Microalbuminuria independently predicts all-cause and cardiovascular mortality in a British population: The European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study

Matthew F Yuyun1, Kay-Tee Khaw1, Robert Luben1, Ailsa Welch1, Sheila Bingham2, Nicholas E Day1 and Nicholas J Wareham1,

1 Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, UK
2 Medical Research Council Dunn Human Nutrition Unit, Cambridge, UK.

Correspondence: Dr Nicholas J Wareham, Department of Public Health and Primary Care, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge CB2 2SR, UK. E-mail: njw1004{at}medschl.cam.ac.uk


    Abstract
 Top
 Abstract
 Methods
 Results
 Discussion
 Conclusion
 References
 
Background In patients with diabetes or hypertension, raised albuminuria is independently associated with an increased risk of all mortality, cardiovascular morbidity and mortality, and renal insufficiency. The role of albuminuria in the general population is still controversial. We therefore undertook this study to examine the relationship between albuminuria and all-cause, cardiovascular disease (CVD) and non-CVD mortality in the general population.

Methods Prospective population-based cohort study of 20 911 individuals aged 40–79 years recruited in 1993–1997 for the EPIC-Norfolk Study (UK) and followed-up for an average of 6.3 years. Random spot urine specimens were collected at baseline and the albumin-to-creatinine ratio measured. Participants were categorized into normoalbuminuria, microalbuminuria, and macroalbuminuria ordered groups. At follow-up, vital status and cause of death were obtained from the UK Office for National Statistics.

Results During follow-up, 934 deaths were registered. Age-adjusted all-cause mortality rate increased significantly across categories of baseline albuminuria (5.3, 5.2, and 6.3/1000 person years (pyrs) across tertiles of normoalbuminuria, 8.7/1000 pyrs for microalbuminuria, and 18.4/1000 pyrs for macroalbuminuria, P < 0.001 for trend); CVD, 1.6, 1.7, 2.1, 4.3, 12.6/1000 pyrs (P < 0.001); and non-CVD, 3.7, 3.5, 4.2, 4.4, 5.8/1000 pyrs (P = 0.052) respectively. The multivariate hazard ratio for all-cause mortality associated with microalbuminuria was 1.48 (95% CI: 1.20, 1.79), and CVD 2.03 (95% CI: 1.55, 2.67). The association with non-CVD mortality was only significant in men.

Conclusions The significant increased risk of all-cause mortality especially from CVD associated with microalbuminuria, suggest that this may be a useful indicator in identifying those in the population at greatest absolute risk of fatal CVD events alongside conventional CVD risk factors.


Keywords Albuminuria, cardiovascular diseases, neoplasms, mortality, risk factor

Accepted 31 July 2003

Raised albuminuria defined as macroalbuminuria (or proteinuria) and microalbuminuria is associated with increased risk of all-cause mortality, cardiovascular disease (CVD) mortality and morbidity, and renal function deterioration in patients with diabetes1–5 and hypertension.6–8 While the predictive role of proteinuria on total and cardiovascular mortality has been observed in the general population,9–11 the impact of microalbuminuria on these outcomes is less certain. Although it has been suggested that microalbuminuria predicts all-cause and cardiovascular mortality in the general population, most of the studies that found significant independent associations either recruited few participants,12,13 or were conducted on individuals with prevalent CVD, those at high risk of CVD, or other population sub-groups.14,15 Other studies have been affected by residual confounding by classical risk factors, including a recently published Dutch study that showed that a twofold increase in urinary albumin excretion was independently associated with 29% increase risk of CVD mortality and a 12% increased risk of non-CVD mortality in the general population.16 In this study residual confounding was likely as classical cardiovascular risk factors like dyslipidaemia and hypertension were assessed from postal questionnaires only.

All previous studies have considered men and women together, and none have considered the sexes separately which is advisable given the differences in CVD event rates between men and women.17 We therefore undertook this study to examine the relationship between levels of albuminuria and all-cause and CVD mortality in men and women recruited to a large UK population-based cohort in which information about classical risk factors is also available. As elevated urinary albumin excretion has also been associated with prevalent malignancies,18 we also examined the prospective relationship with non-CVD mortality.


    Methods
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 Abstract
 Methods
 Results
 Discussion
 Conclusion
 References
 
Study population
Participants in this study were men and women of the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk). Details of recruitment and procedures have been published.19 Briefly, the EPIC-Norfolk Study, part of a 10-country European collaborative study examining the relationship between diet and cancer, is an ongoing population-based prospective cohort study, which has broadened its scope to include endpoints other than cancer and exposures other than diet. Recruitment to EPIC-Norfolk began in March 1993 and was completed at the end of 1997 and participants were followed-up till 31 March 2002. Men and women, aged 40–79 years, resident in Norfolk, UK were recruited using general practice age–sex registers. Of the 77 630 mailed invitations, 30 447 consented to participate and completed a detailed baseline health and lifestyle questionnaire and 25 633 attended a health examination by trained nurses using a standard protocol. During the clinic visit, a random spot urine sample was collected and urinary albumin-to-creatinine ratio (UACR) measured in them later. A total of 25 112 individuals who completed the health and lifestyle questionnaire, were examined by the nurses, and had UACR measured in their urine, constituted our study population. We excluded menstruating women, participants with dipstick haematuria or leucocyturia (1148) and those with baseline history of coronary heart disease, stroke, and cancer (3053), leaving 20 911 individuals (11 268 women and 9643 men) for our analyses. Ethical approval for this study was obtained from the Norwich District Ethics Committee.

Study design
Information about smoking status, prevalent physician diagnosed diabetes, hypertension treatment, hyperlipidaemia, stroke, and coronary heart disease, as well as family history of disease was obtained from a baseline health and lifestyle questionnaire. Body mass index (BMI) was calculated as weight in kg divided by height in m2 (kg/m2), with height measured using free-standing stadiometer, and weight using digital scales (Salter, UK). Blood pressure was measured using an Accutorr Sphygmomanometer (Datascope, UK), after the participant had been seated resting for 5 minutes. Two measurements of systolic and diastolic blood pressure were made and the average of the two used for analyses. Hypertension was defined as physician diagnosed hypertension or systolic blood pressure >=140 mmHg or diastolic blood pressure >=90 mmHg.

Non-fasting total serum cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides were measured on an RA 1000 Technicon analyser (Bayer Diagnostics, Basingstoke, UK), and low density lipoprotein (LDL) cholesterol calculated using the Friedewald formula.20 Dyslipidaemia was arbitrarily defined as baseline treatment for hypercholesterolaemia or total cholesterol >=6.2 mmol/l. During the baseline health check visit, participants were asked to give a random spot urine sample, which was stored frozen at −20°C. Information about menstrual flow on the day of urine collection was obtained from female participants. In 2001–2002 the sample was defrosted and an aliquot assayed for urinary albumin and creatinine. Urinary albumin concentration (mg/l) was measured by immuno-nephelometry21 using the Dade Behring Nephelometer II Analyser (Dade Behring, Germany). Urinary creatinine concentration (mmol/l) was measured by colorimetry22 using the Dade-Behring Dimension AR Analyser (Dade Behring, Germany). UACR (mg/mmol) was calculated. The use of UACR as a measure of albuminuria has been validated against the gold standard urinary albumin excretion rate (UAER) measured on timed urine collections, in random spot urine collection.23 All biochemical analyses were made at the Department of Biochemistry, at Addenbrooke's Hospital, Cambridge, UK. Dipstick urinalysis with Multistix (Bayer Corporation, USA) was used, to detect haematuria and leucocyturia.

Endpoints
Mortality cases were defined as index events that occurred between baseline and follow-up till 31 March 2002. During follow-up, the main outcomes of interest were all-cause mortality, total cardiovascular mortality, fatal coronary heart disease, fatal stroke, other cardiovascular vascular deaths, cancer mortality, and non-CVD non-cancer mortality. Mortality endpoints were obtained from the UK Office for National Statistics (ONS). For these analyses, all-cause mortality was defined as death from any cause, with cause of death obtained from the ONS death certificates. Cardiovascular mortality was defined as death with an underlying cause of death coded as 390–459 using the International classification of Diseases, Ninth Edition (ICD-9) or I00–I99 using the Tenth Edition (ICD-10). Fatal coronary heart disease was defined as death with an underlying cause of death coded as 410–414 (ICD-9) or I20–I25 (ICD-10), and fatal stroke as death with an underlying cause of death coded as 430–438 (ICD-9) or I60–I69 (ICD-10). Other vascular deaths were CVD deaths excluding CHD and stroke. Cancer mortality was defined as death with an underlying cause of death coded as 140–239 (ICD-9) or C00–C97 (ICD-10). The rest were non-CVD/non-cancer deaths.

Statistical analyses
Normoalbuminuria was defined as UACR <2.5 mg/mmol, microalbuminuria as a UACR 2.5–25 mg/mmol, and macroalbuminuria (proteinuria) as UACR >25 mg/mmol.24,25 Those with normoalbuminuria were further divided into tertiles, giving five ordered categories of albuminuria. The normoalbuminuric population was not neatly divisible into tertiles because of the large numbers within each 0.1 mg/mmol of UACR. The test for linear trend of continuous data across categories of albuminuria was the non-parametric Cusick test for trend across ordered groups. The test for linear trend of categorical data was the {chi}2 test for linear trend with one degree of freedom.26 Multivariate Cox regression analysis was used to determine the relationship between mortality and albuminuria. UACR was log-transformed to base two (log2UACR), before any analyses involving the use of UACR as a continuous variable, because the distribution of UACR was highly positively skewed. Excluding participants with microalbuminuria, macroalbuminuria, and diabetes (thus removing extreme high values of UACR), the risk of mortality associated with 0.5-mmg/mol increase in UACR in normoalbuminuric individuals was evaluated. The Wald test was used for testing hypotheses about individual coefficients in the regression analyses, and in all hypothesis testing the risk of Type 1 error was set a priori at P < 0.05. The likelihood ratio test was used to identify the best model. Kaplan–Meier estimates of survival for the three ordered categories of albuminuria were obtained, as well as the {chi}2 test for trend of survival across these albuminuria groups. Statistical analyses were undertaken with STATA for Windows version 7.0 and GENSTAT 5.


    Results
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 Abstract
 Methods
 Results
 Discussion
 Conclusion
 References
 
Baseline characteristics
The prevalence of microalbuminuria was 11.2% in the study population, and was significantly higher in women (13.9%) than men (8.1%) (P < 0.001). Table 1 shows baseline characteristics of the study population by degrees of albuminuria. Urinary albumin excretion significantly and positively correlated with major established cardiovascular risk factors including age, blood pressure, total cholesterol, smoking, diabetes mellitus, and family history of cardiovascular disease but body mass index was borderline.


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Table 1 Baseline characteristics of the study population (all men and women), by categories of albuminuria: The EPIC-Norfolk Study, 1993–2002 (n = 20 911)

 
Mortality rate
During the 6.3 years average follow-up (131 694 person years [pyrs] of follow-up), a total of 934 deaths (550 in men and 384 in women) were registered in the 20 911 men and women aged 40–79 years. The crude all-cause mortality rate was 7.1, 9.1, and 5.4 per 1000 pyrs in the total population, men, and women respectively. All-cause mortality rate increased with increasing age, more than doubling for every decade increase in age (0.9/1000 pyrs [40–49 years], 3.3 [50–59 years], 8.7 [60–69 years], and 22.2 [70–79 years]) in all men and women. A similar pattern was seen for CVD and non-CVD mortality.

As shown in Table 2, the age-adjusted all-cause mortality rate increased with increasing categories of baseline albuminuria. A similar positive trend in mortality rate across categories of albuminuria was seen in all cardiovascular causes of death in both men and women of the EPIC-Norfolk cohort. A significant positive trend of non-CVD mortality was seen only in men, and this was due essentially to non-CVD/non-cancer causes of death. There were no significant differences in the rates of cancer mortality across degrees of albuminuria in the total population (P for trend = 0.725) and in sex-stratified analyses. The two most frequent non-CVD/non-cancer causes of death were respiratory disease (31.5% of all non-CVD/non-cancer deaths), and digestive system (14.6% of all non-CVD/non-cancer deaths) in the total population. The same pattern of non-CVD/non-cancer causes of death was seen in sex-stratified analyses.


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Table 2 Age-adjusted mortality rates (number of events) by categories of albuminuria: The EPIC-Norfolk Study, 1993–2002 (n = 20 911)

 
Mortality risk
Figure 1 shows age-adjusted hazard ratios of all-cause mortality and cause-specific mortality across ordered categories of albuminuria compared with the referent category. There was a significant positive trend of risk across these degrees of albuminuria for all-cause mortality and CVD mortality in both men and women. Table 3 shows the multivariate hazard ratio for mortality associated with albuminuria. Both microalbuminuria and macroalbuminuria independently predicted all-cause mortality and CVD mortality in both men and women, and non-CVD mortality in men. Cancer mortality showed no independent relationship with micro- or macro-albuminuria in both men and women, and the relationship between these levels of exposure and non-CVD mortality seen in men was essentially due to non-CVD/non-cancer causes of mortality. The population-attributable risk of CVD mortality due to raised albuminuria (microalbuminuria and macroalbuminuria combined) was 23.8%. It was calculated as the overall rate of incident CVD deaths in the total EPIC-Norfolk population minus rate in the normoalbuminuric group divided by the overall rate times 100.



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Figure 1 Age-adjusted hazard ratios of all-cause, cardiovascular (CVD), and non-CVD mortality in (a) the total population, (b) men, and (c) women, by categories of baseline albuminuria, compared with the referent category (Normo1). Apart from non-CVD mortality in the total population and in women, the P-value for trend of mortality endpoints across degrees of baseline albuminuria was <0.001. Normo, tertiles of normoalbuminuria; Micro, microalbuminuria (UACR 2.5–25.0 mg/mmol); Macro, macroalbuminuria. P-value for risk trend of <0.001 for all-cause mortality, CVD mortality in men and women, and non-CVD mortality in men across degrees of albuminuria. The EPIC-Norfolk Study, 1993–2002 (n = 20 911)

 

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Table 3 Hazard ratios (95% CI) for all-cause and cause-specific mortality associated with albuminuria (reference category = normoalbuminuria): The EPIC-Norfolk Study, 1993–2002 (n = 20 911)

 
Taking albuminuria as a continuous variable (log2UACR), the hazard ratio for all-cause was 1.14 (95% CI: 1.10, 1.19) in the total population, CVD mortality 1.23 (95% CI: 1.16, 1.31), and non-CVD mortality 1.08 (95% CI: 1.00, 1.14). These correspond to the risk associated with the doubling of UACR or a twofold increase in UACR (i.e. from 1 to 2 mg/mmol or from 10–20 mg/mmol).

Considering urinary albumin as a categorical variable, the two upper tertiles of normoalbuminuria were not significantly different from the lower tertile in multivariate analyses, although the P-value for trend of risk was significant. However, after excluding participants with microalbuminuria, macroalbuminuria, and diabetes (thus removing extreme high values of UACR and thus reducing the positive skewedness), the multivariate-adjusted hazard ratio associated with a 0.5-mmg/mol increase in UACR in those with normoalbuminuria was 1.09 (95% CI: 1.01, 1.16) for all-cause mortality in the total population; 1.13 (95% CI: 1.04, 1.26) for CVD mortality; and 1.05 (95% CI: 0.93, 1.11) for non-CVD mortality.

Subgroup analyses are shown in Table 4. The effect of microalbuminuria on all-cause and CVD mortality in multivariate analyses was higher in those with established cardiovascular risk factors (sex, diabetes, hypertension, smoking, and dyslipidaemia) compared with those without. The difference between the effects of microalbuminuria on mortality risk observed in respective strata of these risk factors was not statistically significant.


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Table 4 Subgroup analyses showing the hazard ratio (95% CI) of microalbuminuria on all-cause mortality, cardiovascular disease (CVD)-mortality, and non-CVD mortality within binary strata of established cardiovascular risk factors: The EPIC-Norfolk Study, 1993–2002 (n = 20 911)

 
Mortality-free survival
Figure 2 shows the Kaplan–Meier free survival curves for all-cause mortality, CVD mortality, and non-CVD mortality by categories of baseline albuminuria in all women and men of the EPIC-Norfolk Study. There was a significant decreasing trend in mortality-free survival by increasing albuminuria category especially for CVD mortality.



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Figure 2 Kaplan–Meier survival curves for mortality, by ordered categories of baseline albuminuria in all men and women. The {chi}2 test for trend of survival across these albuminuria groups was (a) 178.2 (P < 0.001) for all-cause mortality, (b) 202.6 (P < 0.001) cardiovascular disease (CVD) mortality, and (c) 23.9 (P < 0.001) non-CVD mortality. The EPIC-Norfolk Study, 1993–2002 (n = 20 911)

 

    Discussion
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 Abstract
 Methods
 Results
 Discussion
 Conclusion
 References
 
In this study, microalbuminuria was predictive of all-cause and CVD mortality in men and women independently of other established CVD risk factors, with microalbuminuric individuals having approximately a 50% increased risk of all-cause mortality, and about twice the risk of CVD mortality compared with participants with normoalbuminuria in all men and women. A dose–response relationship between degree of albuminuria and mortality risk was observed. A significant association was observed between microalbuminuria and non-CVD mortality only in men, largely attributed to non-CVD/non-cancer causes of mortality, with no association seen with cancer mortality in either gender.

In EPIC-Norfolk, only single random spot urine collections were made, which is likely to result in large random errors in assessing albuminuria given the high intra-individual coefficient of variation (~30–50%).27 Collected urine specimens in the EPIC-Norfolk study were stored at −20°C for 4–8 years before albumin and creatinine were assayed. Some studies have suggested that measuring albumin concentration in frozen urine samples underestimates the real values and therefore limits the ability to diagnose borderline cases of microalbuminuria and macroalbuminuria.28 The large random measurement errors resulting from the use of a single random urine sample and from storage would lead to regression dilution and an underestimation of the size of the relationship between microalbuminuria and mortality. EPIC-Norfolk was designed as a prospective study, which required individuals to be willing to participate and to be followed-up in the long term, rather than to be a population representative sample. Nevertheless, the EPIC-Norfolk population was broadly similar to the general population of England as demonstrated in the Health Survey for England, in terms of anthropometric measures, blood pressure, and serum lipids, though with fewer current smokers than the general population.19

The prevalence of microalbuminuria was higher in women compared with men in EPIC-Norfolk. This may be explained by the fact that urinary creatinine is higher in men compared with women29,30 and UACR may therefore be higher in women compared with men with similar urinary albumin concentration.24,31 Due to this, it has been suggested that a higher threshold cut-off point (3.5 mg/mmol) be used to define microalbuminuria in women, instead of the 2.5 mg/mmol.24,25

If women with normoalbuminuria were misclassified as having microalbuminuria because of the use of a lower cut-point (2.5 mg/mmol instead of 3.5 mg/mmol), then we would expect the hazard ratios for the respective outcomes in women to be biased towards the null.

Microalbuminuria is associated with increased risk of all-cause mortality, and cardiovascular mortality and morbidity in patients with diabetes3,4 and hypertension.8 Although there is still controversy over the role of microalbuminuria in the general population, studies have shown that it predicts all-cause and cardiovascular mortality in the general population and in the elderly.12–14,16,32 These studies were however characterized by small sample sizes12,13,32 or were conducted on individuals with prevalent CVD or those at high risk of CVD or other sub-groups.14,15 Data from the recently published large PREVEND Study in The Netherlands show that a twofold increase in urinary albumin excretion is independently associated with 29% increase risk of CVD mortality and a 12% increased risk of non-CVD mortality in the general population.16 Their observation is consistent with the results obtained by previous smaller studies, indicating the possible significant role urinary albumin excretion plays in the prediction of mortality and CVD endpoints in the general population. However, the findings of PREVEND study were limited by residual confounding from poorly measured classical cardiovascular risk factors like dyslipidaemia and hypertension, which were assessed from postal questionnaires only. Most of the studies previously reported were small in size and had a limited number of fatal endpoints, and therefore were unable to report on secondary endpoints such as non-CVD or cancer, nor were they able to report analyses stratifying by known hypertension and diabetes.

The current EPIC-Norfolk Study indicates that microalbuminuria predicts mortality in a large general population sample independently of other CVD risk factors, with this finding being consistent in sex-stratified analyses. Like the PREVEND Study,16 we found that most of the excess mortality risk in the EPIC-Norfolk cohort was attributed to CVD causes. Although they suggested that the risk of non-CVD mortality associated with microalbuminuria was largely attributed to death from neoplastic disease, we did not find any association with between albuminuria and cancer mortality. Elevated levels of urinary albumin have been reported in malignancies.18 The independent association of albuminuria and non-CVD mortality observed in EPIC-Norfolk men was attributable to non-cancer mortality. The most frequent underlying causes of non-CVD/non-cancer death in these men were respiratory and digestive disease. Many of these cases were also recorded to be incident cases of cardiovascular disease, although this was not was listed as the underlying cause of death. It is possible that misclassification could have occurred in the classification of cause of death or alternatively an incident CVD event may have predisposed these individuals to mortality risk from non-cardiac causes.

Our results show that there is increased risk of CVD mortality associated with high-normal levels of albuminuria. The investigators of the HOPE Study had earlier made a similar observation, when they showed that the risk of CVD events and all-cause mortality was a continuum across deciles of UACR in participants with prevalent CVD, or at high risk of CVD.14

The overall impact of a risk factor on the population depends on its prevalence. In population terms, a rare exposure with a high associated relative risk may be less serious in the total number (or proportion) of deaths or disease it will cause than a very common exposure with a lower relative risk.33 Microalbuminuric and macroalbuminuria individuals had just more than double the risk of dying from a CVD in the EPIC-Norfolk cohort. However, considering the population attributable risk, up to 23.8% of CVD deaths in this population were attributable to raised albuminuria. The population attributable risk therefore gives an idea of where efforts might be usefully made to prevent disease or look for new treatments. However, the usefulness of this parameter is weakened by the fact that it assumes equal effects of other covariates on the exposed and unexposed individuals, which is hardly ever the case.34

Microalbuminuria has also been shown to predict incident non-fatal coronary heart disease in non-diabetic individuals and postmenopausal women in small studies,35–37 but the prospective relationship between microalbuminuria and incident non-fatal coronary heart disease in a large general population sample (including men and/or women with and without diabetes, and pre- and post-menopausal women) is less clear. The association between microalbuminuria and the incidence of stroke in the general population or in non-diabetic individuals is unknown. Large community-based studies examining the role of microalbuminuria on the incidence of non-fatal coronary heart disease and stroke are thus required.

Little is known about the pathophysiological mechanism of the association between albuminuria and CVD to date. However, there is growing support for the suggestion that microalbuminuria may be a reflection of generalized endothelial dysfunction in capillaries (e.g. glomeruli) and arteries,38,39 and that leakage of albumin through the glomerular wall might be a marker of preclinical artheriosclerosis.40 Theoretically, such leakiness may allow for an increased lipid insudation into the large vessel wall, thereby linking microalbuminuria to atherogenesis.40 The finding that microalbuminuria is predictive of CVD mortality could have an aetiological or a prognostic significance or both. Prospective cohort studies in the general population will be needed to examine the aetiological impact of albuminuria on incident primary CVD, as well as its impact on prognosis in patients with established CVD.


    Conclusion
 Top
 Abstract
 Methods
 Results
 Discussion
 Conclusion
 References
 
All-cause and CVD mortality increased significantly across categories of albuminuria, with microalbuminuria being independently associated with an increased in risk of all-cause and CVD mortality in this UK population. In addition to conventional risk factors such as smoking, dyslipidaemia, hypertension, or diabetes, microalbuminuria may therefore be a useful indicator in identifying those at an increased risk of death especially from CVD in all men and women in the community.


KEY MESSAGES

  • Age-adjusted all-cause mortality rate and cardiovascular disease (CVD) mortality rate increases significantly across categories of baseline albuminuria in this population.
  • Microalbuminuria is independently associated with an increased risk of all-cause CVD mortality in both men and women in this population-based cohort.
  • Microalbuminuria was not predictive of cancer mortality in this EPIC-Norfolk population.

 


    Acknowledgments
 
We are grateful to Joanna Camus and Joan Russell for their work on urine and blood samples, and for data handling. EPIC-Norfolk is supported by programme grants from Cancer Research Campaign and Medical Research Council with additional support from the British Heart Foundation, The Stroke Association, Department of Health, Food Standard Agency, Europe Against Cancer Programme, WHO, and the Wellcome Trust.


    References
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 Abstract
 Methods
 Results
 Discussion
 Conclusion
 References
 
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