 326 (43.6)
304 (40.5) 56.2 ⫾ 8.0 31.0 ⫾ 7.0 125.0 ⫾ 16.8 75.8 ⫾ 9.4 134.6 ⫾ 61.8 46.6 ⫾ 13.2 116.9 ⫾ 34.1 188.9 ⫾ 38.5 0.86 ⫾ 0.15 272 (36.8) 232 (30.9) 144 (19.2) 288 (38.4) 323 (43.1)
303 (40.5) 56.8 ⫾ 8.2 31.3 ⫾ 6.4 128.4 ⫾ 18.4 77.3 ⫾ 10.2 145.8 ⫾ 68.9 46.6 ⫾ 13.8 113.7 ⫾ 33.5 188.3 ⫾ 39.2 0.86 ⫾ 0.17 325 (44.4) 292 (39.3) 139 (18.6) 248 (33.2) 320 (43.0)
0.99 ⬍0.001 0.007 ⬍0.001 ⬍0.001 ⬍0.001 0.62 ⬍0.001 0.002 ⬍0.001 ⬍0.001 ⬍0.001 0.16 0.02 0.35
Note: Data presented as number (percent) for categorical variables and mean ⫾ SD for continuous variables. To convert glucose in mg/dL to mmol/L, multiply by 0.0555; cholesterol in mg/dL to mmol/L, multiply by 0.02586; creatinine in mg/dL to mol/L, multiply by 88.4. Abbreviation: Q, quartile. *UACR quartile: Q1, less than 2.7; Q2, 2.7 to less than 5.4; Q3, 5.4 to less than 10.2; and Q4, 10.2 to less than 30 mg/g in men, and Q1, less than 4.3; Q2, 4.3 to less than 7.6; Q3, 7.6 to less than 12.9; and Q4, 12.9 to less than 30 mg/g in women. †Missing numbers in ascending quartiles: 9, 14, 12, and 16. ‡Missing numbers in ascending quartiles: 2, 2, 1, and 4. §Missing numbers in ascending quartiles: 2, 0, 0, and 2. 储Missing numbers in ascending quartiles: 3, 2, 1, and 3.
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Figure 1. Crude incidence rates (per 1,000 person-years) of all CVD events (the first nonfatal CVD or fatal CVD), nonfatal CVD, and fatal CVD by sex-specific UACR quartiles. Microalbuminuria and macroalbuminuria were not included in the main analysis, but were used as a reference. UACR quartiles: less than 2.7, 2.7 to less than 5.4, 5.4 to less than 10.2, and 10.2 to less than 30 mg/g (⬍0.3, 0.3 to ⬍0.6, 0.6 to ⬍1.1, and 1.1 to ⬍3.4 mg/mmol) in men and less than 4.3, 4.3 to less than 7.6, 7.6 to less than 12.9, and 12.9 to less than 30 mg/g (⬍0.5, 0.5 to ⬍0.9, 0.9 to ⬍1.4, 1.4 to ⬍3.4 mg/mmol) in women. P for trend (quartiles 1 to 4) ⬍ 0.001 for all CVD, nonfatal CVD, and fatal CVD events.
Results of Cox proportional hazards models are listed in Table 2. Controlling for conventional CVD risk factors, participants with UACR in quartiles 3 and 4 had 41% and 72% greater risks of developing all CVD events and 118% and 199% greater risks of CVD death, respectively. Additional significant predictors of all CVD events were male sex, older age, diabetes, residence in Oklahoma or North/South Dakota compared with Arizona, lower HDL cholesterol level, higher LDL cholesterol level, higher SBP, use of antihypertensive medication, and current smoking. Additional significant predictors of nonfatal CVD events were male sex, older age, diabetes, residence in Oklahoma or North/South Dakota compared with Arizona, lower HDL cholesterol level, higher LDL cholesterol level, higher SBP, use of antihypertensive medication, current smoking, and former or never drinking. Additional significant predictors of CVD death were male sex, older age, diabetes, higher SBP, and current smoking and drinking. In the analysis of subgroup by diabetes status, in which quartiles of UACR were recomputed within subgroup, participants with diabetes with UACR in the fourth quartile had a 57% higher risk of developing all CVD events, and those with UACR in the upper 2 quartiles had 235% and 321% higher risks of CVD death than those with UACR in the lowest
quartile, controlling for the conventional CVD risk factors, respectively. UACR within the normal range was not associated with risk of nonfatal CVD among participants with diabetes. Participants without diabetes with UACR in the fourth quartile had a 43% higher risk of developing all CVD events, although the association was weak. When albuminuria was considered as a continuous variable, ie, log2-transformed UACR (log2 [UACR]), for every doubling of UACR, risks of developing all CVD events, nonfatal CVD, and fatal CVD increased by 13%, 9%, and 29%, adjusted for the conventional risk factors, respectively (Table 3). In subgroup analysis, for every doubling of UACR, risks of developing all CVD events, nonfatal CVD, and fatal CVD increased by 20%, 13%, and 48% among participants with diabetes and 8% (P ⫽ 0.06), 6% (P ⫽ 0.20), and 13% (P ⫽ 0.16) among participants without diabetes adjusted for the conventional CVD risk factors, respectively. As a reference, Table 4 lists results of repeating the same analysis in the entire cohort (n ⫽ 4,249; median UACR, 10.6 mg/g; minimum and maximum, 0.04 and 65,000 mg/g; first and third quartile partitions, 4.7 and 42.3 mg/g, respectively) and modeling albuminuria as a continuous variable, ie, log2 (UACR). For every dou-
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Xu et al Table 2. Multivariate Hazard Ratios of All CVD Events, Nonfatal CVD, and Fatal CVD All CVD
Variable
All participants UACR* Q2 v Q1 Q3 v Q1 Q4 v Q1 Male v female Age (5 y)‡ BMI (5 kg/m2)‡ Diabetes v nondiabetes Study center OK v AZ ND/SD v AZ HDL (5 mg/dL)‡ LDL (5 mg/dL)‡ SBP (5 mm Hg)‡ Use of antihypertensives (yes v no) Plasma creatinine (mg/dL) Current smoking (yes/no) Current alcohol drinking (yes/no) Participants with diabetes UACR§ Q2 v Q1 Q3 v Q1 Q4 v Q1 Male v female Age (5 y) BMI (5 kg/m2) Duration of diabetes (y) Diabetes treatment (yes v no) Study center OK v AZ ND/SD v AZ HDL (5 mg/dL) LDL (5 mg/dL) SBP (5 mm Hg) Use of antihypertensives (yes v no) Plasma creatinine (mg/dL) Current smoking (yes v no) Current alcohol drinking (yes v no) Participants without diabetes UACR储 Q2 v Q1 Q3 v Q1 Q4 v Q1 Male v female Age (5 y) BMI (5 kg/m2)
Hazard Ratio (95% confidence interval)
Nonfatal CVD
P
Hazard Ratio (95% confidence interval)
⬍0.0001† 1.28 (0.96-1.70) 1.41 (1.07-1.87) 1.72 (1.31-2.27) 1.80 (1.44-2.24) 1.23 (1.15-1.31) 1.07 (0.98-1.16) 1.88 (1.54-2.29)
P
Hazard Ratio (95% confidence interval)
⬍0.0001 ⬍0.0001 0.14 ⬍0.0001
1.35 (1.02-1.79) 1.48 (1.29-1.70) 0.93 (0.89-0.97) 1.03 (1.01-1.04) 1.06 (1.03-1.08)
0.04 ⬍0.0001 0.0007 0.0004 0.0001
1.30 (1.04-1.63) 1.27 (0.67-2.41) 1.51 (1.24-1.83) 0.86 (0.71-1.06)
P
⬍0.0001
0.02 1.21 (0.89-1.65) 1.31 (0.96-1.78) 1.41 (1.04-1.92) 1.68 (1.31-2.15) 1.17 (1.09-1.26) 1.05 (0.95-1.16) 1.84 (1.47-2.31)
⬍0.0001 ⬍0.0001 0.30 ⬍0.0001
1.58 (0.84-2.97) 2.18 (1.21-3.93) 2.99 (1.69-5.30) 2.16 (1.43-3.26) 1.37 (1.22-1.55) 1.04 (0.89-1.22) 2.24 (1.55-3.22)
0.0003 ⬍0.0001 0.62 ⬍0.0001
1.45 (1.04-2.02) 1.55 (1.31-1.82) 0.92 (0.87-0.96) 1.04 (1.02-1.05) 1.06 (1.03-1.10)
0.03 ⬍0.0001 0.0008 ⬍0.0001 0.0001
1.11 (0.68-1.81) 1.24 (0.98-1.58) 0.99 (0.87-1.02) 1.01 (0.98-1.04) 1.05 (1.00-1.10)
0.69 0.07 0.14 0.46 0.05
0.02 0.46 ⬍0.0001
1.29 (0.99-1.66) 1.23 (0.59-2.56) 1.54 (1.24-1.92)
0.05 0.58 0.0001
1.17 (0.77-1.76) 1.08 (0.34-3.47) 1.54 (1.07-2.20)
0.32 0.90 0.02
0.16
0.70 (0.55-0.88)
0.002
1.59 (1.09-2.30)
0.01
0.02 1.08 (0.70-1.65) 1.30 (0.86-1.95) 1.57 (1.05-2.34) 1.44 (1.02-2.04) 1.11 (1.01-1.23) 0.92 (0.81-1.05) 1.02 (0.99-1.04)
Fatal CVD
0.44
0.04 0.03 0.23 0.19
0.97 (0.61-1.56) 1.02 (0.64-1.62) 1.21 (0.77-1.91) 1.37 (0.91-2.05) 1.07 (0.95-1.20) 0.90 (0.78-1.04) 1.02 (0.99-1.04)
1.52 (1.09-2.13)
0.01
1.80 (1.21-2.68) 1.45 (1.18-1.78) 0.88 (0.82-0.95) 1.02 (0.99-1.04) 1.04 (0.99-1.09)
0.0003
0.13 0.30 0.18 0.23
2.35 (0.94-5.90) 3.35 (1.41-7.99) 4.21 (1.79-9.91) 1.84 (1.01-3.35) 1.23 (1.03-1.47) 0.92 (0.73-1.16) 1.02 (0.98-1.06)
0.05 0.02 0.50 0.41
1.62 (1.10-2.40)
0.01
1.56 (0.86-2.82)
0.14
0.004 0.0004 0.002 0.09 0.07
1.91 (1.21-3.01) 1.39 (1.10-1.77) 0.89 (0.82-0.97) 1.02 (0.99-1.04) 1.04 (0.99-1.10)
0.006 0.007 0.01 0.25 0.08
1.40 (0.70-2.83) 1.45 (1.02-2.05) 0.87 (0.76-1.00) 1.04 (1.01-1.08) 1.05 (0.97-1.14)
0.34 0.04 0.05 0.02 0.21
1.07 (0.77-1.48) 0.97 (0.36-2.60) 1.57 (1.17-2.11)
0.71 0.94 0.003
1.04 (0.71-1.51) 0.86 (0.27-2.73) 1.63 (1.16-2.30)
0.86 0.80 0.005
1.00 (0.56-1.79) 0.76 (0.14-4.06) 1.41 (0.85-2.34)
0.89 0.75 0.18
0.99 (0.71-1.37)
0.94
0.81 (0.56-1.19)
0.29
1.40 (0.81-2.43)
0.23
0.05 1.32 (0.92-1.90) 1.37 (0.95-1.97) 1.43 (0.99-2.06) 2.32 (1.72-3.12) 1.28 (1.18-1.39) 1.18 (1.04-1.32)
1.25 (0.83-1.86) 1.35 (0.91-2.01) 1.30 (0.86-1.96) ⬍0.0001 2.11 (1.52-2.95) ⬍0.0001 1.22 (1.11-1.34) 0.008 1.20 (1.04-1.37) (Continued)
0.17
⬍0.0001 ⬍0.0001 0.008
0.27 1.33 (0.62-2.86) 1.16 (0.53-2.51) 1.57 (0.77-3.22) 3.06 (1.63-5.74) 1.48 (1.25-1.75) 1.08 (0.84-1.38)
0.0005 ⬍0.0001 0.57
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Table 2 (Cont’d). Multivariate Hazard Ratios of All CVD Events, Nonfatal CVD, and Fatal CVD All CVD
Variable
Study center OK v AZ ND/SD v AZ HDL (5 mg/dL) LDL (5 mg/dL) SBP (5 mm Hg) Use of antihypertensives (yes v no) Plasma creatinine (mg/dL) Current smoking (yes v no) Current alcohol drinking (yes v no)
Nonfatal CVD
Fatal CVD
Hazard Ratio (95% confidence interval)
P
Hazard Ratio (95% confidence interval)
P
Hazard Ratio (95% confidence interval)
P
1.06 (0.707-1.61) 1.46 (1.19-1.78) 0.96 (0.92-1.02) 1.03 (1.01-1.05) 1.07 (1.03-1.11)
0.79 0.0002 0.19 0.003 0.0001
1.21 (0.73-2.00) 1.62 (1.27-2.06) 0.95 (0.89-1.01) 1.04 (1.02-1.07) 1.08 (1.03-1.12)
0.47 0.0001 0.08 ⬍0.0001 0.0003
0.85 (0.41-1.74) 1.03 (0.73-1.46) 0.99 (0.91-1.09) 0.98 (0.94-1.02) 1.07 (1.01-1.14)
0.65 0.85 0.90 0.30 0.04
1.46 (1.06-2.00) 1.61 (0.68-3.78) 1.49 (1.14-1.93)
0.02 0.28 0.003
1.40 (0.98-2.01) 1.70 (0.64-4.49) 1.53 (1.14-2.01)
0.07 0.29 0.005
1.39 (0.74-2.63) 1.28 (0.23-7.02) 1.50 (0.89-2.52)
0.18 0.78 0.13
0.81 (0.62-1.06)
0.14
0.65 (0.48-0.87)
0.005
2.04 (1.17-3.53)
0.01
Note: All CVD events included the first nonfatal CVD or fatal CVD. To convert cholesterol in mg/dL to mmol/L, multiply by 0.02586; creatinine in mg/dL to mol/L, multiply by 88.4. Abbreviations: Q, quartile; OK, Oklahoma; AZ, Arizona; ND/SD, North/South Dakota. *UACR quartiles: Q1, less than 2.7; Q2, 2.7 to less than 5.4; Q3, 5.4 to less than 10.2; and Q4, 10.2 to less than 30 mg/g [⬍0.3, 0.3 to ⬍0.6, 0.6 to ⬍1.1, and 1.1 to ⬍3.4 mg/mmol] in men, and Q1, less than 4.3; Q2, 4.3 to less than 7.6; Q3, 7.6 to less than 12.9; and Q4, 12.9 to less than 30 mg/g [⬍0.5, 0.5 to ⬍0.9, 0.9 to ⬍1.4, 1.4 to ⬍3.4 mg/mmol] in women. †P for trend test. ‡For every 5-unit increase. §UACR quartiles: Q1, less than 4.8; Q2, 4.8 to less than 8.7; Q3, 8.7 to less than 15.0; Q4, 15.0 to less than 30 mg/g [⬍0.5, 0.5 to ⬍1.0, 1.0 to ⬍1.7, 1.7 to ⬍3.4 mg/mmol] in men, and Q1, less than 5.5; Q2, 5.5 to less than 9.7; Q3, 9.7 to less than 16.0; Q4, 16.0 to less than 30 mg/g [⬍0.6, 0.6 to ⬍1.1, 1.1 to ⬍1.8, 1.8 to ⬍3.4 mg/mmol] in women. 储UACR quartiles: Q1, less than 2.3; Q2, 2.3 to less than 4.5; Q3, 4.5 to less than 8.5; Q4, 8.5 to less than 30 mg/g [⬍0.3, 0.3 to ⬍0.5, 0.5 to ⬍1.0, 1.0 to ⬍3.4 mg/mmol] in men, and Q1, less than 3.8; Q2, 3.8 to less than 6.7; Q3, 6.7 to less than 11.3; Q4, 11.3 to less than 30 mg/g [⬍0.4, 0.4 to ⬍0.8, 0.8 to ⬍1.3, 1.3 to ⬍3.4 mg/mmol] in women.
bling of UACR, risks of developing all CVD events, nonfatal CVD, and fatal CVD increased by 14%, 11%, and 27%, adjusted for conven-
tional CVD risk factors, respectively. In subgroup analysis, for every doubling of UACR, risks of developing all CVD events, nonfatal
Table 3. Hazard Ratios per Doubling of UACR Within the Normal Range Associated With All CVD Events, Nonfatal CVD, and Fatal CVD All CVD
All participants* Hazard ratio (95% confidence interval) P Participants with diabetes† Hazard ratio (95% confidence interval) P Participants without diabetes‡ Hazard ratio (95% confidence interval) P
Nonfatal CVD
Fatal CVD
1.13 (1.06-1.21) 0.0002
1.09 (1.01-1.17) 0.02
1.29 (1.12-1.48) 0.0003
1.20 (1.07-1.34) 0.001
1.13 (0.999-1.28) 0.05
1.48 (1.17-1.87) 0.001
1.08 (0.99-1.18) 0.06
1.06 (0.97-1.17) 0.20
1.13 (0.95-1.34) 0.16
Note: All CVD events include the first nonfatal CVD or fatal CVD. *Models for all participants were adjusted for age, sex, study center, diabetes status, BMI, SBP, use of antihypertensive medication, HDL cholesterol level, LDL cholesterol level, plasma creatinine level, alcohol consumption, and smoking status. †Models for participants with diabetes were adjusted for the same variable as in the model for all participants, but replacing diabetes status with duration of diabetes and diabetes treatment. ‡Models for participants without diabetes were adjusted for all variables as in the model for all participants, except for diabetes status.
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Table 4. Hazard Ratios per Doubling of UACR Associated With All CVD Events, Nonfatal CVD, and Fatal CVD in the Overall Cohort
All participants* Hazard ratio (95% confidence interval) P Participants with diabetes‡ Hazard ratio (95% confidence interval) P Participants without diabetes§ Hazard ratio (95% confidence interval) P
All CVD
Nonfatal CVD
Fatal CVD
1.14 (1.11-1.17) ⬍0.0001
1.11 (1.08-1.15) ⬍0.0001
1.27 (1.22-1.33) ⬍0.0001
1.13 (1.09-1.17) ⬍0.0001
1.09 (1.04-1.13) ⬍0.0001
1.24 (1.18-1.31) ⬍0.0001
1.12 (1.06-1.18) ⬍0.0001
1.11 (1.04-1.18) 0.0008
1.22 (1.11-1.34) ⬍0.0001
Note: All CVD events include the first nonfatal CVD or fatal CVD. *Models for all participants were adjusted for age, sex, study center, diabetes status, BMI, SBP, use of antihypertensive medication, HDL cholesterol level, LDL cholesterol level, plasma creatinine level, alcohol consumption, and smoking status. †Models for participants with diabetes were adjusted for the same variable as in the model for all participants, but replacing diabetes status with duration of diabetes and diabetes treatment. ‡Models for participants without diabetes were adjusted for all variables as in the model for all participants, except for diabetes status.
CVD, and fatal CVD increased by 13%, 9%, and 24% among participants with diabetes and 12%, 11%, and 22% among participants without diabetes, adjusted for conventional CVD risk factors, respectively. DISCUSSION
In this large longitudinal study, higher albuminuria levels within the range of UACR less than 30 mg/g in American Indians aged 45 to 74 years were associated with greater risks of developing all CVD events and CVD deaths independently of other CVD risk factors. Our findings were consistent whether albuminuria was analyzed by quartiles or as a continuous variable. These associations were more pronounced in American Indians with than without diabetes (P for interactions between UACR and diabetes status for risk of all CVD events, nonfatal CVD, and fatal CVD were 0.13, 0.34, and 0.08, respectively). Analysis of the entire cohort, including participants with microalbuminuria or macroalbuminuria, also showed a log-linear association across the entire range of UACR with all CVD events, nonfatal CVD, and fatal CVD in participants with and without diabetes, independent of other established CVD risk factors. Effects of UACR on risk of CVD events were not confounded by serum lipid concentrations. The negative associations between UACR and total and LDL cholesterol levels in univariate analysis were unexpected observations.
Results from the HOPE Study4 indicated that across a wide spectrum of UACRs, greater albuminuria predicted CVD in individuals with or without diabetes. For every 3.5-mg/g (0.4-mg/ mmol) increase in UACR, the risk of CVD increased by 5.9% after adjusting for age and sex. In our study, we observed a log-linear association between UACR within the normal range and risks of all CVD events, nonfatal CVD, and fatal CVD. Among all participants, risks of developing all CVD events, nonfatal CVD, and fatal CVD increased by 13%, 9%, and 29% per doubling of UACR within the normal range, adjusted for the conventional CVD risk factors, respectively. Among participants with diabetes, risks of all CVD events, nonfatal CVD, and fatal CVD increased by 20%, 13%, and 49% for every doubling of UACR within the normal range, respectively. Among participants without diabetes, there was no statistically significant association between albuminuria within the normal range and risk of either nonfatal or fatal CVD. Data from the Framingham Heart Study showed that individuals without hypertension and without diabetes with UACR equal to the sex-specific median value or greater (UACR ⱖ 3.9 mg/g [ⱖ0.4 mg/mmol] in men, ⱖ7.5 mg/g [ⱖ0.8 mg/mmol] in women) have a nearly 3-fold risk of CVD.11 Furthermore, the lack of association between UACR in the normal range and CVD events in participants without diabetes in the SHS may reflect a lack of power in the current
Normal Albuminuria and Cardiovascular Disease
analysis because of the small number of events. Results from the entire cohort showed that albuminuria was a strong independent predictor of all CVD events, nonfatal CVD, and fatal CVD, and the associations were similar in participants with and without diabetes. The underlying mechanism of the association between albuminuria within the normal range and CVD risk is unknown. However, it is well established that abnormal albuminuria indicates generalized vascular dysfunction.23,24 The mechanism by which microalbuminuria is related to systemic and coronary atherosclerosis remains uncertain, although microalbuminuria seems to be a marker for endothelial dysfunction. A recent study of participants with and without diabetes suggested that microalbuminuria emerges later in the course of atherosclerotic process.25 Nonetheless, patients with diabetes with microalbuminuria have increased transcapillary escape rate of albumin.26 Echocardiographic data in the SHS population showed that albuminuria predicted both ventricular and atrial dysfunction.23 Likewise, microalbuminuria related to congestive heart failure in the HOPE Study4 suggests that congestive heart failure or CVD might exert cardiovascular morbidity through both atherosclerosis and congestive heart failure. Primary strengths of the present study are its prospective design, large sample size, long and continuous surveillance and careful confirmation of incident CVD events, inclusion of participants with albuminuria less than the current diagnostic threshold for microalbuminuria, and multivariable-adjusted analyses. A limitation of the current study is that a single random morning urine specimen, rather than multiple specimens or a timed specimen, was collected to measure albumin and creatinine. However, recent guidelines indicate that a spot urine sample (preferably a first-morning specimen) or a random urine specimen is acceptable for albuminuria measurement because the test is performed easily in the clinic and results correlate well with those of 24-hour collections.27 In conclusion, in the SHS cohort of middleaged to elderly American Indians, higher albuminuria levels within the normal range of UACR less than 30 mg/g were associated strongly with higher risks of developing CVD and CVD mortality
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independently of other CVD risk factors. Our findings are in agreement with a growing number of studies suggesting that the upper limit in the definition of normal UACR (30 mg/g) be reconsidered to align with this mounting body of evidence. ACKNOWLEDGMENT The authors acknowledge the assistance and cooperation of the Ak-Chin Tohono O’Odham (Papago)/Pima, Gila River, and Salt River Pima/Maricopa in Arizona; Apache, Caddo, Comanche, Delaware, Fort Sill Apache, Kiowa, and Wichita in Oklahoma; and Oglala Sioux, Cheyenne River Sioux, and Spirit Lake communities in North/South Dakota, without whose support this study would not have been possible. The authors also thank the Indian Health Service hospitals and clinics at each center; the directors of the Strong Heart Study clinics, Betty Jarvis, Dr Tauqeer Ali, Alan Crawford, Marcia O’Leary, and their staffs; and the physicians who performed the mortality and morbidity reviews. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the Indian Health Service.
REFERENCES 1. Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity onset diabetes. N Engl J Med 310:356-360, 1984 2. Deckert T, Yokoyama H, Mathiesen E, et al: Cohort study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in patients with insulin dependent diabetes. BMJ 312:871-874, 1996 3. Dinneen SF, Gerstein HC: The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus: A systematic overview of the literature. Arch Intern Med 157:1413-1418, 1997 4. Gerstein HC, Mann JF, Yi W, et al: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 286:421-426, 2001 5. Bigazzi R, Bianchi S, Baldari D, Campese VM: Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension. J Hypertens 16:1325-1333, 1998 6. Jager A, Kostense PJ, Ruhe HG, et al: Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: Five-year follow-up of the Hoorn Study. Arterioscler Thromb Vasc Biol 19:617-624, 1999 7. Romundstad S, Holmen J, Hallan H, Kvenild K, Ellekjaer H: Microalbuminuria and all-cause mortality in treated hypertensive individuals: Does sex matter? The NordTrøndelag Health Study (HUNT), Norway. Circulation 108: 2783-2789, 2003 8. Hillege HL, Fidler V, Diercks GFH, et al, for the Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group: Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 106:1777-1782, 2002
216 9. Yuyun MF, Khaw KT, Luben R, et al: Microalbuminuria independently predicts all-cause and cardiovascular mortality in a British population: The European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study. Int J Epidemiol 33:189-198, 2004 10. Xu J, Lee ET, Best LG, et al: Association of albuminuria with all-cause and cardiovascular disease mortality in diabetes: The Strong Heart Study. Br J Diabetes Vasc Dis 5:334-340, 2005 11. Arnlov J, Evans JC, Meigs JB, et al: Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: The Framingham Heart Study. Circulation 112:969-975, 2005 12. Wachtell K, Ibsen H, Olsen MH, et al: Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: The LIFE Study. Ann Intern Med 139:901-906, 2003 13. Ibsen H, Olsen MH, Wachtell K, et al: Does albuminuria predict cardiovascular outcomes on treatment with losartan versus atenolol in patients with diabetes, hypertension, and left ventricular hypertrophy? The LIFE Study. Diabetes Care 29:595-600, 2006 14. Lee ET, Welty TK, Fabsitz R, et al: A study of cardiovascular disease in American Indians: Design and methods. The Strong Heart Study. Am J Epidemiol 132:11411155, 1990 15. Howard BV, Lee ET, Cowan LD, et al: Rising tide of cardiovascular disease in American Indians. The Strong Heart Study. Circulation 99:2389-2395, 1999 16. Chasson AL, Grady HJ, Stanley MA: Determination of creatinine by means of automatic chemical analysis. Tech Bull Regist Med Tech 30:207-212, 1957 17. Vasquez B, Flock EV, Savage PJ, et al: Sustained reduction in proteinuria in type 2 (non-insulin dependent) following diet-induced reduction of hyperglycemia. Diabetologia 26:127-133, 1984
Xu et al 18. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:11831197, 1997 19. Lee ET, Cowan LD, Welty TK, et al: All-cause mortality and cardiovascular disease mortality in three American Indian populations, aged 45-74 years, 19841988: The Strong Heart Study. Am J Epidemiol 147:9951008, 1998 20. Knight EL, Curhan GC: Albuminuria: Moving beyond traditional microalbuminuria cut-points. Curr Opin Nephrol Hypertens 12:283-284, 2003 21. Rothman KJ, Greenland S: Modern Epidemiology (ed 2). Philadelphia, PA, Lippincott Williams & Wilkins, 1998 22. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972 23. Liu JE, Robbins DC, Palmieri V, et al: Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: The Strong Heart Study. J Am Coll Cardiol 41:2022-2028, 2003 24. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A: Albuminuria reflects widespread vascular damage: The Steno hypothesis. Diabetologia 32:219-226, 1989 25. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al: Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation 110:32-35, 2004 26. Nannipieri M, Rizzo L, Raputano A, Pilo A, Penno G, Navalesi R: Increased transcapillary escape rate of albumin in microalbuminuric type 2 diabetic patients. Diabetes Care 18:1-9, 1995 27. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification, and stratification. Am J Kidney Dis 39:S7S266, 2002 (suppl)
U
rinary albumin excretion rate, often measured by using urinary albumin-creatinine ratio (UACR) in a single urine sample, has a well-documented association with mortality rates and incidence of cardiovascular disease (CVD). Abnormal UACR levels (ie, microalbuminuria or macroalbuminuria, conventionally defined as UACR ⱖ 30 to ⬍300 mg/g [ⱖ3.4 to ⬍34 mg/mmol] or ⱖ300 mg/g, respectively) were associated with greater risk than “normal” albuminuria (UACR ⬍ 30 mg/g).1-9 This finding also
was reported recently in the Strong Heart Study (SHS), in which CVD mortality rates in persons with diabetes with microalbuminuria and macroalbuminuria were 1.5 and 3.7 times greater than those with normal UACR, respectively.10 Several studies also showed that incidence rates of all CVD events or of CVD death can be predicted by UACR values within the normal range of less than 30 mg/g. For example, among subjects with normal albuminuria in the Framingham Study, the incidence of CVD was greater in
From the Center for American Indian Health Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ; Cornell University Medical Center, New York, NY; Penn Med Lab, MedStar Research Institute, Washington, DC; and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Received July 25, 2006; accepted in revised form October 19, 2006. Originally published online as doi:10.1053/j.ajkd.2006.10.017 on December 26, 2006. Support: This study was supported by cooperative agreement grants U01-HL-41642, U01-HL-41652, and UL01-HL-
41654 from the National Heart, Lung, and Blood Institute and, in part, by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Potential conflicts of interest: None. Address reprint requests to Jiaqiong Xu, Center for American Indian Health Research, University of Oklahoma Health Sciences Center, College of Public Health, 801 NE 13th St, Rm 112, Oklahoma City, OK 73190. E-mail: susan-xu@ ouhsc.edu © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/4902-0006$32.00/0 doi:10.1053/j.ajkd.2006.10.017
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those with a UACR greater than median value than in those with a UACR less than median value.11 In the Heart Outcomes Prevention Evaluation (HOPE) clinical trial, the incidence of cardiovascular events was associated positively with baseline UACR over a normal range of less than 18 mg/g.4 Other studies found cardiovascular end points to be predictable by UACR variation within the normal range9,12,13 or by urine albumin concentration not corrected for creatinine concentration.8 The SHS, a longitudinal population-based study of CVD and its risk factors in men and women aged 45 to 74 years from 13 AmericanIndian communities in central Arizona, Oklahoma, and North and South Dakota,14 showed that CVD was the leading cause of death.15 Because of the high prevalence of diabetes in the SHS, it is important to explore whether variations in albuminuria within the conventional normal range also predict increased risks of all CVD events and CVD death in the presence and absence of diabetes. The information will extend our understanding of what constitutes prognostically normal urinary albumin excretion in individuals without diabetes and in the increasing segment of the population with diabetes. The purpose of this study is to evaluate associations of albuminuria within the traditional normal range with risk of CVD events and CVD death. METHODS Detailed information about the SHS design, survey methods, and laboratory techniques was reported previously.14,15 Briefly, the SHS cohort comprises 4,549 American Indians aged 45 to 74 years at baseline examination (1989 to 1991). Survivors of the entire cohort were reexamined in 1993 to 1995 and 1998 to 1999. Examinations included a personal interview with each participant to obtain demographic data, personal medical history, health habits, and family history of CVD and diabetes; a physical examination including a 12-lead resting electrocardiogram; and a fasting blood sample for various laboratory measurements, including plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, highdensity lipoprotein (HDL) cholesterol, glucose, and creatinine. A random morning urine sample was collected for measurements of creatinine and albumin. Urine creatinine was measured by means of the picric acid method,16 while urine albumin was measured by using a sensitive nephelometric technique.17 Thirty-six urine samples with albumin concentrations less than 0.20 g/dL (⬍2 g/L), the lowest detection limit of the assay, were considered to have values of 0.19 g/dL (1.9 g/L).
209 Height and weight were measured with the participant in light clothing with shoes removed. Body mass index (BMI) was calculated as weight in kilograms/height in m2. Systolic (SBP) and diastolic arterial blood pressures (BPs) were measured 3 times while participants were sitting, and the mean of the last 2 measurements was used to estimate blood pressure. Hypertension is defined as SBP of 140 mm Hg or greater, diastolic BP of 90 mm Hg or greater, or use of antihypertensive medication. Diabetes is defined by American Diabetes Association criteria,18 ie, use of antidiabetic medication or fasting glucose level of 126 mg/dL or greater (ⱖ7.0 mmol/L). Cigarette and alcohol consumption were determined by questionnaire. For this report, the follow-up period is from the baseline examination to December 31, 2002. All CVD events comprised the first nonfatal CVD or fatal CVD that occurred during the follow-up period. Nonfatal CVD included definite myocardial infarction, definite coronary heart disease, and nonfatal stroke. Fatal CVD is defined as death from fatal myocardial infarction, sudden death caused by coronary heart disease, other fatal coronary heart disease, fatal stroke, and other fatal CVD. Criteria and definitions used were described previously.15,19 CVD events that occurred during follow-up were ascertained by annual mortality and morbidity surveillance and at the second and third examinations. Medical records were abstracted and CVD deaths and events were confirmed by mortality and morbidity review committees, as previously reported.14,15,19 Mortality and morbidity follow-up were 99.8% and 99.2% complete, respectively. The Indian Health Service, Institutional Review Boards, and participating tribes approved the study. Informed consent was obtained from all participants. Of 4,549 participants, 4,249 were free of CVD (definite myocardial infarction, coronary heart disease, and stroke) and had a UACR measured at the baseline SHS examination. Among these participants, 3,000 (71%) had normal UACR, 806 (19%) had microalbuminuria, and 443 (10%) had macroalbuminuria. Because microalbuminuria and macroalbuminuria are established independent risk factors for CVD in the SHS,10,15 participants with a UACR of 30 mg/g or greater at the baseline examination were excluded from the main analyses, but were shown separately for comparison. The final subsample consisted of 3,000 participants with a UACR less than 30 mg/g without CVD at the baseline SHS examination. Because urinary albumin and creatinine levels vary with plasma albumin level, creatinine level, and muscle mass, which, in turn, vary by sex, we used sex-specific quartiles of UACR.20 Crude incidence rates of all CVD events, nonfatal CVD, and fatal CVD were computed by quartiles of albuminuria and expressed as cases per 1,000 person-years. Personyears were based on length of follow-up, calculated as number of years from the baseline examination to the first event or censoring. The significance of trends with higher quartiles of UACR was evaluated by using the Mantel trend statistic, modified for person-time denominators.21 Crude incidence rates for all CVD events, nonfatal CVD, and fatal CVD also were calculated for participants with microalbuminuria or macroalbuminuria in the entire cohort. Survival data were analyzed by using statistical methods for censored failure times.22 Cox proportional hazards models were used to examine associations between baseline
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sex-specific quartiles of UACR and all CVD events, nonfatal CVD, and fatal CVD. Variables entered in models included age, sex, study center (Arizona, Oklahoma, North/ South Dakota), presence of diabetes, HDL and LDL cholesterol levels, BMI, SBP, use of antihypertensive medication, plasma creatinine level, smoking and alcohol drinking status, and, for individuals with diabetes, diabetes duration and treatment (insulin alone, insulin with oral hypoglycemic agents, or oral hypoglycemic alone) also were included. Interactions between quartiles of UACR and all covariates were not statistically significant. Tests for trend modeled the median of each quartile-defined category of UACR as a continuous variable in the Cox proportional hazards models. The proportionality assumption of Cox models was assessed by including time-dependent interactions of each covariate with survival time in the model. There was no evidence of violation of this assumption for any covariate. Furthermore, we repeated analyses by modeling log2-transformed UACR as a continuous variable. Analyses were performed using SAS, version 9.00 (SAS Institute, Cary, NC). Statistical significance is defined as 2-tailed P less than 0.05 for all tests.
RESULTS
Table 1 lists baseline characteristics by sexspecific UACR quartiles. There were significant positive relations between UACR and age, BMI,
SBP, diastolic BP, fasting glucose level, and prevalences of diabetes and hypertension. LDL and total cholesterol levels, plasma creatinine level, and prevalence of current smoking were related negatively to UACR. There was no significant relationship between UACR and HDL cholesterol level or prevalences of current alcohol use or use of antihypertensive medication. Average follow-up was 10.4 ⫾ 3.4 (SD) years. During follow-up (31,075 person-years), 495 incident CVD events (91, 110, 128, and 166 events in quartiles 1 to 4 of UACR) were ascertained, as were 383 incident nonfatal CVD (78, 90, 101, and 114 in ascending quartiles of UACR) and 145 CVD deaths (17, 25, 41, and 62 by quartile of UACR). Figure 1 shows crude incidence rates of all CVD events, nonfatal CVD, and fatal CVD by UACR quartiles. Incidence rates of all events increased significantly with ascending quartiles of UACR within the normal range of UACR less than 30 mg/g. As a reference, crude incidence rates of CVD events for persons with microalbuminuria and macroalbuminuria also are shown in Fig 1.
Table 1. Baseline Characteristics by Sex-Specific UACR Quartiles Within the Normal Range for All Participants Sex-Specific UACR quartiles*
Variable
Q1 (n ⫽ 751)
Q2 (n ⫽ 750)
Q3 (n ⫽ 751)
Q4 (n ⫽ 748)
P for Trend
Men Age (y) BMI (kg/m2) SBP (mm Hg) Diastolic BP (mm Hg) Fasting glucose (mg/dL) HDL (mg/dL) LDL (mg/dL) Total cholesterol (mg/dL) Plasma creatinine (mg/dL) Diabetes† Hypertension‡ Antihypertensive drug use Current smoking§ Current drinking储
304 (40.5) 54.7 ⫾ 7.5 30.7 ⫾ 5.9 121.3 ⫾ 16.1 75.0 ⫾ 10.0 113.1 ⫾ 31.2 46.1 ⫾ 12.6 121.2 ⫾ 32.2 193.3 ⫾ 35.8 0.90 ⫾ 0.16 146 (19.7) 204 (27.2) 131 (17.4) 295 (39.4) 339 (45.3)
304 (40.5) 55.3 ⫾ 7.7 29.9 ⫾ 6.0 121.4 ⫾ 15.8 75.2 ⫾ 9.2 117.5 ⫾ 44.8 47.0 ⫾ 14.2 120.9 ⫾ 33.3 193.4 ⫾ 37.2 0.89 ⫾ 0.16 148 (20.1) 189 (25.3) 113 (15.1) 291 (38.8) 326 (43.6)
304 (40.5) 56.2 ⫾ 8.0 31.0 ⫾ 7.0 125.0 ⫾ 16.8 75.8 ⫾ 9.4 134.6 ⫾ 61.8 46.6 ⫾ 13.2 116.9 ⫾ 34.1 188.9 ⫾ 38.5 0.86 ⫾ 0.15 272 (36.8) 232 (30.9) 144 (19.2) 288 (38.4) 323 (43.1)
303 (40.5) 56.8 ⫾ 8.2 31.3 ⫾ 6.4 128.4 ⫾ 18.4 77.3 ⫾ 10.2 145.8 ⫾ 68.9 46.6 ⫾ 13.8 113.7 ⫾ 33.5 188.3 ⫾ 39.2 0.86 ⫾ 0.17 325 (44.4) 292 (39.3) 139 (18.6) 248 (33.2) 320 (43.0)
0.99 ⬍0.001 0.007 ⬍0.001 ⬍0.001 ⬍0.001 0.62 ⬍0.001 0.002 ⬍0.001 ⬍0.001 ⬍0.001 0.16 0.02 0.35
Note: Data presented as number (percent) for categorical variables and mean ⫾ SD for continuous variables. To convert glucose in mg/dL to mmol/L, multiply by 0.0555; cholesterol in mg/dL to mmol/L, multiply by 0.02586; creatinine in mg/dL to mol/L, multiply by 88.4. Abbreviation: Q, quartile. *UACR quartile: Q1, less than 2.7; Q2, 2.7 to less than 5.4; Q3, 5.4 to less than 10.2; and Q4, 10.2 to less than 30 mg/g in men, and Q1, less than 4.3; Q2, 4.3 to less than 7.6; Q3, 7.6 to less than 12.9; and Q4, 12.9 to less than 30 mg/g in women. †Missing numbers in ascending quartiles: 9, 14, 12, and 16. ‡Missing numbers in ascending quartiles: 2, 2, 1, and 4. §Missing numbers in ascending quartiles: 2, 0, 0, and 2. 储Missing numbers in ascending quartiles: 3, 2, 1, and 3.
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Figure 1. Crude incidence rates (per 1,000 person-years) of all CVD events (the first nonfatal CVD or fatal CVD), nonfatal CVD, and fatal CVD by sex-specific UACR quartiles. Microalbuminuria and macroalbuminuria were not included in the main analysis, but were used as a reference. UACR quartiles: less than 2.7, 2.7 to less than 5.4, 5.4 to less than 10.2, and 10.2 to less than 30 mg/g (⬍0.3, 0.3 to ⬍0.6, 0.6 to ⬍1.1, and 1.1 to ⬍3.4 mg/mmol) in men and less than 4.3, 4.3 to less than 7.6, 7.6 to less than 12.9, and 12.9 to less than 30 mg/g (⬍0.5, 0.5 to ⬍0.9, 0.9 to ⬍1.4, 1.4 to ⬍3.4 mg/mmol) in women. P for trend (quartiles 1 to 4) ⬍ 0.001 for all CVD, nonfatal CVD, and fatal CVD events.
Results of Cox proportional hazards models are listed in Table 2. Controlling for conventional CVD risk factors, participants with UACR in quartiles 3 and 4 had 41% and 72% greater risks of developing all CVD events and 118% and 199% greater risks of CVD death, respectively. Additional significant predictors of all CVD events were male sex, older age, diabetes, residence in Oklahoma or North/South Dakota compared with Arizona, lower HDL cholesterol level, higher LDL cholesterol level, higher SBP, use of antihypertensive medication, and current smoking. Additional significant predictors of nonfatal CVD events were male sex, older age, diabetes, residence in Oklahoma or North/South Dakota compared with Arizona, lower HDL cholesterol level, higher LDL cholesterol level, higher SBP, use of antihypertensive medication, current smoking, and former or never drinking. Additional significant predictors of CVD death were male sex, older age, diabetes, higher SBP, and current smoking and drinking. In the analysis of subgroup by diabetes status, in which quartiles of UACR were recomputed within subgroup, participants with diabetes with UACR in the fourth quartile had a 57% higher risk of developing all CVD events, and those with UACR in the upper 2 quartiles had 235% and 321% higher risks of CVD death than those with UACR in the lowest
quartile, controlling for the conventional CVD risk factors, respectively. UACR within the normal range was not associated with risk of nonfatal CVD among participants with diabetes. Participants without diabetes with UACR in the fourth quartile had a 43% higher risk of developing all CVD events, although the association was weak. When albuminuria was considered as a continuous variable, ie, log2-transformed UACR (log2 [UACR]), for every doubling of UACR, risks of developing all CVD events, nonfatal CVD, and fatal CVD increased by 13%, 9%, and 29%, adjusted for the conventional risk factors, respectively (Table 3). In subgroup analysis, for every doubling of UACR, risks of developing all CVD events, nonfatal CVD, and fatal CVD increased by 20%, 13%, and 48% among participants with diabetes and 8% (P ⫽ 0.06), 6% (P ⫽ 0.20), and 13% (P ⫽ 0.16) among participants without diabetes adjusted for the conventional CVD risk factors, respectively. As a reference, Table 4 lists results of repeating the same analysis in the entire cohort (n ⫽ 4,249; median UACR, 10.6 mg/g; minimum and maximum, 0.04 and 65,000 mg/g; first and third quartile partitions, 4.7 and 42.3 mg/g, respectively) and modeling albuminuria as a continuous variable, ie, log2 (UACR). For every dou-
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Variable
All participants UACR* Q2 v Q1 Q3 v Q1 Q4 v Q1 Male v female Age (5 y)‡ BMI (5 kg/m2)‡ Diabetes v nondiabetes Study center OK v AZ ND/SD v AZ HDL (5 mg/dL)‡ LDL (5 mg/dL)‡ SBP (5 mm Hg)‡ Use of antihypertensives (yes v no) Plasma creatinine (mg/dL) Current smoking (yes/no) Current alcohol drinking (yes/no) Participants with diabetes UACR§ Q2 v Q1 Q3 v Q1 Q4 v Q1 Male v female Age (5 y) BMI (5 kg/m2) Duration of diabetes (y) Diabetes treatment (yes v no) Study center OK v AZ ND/SD v AZ HDL (5 mg/dL) LDL (5 mg/dL) SBP (5 mm Hg) Use of antihypertensives (yes v no) Plasma creatinine (mg/dL) Current smoking (yes v no) Current alcohol drinking (yes v no) Participants without diabetes UACR储 Q2 v Q1 Q3 v Q1 Q4 v Q1 Male v female Age (5 y) BMI (5 kg/m2)
Hazard Ratio (95% confidence interval)
Nonfatal CVD
P
Hazard Ratio (95% confidence interval)
⬍0.0001† 1.28 (0.96-1.70) 1.41 (1.07-1.87) 1.72 (1.31-2.27) 1.80 (1.44-2.24) 1.23 (1.15-1.31) 1.07 (0.98-1.16) 1.88 (1.54-2.29)
P
Hazard Ratio (95% confidence interval)
⬍0.0001 ⬍0.0001 0.14 ⬍0.0001
1.35 (1.02-1.79) 1.48 (1.29-1.70) 0.93 (0.89-0.97) 1.03 (1.01-1.04) 1.06 (1.03-1.08)
0.04 ⬍0.0001 0.0007 0.0004 0.0001
1.30 (1.04-1.63) 1.27 (0.67-2.41) 1.51 (1.24-1.83) 0.86 (0.71-1.06)
P
⬍0.0001
0.02 1.21 (0.89-1.65) 1.31 (0.96-1.78) 1.41 (1.04-1.92) 1.68 (1.31-2.15) 1.17 (1.09-1.26) 1.05 (0.95-1.16) 1.84 (1.47-2.31)
⬍0.0001 ⬍0.0001 0.30 ⬍0.0001
1.58 (0.84-2.97) 2.18 (1.21-3.93) 2.99 (1.69-5.30) 2.16 (1.43-3.26) 1.37 (1.22-1.55) 1.04 (0.89-1.22) 2.24 (1.55-3.22)
0.0003 ⬍0.0001 0.62 ⬍0.0001
1.45 (1.04-2.02) 1.55 (1.31-1.82) 0.92 (0.87-0.96) 1.04 (1.02-1.05) 1.06 (1.03-1.10)
0.03 ⬍0.0001 0.0008 ⬍0.0001 0.0001
1.11 (0.68-1.81) 1.24 (0.98-1.58) 0.99 (0.87-1.02) 1.01 (0.98-1.04) 1.05 (1.00-1.10)
0.69 0.07 0.14 0.46 0.05
0.02 0.46 ⬍0.0001
1.29 (0.99-1.66) 1.23 (0.59-2.56) 1.54 (1.24-1.92)
0.05 0.58 0.0001
1.17 (0.77-1.76) 1.08 (0.34-3.47) 1.54 (1.07-2.20)
0.32 0.90 0.02
0.16
0.70 (0.55-0.88)
0.002
1.59 (1.09-2.30)
0.01
0.02 1.08 (0.70-1.65) 1.30 (0.86-1.95) 1.57 (1.05-2.34) 1.44 (1.02-2.04) 1.11 (1.01-1.23) 0.92 (0.81-1.05) 1.02 (0.99-1.04)
Fatal CVD
0.44
0.04 0.03 0.23 0.19
0.97 (0.61-1.56) 1.02 (0.64-1.62) 1.21 (0.77-1.91) 1.37 (0.91-2.05) 1.07 (0.95-1.20) 0.90 (0.78-1.04) 1.02 (0.99-1.04)
1.52 (1.09-2.13)
0.01
1.80 (1.21-2.68) 1.45 (1.18-1.78) 0.88 (0.82-0.95) 1.02 (0.99-1.04) 1.04 (0.99-1.09)
0.0003
0.13 0.30 0.18 0.23
2.35 (0.94-5.90) 3.35 (1.41-7.99) 4.21 (1.79-9.91) 1.84 (1.01-3.35) 1.23 (1.03-1.47) 0.92 (0.73-1.16) 1.02 (0.98-1.06)
0.05 0.02 0.50 0.41
1.62 (1.10-2.40)
0.01
1.56 (0.86-2.82)
0.14
0.004 0.0004 0.002 0.09 0.07
1.91 (1.21-3.01) 1.39 (1.10-1.77) 0.89 (0.82-0.97) 1.02 (0.99-1.04) 1.04 (0.99-1.10)
0.006 0.007 0.01 0.25 0.08
1.40 (0.70-2.83) 1.45 (1.02-2.05) 0.87 (0.76-1.00) 1.04 (1.01-1.08) 1.05 (0.97-1.14)
0.34 0.04 0.05 0.02 0.21
1.07 (0.77-1.48) 0.97 (0.36-2.60) 1.57 (1.17-2.11)
0.71 0.94 0.003
1.04 (0.71-1.51) 0.86 (0.27-2.73) 1.63 (1.16-2.30)
0.86 0.80 0.005
1.00 (0.56-1.79) 0.76 (0.14-4.06) 1.41 (0.85-2.34)
0.89 0.75 0.18
0.99 (0.71-1.37)
0.94
0.81 (0.56-1.19)
0.29
1.40 (0.81-2.43)
0.23
0.05 1.32 (0.92-1.90) 1.37 (0.95-1.97) 1.43 (0.99-2.06) 2.32 (1.72-3.12) 1.28 (1.18-1.39) 1.18 (1.04-1.32)
1.25 (0.83-1.86) 1.35 (0.91-2.01) 1.30 (0.86-1.96) ⬍0.0001 2.11 (1.52-2.95) ⬍0.0001 1.22 (1.11-1.34) 0.008 1.20 (1.04-1.37) (Continued)
0.17
⬍0.0001 ⬍0.0001 0.008
0.27 1.33 (0.62-2.86) 1.16 (0.53-2.51) 1.57 (0.77-3.22) 3.06 (1.63-5.74) 1.48 (1.25-1.75) 1.08 (0.84-1.38)
0.0005 ⬍0.0001 0.57
Normal Albuminuria and Cardiovascular Disease
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Table 2 (Cont’d). Multivariate Hazard Ratios of All CVD Events, Nonfatal CVD, and Fatal CVD All CVD
Variable
Study center OK v AZ ND/SD v AZ HDL (5 mg/dL) LDL (5 mg/dL) SBP (5 mm Hg) Use of antihypertensives (yes v no) Plasma creatinine (mg/dL) Current smoking (yes v no) Current alcohol drinking (yes v no)
Nonfatal CVD
Fatal CVD
Hazard Ratio (95% confidence interval)
P
Hazard Ratio (95% confidence interval)
P
Hazard Ratio (95% confidence interval)
P
1.06 (0.707-1.61) 1.46 (1.19-1.78) 0.96 (0.92-1.02) 1.03 (1.01-1.05) 1.07 (1.03-1.11)
0.79 0.0002 0.19 0.003 0.0001
1.21 (0.73-2.00) 1.62 (1.27-2.06) 0.95 (0.89-1.01) 1.04 (1.02-1.07) 1.08 (1.03-1.12)
0.47 0.0001 0.08 ⬍0.0001 0.0003
0.85 (0.41-1.74) 1.03 (0.73-1.46) 0.99 (0.91-1.09) 0.98 (0.94-1.02) 1.07 (1.01-1.14)
0.65 0.85 0.90 0.30 0.04
1.46 (1.06-2.00) 1.61 (0.68-3.78) 1.49 (1.14-1.93)
0.02 0.28 0.003
1.40 (0.98-2.01) 1.70 (0.64-4.49) 1.53 (1.14-2.01)
0.07 0.29 0.005
1.39 (0.74-2.63) 1.28 (0.23-7.02) 1.50 (0.89-2.52)
0.18 0.78 0.13
0.81 (0.62-1.06)
0.14
0.65 (0.48-0.87)
0.005
2.04 (1.17-3.53)
0.01
Note: All CVD events included the first nonfatal CVD or fatal CVD. To convert cholesterol in mg/dL to mmol/L, multiply by 0.02586; creatinine in mg/dL to mol/L, multiply by 88.4. Abbreviations: Q, quartile; OK, Oklahoma; AZ, Arizona; ND/SD, North/South Dakota. *UACR quartiles: Q1, less than 2.7; Q2, 2.7 to less than 5.4; Q3, 5.4 to less than 10.2; and Q4, 10.2 to less than 30 mg/g [⬍0.3, 0.3 to ⬍0.6, 0.6 to ⬍1.1, and 1.1 to ⬍3.4 mg/mmol] in men, and Q1, less than 4.3; Q2, 4.3 to less than 7.6; Q3, 7.6 to less than 12.9; and Q4, 12.9 to less than 30 mg/g [⬍0.5, 0.5 to ⬍0.9, 0.9 to ⬍1.4, 1.4 to ⬍3.4 mg/mmol] in women. †P for trend test. ‡For every 5-unit increase. §UACR quartiles: Q1, less than 4.8; Q2, 4.8 to less than 8.7; Q3, 8.7 to less than 15.0; Q4, 15.0 to less than 30 mg/g [⬍0.5, 0.5 to ⬍1.0, 1.0 to ⬍1.7, 1.7 to ⬍3.4 mg/mmol] in men, and Q1, less than 5.5; Q2, 5.5 to less than 9.7; Q3, 9.7 to less than 16.0; Q4, 16.0 to less than 30 mg/g [⬍0.6, 0.6 to ⬍1.1, 1.1 to ⬍1.8, 1.8 to ⬍3.4 mg/mmol] in women. 储UACR quartiles: Q1, less than 2.3; Q2, 2.3 to less than 4.5; Q3, 4.5 to less than 8.5; Q4, 8.5 to less than 30 mg/g [⬍0.3, 0.3 to ⬍0.5, 0.5 to ⬍1.0, 1.0 to ⬍3.4 mg/mmol] in men, and Q1, less than 3.8; Q2, 3.8 to less than 6.7; Q3, 6.7 to less than 11.3; Q4, 11.3 to less than 30 mg/g [⬍0.4, 0.4 to ⬍0.8, 0.8 to ⬍1.3, 1.3 to ⬍3.4 mg/mmol] in women.
bling of UACR, risks of developing all CVD events, nonfatal CVD, and fatal CVD increased by 14%, 11%, and 27%, adjusted for conven-
tional CVD risk factors, respectively. In subgroup analysis, for every doubling of UACR, risks of developing all CVD events, nonfatal
Table 3. Hazard Ratios per Doubling of UACR Within the Normal Range Associated With All CVD Events, Nonfatal CVD, and Fatal CVD All CVD
All participants* Hazard ratio (95% confidence interval) P Participants with diabetes† Hazard ratio (95% confidence interval) P Participants without diabetes‡ Hazard ratio (95% confidence interval) P
Nonfatal CVD
Fatal CVD
1.13 (1.06-1.21) 0.0002
1.09 (1.01-1.17) 0.02
1.29 (1.12-1.48) 0.0003
1.20 (1.07-1.34) 0.001
1.13 (0.999-1.28) 0.05
1.48 (1.17-1.87) 0.001
1.08 (0.99-1.18) 0.06
1.06 (0.97-1.17) 0.20
1.13 (0.95-1.34) 0.16
Note: All CVD events include the first nonfatal CVD or fatal CVD. *Models for all participants were adjusted for age, sex, study center, diabetes status, BMI, SBP, use of antihypertensive medication, HDL cholesterol level, LDL cholesterol level, plasma creatinine level, alcohol consumption, and smoking status. †Models for participants with diabetes were adjusted for the same variable as in the model for all participants, but replacing diabetes status with duration of diabetes and diabetes treatment. ‡Models for participants without diabetes were adjusted for all variables as in the model for all participants, except for diabetes status.
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Xu et al
Table 4. Hazard Ratios per Doubling of UACR Associated With All CVD Events, Nonfatal CVD, and Fatal CVD in the Overall Cohort
All participants* Hazard ratio (95% confidence interval) P Participants with diabetes‡ Hazard ratio (95% confidence interval) P Participants without diabetes§ Hazard ratio (95% confidence interval) P
All CVD
Nonfatal CVD
Fatal CVD
1.14 (1.11-1.17) ⬍0.0001
1.11 (1.08-1.15) ⬍0.0001
1.27 (1.22-1.33) ⬍0.0001
1.13 (1.09-1.17) ⬍0.0001
1.09 (1.04-1.13) ⬍0.0001
1.24 (1.18-1.31) ⬍0.0001
1.12 (1.06-1.18) ⬍0.0001
1.11 (1.04-1.18) 0.0008
1.22 (1.11-1.34) ⬍0.0001
Note: All CVD events include the first nonfatal CVD or fatal CVD. *Models for all participants were adjusted for age, sex, study center, diabetes status, BMI, SBP, use of antihypertensive medication, HDL cholesterol level, LDL cholesterol level, plasma creatinine level, alcohol consumption, and smoking status. †Models for participants with diabetes were adjusted for the same variable as in the model for all participants, but replacing diabetes status with duration of diabetes and diabetes treatment. ‡Models for participants without diabetes were adjusted for all variables as in the model for all participants, except for diabetes status.
CVD, and fatal CVD increased by 13%, 9%, and 24% among participants with diabetes and 12%, 11%, and 22% among participants without diabetes, adjusted for conventional CVD risk factors, respectively. DISCUSSION
In this large longitudinal study, higher albuminuria levels within the range of UACR less than 30 mg/g in American Indians aged 45 to 74 years were associated with greater risks of developing all CVD events and CVD deaths independently of other CVD risk factors. Our findings were consistent whether albuminuria was analyzed by quartiles or as a continuous variable. These associations were more pronounced in American Indians with than without diabetes (P for interactions between UACR and diabetes status for risk of all CVD events, nonfatal CVD, and fatal CVD were 0.13, 0.34, and 0.08, respectively). Analysis of the entire cohort, including participants with microalbuminuria or macroalbuminuria, also showed a log-linear association across the entire range of UACR with all CVD events, nonfatal CVD, and fatal CVD in participants with and without diabetes, independent of other established CVD risk factors. Effects of UACR on risk of CVD events were not confounded by serum lipid concentrations. The negative associations between UACR and total and LDL cholesterol levels in univariate analysis were unexpected observations.
Results from the HOPE Study4 indicated that across a wide spectrum of UACRs, greater albuminuria predicted CVD in individuals with or without diabetes. For every 3.5-mg/g (0.4-mg/ mmol) increase in UACR, the risk of CVD increased by 5.9% after adjusting for age and sex. In our study, we observed a log-linear association between UACR within the normal range and risks of all CVD events, nonfatal CVD, and fatal CVD. Among all participants, risks of developing all CVD events, nonfatal CVD, and fatal CVD increased by 13%, 9%, and 29% per doubling of UACR within the normal range, adjusted for the conventional CVD risk factors, respectively. Among participants with diabetes, risks of all CVD events, nonfatal CVD, and fatal CVD increased by 20%, 13%, and 49% for every doubling of UACR within the normal range, respectively. Among participants without diabetes, there was no statistically significant association between albuminuria within the normal range and risk of either nonfatal or fatal CVD. Data from the Framingham Heart Study showed that individuals without hypertension and without diabetes with UACR equal to the sex-specific median value or greater (UACR ⱖ 3.9 mg/g [ⱖ0.4 mg/mmol] in men, ⱖ7.5 mg/g [ⱖ0.8 mg/mmol] in women) have a nearly 3-fold risk of CVD.11 Furthermore, the lack of association between UACR in the normal range and CVD events in participants without diabetes in the SHS may reflect a lack of power in the current
Normal Albuminuria and Cardiovascular Disease
analysis because of the small number of events. Results from the entire cohort showed that albuminuria was a strong independent predictor of all CVD events, nonfatal CVD, and fatal CVD, and the associations were similar in participants with and without diabetes. The underlying mechanism of the association between albuminuria within the normal range and CVD risk is unknown. However, it is well established that abnormal albuminuria indicates generalized vascular dysfunction.23,24 The mechanism by which microalbuminuria is related to systemic and coronary atherosclerosis remains uncertain, although microalbuminuria seems to be a marker for endothelial dysfunction. A recent study of participants with and without diabetes suggested that microalbuminuria emerges later in the course of atherosclerotic process.25 Nonetheless, patients with diabetes with microalbuminuria have increased transcapillary escape rate of albumin.26 Echocardiographic data in the SHS population showed that albuminuria predicted both ventricular and atrial dysfunction.23 Likewise, microalbuminuria related to congestive heart failure in the HOPE Study4 suggests that congestive heart failure or CVD might exert cardiovascular morbidity through both atherosclerosis and congestive heart failure. Primary strengths of the present study are its prospective design, large sample size, long and continuous surveillance and careful confirmation of incident CVD events, inclusion of participants with albuminuria less than the current diagnostic threshold for microalbuminuria, and multivariable-adjusted analyses. A limitation of the current study is that a single random morning urine specimen, rather than multiple specimens or a timed specimen, was collected to measure albumin and creatinine. However, recent guidelines indicate that a spot urine sample (preferably a first-morning specimen) or a random urine specimen is acceptable for albuminuria measurement because the test is performed easily in the clinic and results correlate well with those of 24-hour collections.27 In conclusion, in the SHS cohort of middleaged to elderly American Indians, higher albuminuria levels within the normal range of UACR less than 30 mg/g were associated strongly with higher risks of developing CVD and CVD mortality
215
independently of other CVD risk factors. Our findings are in agreement with a growing number of studies suggesting that the upper limit in the definition of normal UACR (30 mg/g) be reconsidered to align with this mounting body of evidence. ACKNOWLEDGMENT The authors acknowledge the assistance and cooperation of the Ak-Chin Tohono O’Odham (Papago)/Pima, Gila River, and Salt River Pima/Maricopa in Arizona; Apache, Caddo, Comanche, Delaware, Fort Sill Apache, Kiowa, and Wichita in Oklahoma; and Oglala Sioux, Cheyenne River Sioux, and Spirit Lake communities in North/South Dakota, without whose support this study would not have been possible. The authors also thank the Indian Health Service hospitals and clinics at each center; the directors of the Strong Heart Study clinics, Betty Jarvis, Dr Tauqeer Ali, Alan Crawford, Marcia O’Leary, and their staffs; and the physicians who performed the mortality and morbidity reviews. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the Indian Health Service.
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