N-Acetyl-ß-D-Glucosaminidase Does Not Enhance Prediction of Cardiovascular or All-Cause Mortality by Albuminuria in a Low-Risk Population.

Albuminuria is a well known risk factor for cardiovascular disease and mortality, but focus on renal tubular dysfunction as a potential risk factor is growing also. The association between the urinary activity of N-acetyl-ß-D-glucosaminidase (NAG) and cardiovascular risk has been assessed mostly in cross-sectional studies. We studied the cross-sectional associations between urinary NAG and cardiovascular risk factors and the longitudinal associations between NAG, cardiovascular disease, and all-cause mortality in a general population. Urinary NAG/creatinine ratio (NAG ratio) and albumin/creatinine ratio (ACR) were measured in 6834 participants of the Tromsø Study in 1994-1995. During the median 17.5 years of follow-up, 958 myocardial infarctions, 726 ischemic strokes, and 2358 deaths were registered. In multivariable analyses adjusted for albuminuria and cardiovascular risk factors, a baseline NAG ratio in the highest quartile was associated with an increased risk of myocardial infarction (hazard ratio [HR], 1.43; 95% confidence interval [95% CI], 1.16 to 1.76), ischemic stroke (HR, 1.41; 95% CI, 1.10 to 1.80), and all-cause mortality (HR, 1.60; 95% CI, 1.39 to 1.84). Combined, ACR and NAG ratio above median associated with a 48%-80% increased risk for the three end points. However, the NAG ratio did not add significantly to the baseline risk-prediction models when assessed by area under the receiver operating characteristics curve or net reclassification improvement. In conclusion, the nonsignificant improvement of risk prediction does not support the clinical use of NAG ratio in cardiovascular risk assessment in a low-risk group.

Uric acid is associated with microalbuminuria and decreased glomerular filtration rate in the general population during 7 and 13 years of follow-up: The Tromsø Study.

BACKGROUND: The role of uric acid in development of renal dysfunction (RD) remains controversial. Earlier studies have reported inconsistent results, possibly because of their varying ability to adjust for confounding. The impact of longitudinal change in uric acid on renal outcome has not been assessed previously. We aimed to study the impact of change in serum uric acid (SUA) as well as baseline SUA on the development of RD. METHODS: In a prospective cohort study, we assessed the associations between change in SUA during follow-up, baseline SUA and RD (defined as albumin-creatinine-ratio (ACR) ≥1.13 mg albumin/mmol creatinine and/or eGFR < 60 ml/min/1.73 m(2)) in a large cohort from a general population participating in the Tromsø Study (n = 2637). Participants were stratified according to tertiles of change in SUA between baseline (1994/95) and follow-up 13 years later. (upper tertile: SUA increasing group, two lower tertiles: SUA non-increasing group). Logistic regression analysis was applied with RD and each component of RD after 7 and 13 years as the dependent variables. Adjustments were made for baseline eGFR, cardiovascular risk factors, and the use of antihypertensive drugs including diuretics. RESULTS: After excluding participants with RD at baseline, SUA increasers, compared to SUA non-increasers, had a doubled risk of RD after 7 years (odds ratio 2.00, (95 % CI 1.45, 2.75)). Odds ratio for RD in SUA increasers after 13 years was 2.18 (95 % CI 1.71, 2.79). The risk of developing ACR ≥1.13 mg/mmol alone was not significantly increased after 7 years (odds ratio 1.30 (95 % CI 0.90, 1.89), but after 13 years (odds ratio 1.43 (95 % CI 1.09, 1.86)). An increase in baseline SUA of 59 µmol/L (1 mg/dL) gave an odds ratio for RD after 13 years of 1.16 (95 % CI 1.04, 1.29). CONCLUSION: An increase in SUA during follow-up was associated with an increased risk of developing RD after 7 and 13 years.

Cross-sectional analysis of nutrition and serum uric acid in two Caucasian cohorts: the AusDiab Study and the Tromsø study.

BACKGROUND: Hyperuricemia can lead to gout, and may be a risk factor for cardiovascular events, hypertension, diabetes and renal disease. There is well-known link between gout and habitual intake of meat and seafood, however the association between hyperuricemia and micro-and macro-nutrient intake has not been established. METHODS: We studied associations between intakes of food categories, macro-and micronutrients and serum uric acid (SUA) levels in two cross-sectional surveys of Caucasian adults deriving from different food traditions: Australian Diabetes, Obesity and Lifestyle Study 1999/00 (n=9734, age 25-91) and Tromsø Study 4 1994/95 (n = 3031, age 25-69). Dietary intake was calculated from self-administered Food Frequency Questionnaires. In some analyses we stratified according to abdominal obesity status and gender. RESULTS: In both cohorts, lower levels of SUA were found in subjects with higher consumption of carbohydrates, calcium and vitamin B2, while higher fat intake was associated with higher SUA, after adjustment for age, body mass index, estimated glomerular filtration rate, physical activity, total energy intake, use of diuretics, presence of hypertension, diabetes and gout. Among individual food items, high consumption of dairy products, high-fibre bread, cereals and fruits were associated with lower SUA in most subject groups while consumption of meat, eggs, beer and spirits, but not wine, with elevated levels. CONCLUSIONS: Healthy food choices with high intake of carbohydrates, dairy products, fiber and micronutrient-rich foods, and limited intake of fat, beer and spirits, might be recommended to prevent high SUA. Dietary factors seem to have qualitatively similar impact on SUA in obese and non-obese men and women from Australia and Norway.

Uric acid has a J-shaped association with cardiovascular and all-cause mortality in kidney transplant recipients.

The association between serum uric acid and kidney graft and recipient survival is uncertain. During 2000-2011, we measured serum uric acid at week 10 after transplantation. Of 2748 transplanted patients, 2200 (80.1%) attended this visit. After a median follow-up of 7.4 yr, 378 patients had died, 143 from a cardiovascular cause, and 185 patients lost their graft. The third quintile of uric acid levels (357-405 µM) had the lowest mortality risk and was used as reference group. In Cox proportional hazard models adjusting for graft and patient characteristics, the fifth quintile of uric acid levels (>474 µM) was independently associated with cardiovascular mortality (hazard ratio [HR] = 2.87 [1.55-5.32], p = 0.001) and all-cause mortality (HR = 1.57 [1.09-2.25], p = 0.02). Also, the lowest quintile of uric acid levels (<309 µM) showed a trend toward increased risk of cardiovascular mortality (HR = 1.79 [0.90-3.58], p = 0.10) and all-cause mortality (HR = 1.31 [0.89-1.93], p = 0.18). The increased risk at low uric acid levels was confined to diabetic recipients. Uric acid was not associated with death-censored graft loss. In conclusion, uric acid has a J-shaped association with cardiovascular and all-cause mortality in kidney transplant recipients.

Subclinical cardiovascular disease is associated with a high glomerular filtration rate in the nondiabetic general population.

A reduced glomerular filtration rate (GFR) in chronic kidney disease is a risk factor for cardiovascular disease. However, evidence indicates that a high GFR may also be a cardiovascular risk factor. This issue remains unresolved due to a lack of longitudinal studies of manifest cardiovascular disease with precise GFR measurements. Here, we performed a cross-sectional study of the relationship between high GFR measured as iohexol clearance and subclinical cardiovascular disease in the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6), a representative sample of the middle-aged general population. A total of 1521 persons without cardiovascular disease, chronic kidney disease, diabetes, or micro- or macroalbuminuria were examined with carotid ultrasonography and electrocardiography. The GFR in the highest quartile was associated with an increased odds ratio of having total carotid plaque area greater than the median of non-zero values (odds ratio 1.56, 95% confidence interval 1.02-2.39) or electrocardiographic signs of left ventricular hypertrophy (odds ratio 1.62, 95% confidence interval 1.10-2.38) compared to the lowest quartile. The analyses were adjusted for cardiovascular risk factors, urinary albumin excretion, and fasting serum glucose. Thus, high GFR is associated with carotid atherosclerosis and left ventricular hypertrophy and should be investigated as a possible risk factor for manifest cardiovascular disease in longitudinal studies.

Uric acid is associated with future atrial fibrillation: an 11-year follow-up of 6308 men and women--the Tromso Study.

AIMS: Serum uric acid (SUA) has been associated with cardiovascular disease in population studies, but its relation to atrial fibrillation (AF) is largely unknown. The aim of this study was to investigate the association between baseline SUA and future AF in a large population-based cohort. METHODS AND RESULTS: A total of 6308 men and women from a population survey in Tromsø, Norway in 1994-95 were followed-up for 10.8 years. The mean age at baseline was 60 years. Information on angina, myocardial infarction, diabetes, anti-hypertensive and diuretic treatment, physical activity, smoking and alcohol, and measurements of height, weight, blood pressure, SUA, total cholesterol, and high density lipoprotein-cholesterol were obtained at baseline. The outcome measure was first-ever AF, documented on an electrocardiogram. We identified 572 cases of incident AF. In multivariable Cox proportional hazards regression analysis adjusted for cardiovascular risk factors and concomitant diseases, SUA was associated with AF in both sexes. Hazard ratio per 1 SD increase in SUA (91 µmol/L) was 1.40 [95% confidence intervals (CI), 1.14-1.72] in women and 1.17 (95% CI, 1.02-1.36) in men. The upper quartile of SUA conferred a 76% increased risk for AF in women and 49% in men as compared with the lowest quartile. CONCLUSION: This prospective population-based cohort study showed that baseline SUA was associated with an increased risk for future AF in both sexes.

Sex differences in risk factors for retinopathy in non-diabetic men and women: the Tromsø Eye Study.

PURPOSE: To determine the prevalence and risk factors for retinopathy in a nondiabetic population. METHODS: The study population included 5869 participants without diabetes aged 38-87 years from the Tromsø Eye Study, a substudy of the population-based Tromsø Study in Norway. Retinal images from both eyes were graded for retinopathy. We collected data on risk factors from self-report questionnaires, clinical examinations, laboratory measurements and case note reviews. The cross-sectional relationship between potential risk factors and retinopathy was assessed using logistic regression analysis. RESULTS: The overall prevalence of retinopathy was 14.8%. Men had a higher prevalence of retinopathy compared with women (15.9% versus 14.0%, p=0.04). In men, retinopathy was associated with hypertension (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.24-2.04) and HbA1c (OR per %, 1.41; 95% CI, 1.01-1.96). In women, retinopathy was associated with age (OR per 10 years, 1.32; 95% CI, 1.14-1.52), log-transformed urinary albumin excretion (OR per log unit, 1.46; 95% CI, 1.14-1.87) and hypertension (OR, 1.36; 95% CI, 1.08-1.71). In women, retinopathy was associated with very low levels of urinary albumin excretion (urinary albumin/creatinine ratio >0.43 mg/mmol). CONCLUSION: This study confirms results from previous studies on the strong association between blood pressure and retinopathy. A novel finding is the sex differences in risk factors for retinopathy, suggesting a sex difference in the pathogenesis leading to retinopathy.

Uric acid is a risk factor for ischemic stroke and all-cause mortality in the general population: a gender specific analysis from The Tromsø Study.

BACKGROUND: The role of serum uric acid as an independent predictor of cardiovascular disease and death is uncertain in the general population. Adjustments for additional cardiovascular risk factors have not been consistent. We examined the association of serum uric acid with all-cause mortality, ischemic stroke and myocardial infarction in a prospective population based study, with several traditional and non-traditional risk factors for cardiovascular disease included in the model. METHODS: A population-based prospective cohort study was performed among 2696 men and 3004 women. Endpoints were all-cause mortality after 15 years, and fatal or non-fatal myocardial infarction (MI) and ischemic stroke after 12 years. RESULTS: 1433 deaths, 659 MIs and 430 ischemic strokes occurred during follow-up. Fully adjusted Cox regression analyses showed that per 1 SD (87 µmol/L) increase in serum uric acid level, the risk of all-cause mortality increased in both genders (hazard ratios, HR men; 1.11, 95% CI 1.02-1.20, women; 1.16, 1.05-1.29). HRs and 95% CI for stroke were 1.31, 1.14-1.50 in men, 1.13, 0.94-1.36 in women, and 1.22 (1.09, 1.35) in the overall population. No independent associations were observed with MI. CONCLUSION: Serum uric acid was associated with all-cause mortality in men and women, even after adjustment for blood pressure, estimated GFR, urinary albumin/creatinine ratio, drug intake and traditional cardiovascular risk factors. After the same adjustments, serum uric acid was associated with 31% increased risk of stroke in men.

Tromsø eye study: prevalence and risk factors of diabetic retinopathy.

PURPOSE: To determine the prevalence of visual impairment, retinopathy and macular oedema, and assess risk factors for retinopathy in persons with diabetes. METHODS: The present study included 514 participants with diabetes aged 46-87 years from the Tromsø Eye Study, a sub-study of the population-based Tromsø Study in Norway. Visual acuity was measured using an auto-refractor. Retinal images from both eyes were graded for retinopathy and macular oedema. We collected data on risk factor exposure from self-report questionnaires, clinical examinations, laboratory measurements and case note reviews. Regression models assessed the cross-sectional relationship between potential risk factors and diabetic retinopathy. RESULTS: The prevalence of visual impairment (corrected Snellen visual acuity <20/60 in the better-seeing eye) was 1.6%. The prevalence of diabetic retinopathy was 26.8% and macular oedema 3.9%. In a multivariable logistic regression model, retinopathy was associated with longer diabetes duration (odds ratio, OR 1.07, 95% CI 1.03-1.11), insulin use (OR 2.14, 95% CI 1.19-3.85), nonfasting glucose (OR 1.07, 95% CI 1.00-1.15) and microalbuminuria (OR 1.89, 95% CI 1.28-2.81). Sub-group analyses showed association between retinopathy and even low levels of microalbuminuria (1.16 mg/mmol). CONCLUSION: The findings suggest that low levels of microalbuminuria may be a useful risk predictor for identifying individuals with diabetes at high risk of retinopathy. The study confirms previous findings that insulin use, longer diabetes duration and higher levels of blood glucose are associated with retinopathy in persons with diabetes. The prevalence of diabetic retinopathy was similar as reported in other studies.

Physical exercise, fasting glucose, and renal hyperfiltration in the general population: the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6).

BACKGROUND AND OBJECTIVES: Abnormally elevated GFR, or hyperfiltration, is a proposed mechanism for kidney injury in diabetes, prediabetes, and obesity. This study investigated whether lack of physical exercise is associated with hyperfiltration and whether exercise modifies the positive association between fasting glucose and measured GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Renal Iohexol Clearance Survey in Tromsø 6 measured GFR as single-sample plasma iohexol clearance in 1506 members of the general population (age 50-62 years) without diabetes, cardiovascular disease, or kidney disease. Leisure-time physical exercise was assessed by a self-administered questionnaire. Hyperfiltration was defined as GFR above the 90th percentile after adjustment for sex, age, weight, height, and use of renin-angiotensin system inhibitors. RESULTS: High-intensity exercise was associated with lower adjusted odds of hyperfiltration in men (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.28-0.80) but not in women (OR, 1.02; 95% CI, 0.60-1.72). In both sexes, high-intensity exercise modified the association between fasting glucose and GFR. A fasting glucose level 1 mmol/L higher was associated with a GFR that was 7.3 (95% CI, 4.0-10.6) and 6.2 (95% CI, 3.4-9.0) ml/min per 1.73 m(2) higher in men and women who never exercised or exercised with low intensity. There was no association between fasting glucose and GFR in men and women who exercised with high intensity (interaction, P<0.001). CONCLUSIONS: High-intensity exercise was associated with lower odds of hyperfiltration in men and modified the association between glucose and GFR of both sexes in a population without diabetes.

Ambulatory blood pressure is associated with measured glomerular filtration rate in the general middle-aged population.

OBJECTIVES: Hypertension is both a cause and a consequence of kidney disease. Whether there is an association between the earliest stages of elevated blood pressure and variations in kidney function within the normal range in the general population has not been investigated using accurate methodology. METHODS: Glomerular filtration rate (GFR) by iohexol clearance and 24-h blood pressure were measured in a cross-sectional sample (n = 1627) from the general population aged from 50 to 62 years. None of the participants had known cardiovascular disease, chronic kidney disease, or diabetes. RESULTS: In multiple linear regression analyses with multivariate adjustment, GFR was associated with both ambulatory SBP and DBP and their interaction in separate models for daytime and night-time (P < 0.05). For blood pressure in the normotensive range, GFR increased with higher daytime SBP and with night-time SBP and DBP. In the daytime, higher DBP was associated with a slight decrease in GFR. CONCLUSION: GFR was associated with blood pressure in both the normotensive and hypertensive range. Although no conclusion about causality can be drawn from these cross-sectional relationships, they are consistent with the hypotheses of a causal relationship between renal function and blood pressure at a very early stage of hypertension or renal impairment.

The role of cystatin C in improving GFR estimation in the general population.

BACKGROUND: The equations used to estimate glomerular filtration rate (GFR) based on serum creatinine level are limited by their dependence on muscle mass. Although cystatin C level predicts clinical outcomes better than creatinine level in the general population, its role in estimating GFR in the reference range is unclear. Cystatin C level is not influenced by muscle mass, but by several other non-GFR determinants. We investigated whether regression models using cystatin C level alone or in combination with creatinine level in principle would improve GFR estimation in the general population compared with models using creatinine level alone. STUDY DESIGN: Study of diagnostic accuracy. SETTING & PARTICIPANTS: A representative sample (n = 1,621; aged 50-62 years) of the general population in Tromsø, Norway, without coronary heart disease, stroke, diabetes mellitus, or kidney disease. Individuals had participated in the Renal Iohexol Clearance Survey (RENIS-T6), part of the sixth Tromsø Study. INDEX TEST: Performance of multiple linear and fractional polynomial regression models with plasma creatinine and/or cystatin C levels as independent variables and measured GFR as a dependent variable. REFERENCE TEST: Plasma iohexol clearance. OTHER MEASUREMENTS: Creatinine measured with an enzymatic method. Cystatin C measured with a particle-enhanced turbidimetric immunoassay. RESULTS: In internal validation of models with cystatin C, creatinine, or both levels, percentages of GFR estimates within 10% of measured GFR were 61% (95% CI, 58%-63%), 62% (95% CI, 59%-64%), and 68% (95% CI, 65%-70%), respectively. Models with either cystatin C or creatinine level had very similar precision and ability to detect GFR <90 mL/min/1.73 m(2), whereas models based on both markers performed better. LIMITATIONS: Only middle-aged individuals of European ancestry were investigated. Lack of standardization between cystatin C assays. No external validation of regression models. CONCLUSIONS: Models based on cystatin C alone are not superior to those based on creatinine, but models based on both markers can improve GFR estimation in the reference range.

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.

GFR normalized to total body water allows comparisons across genders and body sizes.

The normalization of GFR to a standardized body-surface area of 1.73 m(2) impedes comparison of GFR across individuals of different genders, heights, or weights. Ideally, GFR should be normalized to a parameter that best explains variation in GFR. Here, we measured true GFR by iohexol clearance in a representative sample of 1627 individuals from the general population who did not have diabetes, cardiovascular disease, or kidney disease. We also estimated total body water (TBW), extracellular fluid volume, lean body mass, liver volume, metabolic rate, and body-surface area. We compared two methods of normalizing GFR to these physiologic variables: (1) the conventional method of scaling GFR to each physiologic variable by simple division and (2) a method based on regression of the GFR on each variable. TBW explained a higher proportion of the variation in GFR than the other physiologic variables. GFR adjusted for TBW by the regression method exhibited less dependence on gender, height, and weight compared with the other physiologic variables. Thus, adjusting GFR for TBW by the regression method allows direct comparisons between individuals of different genders, weights, and heights. We propose that regression-based normalization of GFR to a standardized TBW of 40 L should replace the current practice of normalizing GFR to 1.73 m(2) of body-surface area.

Impaired fasting glucose is associated with renal hyperfiltration in the general population.

OBJECTIVE: Increased glomerular filtration rate (GFR), also called hyperfiltration, is a proposed mechanism for renal injury in diabetes. The causes of hyperfiltration in individuals without diabetes are largely unknown, including the possible role of borderline hyperglycemia. We assessed whether impaired fasting glucose (IFG; 5.6-6.9 mmol/L), elevated HbA1c, or hyperinsulinemia are associated with hyperfiltration in the general middle-aged population. RESEARCH DESIGN AND METHODS: A total of 1,560 individuals, aged 50-62 years without diabetes, were included in the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6). GFR was measured as single-sample plasma iohexol clearance. Hyperfiltration was defined as GFR>90th percentile, adjusted for sex, age, weight, height, and use of renin-angiotensin system inhibitors. RESULTS: Participants with IFG had a multivariable-adjusted odds ratio of 1.56 (95% CI 1.07-2.25) for hyperfiltration compared with individuals with normal fasting glucose. Odds ratios (95% CI) of hyperfiltration calculated for a 1-unit increase in fasting plasma glucose (FPG) and HbA1c, after multivariable-adjustment, were 1.97 (1.36-2.85) and 2.23 (1.30-3.86). There was no association between fasting insulin levels and hyperfiltration. A nonlinear association between FPG and GFR was observed (df=3, P<0.0001). GFR increased with higher glucose levels, with a steeper slope beginning at FPG≥5.4 mmol/L. CONCLUSIONS: Borderline hyperglycemia was associated with hyperfiltration, whereas hyperinsulinemia was not. Longitudinal studies are needed to investigate whether the hyperfiltration associated with IFG is a risk factor for renal injury in the general population.

Estimated GFR associates with cardiovascular risk factors independently of measured GFR.

Estimation of the GFR (eGFR) using creatinine- or cystatin C-based equations is imperfect, especially when the true GFR is normal or near-normal. Modest reductions in eGFR from the normal range variably predict cardiovascular morbidity. If eGFR associates not only with measured GFR (mGFR) but also with cardiovascular risk factors, the effects of these non-GFR-related factors might bias the association between eGFR and outcome. To investigate these potential non-GFR-related associations between eGFR and cardiovascular risk factors, we measured GFR by iohexol clearance in a sample from the general population (age 50 to 62 years) without known cardiovascular disease, diabetes, or kidney disease. Even after adjustment for mGFR, eGFR associated with traditional cardiovascular risk factors in multiple regression analyses. More risk factors influenced cystatin C-based eGFR than creatinine-based eGFR, adjusted for mGFR, and some of the risk factors exhibited nonlinear effects in generalized additive models (P<0.05). These results suggest that eGFR, calculated using standard creatinine- or cystatin C-based equations, partially depends on factors other than the true GFR. Thus, estimates of cardiovascular risk associated with small changes in eGFR must be interpreted with caution.

Cystatin C is not a better estimator of GFR than plasma creatinine in the general population.

Accurate measurement of glomerular filtration rate (GFR) is complicated and costly; therefore, GFR is commonly estimated by assessing creatinine or cystatin C concentrations. Because estimates based on cystatin C predict cardiovascular disease better than creatinine, these estimates have been hypothesized to be superior to those based on creatinine, when the GFR is near the normal range. To test this, we measured GFR by iohexol clearance in a representative sample of middle-aged (50-62 years) individuals in the general population, excluding those with coronary heart or kidney disease, stroke or diabetes mellitus. Bias, precision (median and interquartile range of estimated minus measured GFR (mGFR)), and accuracy (percentage of estimates within 30% of mGFR) of published cystatin C and creatinine-based GFR equations were compared in a total of 1621 patients. The cystatin C-based equation with the highest accuracy (94%) had a bias of 3.5 and precision of 18 ml/min per 1.73 m², whereas the most accurate (95%) creatinine-based equation had a bias of 2.9 and precision of 15 ml/min per 1.73 m² The best equation, based on both cystatin C and creatinine, had a bias of 7.6 ml/min per 1.73 m², precision of 15 ml/min per 1.73 m², and accuracy of 92%. Thus, estimates of GFR based on cystatin C were not superior to those based on creatinine in the general population. Hence, the better prediction of cardiovascular disease by cystatin C than creatinine measurements, found by others, may be due to factors other than GFR.

Changes in insulin sensitivity, renal function, and markers of endothelial dysfunction in hypertension--the impact of microalbuminuria: a 13-year follow-up study.

Microalbuminuria (MA) clusters with the metabolic syndrome and insulin resistance and may reflect endothelial dysfunction. Microalbuminuria may also represent renal dysfunction. The aim of the present follow-up study was to assess changes over 13 years in insulin sensitivity, markers of endothelial dysfunction, and renal function in hypertensive subjects with and without MA in 1992-1993, matched for age, sex, and body mass index. Fourteen subjects with and 17 without MA at baseline (1992-1993) participated. At follow-up (2005-2006), MA status was unchanged in 75% of the subjects. The groups had comparable age, blood pressure, body mass index, markers of endothelial dysfunction, and metabolic traits, assessed by oral glucose tolerance test and hyperglycemic clamp. Estimated glomerular filtration rate decreased significantly in the MA group (P = .049) and tended to be lower in the MA than the non-MA group in 2005-2006 (79.9 +/- 24.5 vs 90.8 +/- 13.3 mL min(-1) (1.73 m(2))(-1), P = .2). Urinary albumin excretion in 1992-1993 predicted estimated glomerular filtration rate in 2005-2006 in adjusted analysis (beta = -0.47, P = .006). Estimated glomerular filtration rate less than 60 mL min(-1) (1.73 m(2))(-1) was more frequent in the MA than non-MA group at follow-up (P = .03). In conclusion, long-standing MA was not associated with progression of metabolic disturbances or markers of endothelial dysfunction in hypertensive individuals. A decline in renal function predicted by urinary albumin excretion was suggested. Microalbuminuria may not be a metabolic trait, but a marker mainly of renal endothelial dysfunction.

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.