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• W2007236646 abstract "Objectives and design. Recent studies have shown that albuminuria accompanied by evidence of subclinical inflammation is more strongly associated with metabolic abnormalities and the development of atherosclerosis than albuminuria alone. The aim of this population-based prospective study was to examine the combined effect of albuminuria and inflammatory markers on all-cause and cardiovascular-mortality in nondiabetic individuals without macroalbuminuria. Subjects and methods. Urinary albumin and creatinine, some inflammatory markers (fibrinogen, white blood cell and monocyte count) and cardiovascular risk factors were measured in 5702 persons in Tromsø, Norway. Baseline data were collected in 1994–1995 and follow-up was through 2005. Results. For a one standard deviation higher value of the log-transformed ratio between albumin and creatinine (ACR), the mortality rate ratio for all-cause mortality was 1.21 when adjusted for age, gender, established cardiovascular risk factors as well as fibrinogen and white blood cell count (P < 0.001). The corresponding mortality rate ratio for cardiovascular mortality was 1.24 (P < 0.001). Persons in the upper quartile of both ACR and either of the inflammatory markers had an age- and gender-adjusted all-cause and cardiovascular mortality rate that was four times that of subjects in the lowest quartiles (P < 0.001). Conclusion. ACR predicts all-cause and cardiovascular mortality in persons without known diabetes and macroalbuminuria. The mortality is especially high amongst individuals with elevated levels of both ACR and inflammatory markers. Microalbuminuria was originally used to indicate early signs of nephropathy in diabetes, but numerous studies have found that microalbuminuria also predicts all-cause and cardiovascular mortality even in subjects without diabetes [1, 2]. Recent studies have shown that the risk of cardiovascular disease, cardiovascular death and death because of all causes is increased also at levels well below the usually defined cut-off levels for pathological albuminuria, independently of diabetes [3-8]. Albuminuria is therefore thought to reflect not only dysfunction of the glomeruli, but also generalized vascular dysfunction. Both endothelial dysfunction and chronic inflammation are associated with cardiovascular mortality, and recent studies have shown that albuminuria accompanied by evidence of subclinical inflammation is more strongly associated with metabolic abnormalities [9], high blood pressure [10] and the development of atherosclerosis [11] than albuminuria alone. To our knowledge, the combined effect of albuminuria and inflammatory markers on mortality has not been examined in nondiabetic subjects. The first aim of the present population-based, prospective study was therefore to examine whether albuminuria predicts all-cause mortality and cardiovascular mortality in subjects without known diabetes, both without and with adjustment for three different inflammatory markers (fibrinogen, white blood cell count or monocyte count). The second aim was to assess the combined effect of albuminuria and these markers of inflammation on mortality rates, i.e., whether the combined effect of high levels of both factors exceeded the risk predicted by a multiplicative model. The Tromsø Study is a population-based, longitudinal study of inhabitants in the municipality of Tromsø, Norway. The regional ethical committee has approved the study and the participating subjects have given informed consent. At the fourth survey in 1994–1995, all inhabitants aged 55–74 years and 5–10% random samples of the other 5-year birth cohorts older than 24 years of age were invited to participate in the survey. In the age groups 25–54, 55–74 and 75–84 years, 1751, 7158 and 148 subjects were eligible for having measurements of albuminuria and 1205, 5617 and 80 participated, respectively. In total, 6902 (76% of the eligible population) attended. Amongst the 6902 individuals who attended the examination, 110 persons either withdrew their data or had missing measurements of urinary albumin or creatinine. We excluded 239 persons reporting diabetes and/or use of medication for diabetes and 851 with bacteruria or haematuria on any day when urine samples were collected or macroalbuminuria (albumin-to-creatinine ratios (ACR) >25 mg mmol−1). Thus, 5702 subjects were included. Information about smoking habits, prevalent diabetes mellitus, angina pectoris, previous myocardial infarction, stroke, treatment for hypertension and physical activity was collected from self-administered questionnaires [12]. Fresh urine samples from the first morning urine from three consecutive days were used to assess microalbuminuria. Albumin and creatinine were measured by turbidimetry on a Cobas Mira S with kits from ABX Diagnostics, Parc Euromedecine, Montpellier, France. The ratio between albumin and creatinine (ACR) (mg albumin per mmol creatinine) was computed, and the mean of the three ratios was used in the analyses. The between-assay coefficient of variation for all determinations of albumin, creatinine and the albumin-creatinine ratio was less than 4% throughout the range of concentrations. Serum creatinine was measured by the HiCo Creatinine Jaffé method with a kinetic colorimetric assay on automated clinical chemistry analysers (Boehringer-Mannheim, Mannheim, Germany) and estimated glomerular filtration rate was calculated using the abbreviated (4-variable) Modification of Diet in Renal Disease equation [13]. Measurements of height, body weight, blood pressure, nonfasting serum lipids, glycated haemoglobin, fibrinogen and counts of white blood cells and monocytes were performed as described previously [14]. The measurements of glycated haemoglobin were available for 5254 persons, measurements of fibrinogen and white blood cells counts were available for 5441 persons, and monocyte count in addition to fibrinogen and white blood cell count was available for 5254 persons. ACR (log-transformed) showed relatively low but statistically significant (P < 0.001) correlations with these markers of inflammation (r = 0.15, r = 0.07 and r = 0.09, respectively). White blood cell count and monocyte count correlated with each other (r = 0.59, P < 0.001). Individual information on death and emigration was gathered by linkage to Statistics Norway (Oslo, Norway). The unique national 11-digit identification number of every Norwegian citizen ensured linkage of data from the Tromsø Study with this registry. Thus, no person was missed during follow-up. For all-cause mortality, follow-up time was assigned from the date of the baseline examination to the date of death, the date of emigration from Norway, or to the end of follow up (December 31, 2005). For cardiovascular mortality, follow-up time was assigned from the date of the baseline examination to the date of cardiovascular death (ICD 9: 390-459, ICD 10: I01-I99) or to the date of censoring [emigration, death from other causes or end of follow up (December 31, 2005)]. Differences between the survivors and nonsurvivors with regard to baseline characteristics were tested using analysis of covariance. When ACR was included in an analysis as a continuous variable, the value was logarithmically transformed [log (ACR + 0.1)] before statistical testing was performed. The participants were divided into groups according to quartiles of ACR. We estimated the mortality rate ratio (MRR) for all-cause and cardiovascular mortality amongst subjects at different ACR-levels by use of Cox regression analysis. Adjustments were made for age, gender, body mass index, systolic blood pressure, serum total cholesterol, serum HDL cholesterol, ever use of medication for hypertension and smoking (current/ex-smoker/never smoker), physical inactivity and prevalent cardiovascular disease. In separate analyses, additional adjustments were made for fibrinogen, white blood cell and monocyte count. Linear interaction terms ‘ACR × fibrinogen’ and ‘ACR × white blood cell count’ and ‘ACR × monocyte count’ were included in the models in other separate analyses, with ACR and the inflammation indicators represented by successive integers corresponding to quartiles. Survival curves adjusted for age and gender, generated by the Cox analyses, were used to describe the risk of all-cause and cardiovascular mortality during follow-up as a function of the time. A two-sided P-value < 0.05 was considered statistically significant. The data were analysed using spss 14.0 for Windows (SPSS, Chicago, IL). Amongst the 5702 persons (2699 women and 3003 men) included in the study, 867 subjects died during 58281 person-years of follow-up. In 341 subjects, cardiovascular diseases were the underlying cause of death, with myocardial infarction and stroke being the cause of 178 and 79 deaths, respectively. The mean follow-up time was 10.2 years (range 47 days–11.3 years). The baseline characteristics of the study groups are presented in Table 1. Significant differences between survivors and nonsurvivors were found with respect to age, gender, body mass index, systolic blood pressure, serum total cholesterol, estimated glomerular filtration rate, HbA1c, prevalence of current smoking, physical inactivity, cardiovascular disease, ever use of medication for hypertension, ACR, fibrinogen, monocyte and white blood cell count. With subjects divided into groups according to ACR-quartiles at baseline, Table 2 and Fig. 1 show that the age- and gender-adjusted mortality risk increased with increasing levels of ACR. The trend was somewhat attenuated, but still highly statistically significant, after adjustments for body mass index, systolic blood pressure, medication for hypertension (current or previous), total serum cholesterol, serum HDL cholesterol, smoking, physical inactivity and prevalent cardiovascular disease in addition to age and gender. Further adjustments for fibrinogen and white blood cell count indicated no confounding by these inflammatory markers. Despite the pronounced overall trend, subjects in the three groups corresponding to the lowest levels of ACR had rather similar risk estimates. Age and gender-adjusted survival plots for all-cause mortality (top panel) and cardiovascular mortality (lower panel) according to quartiles of ACR. Because the trends over the quartiles of ACR did not differ significantly between men and women (P ≥ 0.4 after multiple adjustments), we do not present the results from the analyses stratified by gender. For each standard deviation (SD) increase in the log-transformed ACR-level, the MRR for all-cause mortality was 1.30 when adjusted for age and gender (P < 0.001), and 1.23 when adjusted for age, gender, body mass index, systolic blood pressure, medication for hypertension (current or previous), total serum cholesterol, serum HDL cholesterol, smoking, physical inactivity and prevalent cardiovascular disease (P < 0.001). The MRR was 1.21 (P < 0.001) after further adjustments for fibrinogen and white blood cell count. The corresponding MRRs for cardiovascular mortality were 1.39 and 1.27 and 1.24, respectively (P < 0.001). Excluding the 743 persons with self-reported cardiovascular disease at baseline gave similar results; for a one SD higher value for the log-transformed ACR, MRR for all-cause and cardiovascular mortality was 1.21 and 1.28, respectively (P < 0.001) after multiple adjustments. A total of 38 subjects died within the first year of follow-up, and again only minor changes of the MRRs were found after the exclusion of these subjects (MRR = 1.21 and 1.26 for all-cause and cardiovascular mortality, respectively, P < 0.001). High blood pressure is related to ACR as well as to mortality. We adjusted for systolic blood pressure and use of medication for hypertension. In a specific analysis, we excluded 1856 persons who were either present users of medication for hypertension or had a systolic blood pressure >160 mmHg or a diastolic blood pressure >95 mmHg; for a one SD higher value for the log-transformed ACR, MRR for all-cause and cardiovascular mortality was 1.22 (P < 0.001) and 1.29 (P = 0.001), respectively, after multiple adjustments. The major part of our study population had normal renal function. Only 296 persons (5%) had estimated glomerular filtration rate <60 mL min−1 1.73 m−2, and the MRR for all-cause and cardiovascular mortality were essentially the same with adjustments for estimated glomerular filtration rate, in addition to age, gender, body mass index, systolic blood pressure, medication for hypertension (current or previous), total serum cholesterol, serum HDL cholesterol, smoking, physical inactivity and prevalent cardiovascular disease (1.23 and 1.27, respectively, P < 0.001). In the 5254 persons with measurements of glycated haemoglobin available, the relationship between ACR and MRR was similar after adjustment for glycated haemoglobin (results not shown). Moreover, we excluded 360 subjects with glycated haemoglobin levels ≥6.0% (and thus possible cases of diabetes), but the results hardly changed. For each SD increase in the log-transformed ACR, MRR for all-cause mortality was 1.23 and 1.25, before and after the exclusion, respectively. For cardiovascular mortality, the respective MRR was 1.27 and 1.29. When ACR and fibrinogen (both as continuous variables) were included in the same model, they both predicted all-cause as well as cardiovascular mortality independently (P < 0.001). Similarly, the white blood cell count and monocyte count were independent risk factors for both all-cause and cardiovascular mortality when ACR was adjusted for (P < 0.001). The levels of ACR, fibrinogen, white blood cell and monocyte count were categorized into quartiles. Tables 3 and 4 show the combined effect of ACR and fibrinogen, and ACR and white blood cell count on mortality risk. The results for ACR and monocytes (not presented in the tables) were similar to those of ACR and white blood cell count. The association between ACR and mortality, in general, was seen consistently within the quartiles of each inflammatory marker. Similarly, relationships between the markers of inflammation and mortality were suggested within the quartiles of ACR. The highest risks were found in subjects with high ACR and high levels of fibrinogen or white blood cell or monocyte count. Six to seven percent of the population who were in the upper quartile both with regard to ACR and fibrinogen, white blood cells or monocytes had a statistically significant age- and gender-adjusted all-cause and mortality rate that was approximately four times as high as that of subjects in the lowest quartiles (P < 0.001) (Table 3). Similar results were found for cardiovascular mortality (Table 4). Adjustment for possible confounders reduced these estimates of the mortality rate ratios to some extent (Tables 3 and 4). Two persons had very high white blood cell readings (>20 × 109 L−1), but the exclusion of these persons did not influence the results. The interaction terms for ACR and fibrinogen or white blood cell count or monocytes were not statistically significant (P ≥ 0.8 and P ≥ 0.1 for all-cause and cardiovascular mortality, respectively, after multiple adjustments). Thus, although high levels of both ACR and fibrinogen or white blood cells or monocytes increased mortality substantially, this was no more than a multiplicative model would imply. This study showed that ACR predicts all-cause and cardiovascular mortality in persons without known diabetes and macroalbuminuria. The mortality was high especially amongst individuals with elevated levels of both ACR and our markers of inflammation (fibrinogen, white blood cell and monocyte count). The positive associations between ACR and mortality were consistent with results of previous studies [1-8]. However, we showed that ACR (even below the usually defined cut-off levels for pathological albuminuria) predicted mortality independently of several inflammatory markers. In a study of patients with diabetes type 2, it was shown that albuminuria and fibrinogen predicted cardiovascular mortality independently of each other and that the combination of the two factors identified persons with elevated mortality [15]. To the best of our knowledge, this topic has not been examined in subjects without diabetes, and our study therefore extends the latter findings from subjects with diabetes to subjects of the general population without diabetes. Today, it is widely accepted that inflammation is important at all stages of the atherosclerotic process [16, 17]. Inflammatory markers have also been related to the progression of renal disease in elderly community-dwelling individuals [18] and to the progression from microalbuminuria to overt nephropathy in patients with type 1 diabetes [19], which again is associated with a high risk of early death. Moreover, microalbuminuria is associated with increased insulin resistance and is one of the components of the metabolic syndrome [20], a strong risk factor for cardiovascular disease. Just recently, insulin resistance has been explained partly by inflammatory processes [21]. In a prior study, we examined the relationship between ACR and the development of carotid atherosclerosis in nondiabetic persons [11]. We found that fibrinogen modified the relationship between ACR and the development of plaques in previously plaque-free subjects. In persons with established atherosclerosis, however, the interaction between fibrinogen and ACR on plaque growth was present only in those with minimal atherosclerosis at baseline. Inflammation modifies the relationship between microalbuminuria and blood pressure [10]. Moreover, microalbuminuria accompanied by evidence of inflammation is strongly associated to metabolic abnormalities, whereas isolated microalbuminuria may represent a more benign profile [9]. Thus, it has been hypothesized that ‘inflammatory microalbuminuria’ may precede and perhaps predispose to the development of cardiovascular abnormalities [9]. Our results show that increased ACR in combination with inflammation is associated with especially high cardiovascular mortality. We found that persons in the upper quartile of both ACR and any of the three inflammatory markers included in our study had an age- and gender-adjusted all-cause and cardiovascular mortality rate that was four times that of subjects who were in the lowest quartiles with regard to both ACR and markers of inflammation. Even if these mortality rates may not be significantly higher than expected from a multiplicative model, our results could still have clinical implications and remind the clinician that these patients are at a particularly high risk. For simple prognostic purposes, the results from the analyses adjusted for age and gender only may be the most relevant as the clinician cares for the individual, the patient. Whether the association can be explained by other covariates may be of minor importance in this context. Studies examining whether anti-inflammatory strategies are beneficial in these individuals are warranted. The present study has several strengths and some limitations. One strength is that a strict definition of albuminuria was applied, as urine samples from all patients were cultured and patients with bacteruria were excluded from the analysis. Another strength is that the study is longitudinal and population-based, comprising a large group of subjects with a high attendance rate (76% before exclusions of subjects with e.g. diabetes). However, because our study population consisted of subjects who were able to visit our research center, frail individuals with cardiovascular diseases, higher cardiovascular risk factor levels and higher ACR may have been underrepresented. Thus, nonparticipation may have weakened the relationship between high ACR and mortality. Furthermore, random misclassifications may have occurred because of measurement errors of ACR, which may lead to weaker relationships. Moreover, we cannot exclude the possibility of residual confounding by measured as well as unmeasured variables. Finally, the study might have been strengthened if other markers of inflammation such as CRP had been available. In our study, we excluded subjects with diabetes. Yet many subjects with diabetes type 2 are not aware that they have the disease. It is therefore reassuring that adjustments for glycated haemoglobin or the exclusion of persons with glycated haemoglobin ≥6.0% did not influence our findings. We conclude that ACR predicts all-cause and cardiovascular mortality in persons without known diabetes and macroalbuminuria, and that the mortality is especially high amongst individuals with elevated levels of both ACR and inflammatory markers. There are no conflicts of interest. The study was financed through the Research Council of Norway and the Northern Norway Regional Health Authority." @default.
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• W2007236646 title "The combined effect of albuminuria and inflammation on all-cause and cardiovascular mortality in nondiabetic persons" @default.
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