Screening for albuminuria has been advocated because it is associated with cardiovascular morbidity and all-cause mortality. The “gold standard” to assess albuminuria is 24-hour urinary albumin excretion (UAE). Because 24-hour urine collection is cumbersome, guidelines suggest measuring albuminuria in a first morning void, either as urinary albumin concentration (UAC) or adjusted for creatinine concentration, the albumin:creatinine ratio (ACR). To decide which albuminuria measure to use in clinical practice, it is essential to know which best predicts clinical outcome. In a sample representative of the Groningen (the Netherlands) population (n = 3,414), the authors compared UAC, ACR, and UAE as predictors of cardiovascular events and all-cause mortality. During a median follow-up of 7.5 years, which ended December 31, 2005, they observed 278 events (a major adverse cardiovascular event or mortality). The area under the receiver operating characteristic curve predicting events was 0.65 for UAE, 0.62 for UAC (P = 0.06 vs. UAE), and 0.66 for ACR (P = 0.80 vs. UAE; P = 0.01 vs. UAC). When sex-specific subgroups were considered, UAE was superior to UAC in predicting outcome (P = 0.04) for females, whereas, for males as well as females, no difference was found between ACR and UAE. To predict cardiovascular morbidity and all-cause mortality, measuring ACR in a first-morning-void urine sample is a good alternative to measuring 24-hour UAE.
Because urinary albumin excretion (UAE) is a marker of cardiovascular (CV) risk, some have proposed screening the general population; however, it is unknown how the predictive power of a single screening value changes over time. In this study, data of 8496 individuals in a community-based, prospective cohort were used to evaluate this question. For each doubling of baseline UAE, the hazard ratio (HR) for a CV event was 1.36 (95% confidence interval [CI] 1.31 to 1.42). Baseline UAE similarly predicted events occurring >5 yr after baseline, suggesting that it remains a good predictor during at least the first 5 yr after measurement. Approximately 4 yr after baseline, UAE was measured again in 6800 individuals. Once again, high UAE (>75th percentile) predicted subsequent CV events, whether defined using the baseline UAE or follow-up UAE (HR 3.39 [95% CI 2.58 to 4.45] and HR 2.50 [95% CI] 1.90 to 3.29, respectively; P = 0.3 for difference). Finally, compared with individuals with consistently low UAE, individuals who progressed from low to high UAE during follow-up had a significantly higher risk for CV events (HR 3.68; 95% CI 2.45 to 5.53). In conclusion, UAE remains a good predictor of CV events during the first 5 yr after measurement, but repeating the measurement several years later also detects progression of UAE, which is also associated with increased CV risk. Future studies are required to determine the optimal interval of repeat testing and its cost-effectiveness.
Statins improve cardiovascular outcome, but less is known on the renal outcome. We, therefore, studied the relationship between the use of statins and urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in two settings: a randomized controlled trial (RCT) and an observational cohort study, in which patients were included to study the impact of an elevated UAE on renal and cardiovascular prognosis.We used data from the Prevention of REnal and Vascular ENd-stage Disease Intervention trial (PREVEND-IT) and the PREVEND cohort study. The PREVEND-IT subjects (788 with a UAE 15-300 mg/day) received pravastatin 40 mg/day vs placebo and/or fosinopril 20 mg/day vs placebo in a 2x2 factorial-RCT design. Of the 3440 cohort subjects, 469 used statins during the 4-year follow-up period. Multivariate-regression adjusted for confounding factors and the propensity score was used to estimate the relation between statin use and UAE and GFR.In the RCT, pravastatin did not change UAE or GFR, neither in fosinopril yes/no subgroups. In the observational cohort, statin use was associated with a rise in UAE (+12.1%), compared with statin non-use (+3.6%, P<0.001). This rise was most pronounced in those on statins prior to the first screening [+24.8% (95% CI: 11.9-39.2)], those using statins>3 years [+18.5% (7.3-30.8)] and those with >1 or >2 defined daily doses (+15.7 and +17.3%, respectively). These differences remained significant after adjustment for relevant variables and propensity score. The rise in UAE could not be attributed to a higher dose or a specific statin. GFR fell in 4 years in both statin users and non-users (4.6+/-13.5 and 2.4+/-11.2, respectively). The fall in GFR between groups was not different after adjustment (P=0.11).We conclude from the RCT data that statins do not lower UAE in subjects selected because of an elevated UAE instead of hyperlipidaemia. In the observational cohort study, the use of statins similarly was not associated with a fall in UAE; UAE instead increased. Statin treatment was not associated with a significant change in GFR in these subjects with only modestly impaired GFR.
The Kidney Disease Outcomes Quality Initiative guidelines aim to define chronic kidney disease (CKD) and classify its stages. Stage 3 CKD generally receives more attention than stage 1 or 2, because the more impaired glomerular filtration rate (GFR) in stage 3 suggests a higher cardiovascular and renal risk. In this study we evaluated cardiovascular and renal outcome in subjects with stage 1 and 2 CKD. For comparison, we also studied these outcomes in stage 3 CKD.We used data of 8495 subjects of the PREVEND study, a prospective community-based cohort study, with data on urinary albumin excretion (UAE) and serum creatinine available. As measure of cardiovascular outcome, combined cardiovascular morbidity and mortality was used. As renal outcome, mean annual change of estimated GFR (eGFR) was used.6905 subjects had no CKD; 243, 856 and 491 subjects had stage 1, 2 and 3 CKD, respectively. During a median follow-up of 7.5 years 565 cardiovascular events occurred. Incidence rates of cardiovascular events were higher (P < 0.001 for all groups) in subjects with stage 1-3 CKD (17.2, 22.2 and 20.9 events/1000 person-years, respectively) than in subjects without CKD (7.0 events/1000 person-years). Using subjects without CKD as reference, age- and sex-adjusted hazard ratios [HR (95% CI)] were 2.2 (1.5-3.3), 1.6 (1.3-2.0) and 1.3 (1.0-1.7), respectively. Compared to subjects without CKD but similar baseline eGFR, subjects with stage 1 or 2 CKD showed a larger decline in eGFR (-1.1 versus -1.5 and -0.2 versus -0.6 ml/min/1.73 m(2)/year, respectively, both P < 0.01). When subjects with stage 3 CKD were stratified according to the absence or presence of a UAE >30 mg/24 h, age- and sex-adjusted HRs for CVD were 1.0 (0.7-1.4) and 1.6 (1.1-2.3) and the change in eGFR was 0.2 versus -0.3 ml/min/1.73 m(2)/year, respectively.Subjects with stage 1 or 2 CKD have an increased risk for adverse cardiovascular and renal outcome and should receive equal attention as subjects with stage 3 CKD. Subdividing stage 3 CKD according to the presence or absence of a UAE >30 mg/24 h improves risk stratification within this stage.
OBJECTIVE—To investigate urinary albumin excretion (UAE) and its relation with C-reactive protein (CRP) and the metabolic syndrome in the prediction of the development of type 2 diabetes. RESEARCH DESIGN AND METHODS—We used data from the Prevention of Renal and Vascular End Stage Disease (PREVEND) study, an ongoing, community-based, prospective cohort study initiated in 1997 in the Netherlands. The initial cohort consisted of 8,592 subjects. After 4 years, 6,894 subjects participated in a follow-up survey. Subjects with diabetes at baseline or missing data on fasting glucose were excluded, leaving 5,654 subjects for analysis. The development of type 2 diabetes, defined as a fasting glucose ≥7.0 mmol/l and/or the use of antidiabetic medication, was used as the outcome measure. UAE was calculated as the mean UAE from two consecutive 24-h urine collections. Logistic regression models were used, with the development of type 2 diabetes as the dependent variable. RESULTS—Of the 5,654 subjects for whom data were analyzed, 185 (3.3%) developed type 2 diabetes during a mean follow-up period of 4.2 years. UAE, CRP, and the presence of the metabolic syndrome at baseline were significantly associated with the incidence of type 2 diabetes (P < 0.001 for all variables). In a univariate model, the odds ratio (OR) for UAE was 1.59 (95% CI 1.42–1.79). In our full model, adjusted for age, sex, number of criteria of metabolic syndrome, and other known risk factors for the development of type 2 diabetes (including fasting insulin), the association between UAE and type 2 diabetes remained significant (OR 1.53, 95% CI 1.25–1.88, P < 0.001). There was a significant interaction between UAE and CRP (P = 0.002). After CRP was stratified into tertiles, the ORs for the association between baseline UAE and the development of type 2 diabetes were 2.2 (1.47–3.3), 1.33 (0.96–1.84), and 1.04 (0.83–1.31) for the lowest to highest tertiles, respectively. CONCLUSIONS—UAE predicts type 2 diabetes independent of the metabolic syndrome and other known risk markers of development of type 2 diabetes. The predictive value of UAE was modified by the level of CRP.
The hypothesis that high urinary albumin excretion (UAE; indicating mild renal damage) may precede development of hypertension was tested, and the relation among UAE, GFR, and development of hypertension was investigated. Data of 4635 patients of a prospective cohort study who participated in an extensive screening in 1997 to 1998 and 2001 to 2003 at our outpatient unit and were normotensive at baseline were used. Hypertension was defined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria, UAE was measured in two consecutive 24-h urine samples, and GFR was calculated with the modified Modification of Diet in Renal Disease formula. Mean follow-up was 4.3 yr. Baseline UAE was significantly associated with the risk for developing hypertension (odds ratio 2.29; 95% confidence interval 1.77 to 2.95 per 10-fold increase of UAE). This association was independent of potential confounders. An interaction between UAE and GFR was found (P = 0.030), indicating that with elevated UAE and lowered GFR, but still within the normal range, the risk for developing hypertension was highest. In conclusion, these findings support the hypothesis that mild renal damage may precede the development of hypertension.
