Albuminuria is associated with atherothrombotic events and all-cause mortality in patients with and without diabetes. However, it is not known whether albuminuria is associated with atherosclerosis per se in the same manner. The present study included 914 consecutive white patients who had been referred for coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Albuminuria was defined as a urinary albumin/creatinine ratio ≥30 μg/mg. Microalbuminuria was defined as 30 to 300 μg albumin/mg creatinine, and macroalbuminuria as a urinary albumin/creatinine ratio of ≥300 μg/mg. The prevalence of stenoses of ≥50% was significantly greater in patients with albuminuria than in those with normoalbuminuria (66% vs 51%; p <0.001). Logistic regression analysis, adjusted for age, gender, diabetes, smoking, hypertension, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, body mass index, estimated glomerular filtration rate, and the use of angiotensin-converting enzyme inhibitors/angiotensin II antagonists, aspirin, and statins, confirmed that albuminuria was significantly associated with stenoses ≥50% (standardized adjusted odds ratio [OR] 1.68, 95% confidence interval [CI] 1.15 to 2.44; p = 0.007). The adjusted OR was 1.54 (95% CI 1.03 to 2.30; p = 0.034) for microalbuminuria and 2.55 (95% CI 1.14 to 5.72; p = 0.023) for macroalbuminuria. This association was significant in the subgroup of patients with type 2 diabetes (OR 1.66, 95% CI 1.01 to 2.74; p = 0.045) and in those without diabetes (OR 1.42, 95% CI 1.05 to 1.92; p = 0.023). An interaction term urinary albumin/creatinine ratio*diabetes was not significant (p = 0.579). In conclusion, micro- and macroalbuminuria were strongly associated with angiographically determined coronary atherosclerosis in both patients with and those without type 2 diabetes mellitus, independent of conventional cardiovascular risk factors and the estimated glomerular filtration rate.
The association of albuminuria with the angiographically determined coronary artery state is unclear. We, therefore, investigated the association of albuminuria with angiographically determined coronary atherosclerosis, independent of conventional risk factors and the estimated glomerular filtration rate (eGFR) in a large series of consecutive patients with coronary artery disease who had undergone angiography, including patients with and without diabetes mellitus.
Methods
From August 2005 through December 2007, we enrolled 914 consecutive white patients who had been referred for coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD) on the basis of the current guidelines. The patients who had experienced myocardial infarction or acute coronary syndrome within 3 months before the baseline angiogram were not enrolled. Five patients with type 1 diabetes were excluded from the analyses. Thus, the data have been reported for 909 patients.
Information on the conventional cardiovascular risk factors was obtained by a standardized interview. Also, the systolic/diastolic blood pressure was measured using the Riva-Rocci method with the patient at rest in a sitting position on the day of hospital entry and ≥5 hours after hospitalization. Hypertension was defined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Type 2 diabetes mellitus was diagnosed according to the World Health Organization criteria. The height and weight were recorded, and the body mass index was calculated as the body weight in kilograms divided by the height in square meters.
Coronary angiography was performed using the Judkins technique, as described in a former protocol with another population. Coronary artery stenoses with lumen narrowing ≥50% were considered significant. To obtain a measure of the overall atherosclerosis load of the coronary arteries, the extent of CAD was defined as the number of significant coronary stenoses in a given patient, as described previously. The Ethics Committee of the University of Innsbruck approved the present study, and all participants gave written informed consent.
Venous blood samples were collected after an overnight fast of 12 hours before angiography was performed, and laboratory measurements were performed using fresh serum samples, as described previously. The serum levels of total cholesterol, low-density lipopoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were determined by using enzymatic hydrolysis and precipitation techniques on a Hitachi-Analyzer 717 or 911 (QuantolipLDL, QuantolipHDL; Roche, Basel, Switzerland). All patients without known diabetes underwent an oral glucose tolerance test with 75 g glucose.
Urinary albumin excretion was expressed as the albumin/creatinine concentration ratio in a random morning urine specimen. The urinary albumin concentration was determined using immunoturbidometry (Tina-quant Albumin Gen.2 Assay, Roche Diagnostics, Basel, Switzerland). Both serum and urinary creatinine concentrations were measured using the modified Jaffé method (Creatinine Jaffé Gen.2 Assay, Roche Diagnostics). Albuminuria was defined as a urinary albumin/creatinine ratio (ACR) of ≥30 μg/mg. Microalbuminuria was defined as 30 to 300 μg albumin/mg creatinine, and macroalbuminuria as a urinary ACR of ≥300 μg/mg.
Because the Modification of Diet in Renal Disease eGFR had been evaluated in patients with kidney disease and tends to underestimate the GFR in patients with a GFR >60 ml/min/1.73 m 2 , the eGFR was assessed using the quadratic Mayo Clinic equation. This equation has been shown to give a more accurate estimate of the GFR than the former equation in patients with nearly normal renal function. If the serum creatinine was <0.8 mg/dl, 0.8 mg/dl was inserted as the value for serum creatinine, as reported previously.
Differences in patient characteristics were tested for statistical significance using the chi-square test for categorical variables. The Mann-Whitney U test and Kruskal-Wallis test were used for continuous variables, as appropriate. Adjusted odds ratios (ORs) for the presence of significant stenoses were derived from the logistic regression models. For these analyses, the continuous variables were z-transformed. The predictors for the continuous variable, ACR, were derived from analysis of covariance. The results are given as the mean ± SD, unless noted otherwise. Statistical significance was defined as 2-tailed p <0.05, and the analyses were performed using the Statistical Package for Social Sciences, version 11.0, for Windows (SPSS, Chicago, Illinois).
Results
Overall, the characteristics of our study population were typical for a cohort undergoing coronary angiography for the evaluation of CAD. Coronary angiography revealed significant CAD in 498 patients (55%). Their mean age was 65 ± 11 years, with a preponderance of men (63%), and a high prevalence of patients with type 2 diabetes (25%), hypertension (82%), and smoking (59%). Of our patients, 71% were taking aspirin, 47% taking statins, 1% taking fibrates, 32% taking angiotensin-converting enzyme inhibitors, and 12% taking angiotensin II receptor blocking agents. Of the patients with type 2 diabetes mellitus, 19%, 24%, 39%, and 2% were taking—alone or combined—insulin, sulfonylurea, metformin, and glitazones, respectively.
Albuminuria was detected in 211 of our patients (23%); 169 (19%) had microalbuminuria and 42 (4%) macroalbuminuria. The characteristics of our patients are summarized in Table 1 with respect to the presence of micro- or macroalbuminuria.
| Variable | No Albuminuria | Microalbuminuria | Macroalbuminuria | p Value |
|---|---|---|---|---|
| Age (years) | 64 ± 11 | 69 ± 10 | 67 ± 10 | <0.001 |
| Type 2 diabetes mellitus | 20% | 39% | 55% | <0.001 |
| Body mass index (kg/m 2 ) | 27.6 ± 4.2 | 27.9 ± 4.8 | 29.4 ± 5.1 | 0.032 |
| Hypertension | 80% | 86% | 93% | 0.030 |
| Systolic blood pressure (mm Hg) | 136 ± 17 | 140 ± 19 | 143 ± 18 | 0.002 |
| Diastolic blood pressure (mm Hg) | 82 ± 9 | 83 ± 12 | 84 ± 10 | 0.244 |
| Smoking | 57% | 63% | 71% | 0.087 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 99.3 ± 16.3 | 90.5 ± 21.5 | 87.1 ± 22.1 | <0.001 |
| Total cholesterol (mg/dl) | 196 ± 46 | 194 ± 50 | 182 ± 50 | 0.155 |
| Low-density lipoprotein (mg/dl) | 129 ± 41 | 127 ± 45 | 111 ± 35 | 0.025 |
| High-density lipoprotein (mg/dl) | 57 ± 16 | 55 ± 15 | 55 ± 16 | 0.502 |
| Triglycerides (mg/dl) | 137 ± 84 | 137 ± 75 | 156 ± 154 | 0.359 |
| Fasting glucose (mg/dl) | 103 ± 31 | 115 ± 41 | 127 ± 42 | <0.001 |
| Hemoglobin A1c (%) | 6.0 ± 0.9 | 6.4 ± 1.3 | 6.7 ± 1.3 | <0.001 |
| C-reactive protein (mg/dl) | 0.40 ± 0.73 | 0.50 ± 0.62 | 0.69 ± 0.75 | 0.012 |
In a logistic regression model, the presence of diabetes (adjusted OR 2.67, 95% confidence interval [CI] 1.84 to 3.86; p <0.001), smoking (OR 1.70, 95% CI 1.17 to 2.47; p = 0.006), eGFR (standardized adjusted OR 0.621, 95% CI 0.50 to 0.76; p <0.001), and age (OR 1.25, 95% CI 1.00 to 1.56; p = 0.049) were significantly associated with albuminuria. However, gender, body mass index, hypertension, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were not.
The prevalence of stenoses ≥50% was significantly greater in patients with albuminuria compared to those without (66 vs 51%; p <0.001). An apparent dose–response relation was found between the severity of albuminuria and the presence of significant CAD. The prevalence of significant coronary stenoses increased significantly from 51% in patients with normoalbuminuria to 65% in patients with microalbuminuria to 71% in patients with macroalbuminuria (p trend = 0.001; Figure 1 ). The extent of CAD was significantly greater in both patients with micro- and macroalbuminuria compared to patients with normoalbuminuria (1.8 ± 2.0 and 1.7 ± 1.8 vs 1.2 ± 1.6; p <0.001 and p = 0.021, respectively).
Logistic regression analysis, adjusted for age, gender, diabetes, smoking, hypertension, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, and body mass index, confirmed that albuminuria was significantly associated with significant CAD (OR = 1.47, 95% CI 1.03 to 2.10; p = 0.032). Additional adjustment for the eGFR (OR 1.51, 95% CI 1.06 to 2.16; p = 0.024) and the use of angiotensin-converting enzyme inhibitors/angiotensin II antagonists, aspirin, and statins corroborated this association (OR 1.68, 95% CI 1.15 to 2.44; p = 0.007). Taken separately, the categorical variable, microalbuminuria, exhibited an OR of 1.54 (95% CI 1.03 to 2.30; p = 0.034) and that of macroalbuminuria an OR 2.55 (95% CI 1.14 to 5.72; p = 0.023) for significant stenoses in the fully adjusted model compared to patients with normoalbuminuria. Similar results were obtained when, instead of dichotomous albuminuria criteria, continuous measures of urinary albumin excretion were entered into the fully adjusted model ( Figure 2 ).
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