Urinary orosomucoid is associated with diastolic dysfunction and carotid arteriopathy in the general population. Cross-sectional data from the Tromsø study.

Objectives. Urinary albumin excretion is a risk marker for cardiovascular disease (CVD). Studies suggest that urinary orosomucoid may be a more sensitive marker of general endothelial dysfunction than albuminuria. The aim of this population-based cross-sectional study was to examine the associations between urinary orosomucoid to creatinine ratio (UOCR), urinary albumin to creatinine ratio (UACR) and subclinical CVD. Design. From the Tromsø Study (2007/2008), we included all men and women who had measurements of urinary orosomucoid (n = 7181). Among these, 6963 were examined with ultrasound of the right carotid artery and 2245 with echocardiography. We assessed the associations between urinary markers and subclinical CVD measured as intima media thickness of the carotid artery, presence and area of carotid plaque and diastolic dysfunction (DD). UOCR and UACR were dichotomized as upper quartile versus the three lowest. Results. High UOCR, adjusted for UACR, age, cardiovascular risk factors and kidney function, was associated with presence of DD in men (OR: 3.18, 95% CI [1.27, 7.95], p = .013), and presence of plaque (OR: 1.20, 95% CI [1.01, 1.44], p = .038) and intima media thickness in women (OR: 1.34, 95% CI [1.09, 1.65], p = .005). Analyses showed no significant interaction between sex and UOCR for any endpoints. UACR was not significantly associated with DD, but the associations with intima media thickness and plaque were of magnitudes comparable to those observed for UOCR. Conclusions. UOCR was positively associated with subclinical CVD. We need prospective studies to confirm whether UOCR is a clinically useful biomarker and to study possible sex differences.

The Association Between Adiponectin, Serum Uric Acid and Urinary Markers of Renal Damage in the General Population: Cross-Sectional Data from the Tromsø Study.

BACKGROUND/AIMS: Uric acid may cause renal damage, whereas adiponectin in some studies has been reported to have renoprotective properties. The renoprotective role of adiponectin under the influence of hyperuricemia has not been explored. We assessed the cross-sectional association between adiponectin, serum uric acid (SUA) and urinary biomarkers of glomerular and tubular damage (albumin-creatinine ratio [ACR] and N-acetyl-ß-D-glucosaminidase-creatinine ratio [NAG-CR]) in a large cohort from a general population. METHODS: Three urine specimens from 7062 persons, participating in the Tromsø Study, were collected. The adjusted associations between adiponectin and SUA as independent variables, and ACR ≥1.13 mg/mmol (albuminuria) and the upper gender specific 15 percentile of NAG-CR (high NAG-CR) as dependent variables, were assessed. RESULTS: Mean (standard deviation) age of the participants was 63.5 (9.2) years. Adiponectin was positively associated with albuminuria and high NAG-CR. SUA was associated with albuminuria (odds ratio [OR] 1.13; 95% Confidence Interval [CI] 1.05-1.21 per 59 µmol/L increase), but not with NAG-CR. There were no statistically significant interactions between SUA and adiponectin. CONCLUSIONS: Unexpectedly, adiponectin was positively associated with both urinary markers of renal damage. SUA was positively associated with albuminuria only. SUA and adiponectin added little beyond traditional cardiovascular risk factors to predict renal damage and did not interact in their associations with the urinary biomarkers. Longitudinal studies are needed before firm conclusions can be made.

Cystatin C as risk factor for cardiovascular events and all-cause mortality in the general population. The Tromsø Study.

BACKGROUND: Glomerular filtration rate<60 mL/min/1.73 m2 is associated with increased cardiovascular risk. Cystatin C is believed to be a better tool than creatinine for detection of mild renal dysfunction (>60 mL/min/1.73 m2) and possibly a more sensitive marker for cardiovascular risk and all-cause mortality. We examined the association of cystatin C with cardiovascular morbidity and all-cause mortality in a prospective population-based study. METHODS: Cystatin C was measured in 2852 men and 3153 women in the Tromsø Study 1994/95. Gender-specific associations during 12 years of follow-up for all-cause mortality and 9.5 years for myocardial infarction (MI) and ischaemic stroke were assessed (Cox proportional hazard ratios, HRs). RESULTS: During follow-up, 591 MIs, 293 ischaemic strokes and 1262 deaths occurred. In women, HR for all-cause mortality was increased in the upper cystatin C quartile (≥0.93 mg/L) compared with the lowest quartile (≤0.73 mg/L); 1.38, 95% confidence interval 1.04-1.84. A significant interaction with gender was observed. One SD (0.17 mg/L) increase in cystatin C was associated with 9% higher risk of death in women, also when persons with a cancer history were excluded. Crude HRs for MI and ischaemic stroke were increased in both genders, but the associations did not persist after multivariable adjustments. No independent associations with end points were observed in non-gender-specific analyses. CONCLUSIONS: Cystatin C was not independently associated with fatal and non-fatal MI or ischaemic stroke in the general population. However, cystatin C was a risk factor for all-cause mortality in women.

Albuminuria, metabolic syndrome and the risk of mortality and cardiovascular events.

AIM: Increased urinary albumin-excretion is a cardiovascular risk-factor. The cardiovascular risk of the metabolic syndrome (MetS) is debated. The aim of the present prospective, population-based study of non-diabetic individuals was to examine the association between low-grade urinary albumin-excretion, MetS, and cardiovascular morbidity and all-cause mortality. METHODS: 5215 non-diabetic, non-proteinuric men and women participating in the Tromsø Study 1994-1995 were included. Urinary albumin-creatinine ratio (ACR) was measured in three urine samples. The participants were categorized into four groups by the presence/absence of MetS (the International Diabetes Federation definition) and ACR in the upper tertile (>or=0.75 mg/mmol). RESULTS: Median follow-up time was 9.6 years for first ever myocardial infarction, 9.7 years for ischemic stroke and 12.4 years for mortality. High ACR (upper tertile)/MetS was associated with increased risk of myocardial infarction (hazard ratio (HR) 1.75; 95% confidence interval (CI): 1.30-2.37, p<0.001), stroke (HR 2.48; 95% CI: 1.66-3.71, p<0.001), and all-cause mortality (HR 1.63; 95% CI: 1.32-2.01, p<0.001) compared to reference (low ACR/no MetS). Similar associations were found for the high ACR/no MetS group. Low ACR/MetS was associated with myocardial infarction only (HR 1.82; 95% CI: 1.39-2.37, p<0.001). MetS predicted neither stroke nor mortality. Adjusted for its individual components, MetS was not associated with any end-point. CONCLUSIONS: ACR>or=0.75 mg/mmol was associated with cardiovascular morbidity and all-cause mortality independently of MetS. MetS was not associated with any end-point beyond what was predicted from its components. Thus, low-grade albuminuria, but not MetS, may be used for risk stratification in non-diabetic subjects.

Predictors of change in estimated GFR: a population-based 7-year follow-up from the Tromso study.

BACKGROUND: Chronic kidney disease is associated with increased cardiovascular mortality, and even mild impairment of renal function is a cardiovascular risk factor. Several studies have investigated the risk factors for the development of end-stage renal disease, but little is known about predictors of change in renal function in the general population. METHODS: The present study included 2249 men and 2192 women without signs of kidney disease at baseline who were followed for 7 years from 1994 to 1995 in the Tromsø Study. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease study equation. Gender-specific multiple linear regression analyses were used to assess predictors of change in eGFR (DeltaGFR). RESULTS: Change in eGFR, measured in ml/min/1.73 m(2)/year, was associated with systolic blood pressure (SBP) [beta-value for a 10-mmHg increase in SBP, men = -0.14, 95% confidence interval (CI) = -0.18 to -0.09; women = -0.07, 95% CI = -0.11 to -0.03] and fibrinogen [beta-value for 1 SD increase in fibrinogen, men (1 SD: 0.85 g/L) = -0.12, 95% CI -0.20 to -0.03; women (1 SD: 0.80) = -0.11, 95% CI -0.20 to -0.02]. High alcohol consumption in men and high physical activity in women predicted an increase in eGFR. Higher albumin/creatinine ratio was associated with a decline in eGFR in men only. CONCLUSIONS: Some risk factors for change in GFR seem to be gender specific but both high SBP and high levels of fibrinogen contribute to a more rapid decline in GFR for both men and women.

Cardiovascular risk-factors predict progression of urinary albumin-excretion in a general, non-diabetic population: a gender-specific follow-up study.

Increased urinary albumin-excretion (UAE) predicts cardiovascular events and clusters with the metabolic syndrome. The aim of this population-based, prospective study was to assess the relationship between baseline and longitudinal changes in cardiovascular risk-factors and 7 years' increase in UAE. Three thousand and four hundred non-diabetic participants (1838 men, 1562 women) of the Tromsø studies in 1994/1995 and 2001/2002 were included. In each survey, first-void spot-urine-samples were collected, and albumin-creatinine ratio (ACR) was calculated. Change in ACR (DeltaACR) was dichotomized into upper vs. the three lower quartiles. Median UAE in the population did not increase during follow-up. Baseline predictors for DeltaACR in the upper quartile were: age (OR 1.32 per 5 years, 95% CI 1.22-1.43), HbA1c (OR 1.43 per %, 95% CI 1.08-1.91) and waist circumference (OR 1.11 per 5 cm, 95% CI 1.04-1.19) in men, and age (OR 1.14 per 5 years, 95% CI 1.04-1.25) and current smoking (OR 1.71, 95% CI 1.27-2.30) in women. Systolic blood pressure and estimated glomerular filtration rate were predictors without gender-specificity. Clustering of three or more metabolic traits did not predict ACR increase independently. Protective factors against ACR increase were initiation of antihypertensive treatment in women (OR 0.59, 95% CI 0.39-0.87) and hard physical activity in men (OR 0.70, 95% CI 0.51-0.96). In summary, cardiovascular risk-factors at baseline predicted ACR increase, but initiation of antihypertensive therapy (women) and physical activity (men) seemed to protect from ACR increase during follow-up. Endpoint-data are needed to explore the clinical significance of low-grade UAE increase.

Metabolic risk factors associated with serum creatinine in a non-diabetic population.

Insulin resistance, low HDL-cholesterol and microalbuminuria are important components of the metabolic syndrome as defined by WHO. Insulin resistance and low HDL-cholesterol are also common in chronic kidney disease (CKD), but it is not clear whether they are early or late phenomenons in the development of renal failure. This study examined whether low-grade albuminuria (microalbuminuria), lipoprotein fractions, and the insulin/glucose ratio (IGR)-a surrogate marker of insulin resistance-were related to renal function (expressed as serum creatinine) in persons without diabetes and with apparently normal renal function. The study included 4,131 men and women aged 55-75 years from the cross-sectional Tromsø IV survey (1994-1995). Lifestyle factors, waist circumference and blood pressure were included in the analyses. Gender stratified multivariate analysis was used to assess the relationship between serum creatinine and microalbuminuria, lipoprotein fractions and IGR. Serum creatinine was positively associated with microalbuminuria in men (beta = 2.50, 95% confidence interval (CI) 0.66-4.34), but not in women. HDL-cholesterol and IGR were strongly associated with creatinine in both genders (HDL-cholesterol: Men: beta = -4.82, 95% CI -6.27 to -3.37; women: beta = -2.12, 95% CI -3.28 to -0.96. IGR: Second, third and fourth quartile compared with first quartile, men: beta = 0.94, 95% CI -0.63 to 2.51; 2.10, 95% CI 0.52-3.69 and 2.40, 95% CI 0.75-4.04; women: beta = 1.91, 95% CI 0.59-3.22; 2.61, 95% CI 1.28-3.95 and 3.20, 95% CI 1.80-4.60). These findings suggest that even early impairment of renal function may be associated with insulin resistance and dyslipidemia, regardless of renal albumin leakage.