Very low level of microalbuminuria is associated with increased risk of death in subjects with cardiovascular or cerebrovascular diseases

BACKGROUND: The original definition of microalbuminuria (20-200 microg min-1 or 15-150 microg min-1 overnight) is based on studies of patients with diabetes, in whom microalbuminuria was associated with increased risk of chronic renal failure. In a recent report an overnight urinary albumin excretion (UAE) above only 5 microg min-1 was strongly predictive of coronary heart disease and death in the general population. The aim of the present study was to investigate if this cut-off level also has prognostic value in a population with cardiovascular or cerebrovascular disease. METHODS AND RESULTS: In The Third Copenhagen City Heart Study in 1992-1994, 491 men and women aged 30-80 years with a history of coronary heart disease or stroke delivered a timed overnight urine sample. They were followed by registers with respect to vital status until 2004. During follow-up, 141 of the 491 participants died. The relative risk of death in subjects with UAE above 5 microg min-1 compared with subjects with lower UAE was 2.0 (1.4-2.8; P<0.001). It was unaffected [RR 1.9 (1.3-2.7); P<0.005] by adjustment for age, sex, blood pressure, diabetes, lipoproteins, renal creatinine clearance, smoking and body mass index. CONCLUSIONS: Subjects with cardiovascular or cerebrovascular disease have about 100% higher risk of death if microalbuminuria defined as UAE above 5 microg min-1 is present. Measurements of UAE should be included in the risk assessment in subjects with cardiovascular or cerebrovascular disease. This study supports the definition of microalbuminuria as UAE above 5 microg min-1.     

Low muscular mass and overestimation of microalbuminuria by urinary albumin/creatinine ratio

Microalbuminuria is a mild urinary albumin elevation and is associated with cardiovascular disease. Urinary albumin/creatinine ratio is recommended for microalbuminuria assessment, because it reflects urinary albumin excretion. Muscular mass could affect albumin/creatinine ratio, because urinary creatinine reflects muscular mass. The study investigated high albumin/creatinine ratio attributed to low urinary creatinine without microalbuminuria. The Gubbio Population Study for ages 45 to 64 collected data on weight, skinfold, urinary albumin, urinary creatinine, and coronary heart disease. Weight and skinfold thickness were used to calculate fat and nonfat mass and urinary creatinine as a marker of muscular mass. Microalbuminuria was defined as urinary albumin of 20 to 199 microg/min and high albumin/creatinine ratio as a ratio of 17 to 250 microg/mg in men and of 25 to 355 microg/mg in women. Persons with macroalbuminuria (urinary albumin > or =200 microg/min) were excluded to focus analyses on microalbuminuria. Coronary heart disease was defined by ECG and questionnaire. The target cohort consisted of 1623 men and women, ages 45 to 64. Prevalence was 8.5% for high albumin/creatinine ratio (n=138), 4.3% for microalbuminuria (n=69), 5.2% for high albumin/creatinine ratio without microalbuminuria (n=85), and 1.0% for nonhigh albumin/creatinine ratio with microalbuminuria (n=16). High albumin/creatinine ratio without microalbuminuria was inversely associated with nonfat mass and urinary creatinine (P<0.04). Compared with persons with a nonhigh albumin/creatinine ratio, coronary heart disease was more prevalent in persons with a high albumin/creatinine ratio and microalbuminuria (18.9% and 7.1%; P=0.002), not in persons with a high albumin/creatinine ratio without microalbuminuria (8.2% and 7.1%; P=0.706). A high albumin/creatinine ratio in persons with low muscle mass indicates low urinary creatinine more often than microalbuminuria and cardiovascular disease.     

Plasma lipids and urinary albumin excretion rate in Type 1 diabetes mellitus: the EURODIAB IDDM Complications Study.

AIMS: To examine the relationship between increased urinary albumin excretion rate and fasting plasma lipids among male and female respondents to the EURODIAB IDDM Complications Study, and attempt to explain inconsistencies in previous reports. METHODS: A cross-sectional study of 3250 randomly selected Type 1 diabetic patients from 31 diabetes clinics in 16 European countries was carried out between 1989 and 1990. Plasma lipids and urinary albumin were measured centrally. The present analysis was confined to the subgroup of 2205 patients attending after a 10-12 h overnight fast. Mean age was 33 years (SD 10) and mean duration of Type 1 diabetes mellitus was 15 years (SD 9). RESULTS: The prevalence of microalbuminuria (24-h urinary albumin excretion rate 20-200 microg/min) was 21.7% (95% confidence interval 19.9-23.5) and macroalbuminuria (24-h urinary albumin excretion rate > 200 microg/min) 7.8% (6.6-9.0). In comparison to patients with normal urinary albumin excretion rate (< 20 microg/min), and after controlling for age, sex, glycaemic control, duration of diabetes and current smoking, macroalbuminuria was associated with significantly (P<0.01) increased fasting plasma triglycerides, cholesterol, LDL-cholesterol, cholesterol:HDL-cholesterol ratio and, in women, reduced HDL-cholesterol. In men and women with microalbuminuria, the only significant association was with increased plasma triglycerides. CONCLUSIONS: These data confirm that there is an association between fasting plasma lipids and increasing urinary albumin excretion rate in European Type 1 diabetic patients. In microalbuminuric patients, however, the association was weaker than previously reported and partly explained by confounding factors.     

Arterial hypertension, microalbuminuria, and risk of ischemic heart disease

Albumin excretion in urine is positively correlated with the presence of ischemic heart disease and atherosclerotic risk factors. We studied prospectively whether a slight increase of urinary albumin excretion, ie, microalbuminuria, adds to the increased risk of ischemic heart disease among hypertensive subjects. In 1983 and 1984, blood pressure, urinary albumin/creatinine concentration ratio, plasma total and HDL cholesterol levels, body mass index, and smoking status were obtained in a population-based sample of 2085 subjects, aged 30 to 60 years, who were free from ischemic heart disease, diabetes mellitus, and renal or urinary tract disease. Untreated arterial hypertension or borderline hypertension was present in 204 subjects, who were followed until 1993 by the National Hospital and Death Certificate Registers with respect to development of ischemic heart disease. During 1978 person-years, 18 (9%) of the hypertensive subjects developed ischemic heart disease. Microalbuminuria, defined as a urinary albumin/creatinine ratio above the upper decile (1.07 mg/mmol), was the strongest predictor of ischemic heart disease, with an unadjusted relative risk of 4.2 (95% CI 1.5 to 11.9, P=0.006) and a relative risk of 3.5 (95% CI 1.0 to 12.1, P=0.05) when adjusted for all other atherosclerotic risk factors, including age and gender. In conclusion, microalbuminuria confers a 4-fold increased risk of ischemic heart disease among hypertensive or borderline hypertensive subjects. Urinary albumin excretion should be measured regularly in a hypertension clinic, and a rigorous control of blood pressure and of other atherosclerotic risk factors is recommended in hypertensive patients with microalbuminuria.     

The importance of microalbuminuria as a cardiovascular risk indicator: A review

The present review describes the knowledge of microalbuminuria as a cardiovascular risk indicator. Microalbuminuria is usually defined as a urinary albumin excretion rate of 30 to 300 mg in a 24 h urine collection, or as a urinary albumin excretion rate of 20 to 200 mg/min in a timed overnight urine collection, although microalbuminuria was demonstrated to be a predictor for cardiovascular events at levels below these conventional cut-off values. More than one consecutive urine collection is preferred given the high day to day variability of urinary albumin excretion. Microalbuminuria is frequently present and a known cardiovascular risk indicator in diabetic populations. Also, in hypertensive and general populations, microalbuminuria is common and has been associated with an adverse atherogenic risk profile and a higher prevalence of cardiovascular disease. Moreover, evidence strongly suggests that microalbuminuria is also an independent predictor of cardiovascular disease in these populations. However, more prospective studies are needed to elucidate fully the value of microalbuminuria as a cardiovascular risk indicator in hypertensive and general populations. Generalized endothelial dysfunction has been hypothesized to be the underlying factor for microalbuminuria on one hand and the underlying factor for increased cardiovascular risk on the other. In this respect, the loss of the glycosaminoglycan heparin sulphate might be an important pathophysiological mechanism. This hypothesis needs further clarification, especially in nondiabetic populations.     

Albumin excretion and vascular deaths in NIDDM

Summary Non-insulin-dependent diabetes mellitus (NIDDM) is associated with premature mortality, generally thought to be exaggerated in patients with microalbuminuria. This prospective 8-year follow-up study aimed to determine outcome, mortality and cause of death in NIDDM patients with abnormal urinary albumin excretion compared to those with normal albumin excretion. We recruited 153 NIDDM patients with abnormal urinary albumin excretion and 153 control subjects with albumin excretion within the normal non-diabetic range, matched for age, sex and duration of diabetes, from three University hospital diabetic clinics in Newcastle upon Tyne. The outcome measures were status at follow-up, mortality and cause of death. Subjects with abnormal albumin excretion had a significantly higher 8-year mortality than matched control subjects (Odds Ratio 1.47, p=0.02; 108 vs 66 per 1000 person years follow-up, p<0.001). This difference was seen at all levels of abnormal albumin excretion, from just outside the normal range (10.6–29.9 g/min: 104 vs 61 per 1000 person years follow-up, p<0.001) to more conventional definitions of microalbuminuria (30 g/min: 111 vs 71 per 1000 person years follow-up, p<0.01). Those with abnormal albumin excretion had an excess of vascular deaths compared to matched control subjects (Odds Ratio 1.70, p = 0.009), again at different levels of albumin excretion (10.6–29.9 g/min p<0.01, 30–150 g/min p<0.05). On multivariate analysis, age, initial ischaemic heart disease and initial albumin excretion rates were independent predictors of death from all causes. Even a minor elevation of albumin excretion above the normal non-diabetic range is associated with excess mortality from vascular causes in NIDDM.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - AER albumin excretion rate - SBP systolic blood pressure - DBP diastolic blood pressure - CI confidence interval - MAP mean arterial pressure     

Urinary albumin excretion. An independent predictor of ischemic heart disease.

Cross-sectional studies suggest that an increased urinary albumin excretion rate is associated with cardiovascular disease, dyslipidemia, and hypertension. The purpose of this study was to analyze prospectively whether the urinary albumin-to -creatinine (A/C) ratio can independently predict ischemic heart disease (IHD) in a population-based cohort. In 1983, urinary albumin and creatinine levels were measured, along with the conventional atherosclerotic risk factors, in 2085 consecutive participants without IHD, renal disease, urinary tract infection, or diabetes mellitus. The participants were followed up until death, emigration, or December 31, 1993. IHD was defined as a hospital discharge diagnosis or cause of death including the diagnoses ICD-8 and 410 to 414. Seventy-nine individuals developed IHD during the 21 130 person-years of follow-up. They were characterized by a preponderance of males and higher age, body mass index, blood pressure, lipoproteins, and proportion of current smokers. Microalbuminuria was defined as an A/C ratio) >90 percentile (>0.65 mg/mmol). When adjusted for other risk factors, the relative risk of IHD associated with microalbuminuria was 2.3 (95% CI, 1.3 to 3.9, P=0.002), and the 10-year disease-free survival decreased from 97% to 91% (P<0.0001) when microalbuminuria was present. An interaction between microalbuminuria and smoking was observed, and the presence of microalbuminuria more than doubled the predictive effect of the conventional atherosclerotic risk factors for development of IHD. It is concluded that microalbuminuria is not only an independent predictor of IHD but also substantially increases the risk associated with other established risk factors.     

Silent myocardial ischemia and microalbuminuria in asymptomatic subjects with non-insulin-dependent diabetes mellitus

Microalbuminuria is an increase in urinary albumin not detected by conventional dipstick testing and is present in 20% of patients with non-insulin-dependent diabetes mellitus (NIDDM). Mortality in NIDDM patients with microalbuminuria is 60% at 8 years and is mainly due to cardiovascular disease. Because many deaths occur without warning symptoms, we have compared the prevalence and severity of silent myocardial ischemia in asymptomatic NIDDM patients with and without microalbuminuria. We have performed a cross-sectional, case-control study of asymptomatic NIDDM patients attending hospital diabetes clinics. Forty-three patients with microalbuminuria were matched for age, gender, diabetes duration, and smoking status with 43 normoalbuminuric patients. A symptom-limited exercise stress test was performed and reported blind to patient status. The degree of electrocardiographic ST-segment depression, exercise time, work performed, and maximum heart rate with exercise were recorded. Patients with microalbuminuria had a higher prevalence of ischemic response (>1 mm ST depression) (65% vs 40%, p = 0.016), reduced total exercise time (5 vs 7 minutes, p <0.001), reduced work (6 vs 8 METs, p <0.001), and reduced age-predicted maximum heart rate (94% vs 101%, p = 0.004). In multiple logistic regression, albumin excretion rate was shown to be the strongest independent predictor of ischemic response (p = 0.03). Silent myocardial ischemia is common in asymptomatic NIDDM patients but is more common in those with microalbuminuria. In these subjects, the higher prevalence of ischemic response at low workloads suggests a higher probability of future coronary events, and possibly a higher probability of potentially treatable coronary artery disease.     

Prevalence of micro- and macroalbuminuria,arterial hypertension,retinopathy and large vessel disease in European Type 2 (non-insulin-dependent) diabetic patients

Summary The prevalence of micro- and macroalbuminuria was determined in Type 2 (non-insulin-dependent) diabetic patients, less than 76 years of age, attending a diabetic clinic during 1987. All eligible patients (n=557) were asked to collect a 24-h urine sample for quantitative albumin analysis. Urine collections were obtained in 296 males and 253 females (96%). Normoalbuminuria were defined as urinary albumin excretion30 mg/24 h (n=323), microalbuminuria as 31–299 mg/24 h (n=151), and macroalbuminuria as 300 mg/ 24 h (n=75). The prevalence of macroalbuminuria was significantly higher in males (20%) than in females (6%), while the prevalence of microalbuminuria was almost identical in males (26%) and females (29%). The prevalence of arterial hypertension increased with increased albuminuria, being 48%, 68%, and 85% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. Prevalence of proliferative retinopathy rose with increasing albuminuria, being 2%, 5% and 12% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. Prevalence of coronary heart disease, based on Minnesota coded electrocardiograms, was more frequent in patients with macroalbuminuria (46%) compared to patients with microalbuminuria (26%) and patients with normoalbuminuria (22%). Foot ulcers were more frequent in micro- and macroalbuminuric patients, being 13% and 25%, respectively, compared to 5% in patients with normoalbuminuria. This cross-sectional study has revealed a high prevalence of microalbuminuria (27%) and macroalbuminuria (14%) in Type 2 diabetic patients. Patients with raised urinary albumin excretion are characterized by obesity, elevated haemoglobin A_lc, increased frequency of arterial hypertension, proliferative retinopathy, coronary heart disease and foot ulcers. Thus, these findings suggest that urinary excretion of albumin should be monitored routinely in patients with Type 2 diabetes.     

Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients

Urinary endothelin (ET)-1 excretion is present in non-insulin dependent diabetes (NIDDM) patients with microalbuminuria, and an increase in circulating ET-1 precedes the microalbuminuric phase of renal injury related to diabetes. The aim of the present study was to determine whether various drugs alter urinary ET-1 levels and urinary albumin excretion (UAE) in NIDDM patients with microalbuminuria. Forty-five NIDDM patients with microalbuminuria were randomly assigned to three groups: those treated with pioglitazone at 30 mg/day (n=15), those treated with glibenclamide at 5 mg/day (n=15), and those treated with voglibose at 0.6 mg/day (n=15). Patients received these drugs for 3 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in these patients before and after treatment. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little among the three groups. UAE in the 45 NIDDM patients (156.2+/-42.8 microg/min) was greater than that in 30 healthy controls (8.2+/-2.6 microg/min) (P<.001). Urinary ET-1 levels in the NIDDM patients (8.7+/-1.3 ng/g urinary creatinine (UC)) were significantly higher than that in the controls (2.4+/-0.2 ng/g UC) (P<.01). Plasma ET-1 levels, however, in the NIDDM patients (1.3+/-0.4 pg/ml) did not differ significantly from the levels in healthy controls (1.0+/-0.6 pg/ml). Pioglitazone but no glibenclamide or voglibose reduced UAE from 142.8+/-42.2 to 48. 4+/-18.2 microg/min (P<.01) and urinary ET-1 levels from 8.6+/-1.3 to 3.4+/-0.5 ng/g UC (P<.01). These data suggest pioglitazone to be effective in reducing UAE and urinary ET-1 concentrations in NIDDM patients with microalbuminuria.     

Prevalence of microalbuminuria in children with Type 1 (insulin-dependent) diabetes mellitus

Summary The prevalence of microalbuminuria was determined in children aged 7 to 18 years with Type 1 (insulin-dependent) diabetes of more than 2 years' duration. All patients (n =102) attending 2 diabetes clinics were asked to collect 2 overnight timed urine samples for albumin analysis by radioimmunoassay. Complete urine collection was obtained in 97 patients (95%). Overnight urinary albumin excretion rates were also measured in 36 healthy children matched for age and sex. Nineteen of the 97 patients (20%) had microalbuminuria, i. e. overnight urinary albumin excretion rates above the upper normal level (14 g/min) in both urine collections. Microalbuminuria was only demonstrated in patients aged 15 years, prevalence 37% (19/52 patients). Arterial blood pressure was elevated, mean 122/84±11/9mmHg, in the microalbuminuric group (19 patients) compared to the age-matched normoalbuminuric diabetic group (33 patients), mean 117/74±10/10 mm Hg,p < 0.001. The prevalence of simplex retinopathy was identical in these two groups, i. e. 25%. Glycosylated haemoglobin was slightly higher in the microalbuminuric patients,p < 0.10. Our cross-sectional study reveals a high prevalence (37%) of persistent microalbuminuria, a stage highly predictive of later development of diabetic nephropathy, in Type 1 diabetic children aged 15 years.     

Microalbuminuria as a marker of cardiovascular risk in patients with type 2 diabetes

Diabetes is a major risk factor for coronary artery disease and most patients with diabetes die of cardiovascular complications. Reduction of cardiovascular risk is therefore a high priority in the management of patients with diabetes. Microalbuminuria is an important predictor of cardiovascular events and forms one of the components of the insulin resistance/metabolic syndrome, which confers a particularly high risk of cardiovascular death. The currently available glucose-lowering agents vary considerably in their ability to reduce microalbuminuria. The sulfonylureas and metformin appear to have little effect on microalbuminuria expressed as urinary albumin/creatinine ratio, while the thiazolidinediones have unique effects on this risk factor, in parallel with their effects on insulin resistance. In two 1-year European multicenter, randomized, double-blind monotherapy trials (n=2444), pioglitazone produced similar reductions in urinary albumin/creatinine ratio to gliclazide and greater reductions than metformin (P<0.001). Similarly, two further 1-year European multicenter, randomized, double-blind trials assessed the effects of add-on therapy (n=1269) on urinary albumin/creatinine ratio. In the first study, urinary albumin/creatinine ratio was reduced by pioglitazone add-on to sulfonylurea (-15%), but was largely unaffected by metformin add-on to sulfonylurea (2%; P<0.05). In the second, urinary albumin/creatinine ratio was also reduced by pioglitazone add-on to metformin (-10%), but increased by gliclazide add-on to metformin (6%, P<0.05). The results of these studies indicated that compared with metformin or gliclazide, pioglitazone may provide therapeutic benefits, over and above those due to improved glycemic control. These include significant reductions in urinary albumin/creatinine ratio, a known cardiovascular risk marker.     

Long-term impact of systolic blood pressure and glycemia on the development of microalbuminuria in essential hypertension

The objective was to assess the temporal impact of factors related to the development of microalbuminuria during the follow-up of young adult normoalbuminurics with high-normal blood pressure or at stage 1 of essential hypertension. Prospective follow-up was conducted on 245 normoalbuminuric hypertensive subjects (mean age 40.9 years; 134 men; blood pressure 139.7/88.6 mm Hg; body mass index 28.5 kg/m2) never treated previously with antihypertensive drugs, with yearly urinary albumin excretion measurements, until the development of microalbuminuria. After enrollment, patients were placed on usual care including nonpharmacological treatment or with an antihypertensive drug regime to achieve a blood pressure of <135/85 mm Hg. Thirty subjects (12.2%) developed microalbuminuria after a mean follow-up of 29.9 months (range 12 to 144 months), 2.5 per 100 patients per year. Baseline urinary albumin excretion (hazard ratio, 1.07; P=0.006) and systolic blood pressure during the follow-up (hazard ratio, 1.03; P=0.008) were independent factors related to the follow-up urinary albumin excretion in a Cox proportional hazard model. A significant increase in the risk of developing microalbuminuria for urinary albumin excretion at baseline >15 mg per 24-hour systolic blood pressure >139 mm Hg and a positive trend in fasting glucose were observed in the univariate analyses. However, in the multivariate analysis, only the baseline urinary albumin excretion and the trend of fasting glucose were independently related to the risk of developing microalbuminuria. In mild hypertensives, the development of microalbuminuria was linked to insufficient blood pressure control and to a progressive increment of glucose values.     

Microalbuminuria in essential hypertension

Microalbuminuria (urinary albumin excretion equal to 30-300 mg/24 h) is a reliable indicator of premature cardiovascular mortality in diabetic patients and in the general population. In insulin-dependent and non-insulin-dependent diabetes mellitus microalbuminuria is a marker of initial diabetic nephropathy and predicts the evolution toward renal insufficiency. In essential hypertension the clinical and prognostic role of microalbuminuria is more controversial. While it is a recognised marker of cardiovascular complications and a reliable predictor of ischaemic heart disease, its prognostic value on the risk of progressive renal alterations is still uncertain because no prospective studies, taking microalbuminuria as a selection criterion and renal insufficiency as an end point, are available. Blood pressure control with antihypertensive drugs is accompanied by a reduction in urinary albumin excretion. The favourable effects of antihypertensive agents on microalbuminuria appear to be proportional to blood pressure reduction, but angiotensin-converting enzyme inhibitors and angiotensin-II-receptor antagonists show an additional beneficial effect on urinary albumin excretion. Whether the reduction of microalbuminuria obtained through pharmacological intervention has favourable prognostic implications remain to be demonstrated. However, screening for microalbuminuria is a relatively easy and inexpensive procedure and reveals a potentially treatable abnormality. Thus, considering that microalbuminuria identifies hypertensive subjects at higher risk than standard, urinary albumin excretion should be routinely measured in hypertensive patients and, in the presence of microalbuminuria, antihypertensive treatment should be intensified in order to obtain an optimal blood pressure control.     

The association between metabolic syndrome, microalbuminuria and impaired renal function in the general population: impact on cardiovascular disease and mortality

OBJECTIVE: Microalbuminuria and metabolic syndrome are both associated with cardiovascular disease (CVD). The aim of this study was to determine the potential association between numbers of components in the metabolic syndrome, different levels of microalbuminuria and renal function. We also aimed to determine the risk of death and CVD at different levels of microalbuminuria and renal function and numbers of components in the metabolic syndrome. DESIGN: Population-based observational follow-up study. SETTING: Epidemiological research unit (Copenhagen City Heart Study). SUBJECTS: A total of 2,696 men and women, 30-70 years of age. BASELINE MEASURES: Urinary albumin excretion (UAE), creatinine clearance and metabolic risk factors were measured in 1992-1994. MAIN OUTCOME MEASUREMENTS: The participants were followed prospectively by registers until 1999-2000 with respect to CVD, and until 2004 with respect to death. RESULTS: We found a strong association between microalbuminuria and the metabolic syndrome: 2% with none and 18% with five metabolic risk factors had microalbuminuria (P < 0.001). No association between impaired renal function defined as creatinine clearance <60 mL min(-1) and the metabolic syndrome was found. Microalbuminuria was associated with increased risk of death and CVD to a similar extend as the metabolic syndrome, irrespective of concomitant presence of metabolic syndrome (RR approximately 2; P < 0.001). Impaired renal function was not associated with increased risk of death and CVD in subjects with the metabolic syndrome. CONCLUSIONS: Microalbuminuria (UAE >5 microg min(-1)) confers increased risk of death and CVD to a similar extent as the metabolic syndrome.     

Coronary heart disease and urinary albumin excretion rate in Type 2 (non-insulin-dependent) diabetic patients

Summary Associations between overnight urinary albumin excretion rate and prevalent coronary heart disease and its major risk factors were examined in a cross-sectional study of 141 Type 2 (non-insulin-dependent) diabetic patients. Mean albumin excretion rate was higher in men (geometric mean 13.5 g/min; 95% confidence interval 10.3–17.6) than women (7.5 g/min; 5.7–9.8, p<0.01). In diabetic men and women mean albumin excretion rate was higher in those with electrocardiographic and/or symptomatic evidence of coronary heart disease than in those without (men, 23.1 g/ min; 95% confidence interval 13.7–39.0 versus 10.6 g/min; 7.9–14.2, p<0.01, women, 13.7 g/min; 8.0–23.5 versus 5.4 g/min; 4.2–6.8, p<0.01). Multiple logistic regression analysis was used to allow for confounding between variables. In the diabetic group as a whole, raised albumin excretion rate (p<0.001), gender (p<0.05) and systolic blood pressure (p=0.06) entered the best model for coronary heart disease prediction. In women, albumin excretion rate alone (p<0.01) and in men albumin excretion rate (p<0.01) and age (p=0.05) entered the best models. We conclude that albumin excretion rate is significantly associated with coronary heart disease morbidity after taking into account the confounding effects of raised blood pressure and other cardiovascular risk factors.     

Salivary secretion of albumin in type 1 (insulin-dependent) diabetes

The concentration of albumin in saliva is low in healthy humans. To determine whether alterations in capillary permeability in diabetes affects the salivary glands, the concentration of albumin in parotid saliva was measured in 26 Type 1 (insulin-dependent) diabetic patients, and compared to 32 non-diabetic control subjects. The diabetic patients were subdivided into 3 groups on the basis of the urinary excretion of albumin in timed overnight collections of urine: (1) normal albumin excretion (less than 30 micrograms/min) n = 13; (2) microalbuminuria (30-300 micrograms/min) n = 7, and (3) macroalbuminuria (greater than 300 micrograms/min) n = 6. Saliva was collected for one minute following stimulation with 1 ml 10% citric acid, and the concentration of albumin was measured by a sensitive ELISA method. No significant difference in salivary albumin concentration was found between the control group and any of the diabetic groups. Thus, although urinary albumin excretion was increased, suggesting altered capillary permeability, simultaneous leakage of albumin into saliva was not observed. Measurement of salivary albumin concentration does not, therefore, provide a marker of occult microvascular disease in diabetes.     

Mediators of inflammation correlate with microalbuminuria in patients with non-Hodgkin's lymphoma

Recent studies have demonstrated a high frequency of minor glomerular leakage of albumin in cancer patients. Pathogenic mechanisms of increased urinary albumin excretion (UAE) in malignancies remain to be clarified. We have attempted to identify whether microalbuminuria in lymphoma patients is associated with inflammatory mediators and the acute-phase response. UAE, urinary excretion of beta2-microglobulin and IgG, and serum levels of interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha) and C-reactive protein (CRP) were determined in 113 patients with newly diagnosed non-Hodgkin's lymphoma. We demonstrated a high frequency of microalbuminuria (>or= 20 microg/min) and UAE correlated strongly with serum levels of CRP, IL-6 and TNF-alpha. UAE, CRP, IL-6 and TNF-alpha were significantly higher in patients with advanced disease stage, B symptoms and in high-risk patients according to the International Prognostic Index. Urinary excretion of beta2-microglobulin was unaffected in patients with increased UAE. However, UAE was significantly correlated with urinary excretion of IgG, suggesting an altered size selectivity of the glomerular filtration barrier. This is the first study that shows a direct correlation between microalbuminuria and proinflammatory cytokines in malignancies, indicating a pathogenic relationship between inflammation and glomerular leakage of albumin. Future efforts should focus on the pathophysiological cause-effect mechanisms and larger studies are needed to confirm the clinical significance of UAE.     

Microalbuminuria in diabetes: a population study of the prevalence and an assessment of three screening tests

A single observer reviewed 842 of the 917 known diabetic patients registered with 40 GPs in the Poole area. A midstream urine specimen was tested for proteinuria using Albustix (Ames) and cultured to detect bacterial infection. After the first 3 months of the survey, the aliquot of this specimen was frozen for later determination of the random albumin/creatinine ratio (R-Alb/Creat). Patients were requested to submit a timed overnight urine collection for estimation of urinary albumin excretion rate (AER). Of the 842 patients reviewed, 493 (59%) submitted timed overnight urine collections; 43 were excluded because of urinary infection and/or proteinuria. One hundred and thirty-three (30%) of 450 diabetic patients were found to have microalbuminuria, although only 31 (7%) had an AER greater than 30 micrograms/min. Six hundred and seven urine samples were collected for R-Alb/Creat but 68 were excluded because of infection and/or proteinuria; in 10 further samples urinary creatinine was not measured. Two hundred and four (38%) of 532 diabetic patients were found to have an elevated R-Alb/Creat. There was a significant correlation between AER and R-Alb/Creat (r = 0.32, p less than 0.001) but a considerable number of patients showed either a normal AER and high R-Alb/Creat or the reverse. The value of R-Alb/Creat or an overnight urinary albumin concentration, or an overnight urinary albumin/creatinine ratio (ON-Alb/Creat) as screening tests to predict AER greater than 30 micrograms/min was assessed. An ON-Alb/Creat greater than 2.0 mg/mmol was the optimal screening test (sensitivity 96% and specificity 99.7%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased urinary albumin excretion aggregates with atherosclerotic risk factors in type 2 (non-insulin-dependent) diabetes mellitus

Supranormal urinary albumin excretion (microalbuminuria) is an early indicator of microangiopathy, i.e. diabetic nephropathy, and is associated with higher cardiovascular mortality in both type 1 and type 2 diabetes. The relationship between the presence of microalbuminuria and some atherosclerotic risk factors has been evaluated in 318 (170 male, 148 female) type 2 (non-insulin-dependent) diabetic subjects [age 63±10 years; known duration of diabetes 10.9±8.8 years; age at diabetes diagnosis 52±11 years; systolic blood pressure (BP) 150±23 mmHg; diastolic BP 86±11 mmHg (mean±SD)]. In early morning urine samples, albumin (immunonephelometry) and creatinine were assayed. On the basis of the albumin/creatinine ratio (A/C, mg/mmol), patients were categorized as normoalbuminuric (Na; A/C<2.0;n=159, 50%), microalbuminuric (ma; A/C 2–20;n=135, 42.5%) or macroalbuminuric (Ma; A/C >20;n=24, 7.5%). The three groups were closely matched for age, age at diagnosis, duration of diabetes, and fasting plasma and urinary glucose levels. Systolic and diastolic BP rose progressively with increasing urinary A/C ratio levels. While high-density lipoprotein (HDL) cholesterol was unaffected by albuminuria, total cholesterol (218±45 vs 198±43 mg/dl,P<0.001) and low-density lipoprotein (LDL) cholesterol (145±42 vs 131±38 mg/dl,P<0.05) levels were higher in microalbuminuric than in normoalbuminuric patients. Further, a significant correlation (r=0.16,P<0.01) existed between albuminuria and triglyceride concentrations. Prevalence of arterial hypertension, defined as BP160/95 mmHg and/or drug treatment (Na, 51%; ma, 65%; Ma, 78%;P<0.001) and obesity, defined as body mass index (BMI)>30 (Na, 15%; ma, 26%; Ma, 32%;P<0.05) rose with increasing A/C ratios. Both coronary heart disease (30% vs 15%) and intermittent claudication (18% vs 7%) were more frequent in microalbuminuric than in normoalbuminuric subjects. Finally, multiple stepwise regression analysis showed that urinary albumin excretion is significantly and independently associated with coronary heart disease and intermittent claudication, also taking into account hypertension and other established cardiovascular risk factors. In type 2 diabetes microalbuminuria tends to aggregate with risk factors for atherosclerotic vascular disease, e.g. increased prevalence of hypertension and obesity, elevated total and LDL cholesterol, and raised triglycerides levels. These abnormalities may only explain the excess of cardiovascular morbidity and mortality in part. Microalbuminuria per se may be an important and independent cardiovascular risk factor.