Wilbert M.T. Janssen

Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population

Background—For the general population, the clinical relevance of an increased urinary albumin excretion rate is still debated. Therefore, we examined the relationship between urinary albumin excretion and all-cause mortality and mortality caused by cardiovascular (CV) disease and non-CV disease in the general population. Methods and Results—In the period 1997 to 1998, all inhabitants of the city of Groningen, the Netherlands, aged between 28 and 75 years (n=85 421) were sent a postal questionnaire collecting information about risk factors for CV disease and CV morbidity and a vial to collect an early morning urine sample for measurement of urinary albumin concentration (UAC). The vital status of the cohort was subsequently obtained from the municipal register, and the cause of death was obtained from the Central Bureau of Statistics. Of these 85 421 subjects, 40 856 (47.8%) responded, and 40 548 could be included in the analysis. During a median follow-up period of 961 days (maximum 1139 days), 516 deaths with known cause were recorded. We found a positive dose-response relationship between increasing UAC and mortality. A higher UAC increased the risk of both CV and non-CV death after adjustment for other well-recognized CV risk factors, with the increase being significantly higher for CV mortality than for non-CV mortality (P =0.014). A 2-fold increase in UAC was associated with a relative risk of 1.29 for CV mortality (95% CI 1.18 to 1.40) and 1.12 (95% CI 1.04 to 1.21) for non-CV mortality. Conclusions—Urinary albumin excretion is a predictor of all-cause mortality in the general population. The excess risk was more attributable to death from CV causes, independent of the effects of other CV risk factors, and the relationship was already apparent at levels of albuminuria currently considered to be normal.

Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria

Background—Microalbuminuria is associated with increased risk of cardiovascular events. We assessed whether therapeutic intervention aimed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects (15 to 300 mg/24 hours). Methods and Results—From the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort (n=8592), 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial (PREVEND IT). Of these subjects, 864 were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity. Mean age was 51±12 years; 65% of subjects were male, and 3.4% had a previous cardiovascular event. Mean cholesterol level was 5.8±1.0 mmol/L, mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg, and median urinary albumin excretion was 22.8 (15.8 to 41.3) mg/24 hours. The primary end point occurred in 45 subjects (5.2%). Fosinopril reduced urinary albumin excretion by 26% (P<0.001). Subjects treated with fosinopril showed a 40% lower incidence of the primary end point (hazard ratio 0.60 [95% CI 0.33 to 1.10], P=0.098, log-rank). Pravastatin did not reduce urinary albumin excretion, and subjects treated with pravastatin showed a 13% lower incidence of the primary end point than subjects in the placebo group (0.87 [0.49 to 1.57], P=0.649, log-rank). Conclusions—In microalbuminuric subjects, treatment with fosinopril had a significant effect on urinary albumin excretion. In addition, fosinopril treatment was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.

A central body fat distribution is related to renal function impairment, even in lean subjects

BACKGROUND Overweight and obesity are believed to be associated with renal damage. Whether this depends on fat distribution is not known. We hypothesize that in addition to overweight, fat distribution may be associated with renal function abnormalities. METHODS We studied the relation between body weight and fat distribution and microalbuminuria and elevated or diminished filtration in 7,676 subjects without diabetes. Microalbuminuria is defined as urinary albumin excretion (UAE) of 30 to 300 mg/24 h. Elevated and diminished filtration are defined as filtration plus or minus 2 SDs of a nondiabetic lean group with a peripheral fat distribution and UAE of 0 to 15 mg/24 h, corrected for age and sex. The total population was divided into six groups according to body weight (overweight is defined as body mass index [BMI] > 25 and < or = 30 kg/m2; obesity, as BMI > 30 kg/m2) and fat distribution. RESULTS In logistic regression analysis, obese subjects with central fat distribution had a greater risk for microalbuminuria (relative risk, 1.7; 95% confidence interval, 1.19 to 2.35). Obese subjects with either peripheral or central fat distribution had a greater risk for elevated filtration (relative risk, 3.2; 95% confidence interval, 1.19 to 8.47; relative risk, 2.6; 95% confidence interval, 1.59 to 4.28, respectively). Furthermore, subjects with central fat distribution, either lean, overweight, or obese, had a greater risk for diminished filtration (relative risk, 1.9; 95% confidence interval, 1.19 to 3.12; relative risk, 2.0; 95% confidence interval, 1.19 to 3.19; and relative risk, 2.7; 95% confidence interval, 1.46 to 4.85, respectively). Finally, by dividing waist-hip ratio (WHR) into quartiles, greater WHR was associated with a greater risk for diminished filtration, even when corrected for BMI. CONCLUSION Not only overweight and obese subjects, but also lean subjects with central fat distribution are at risk for diminished filtration. Therefore, a central pattern of fat distribution, not overweight or obesity by itself, seems to be important for renal impairment.

Smoking Is Related to Albuminuria and Abnormal Renal Function in Nondiabetic Persons

In recent years, it has become apparent that cigarette smoking is associated with excessive morbidity and mortality in various diseases (1), most prominently cardiovascular and lung diseases (2). Recently, however, the adverse effects of smoking on renal function have gained more attention (3), mainly through investigation in diabetic patients. In these patients, smoking is related to such variables of renal dysfunction as albuminuria (4-8) and hyperfiltration (9), which may accelerate the progression to loss of renal function (10). The adverse effects of smoking on renal function have not been investigated extensively in nondiabetic persons. Several studies show a relation between smoking and albuminuria (11, 12), but there is little information about the effects of smoking on glomerular filtration rate (GFR). The two studies that have addressed this question (13, 14) were small and do not offer information on the effect of smoking at a population level. We hypothesized that in nondiabetic persons, smoking is related to abnormal renal function manifested by albuminuria and elevated or decreased GFR. To test this hypothesis, we studied the cross-sectional relations among smoking, albuminuria, and GFR in a large cohort created to study the causes and consequences of microalbuminuria in nondiabetic persons. Methods Study Sample Our study is part of the ongoing PREVEND (Prevention of REnal and Vascular ENd stage Disease) Study, which takes place in Groningen, the Netherlands. All city inhabitants 28 to 75 years of age (n =85 421) were asked to send in a morning urine sample and to fill out a short questionnaire on demographic characteristics and cardiovascular history. Of these 85 421 persons, 40 856 (47.8%) responded. From this cohort, we selected persons with a urinary albumin concentration of at least 10 mg/L (n =7768) and a randomly selected control group with a urinary albumin concentration less than 10 mg/L (n =3395). Details of this protocol have been described elsewhere (15). Of these 11 163 persons, 8592 completed two invited visits to the outpatient clinic; participants who used insulin or were pregnant were excluded. The study was approved by the medical ethics committee of the Groningen University Hospital and was conducted in accordance with the guidelines of the Declaration of Helsinki. All participants attending the outpatient clinic gave written informed consent. Study Design The screening program in the outpatient clinic consisted of two visits. At the first visit, participants completed a self-administered questionnaire on demographic characteristics, cardiovascular and renal history, drug use, alcohol consumption, and smoking. After removal of shoes and heavy clothing, weight was measured to the nearest 0.5 kg with a seca balance scale (seca Vogel & Halke GmbH & Co., Hamburg, Germany). Height was measured to the nearest 0.5 cm. Minimum waist circumference was measured on bare skin at the natural indentation between the 10th rib and the iliac crest (16). At each visit, blood pressure was measured in the supine position every minute for 10 and 8 minutes, respectively, with an automatic DINAMAP XL Model 9300 series monitor (Critikon, Tampa, Florida). Participants received oral and written instructions on how to collect 24-hour urine samples on 2 consecutive days in the last week before the second clinic visit. They were asked to postpone collection in case of fever, urinary tract infection, or menstruation and to refrain from heavy exercise as much as possible during the 24 hours that collection was being performed. Participants were asked to store the urine cold (at 4 C) for no more than 4 days before the second visit. Measurements of urinary volume and albumin and creatinine concentrations were performed in each collection. At the second visit, blood was drawn after an overnight fast for determination of plasma glucose level, serum creatinine concentration, and cholesterol level. Calculations Systolic and diastolic blood pressure were calculated as the mean of the last two measurements at the two visits. Body mass index was calculated as the ratio between weight (kg) and height squared (m2). Body surface area was calculated according to the method of DuBois and DuBois (17). Glomerular filtration rate was defined as the mean of the two creatinine clearance values based on 24-hour urinary creatinine excretions divided by plasma creatinine concentration and corrected for body surface area (mL s 1 m 2). Albumin excretion is given as the mean of the two values for 24-hour urine excretion. Laboratory Methods Urinary albumin concentration was determined by using nephelometry with a threshold of 0.23 g/L and intra-assay and interassay coefficients of variation of 4.3% or less and 4.4% or less, respectively (Dade Behring Diagnostic, Marburg, Germany). Plasma glucose level, serum cholesterol level, and serum and urinary creatinine concentrations were determined by using Kodak Ektachem dry chemistry (Eastman Kodak, Rochester, New York). Urinary leukocytes and erythrocytes were measured by using strip testing (Nephur Test+ Leuco, Boehringer Mannheim, Mannheim, Germany). Data Handling and Definitions We excluded 433 persons because of erythrocyturia or leukocyturia (erythrocyte count>50 cells/L or leukocyte count>75 cells/L, or leukocyte count of 75 cells/L and erythrocyte count>5 cells/L). In addition, 239 persons were excluded because of diabetes, which was defined as a fasting plasma glucose level of at least 7.8 mmol/L (140.5 mg/dL), a nonfasting plasma glucose level of at least 11.1 mmol/L (200 mg/dL), or the use of oral antidiabetic drugs. Another 147 persons were excluded because of missing data on albuminuria, erythrocyturia, leukocyturia, smoking, or plasma glucose levels, and 297 persons were excluded because they had stopped smoking less than 1 year previously and therefore did not match the definition of current or former smokers. A total of 7476 persons were eligible for analysis. Most participants were white, 68 (1%) were black, and 155 (2%) were Asian. Participants were divided into three categories: nonsmokers, current smokers, and former smokers (those who had stopped smoking more than 1 year before). Current smokers were divided into two groups: those who smoked 20 or fewer cigarettes/d and those who smoked more than 20 cigarettes/d. The classic definition was used for microalbuminuria: that is, an albumin excretion of 30 to 300 mg/24 h. Because it has been suggested that the cardiovascular and renal risk associated with albuminuria may begin at an even lower cutoff point than is now considered pathologic (18, 19), we also defined a group with high normal albumin excretion (15 to 30 mg/24 h). An elevated or decreased GFR was defined as a creatinine clearance that exceeded or was less than two times the standard deviation of the mean value in a group of nondiabetic, nonsmoking persons who had an albumin excretion of 0 to 15 mg/24 h (15, 20). The mean creatinine clearance was obtained by using linear regression analysis and was adjusted for age and sex. Obesity was defined as a body mass index greater than 30 kg/m2. Hypertension was defined as systolic blood pressure of at least 160 mm Hg, diastolic blood pressure of at least 95 mm Hg, or use of antihypertensive medication. Hypercholesterolemia was defined as a total serum cholesterol level of at least 6.5 mmol/L (251.0 mg/dL), a total serum cholesterol level of at least 5.0 mmol/L (193.1 mg/dL) in persons with previous myocardial infarction, or use of lipid-lowering medications. Statistical Analysis All calculations were performed by using SPSS software, version 9.0 (SPSS, Inc., Chicago, Illinois). Continuous data are reported as the mean SD. Skewed distributions are reported as the median value with 25th and 75th percentiles. All P values are two-tailed, and a P value less than 0.05 was considered statistically significant. Differences among nonsmokers, current smokers, and former smokers were assessed by using chi-square analysis or analysis of variance. To investigate the relation between smoking and high normal albuminuria, microalbuminuria, an elevated GFR, or a decreased GFR, we used logistic regression analysis. Stepwise logistic regression analysis was used to test the independent relation among the three smoking groups and microalbuminuria, high normal albuminuria, elevated GFR, and decreased GFR. Odds ratios were estimated after adjustment for possible confounding factors, such as age, sex, body mass index, systolic and diastolic blood pressure, use of antihypertensive medication, serum cholesterol levels, use of lipid-lowering medications, plasma glucose levels, and consumption of more than three units of alcohol per day. The calculated odds ratios and 95% CIs are expressed as an approximation of relative risk. Role of the Funding Source The funding source had no role in the collection, interpretation, or analysis of the data or in the decision to submit the report for publication. Results Characteristics of the study sample are shown in Table 1. Current smokers ( 20 and>20 cigarettes/d) and former smokers had increased median albumin excretion and were more likely to have high normal albuminuria and microalbuminuria than nonsmokers. Serum creatinine concentration and creatinine clearance did not differ significantly among the two smoking groups and the nonsmoking group. However, former smokers had a significantly higher serum creatinine concentration and a significantly lower creatinine clearance than the other three groups. Of interest, significantly more current smokers than nonsmokers had elevated or decreased GFR. The percentage of former smokers who had an elevated GFR was lower than that of current smokers and greater than that of nonsmokers, whereas the percentage of former smokers who had a decreased GFR was significantly lower than that of current smokers and was similar to that of nonsmokers. Incidence of elevated or d

Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial

Objective To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose. Design Multicentre crossover randomised controlled trial. Setting Outpatient clinics in the Netherlands. Participants 52 patients with non-diabetic nephropathy. Interventions All patients were treated during four 6 week periods, in random order, with angiotensin receptor blockade (valsartan 320 mg/day) or placebo, each combined with, consecutively, a low sodium diet (target 50 mmol Na+/day) and a regular sodium diet (target 200 mmol Na+/day), with a background of ACE inhibition (lisinopril 40 mg/day) during the entire study. The drug interventions were double blind; the dietary interventions were open label. Main outcome measures The primary outcome measure was proteinuria; the secondary outcome measure was blood pressure. Results Mean urinary sodium excretion, a measure of dietary sodium intake, was 106 (SE 5) mmol Na+/day during a low sodium diet and 184 (6) mmol Na+/day during a regular sodium diet (P<0.001). Geometric mean residual proteinuria was 1.68 (95% confidence interval 1.31 to 2.14) g/day during ACE inhibition plus a regular sodium diet. Addition of angiotensin receptor blockade to ACE inhibition reduced proteinuria to 1.44 (1.07 to 1.93) g/day (P=0.003), addition of a low sodium diet reduced it to 0.85 (0.66 to 1.10) g/day (P<0.001), and addition of angiotensin receptor blockade plus a low sodium diet reduced it to 0.67 (0.50 to 0.91) g/day (P<0.001). The reduction of proteinuria by the addition of a low sodium diet to ACE inhibition (51%, 95% confidence interval 43% to 58%) was significantly larger (P<0.001) than the reduction of proteinuria by the addition of angiotensin receptor blockade to ACE inhibition (21%, (8% to 32%) and was comparable (P=0.009, not significant after Bonferroni correction) to the reduction of proteinuria by the addition of both angiotensin receptor blockade and a low sodium diet to ACE inhibition (62%, 53% to 70%). Mean systolic blood pressure was 134 (3) mm Hg during ACE inhibition plus a regular sodium diet. Mean systolic blood pressure was not significantly altered by the addition of angiotensin receptor blockade (131 (3) mm Hg; P=0.12) but was reduced by the addition of a low sodium diet (123 (2) mm Hg; P<0.001) and angiotensin receptor blockade plus a low sodium diet (121 (3) mm Hg; P<0.001) to ACE inhibition. The reduction of systolic blood pressure by the addition of a low sodium diet (7% (SE 1%)) was significantly larger (P=0.003) than the reduction of systolic blood pressure by the addition of angiotensin receptor blockade (2% (1)) and was similar (P=0.14) to the reduction of systolic blood pressure by the addition of both angiotensin receptor blockade and low sodium diet (9% (1)), to ACE inhibition. Conclusions Dietary sodium restriction to a level recommended in guidelines was more effective than dual blockade for reduction of proteinuria and blood pressure in non-diabetic nephropathy. The findings support the combined endeavours of patients and health professionals to reduce sodium intake. Trial registration Netherlands Trial Register NTR675.

Rationale, design, and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive, nonhypercholesterolemic subjects with microalbuminuria (the prevention of REnal and vascular ENdstage disease intervention trial [PREVEND IT])

This study describes the rationale, design, and baseline characteristics of a trial to determine whether treatment with fosinopril 20 mg/day and/or pravastatin 40 mg/ day will prevent cardiovascular and renal disease in nonhypertensive (RR <160/100 mm Hg and not using antihypertensive medication) and nonhypercholesterolemic (total cholesterol <8.0 or <5.0 mmol/L in case of previous myocardial infarction and not using lipid lowering medication) men and women with persistent microalbuminuria (urinary albumin excretion >10 mg/L once in an early morning spot urine and 15 to 300 mg/24-hour at least once in two 24-hour urine collections). The Prevention of REnal and Vascular ENdstage Disease Intervention Trial is a single-center, double-blind, randomized, placebo-controlled trial with a 2 x 2 factorial design. The 864 randomized subjects will be monitored for a minimum of 4 years and a maximum of 5 years. The primary efficacy parameter is defined as the combined incidence of all-cause mortality or hospital admission for documented (1) nonfatal myocardial infarction, (2) myocardial ischemia, (3) heart failure, (4) peripheral vascular disease, (5) cerebrovascular accident and/or (6) end-stage renal disease.

Low levels of urinary albumin excretion are associated with cardiovascular risk factors in the general population

Abstract Microalbuminuria is associated with both an increased prevalence of cardiovascular risk factors and greater renal and cardiovascular morbidity. We questioned whether in the general population such associations can be found at lower levels of urinary albumin excretion than that of classically defined microalbuminuria. To that purpose urinary albumin concentration was measured in 40619 subjects aged 28 to 75 years. The subjects filled in a questionnaire on cardiovascular risk factors and events and were divided in deciles according to their urinary albumin concentration. Smoking was associated with albuminuria in the fifth or higher decile of urinary albumin concentration, that is with an albumin concentration of 5.1 mg/l and higher. The lower cut-off point for a positive association with hypertension was 8.8 mg/l, and for diabetes 11.2 mg/l. Family history for cardiovascular disease and hyperlipidaemia were not associated with albuminuria. We conclude that urinary albumin concentrations far below the microalbuminuric range are associated with increased prevalence of established cardiovascular risk factors. Family history for cardiovascular disease and hyperlipidaemia seems to behave differently. These data emphasize the need for more studies on the impact of albuminuria on the prediction of cardiovascular and renal disease in the general population.

Role of the Endothelin-1 Gene Locus for Renal Impairment in the General Nondiabetic Population

A decreased GFR in the range of mild renal insufficiency and an increased urinary albumin excretion (UAE) rate in the range of microalbuminuria are important cardiovascular risk factors. Endothelin-1 (ET-1) has been suggested to be a major disease promoting factor in renal disease. The role of the ET-1 gene locus (EDN1) for renal function in the general nondiabetic population was evaluated. To explore the overall relevance of EDN1, two suitable single-nucleotide polymorphisms, EDN1 K198N and EDN1 T-1370G, were selected, and haplotype analysis was performed. Determined were genotypes in 7291 nondiabetic subjects from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Genetic analysis was related to UAE and GFR as continuous variables and to microalbuminuria and diminished filtration as dichotomous traits. In a logistic regression analysis, no significant higher risk for increased UAE, microalbuminuria, decreased GFR, or diminished filtration could be observed for either single-nucleotide polymorphism separately. Haplotype analysis revealed that individuals with the homozygous G-N haplotype (compound EDN1 -1370GG/198NN genotype) have a lower GFR than the remaining subjects (P < 0.05) and exhibit a significant higher risk for the presence of a diminished filtration (relative risk, 2.4; 95% confidence interval, 1.07 to 5.33; P < 0.05). Further analysis demonstrated no association between this haplotype and UAE or plasma ET-1 levels. Although a functional relevance of the EDN1 G-N haplotype itself remains unclear, the data demonstrate that genetic variation at the EDN1 locus has a significant effect on glomerular filtration but not on UAE in the general nondiabetic population.

Relation Between Albumin in the Urine and Electrocardiographic Markers of Myocardial Ischemia in Patients Without Diabetes Mellitus

We demonstrated that in a large nondiabetic population, a graded continuous relation was present between the level of urinary albumin excretion and ischemic electrocardiographic abnormalities, without an apparent threshold. These data suggest that the level of urinary albumin excretion can be used to establish cardiovascular risk in the population at large.

Effects of Vitamin D Receptor Activation and Dietary Sodium Restriction on Residual Albuminuria in CKD: The ViRTUE-CKD Trial

Reduction of residual albuminuria during single-agent renin-angiotensin-aldosterone blockade is accompanied by improved cardiorenal outcomes in CKD. We studied the individual and combined effects of the vitamin D receptor activator paricalcitol (PARI) and dietary sodium restriction on residual albuminuria in CKD. In a multicenter, randomized, placebo (PLAC)-controlled, crossover trial, 45 patients with nondiabetic CKD stages 1-3 and albuminuria >300 mg/24 h despite ramipril at 10 mg/d and BP<140/90 mmHg were treated for four 8-week periods with PARI (2 μg/d) or PLAC, each combined with a low-sodium (LS) or regular sodium (RS) diet. We analyzed the treatment effect by linear mixed effect models for repeated measurements. In the intention-to-treat analysis, albuminuria (geometric mean) was 1060 (95% confidence interval, 778 to 1443) mg/24 h during RS + PLAC and 990 (95% confidence interval, 755 to 1299) mg/24 h during RS + PARI (P=0.20 versus RS + PLAC). LS + PLAC reduced albuminuria to 717 (95% confidence interval, 512 to 1005) mg/24 h (P<0.001 versus RS + PLAC), and LS + PARI reduced albuminuria to 683 (95% confidence interval, 502 to 929) mg/24 h (P<0.001 versus RS + PLAC). The reduction by PARI beyond the effect of LS was nonsignificant (P=0.60). In the per-protocol analysis restricted to participants with ≥95% compliance with study medication, PARI did provide further albuminuria reduction (P=0.04 LS + PARI versus LS + PLAC). Dietary adherence was good as reflected by urinary excretion of 174±64 mmol Na+ per day in the combined RS groups and 108±61 mmol Na+ per day in the LS groups (P<0.001). In conclusion, moderate dietary sodium restriction substantially reduced residual albuminuria during fixed dose angiotensin-converting enzyme inhibition. The additional effect of PARI was small and nonsignificant.