Albuminuria is an important indicator of cardiovascular risk. However, whether albuminuria predicts cardiovascular events independently of the baseline coronary artery state has not yet been investigated. We measured urinary albumin and creatinine concentrations in 867 consecutive patients who underwent coronary angiography for the evaluation of suspected or established stable coronary artery disease (CAD). Albuminuria was defined as a urinary albumin to creatinine ratio of 30 μg/mg or greater. Prospectively, we recorded the vascular events over 3.2 ± 1.2 years. From our patients, 318 had neither albuminuria nor significant CAD (i.e., coronary stenoses ≥50%) at baseline angiography, 69 had albuminuria but no significant CAD, 343 did not have albuminuria but significant CAD, and 137 had both albuminuria and significant CAD. Compared with the event rate among patients with neither albuminuria nor significant CAD (8.2%), event rates were significantly higher in patients with albuminuria without significant CAD (18.8%; p = 0.002) and in normoalbuminuric patients with significant CAD (19.2%; p <0.001); it was highest in patients with both albuminuria and significant CAD (33.6%; p <0.001). Importantly, event rates were similar in patients with albuminuria free of significant CAD and those with significant CAD but normoalbuminuria (p = 0.767). In conclusion, this is the first study demonstrating that albuminuria per se is a CAD risk equivalent after adjusting for the angiographically proven atherosclerotic state at baseline.
An important limitation of the existing prospective epidemiologic studies is that the coronary artery state at baseline was not known. Because albuminuria represents a state of evolving coronary atherosclerosis, coronary artery disease (CAD) is frequently present in these patients although clinically silent. Hence, baseline asymptomatic CAD in patients with albuminuria might account for their increased vascular risk, which then would erroneously be attributed to the presence of albuminuria per se. We, therefore, aimed at investigating the independent and joint impact of the presence of albuminuria and the baseline coronary artery state (as a measure of atherosclerotic disease) on cardiovascular events in patients who underwent coronary angiography. Second, we investigated the predictive power of albuminuria on vascular events in the subgroup of patients with angiographically proven CAD.
Methods
From 2005 to 2007, we enrolled 908 consecutive white patients who were referred for coronary angiography for the evaluation of established or suspected stable CAD on the basis of the current guidelines. Patients who had experienced myocardial infarction or acute coronary syndrome within 3 months before the baseline angiography were not enrolled in this study. Five patients with type 1 diabetes were excluded from the analyses.
Information on conventional cardiovascular risk factors was obtained by a standardized interview, and systolic blood pressure was measured by the Riva-Rocci method under resting conditions in a sitting position at the day of hospital entry at least 5 hours after hospitalization. Hypertension was defined according to the 2013 European Society of Cardiology/European Society of Hypertension guidelines, and diabetes was diagnosed according to the World Health Organization criteria. Height and weight were recorded, and body mass index (BMI) was calculated as body weight (kg)/height (m)².
Overall, 71% of our patients were on aspirin, 47% on statins, 31% on angiotensin-converting enzyme (ACE) inhibitors, and 12% on angiotensin II receptor blocking agents. Among patients with T2DM, 39% were not receiving any antidiabetic medication, and 20%, 25%, 39%, and 2% were receiving—alone or in combination—insulin, sulfonylurea, metformin, and glitazones, respectively.
Coronary angiography was performed using the Judkins technique. Coronary artery stenoses with lumen narrowing of 50% or more were considered significant, and patients with any visible arterial lesions were recorded as having CAD. The study complies with the Declaration of Helsinki. 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 from fresh serum samples, as described previously. The serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were determined using enzymatic hydrolysis and precipitation techniques (QuantolipLDL, QuantolipHDL; Roche, Basel, Switzerland) on a Hitachi-Analyzer 717 or 911. All patients without known diabetes underwent an oral glucose tolerance test with 75 g glucose.
Urinary albumin excretion (UAE) was expressed as the albumin/creatinine concentration ratio in a random morning urine specimen. Urinary albumin concentration was determined by immunoturbidometry (Tina-quant Albumin Gen.2 Assay, Roche Diagnostics). Both serum and urinary creatinine concentrations were measured with a modified Jaffé method (Creatinine Jaffé Gen.2 Assay, Roche Diagnostics). Elevated UAE was defined as a urinary albumin to creatinine ratio (ACR) of 30 μg/mg or greater. The estimated glomerular filtration rate (eGFR) was assessed by the quadratic Mayo Clinic equation, which in patients with nearly normal renal function has been shown to give more accurate estimates of GFR than the modification of diet in renal disease equation.
During an average follow-up time of 3.2 ± 1.2 years, we recorded fatal and nonfatal cardiovascular end points, including vascular death (fatal myocardial infarction, sudden cardiac death, fatal ischemic stroke, and mortality from congestive heart failure because of CAD), nonfatal myocardial infarction, nonfatal ischemic stroke, and need for coronary artery bypass grafting and percutaneous coronary intervention or for noncoronary revascularizations. Follow-up data were available for 867 patients (96%). Patients underwent follow-up visits at our institution, where information on the cardiovascular end points was obtained by a standardized interview. Study end points reported by the patients were cross-checked against medical records. Further, follow-up data were collected by telephone contacts with patients and family physicians, and mortality was ascertained through a national registry of death.
Differences in baseline characteristics were tested for statistical significance with the chi-square test for categorical variables; the Mann-Whitney U test was used for continuous variables, as appropriate. The Wilcoxon-Gehan statistics was used to compare differences in the cumulative incidence rates of vascular events. Adjusted hazard ratios (HRs) for the incidence of vascular events were derived from Cox proportional hazards models. For these analyses, continuous variables were z-transformed. The proportional hazard assumption was verified by calculating time by covariate interaction terms. Results are given as mean ± SD if not denoted otherwise. Statistical significance was defined as 2-tailed p value <0.05, and analyses were performed with the software package SPSS 11.0 for Windows (SPSS, Inc., Chicago, Illinois).
Results
Baseline coronary angiography revealed significant coronary stenosis ≥50% in 480 (55%) patients. At baseline, mean ACR was 63 ± 212, and we detected the presence of albuminuria in 206 (24%) of our patients. The prevalence of significant CAD was higher when patients with albuminuria were compared with patients with normoalbuminuria (67% vs 52%, respectively, p <0.001). The main clinical characteristics of our patients with respect to albuminuria and the coronary artery state are listed in Table 1 .
| Variable | Albuminuria | |||||
|---|---|---|---|---|---|---|
| No | Yes | |||||
| CAD − (n = 318) | CAD + (n = 343) | p Value | CAD − (n = 69) | CAD + (n = 137) | p Value | |
| Age (yrs) | 64 ± 11 | 65 ± 11 | 0.034 | 66 ± 9 | 69 ± 10 | 0.007 |
| Men | 49 | 76 | <0.001 | 51 | 69 | 0.009 |
| Type 2 diabetes | 15 | 22 | 0.021 | 30 | 47 | 0.025 |
| Hypertension | 77 | 82 | 0.145 | 78 | 91 | 0.009 |
| Smoker | 51 | 60 | 0.023 | 47 | 73 | <0.001 |
| BMI (kg/m²) | 27.9 ± 4.5 | 27.2 ± 3.9 | 0.041 | 28.6 ± 5.8 | 28.1 ± 4.3 | 0.817 |
| Hemoglobin A1c (%) | 5.9 ± 0.9 | 6.0 ± 0.8 | 0.177 | 6.3 ± 1.3 | 6.5 ± 1.2 | 0.154 |
| Triglycerides (mg/dl) | 139 ± 89 | 132 ± 80 | 0.358 | 126 ± 79 | 149 ± 103 | 0.031 |
| Total cholesterol (mg/dl) | 202 ± 44 | 192 ± 47 | 0.004 | 193 ± 51 | 191 ± 49 | 0.740 |
| LDL (mg/dl) | 132 ± 40 | 126 ± 42 | 0.041 | 126 ± 45 | 123 ± 43 | 0.616 |
| HDL (mg/dl) | 59 ± 17 | 55 ± 16 | <0.001 | 58 ± 17 | 54 ± 14 | 0.106 |
| Systolic blood pressure (mm Hg) | 135 ± 18 | 136 ± 17 | 0.852 | 139 ± 18 | 142 ± 20 | 0.500 |
| C-reactive protein (mg/dl) | 0.4 ± 0.5 | 0.4 ± 0.9 | 0.466 | 0.5 ± 0.6 | 0.5 ± 0.7 | 0.711 |
During the follow-up period, we recorded 149 first clinical events representing the composite end point (30 vascular deaths, 28 nonfatal myocardial infarctions, 15 nonfatal ischemic strokes, 11 coronary artery bypass graftings, 34 percutaneous coronary interventions, and 31 revascularizations at the carotid or peripheral arteries). Thus, the overall incidence rate of end points was 17%.
The incidence of vascular events was significantly higher among patients with albuminuria than in patients with normoalbuminuria (29% vs 14%, respectively, p <0.001; Figure 1 ). After adjustment for age, gender, BMI, diabetes, smoking, blood pressure, LDL cholesterol, HDL cholesterol, eGFR, and the use of ACE inhibitors/angiotensin II antagonists, the ACR conferred a significantly increased vascular risk (standardized adjusted HR 1.17 [1.05–1.29], p = 0.003). This predictive power was not attenuated after further adjustment for the presence of significant CAD at coronary angiography (HR 1.13 [1.02–1.26], p = 0.017). Similar results were obtained, when instead of the continuous variable ACR, the dichotomous criterion albuminuria was entered into Cox regression analyses (unadjusted HR 2.13 [1.54–2.96], p <0.001). This result remained robust in the fully adjusted model (adjusted HR 1.68 [1.17–2.41], p = 0.005).
Regarding the predictive power of angiographically proven CAD at baseline, the incidence of vascular events was significantly higher in patients with stenoses ≥50% compared with patients without stenoses (23% vs 10%, respectively, p <0.001; Figure 2 ). Multivariable Cox analysis adjusting for age, gender, BMI, diabetes, smoking, blood pressure, LDL cholesterol, HDL cholesterol, eGFR, and the use of ACE inhibitors/angiotensin II antagonists showed that the coronary artery state was still significantly associated with clinical vascular events (adjusted HR 2.26 [1.54–3.34], p <0.001). Additional adjustment for the ACR confirmed this association (HR 2.18 [1.48–3.22], p <0.001). Cox analysis in which both the coronary artery state and the presence of albuminuria were included showed that besides albuminuria (previously mentioned) also the coronary artery state was still significantly associated with vascular events in the fully adjusted model (HR 2.16 [1.47–3.19], p <0.001). An interaction term presence of significant stenoses by albuminuria was not significant (p = 0.400), indicating that the baseline coronary artery state did not significantly modulate the impact of the presence of albuminuria on the risk of clinical vascular events.
