Microalbuminuria in patients with Type 2 diabetes mellitus from general practice: course and predictive value.

AIMS: To assess the course of microalbuminuria in patients with Type 2 diabetes mellitus in general practice and the predictive value of urinary albumin concentration on all-cause mortality, cardiovascular mortality and cardiovascular morbidity. METHODS: Cohort study in Type 2 diabetic patients tested for microalbuminuria in 1992, and re-tested in 1998. During follow-up all cardiovascular morbidity and mortality were recorded. RESULTS: Of the original sample of 317 patients, 163 patients were re-tested. The mean change in urinary albumin concentration was +16.2 mg/l (range -122.0 to +602 mg/l). Seventy-five per cent of the patients without microalbuminuria in 1992 still had no microalbuminuria in 1998 and 40% of those with microalbuminuria in 1992 reverted to normoalbuminuria in 1998. Cox survival analysis, stratified for age, showed that microalbuminuria at baseline resulted in a risk ratio of all-cause mortality of 1.4 (95% confidence interval 0.8-2.7), of cardiovascular mortality of 1.2 (0.5-2.8) and of new cardiovascular events (including cardiovascular mortality) of 1.4 (0.8-2.3). CONCLUSIONS: In the majority of patients the change of urinary albumin excretion was small, but the range was wide. A weak non-significant relationship between microalbuminuria and all-cause mortality and cardiovascular morbidity was observed.     

The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up

BACKGROUND: Few data are available on the long-term impact of type 2 diabetes mellitus on total mortality and fatal coronary heart disease (CHD) in women. METHODS: We examined prospectively the impact of type 2 diabetes and history of prior CHD on mortality from all causes and CHD among 121 046 women aged 30 to 55 years with type 2 diabetes in the Nurses' Health Study who were followed up for 20 years from 1976 to 1996. RESULTS: During 20 years of follow-up, we documented 8464 deaths from all causes, including 1239 fatal CHD events. Compared with women with no diabetes or CHD at baseline, age-adjusted relative risks (RRs) of overall mortality were 3.39 (95% confidence interval [CI], 3.08-3.73) for women with a history of diabetes and no CHD at baseline, 3.00 (95% CI, 2.50-3.60) for women with a history of CHD and no diabetes at baseline, and 6.84 (95% CI, 4.71-9.95) for women with both conditions at baseline. The corresponding age-adjusted RRs of fatal CHD across these 4 groups were 1.0, 8.70, 10.6, and 25.8, respectively. Multivariate adjustment for body mass index and other coronary risk factors only modestly attenuated the RRs. Compared with nondiabetic persons, the multivariate RRs of fatal CHD across categories of diabetes duration (< or =5, 6-10, 11-15, 16-25, >25 years) were 2.75, 3.63, 5.51, 6.38, and 11.9 (P< .001 for trend), respectively. The combination of prior CHD and a long duration of clinical diabetes (ie, >15 years) was associated with a 30-fold (95% CI, 20.7-43.5) increased risk of fatal CHD. CONCLUSIONS: Our data indicate that among women, history of diabetes is associated with dramatically increased risks of death from all causes and fatal CHD. The combination of diabetes and prior CHD identifies particularly high-risk women.     

Mortality and morbidity in relation to changes in albuminuria,glucose status and systolic blood pressure: an analysis of the ONTARGET and TRANSCEND studies

Aims/hypothesis

Urinary albumin excretion is a strong predictor of cardiovascular disease. It is uncertain whether improvement from microalbuminuria or deterioration from normoalbuminuria over time in patients with differing changes in glucose and BP change their cardiovascular risk.

Methods

Data on mortality, cardiovascular and renal outcomes were analysed in 22,984 patients from two large parallel randomised clinical trials followed for 56 months. A central laboratory analysed first morning spot urine samples at baseline and after 24 months, and events were recorded over the subsequent 32 months. Patients were stratified by changes in albuminuria, glucose status and mean systolic BP over 2 years.

Results

There was a strong association between albuminuria status and all-cause and cardiovascular mortality and combined cardiovascular and renal endpoints (all p?p?=?0.0004).

Conclusions/interpretation

Patients who showed improvement to normoalbuminuria over 2 years were at lower risk of all-cause and cardiovascular mortality and of cardiovascular and renal events than those who deteriorated to microalbuminuria over time. Albuminuria over time was significantly better than glucose status and BP control in predicting mortality and both cardiovascular and renal outcomes in patients at a high cardiovascular risk.     

Microalbuminuria cannot predict cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus

In order to examine whether the existence of microalbuminuria can predict the development of overt proteinuria and cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM), we investigated 47 patients for a 10-year follow-up period. Patients were divided into two groups by the initial values of urinary albumin excretion rates. The percentage of patients who developed overt proteinuria during the follow-up period was significantly higher in patients who were initially classified as microalbuminuric group (63.6%) than in normoalbuminuric group (17.4%). During the follow-up period, one of the patients with normoalbuminuria had died of congestive heart failure, while four of those with microalbuminuria had died; one of stroke and three from noncardiovascular diseases. These results indicate that the existence of microalbuminuria had the predictive power for the development of overt proteinuria, but not for cardiovascular death in Japanese subjects with NIDDM.     

Insulin resistance precedes the appearance of albuminuria in non-diabetic subjects: 6 years follow up study

Microalbuminuria is a marker of increased risk of cardiovascular mortality in type 1 and type 2 diabetes, and in non-diabetic subjects. Little is known about the association between prospective changes of microalbuminuria and the risk factors of atherosclerosis, or gene polymorphism in non-diabetic subjects. We conducted a 6-year prospective study of risk factors for progression of albuminuria in non-diabetic subjects. The participants were 116 non-diabetic subjects who consecutively underwent medical examinations for Japanese-Americans living in Hawaii. In the baseline examination in 1992, normoalbuminuria was found in all subjects. After 6 years, 101 subjects remained normoalbuminuria (non-progressors), 15 subjects changing from normoalbuminuria to microalbuminuria or proteinuria and were defined as progressors. In progressors, compared with non-progressors, the fasting insulin level and HOMA-R were significantly higher at 3 years follow-up, and the systolic and diastolic pressure and Sigma insulin level were significantly higher at 6 years follow-up. Insulin resistance appeared earlier than the appearance of hypertension and albuminuria. In progressors, there was no significant correlation with angiotensin-converting enzyme (ACE) genotype or angiotensinogen (AGT) genotype compared with non-progressors. Therefore, the appearance of insulin resistance should be regarded as a remarkable mediator of albuminuria.     

Reduced glomerular filtration rate and cardiovascular damage in diabetes: a key role for abnormal albuminuria

There is general agreement that a fall rate in glomerular filtration rate (GFR) is the principal endpoint in diabetics with renal disease, and that abnormal albuminuria (including microalbuminuria) is an important intermediate end-point. The relative roles of blood pressure (BP) elevation and abnormal albuminuria in the prediction and genesis of renal disease are a matter of debate, and are further analysed in this paper. New studies show that neither genetic predisposition to hypertension (parental BP) nor parental abnormal albuminuria can be used to predict renal disease in patients with type 1 (insulin-dependent) diabetes. However, parental predisposition to proteinuria seems to be important to certain types of patients with type 2 (non-insulin-dependent) diabetes. Cross-sectional as well as follow-up studies document that GFR is generally well preserved in microalbuminuria (in both type 1 and type 2 patients), while the transition to clinical proteinuria is associated with a decline in GFR. Thus, prevention of overt proteinuria is important in clinical trials in microalbuminuric patients. In type 1 diabetes clear ultrastructural changes have been documented with microalbuminuria and a good correlation between abnormal albuminuria and structural damage is seen. Structural damage in normo- and microalbuminuric patients correlates poorly with BP. New studies in type 1 diabetes document that microalbuminuria (but not elevated BP) predicts not only clinical diabetic nephropathy but also end-stage renal failure and mortality. In type 2 diabetes microalbuminuria is the strongest predictor of mortality, whereas BP elevation is not a predictor. Several studies now document that antihypertensive treatment, especially with inhibitors of angiotensin converting enzyme, is able to reverse or reduce abnormal albuminuria, even in non-hypertensive type 1 patients, and possibly preserve GFR. Therefore, microalbuminuria may be the main indicator for starting antihypertensive treatment in these patients. With respect to organ damage in the retina, abnormal albuminuria is an important indicator of the risk of severe diabetic retinopathy. BP elevation seems not to be an initiating factor, but rather aggravates established retinopathy. Left ventricular hypertrophy has a stronger correlation with BP elevation than normoalbuminuria, suggesting that left ventricular hypertrophy is at least partially a phenomenon secondary to elevated BP in diabetic patients with abnormal albuminuria. Generally, abnormal albuminuria is a strong indicator of cardiovascular renal damage in diabetic patients and in most organs is a stronger factor than elevated BP.     

Differential effects of beta-blockers on albuminuria in patients with type 2 diabetes

Increases in the cardiovascular risk marker microalbuminuria are attenuated by blood pressure reduction using blockers of the renin-angiotensin system. Such changes in microalbuminuria have not been observed when beta-blockers are used. A prespecified secondary end point of the Glycemic Effects in Diabetes Mellitus Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial was to examine the effects of different beta-blockers on changes in albuminuria in the presence of renin-angiotensin system blockade. Participants with hypertension and type 2 diabetes were randomized to either metoprolol tartrate (n=737) or carvedilol (n=498) in blinded fashion after a washout period of all antihypertensive agents except for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Blinded medication was titrated to achieve target blood pressure, with a-5 month follow-up period. The current analysis examined microalbuminuria, using spot urine albumin:creatinine, in participants who had values at screening and trial end. A greater reduction in microalbuminuria was observed for those randomized to carvedilol (-16.2%Delta; 95% confidence interval, -25.3, -5.9; P=0.003). Of those with normoalbuminuria at baseline, fewer progressed to microalbuminuria on carvedilol versus metoprolol (20 of 302 [6.6%] versus 48 of 431 [11.1%], respectively; P=0.03). Microalbuminuria development was not related to differences in blood pressure or achievement of blood pressure goal (68% carvedilol versus 67%, metoprolol). Presence of metabolic syndrome at baseline was the only independent predictor of worsening albuminuria throughout the study (P=0.004). Beta-blockers have differential effects on microalbuminuria in the presence of renin-angiotensin system blockade. These differences cannot be explained by effects on blood pressure or alpha1-antagonism but may relate to antioxidant properties of carvedilol.     

Relation of albuminuria to angiographically determined coronary arterial narrowing in patients with and without type 2 diabetes mellitus and stable or suspected coronary artery disease

Albuminuria is associated with atherothrombotic events and all-cause mortality in patients with and without diabetes. However, it is not known whether albuminuria is associated with atherosclerosis per se in the same manner. The present study included 914 consecutive white patients who had been referred for coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Albuminuria was defined as a urinary albumin/creatinine ratio ≥ 30 μg/mg. Microalbuminuria was defined as 30 to 300 μg albumin/mg creatinine, and macroalbuminuria as a urinary albumin/creatinine ratio of ≥ 300 μg/mg. The prevalence of stenoses of ≥ 50% was significantly greater in patients with albuminuria than in those with normoalbuminuria (66% vs 51%; p <0.001). Logistic regression analysis, adjusted for age, gender, diabetes, smoking, hypertension, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, body mass index, estimated glomerular filtration rate, and the use of angiotensin-converting enzyme inhibitors/angiotensin II antagonists, aspirin, and statins, confirmed that albuminuria was significantly associated with stenoses ≥ 50% (standardized adjusted odds ratio [OR] 1.68, 95% confidence interval [CI] 1.15 to 2.44; p = 0.007). The adjusted OR was 1.54 (95% CI 1.03 to 2.30; p = 0.034) for microalbuminuria and 2.55 (95% CI 1.14 to 5.72; p = 0.023) for macroalbuminuria. This association was significant in the subgroup of patients with type 2 diabetes (OR 1.66, 95% CI 1.01 to 2.74; p = 0.045) and in those without diabetes (OR 1.42, 95% CI 1.05 to 1.92; p = 0.023). An interaction term urinary albumin/creatinine ratio*diabetes was not significant (p = 0.579). In conclusion, micro- and macroalbuminuria were strongly associated with angiographically determined coronary atherosclerosis in both patients with and those without type 2 diabetes mellitus, independent of conventional cardiovascular risk factors and the estimated glomerular filtration rate.     

Differences in HDL-cholesterol:apoA-I + apoA-II ratio and apoE phenotype with albuminuric status in Type I diabetic patients

Aims/hypothesis. To examine whether the HDL-cholesterol:apoA-I + apoA-II ratio and the ?2 allele are related to albuminuria at baseline and whether they are risk factors for progression of albuminuria in a cohort study of patients with Type I (insulin-dependent) diabetes mellitus.¶Methods. At baseline, the study cohort comprised 617 patients, aged 15–60 years, from seven European diabetic centres of the EURODIAB study. Albumin excretion rate, measured in a central laboratory, was categorised as normoalbuminuria at 20 μg/min or less, microalbuminuria between 20 and 200 μg/min or macroalbuminuria at 200 μg/min or over. Of the 250 patients who were normoalbuminuric at baseline and had follow-up albuminuria measurements, 34 patients were defined as early progressors.¶Results. At baseline, the mean HDL-cholesterol:apoA-I + apoA-II ratio was lower in macroalbuminuric patients (0.79, 95 % CI:0.74–0.83) compared with normoalbuminuric (0.88, 95 % CI:0.87–0.90) patients (p = 0.0002, adjusted for age and sex). At follow-up, 34 patients who progressed from normoalbuminuria to microalbuminuria or macroalbuminuria also had a slightly lower baseline ratio (0.85, 95 % CI:0.80–0.89) than those 216 who remained normoalbuminuric (0.89, 95 % CI:0.87–0.92) (adjusted p = 0.08). Neither of these relations were independent of LDL-cholesterol or fasting triglyceride. There was no association of the ?2 allele with albuminuria either at baseline (OR = 1.4, 95 % CI:0.7–2.8) or with progression of albuminuria (OR = 0.4, 95 % CI:0.1–3.5).¶Conclusion/interpretation. There is an inverse relation of HDL-cholesterol:apoA-I + apoA-II ratio with albuminuria at baseline. This lower ratio in microalbuminuric or macroalbuminuric patients could contribute to the increased risk of cardiovascular disease associated with nephropathy. There is weak evidence that HDL-composition is a risk factor for progression of albuminuria and no association of the ?2 allele with diabetic nephropathy. [Diabetologia 2000 43: 1353–1359]     

Microalbuminuria, cardiovascular risk factors and cardiovascular morbidity in a British population: the EPIC-Norfolk population-based study.

BACKGROUND: Microalbuminuria is independently associated with increased cardiovascular risk and renal function deterioration in diabetes and hypertension, but the clinical relevance of raised albuminuria in the general population is less certain. We examined the prevalence of microalbuminuria and its relationship to cardiovascular risk factors and cardiovascular morbidity in the UK general population. METHODS: Cross-sectional population-based study of 23,964 individuals, aged 40-79 years recruited in 1993-1997 for the EPIC-Norfolk Study. Smoking status, prevalent physician diagnosed diabetes, hypertension, cardiovascular disease and cancer were derived from a health and lifestyle questionnaire. Albumin-to-creatinine ratios were estimated from random spot urine specimens collected at the survey visit, and using these ratios participants were categorized into normoalbuminuria, microalbuminuria (2.5-25 mg/mmol), and macroalbuminuria. RESULTS: The prevalence of microalbuminuria and macroalbuminuria was 11.8% and 0.9% respectively in the total population and significantly higher in women (14.4%) compared with men (8.9%) (P<0.001). Independent determinants of microalbuminuria were age, sex, systolic blood pressure and current smoking. Microalbuminuria was independently associated with cardiovascular morbidity, after adjusting for known cardiovascular risk factors, with odds ratio (95% confidence interval) for prevalent cardiovascular disease of 1.30 (1.12-1.51) in all men and women. CONCLUSION: Microalbuminuria was present in approximately 12% of this population. It was independently associated with cardiovascular risk factors and prevalent cardiovascular disease. Microalbuminuria may be a useful indicator of high absolute cardiovascular risk in the community but prospective data are needed to establish its independent predictive value for future events.     

Risk factors for hospitalization in people with diabetes.

OBJECTIVE: To determine factors predicting hospitalization in people with diabetes. METHODS: Two population-based groups with diabetes were examined at baseline (1980-1982), 4 years (1984-1986), and 10 years (1990-1992). The younger-onset group (n = 777) consisted of all persons diagnosed as having diabetes before age 30 years who were taking insulin, and the older-onset group (n = 542) consisted of a sample of persons diagnosed after age 30 years. At the 10-year examination, participants were asked if they had been hospitalized in the previous year. Factors from the 4-year examination were examined for their ability to predict hospitalization at the 10-year examination. RESULTS: In the younger-onset group, 25.5% reported being hospitalized. In logistic models, glycosylated hemoglobin level (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.16-1.39 for a 1% increment) and hypertension (OR, 1.60; 95% CI, 1.08-2.38) predicted hospitalization. Factors that were not significant included age, sex, systolic and diastolic blood pressures, body mass, smoking status, and alcohol consumption. In the older-onset group, 30.8% reported being hospitalized. In logistic models, only glycosylated hemoglobin level (OR, 1.16; 95% CI, 1.06-1.29 for a 1% increment) predicted hospitalization. CONCLUSIONS: Glycemic control is subject to intervention. Better control may decrease hospitalization among people with diabetes. Thus, there is considerable potential for reducing health care costs.     

Nifedipine and enalapril equally reduce the progression of nephropathy in hypertensive type 2 diabetics.

The Japan Multicenter Investigation of Antihypertensive Treatment for Nephropathy in Diabetics (J-MIND) study was conducted to evaluate the effect of nifedipine retard or enalapril on nephropathy in hypertensive patients with type 2 diabetes. A total of 436 patients with normoalbuminuria [urinary albumin excretion rate (AER) <30 mg/day] or microalbuminuria [AER: 30-300 mg/day] were randomized to receive nifedipine retard or enalapril and were followed for 24 months. There were no differences in baseline characteristics between the two groups (the mean AER was 45 and 42 mg/day, respectively). Intent-to-treat analysis showed no significant difference in AER after 2 years, although the mean AER increased to 64 and 74 mg/day in the nifedipine retard and enalapril groups, respectively. The AER increased in patients with normoalbuminuria, whereas it did not change in those with microalbuminuria. There were no differences between the two groups with respect to progression from normoalbuminuria to microalbuminuria, progression from microalbuminuria to overt proteinuria, and regression from microalbuminuria to normoalbuminuria. The incidence of cardiovascular events was also similar in both groups. In conclusion, nifedipine retard and enalapril had a similar effect on nephropathy in hypertensive type 2 diabetic patients without overt proteinuria.     

Body mass index and total and cardiovascular mortality in men with a history of cardiovascular disease

BACKGROUND: Previous studies designed to identify an association between body mass index (BMI) (calculated as weight in kilograms divided by the square of height in meters) and cardiovascular or total mortality in populations with known atherosclerotic disease have shown conflicting results. In this study, we used the Physicians' Health Study enrollment cohort to examine the risk of total and cardiovascular mortality among men reporting a history of myocardial infarction or stroke, excluding those who reported a history of cancer. METHODS: Cause-specific death was ascertained for 5010 men during a mean follow-up of 5.0 years. End points were classified as total deaths and deaths due to cardiovascular causes. Four BMI categories (<22.0, 22.0-24.9 [referent], 25.0-27.9, and > or =28.0) were created a priori. We used proportional hazards models to calculate age and multivariate-adjusted relative risks (RRs) for each BMI category for each end point. RESULTS: Compared with men with a BMI of 22.0 to 24.9, men with a BMI of 28.0 or greater had an age-adjusted RR of 1.11 (95% confidence interval [CI], 0.91-1.36), a multivariate RR of 1.04 (95% CI, 0.84-1.28) in a model that did not include biological mediators of obesity, and a multivariate RR of 1.06 (95% CI, 0.78-1.44) in a model that included these mediators. The RRs for cardiovascular mortality were similar, at 1.07 (95% CI, 0.85-1.35), 1.01 (95% CI, 0.79-1.29), and 1.01 (95% CI, 0.71-1.43), respectively. A BMI of less than 22.0 was associated with a small increased risk of total mortality and cardiovascular mortality. CONCLUSION: These findings indicate that elevated BMI may not be strongly associated with total or cardiovascular mortality among men with previously manifested coronary artery disease.     

The emerging concept of chronic kidney disease without clinical proteinuria in diabetic patients

The natural history of diabetic nephropathy was defined in the 1980s on the basis of longitudinal studies undertaken in patients with type 1 and type 2 diabetes. However, an increasing number of studies have indicated that certain diabetic patients do not present with the same evolution as was then defined: for example, some often have significant initial deterioration of glomerular filtration rate whereas, in others, microalbuminuria is reduced spontaneously. Chronic kidney disease (CKD) may be accompanied, rather than preceded, by macroalbuminuria, or it may develop in patients with microalbuminuria or even in those with albuminuria levels that revert to normal. CKD can also develop in patients whose albuminuria levels remain normal. Progression to macroalbuminuria is, in fact, less frequent than regression to normoalbuminuria or no change in microalbuminuria status in diabetic patients with microalbuminuria, especially in type 1 diabetes. Some experience progressive deterioration of renal function due to diabetes without developing significant proteinuria: this is seen fairly frequently and can affect 50% of patients with renal insufficiency. Such cases are more often older patients treated with renin-angiotensin system blockers who usually have a history of cardiovascular disease. Evolution to end-stage renal disease is slower in this subgroup of patients, although histological analyses may show surprisingly advanced glomerular lesions. The main parameters of surveillance remain regular monitoring of glycaemia, and control of blood pressure and the evolution of initial albuminuria levels. Nevertheless, why some patients exhibit conventional diabetic nephropathy while others have slower declines in renal function associated with normal albuminuria levels or microalbuminuria is unclear. It is hoped that the new pathological classification of diabetic nephropathy will help in our understanding of these discrepancies.     

Microalbuminuria presents the same vascular risk as overt CVD in type 2 diabetes

OBJECTIVES: We attempted to assess whether microalbuminuria conferred the same cardiovascular risk as overt CVD in type 2 diabetic patients. MATERIAL AND METHODS: A prospective cohort study including 436 type 2 diabetic patients (64.8+/-9.2 years old) without proteinuria, with follow-up until any cardiovascular event occurred, was performed. Patients were classified into four groups: group 0, non baseline CVD and normoalbuminuria; group 1, non baseline CVD and microalbuminuria; group 2, baseline CVD and normoalbuminuria; group 3, baseline CVD and microalbuminuria. Cox's multivariate regression models were used to assess the risk ratio (RR) associated with each variable. RESULTS: The median follow-up time was 7.6 years. Incidence rates of cardiovascular events per 1000 patient-years increased from groups 0 to 3 (23.8, 63.4, 74.1, 85.6; p<0.0001). Multivariate RR for incident CVD in groups 1, 2 and 3 in relation to group 0 were 2.8 (95% confidence interval (CI) 1.7-4.6; p<0.0001), 2.7 (95% CI 1.6-4.6; p<0.0001) and 2.9 (95% CI 1.6-5.4; p=0.001), respectively. No significant differences were seen between groups 1 and 2. CONCLUSIONS: We suggest that patients with microalbuminuria are at very high vascular risk and should share the same objectives of a vascular risk-factor control as patients with overt CVD.     

Association of low-grade inflammation with nephropathy in type 2 diabetic patients: role of elevated CRP-levels and 2 different gene-polymorphisms of proinflammatory cytokines.

BACKGROUND: Chronic inflammatory processes are thought to play a key role in the development of micro- and macrovascular complications in type 2 diabetes mellitus. An association between low -grade inflammation and type 2 diabetes has been described in some studies. We assayed the association of two frequent polymorphisms in proinflammatory cytokines: the interleukin 6 G(-174)C promoter polymorphism [IL-6G(-174)C], the exon 2 interleukin receptor antagonist insertion deletion polymorphism [IL1RA]) and serum CRP levels with the prevalence of diabetic nephropathy in patients suffering from type 2 diabetes mellitus. SUBJECTS AND METHODS: A total of 141 patients with type 2 diabetes mellitus, with and without diabetic nephropathy was genotyped for the above mentioned polymorphisms: 66 with normoalbuminuria, 31 with microalbuminuria and 44 with macroalbuminuria. CRP levels were analysed by a high sensitivity - immunnephelometric assay. RESULTS: While a significant association be-tween macroalbuminuria and CRP could be observed (p<0,015), no associations were found between IL-6G(-174)C or IL1RA genotype and any stage of nephropathy. CRP-levels were similar in the 3 different IL-6G(-174)C genotypes as well as in the 2 IL1RA genotypes. CONCLUSIONS: In type 2 diabetic subjects elevated CRP levels are associated with an increased prevalence of albuminuria. The two investigated proinflammatory polymorphisms do not seem to contribute to initiation of nephropathy in type 2 diabetic patients but we cannot exclude effects of these polymorphisms on course of nephropathy.     

Proteinuria reduction: Mandatory consideration or option when selecting an antihypertensive agent?

Proteinuria is a known risk factor for both cardiovascular disease and progression of established kidney disease. Observational studies and intervention trials have established that even low levels of albuminuria (microalbuminuria) are associated with increased risk for cardiovascular morbidity and mortality in general, and especially in highrisk populations such as those with diabetes mellitus. People with hypertension are at increased risk for proteinuria and arguably should be treated with regimens that not only lower blood pressure but also reduce proteinuria. Clinical trials indicate that lowering proteinuria in those with chronic kidney disease is associated with reduced risk for progression to end-stage kidney disease and cardiovascular outcomes. Many of these trials employ antihypertensive agents that block the renin-angiotensin-aldosterone system (RAAS), and indicate that these drugs are, in general, more effective than other antihypertensive regimens for reducing proteinuria. In addition, several small studies suggest that nondihydropyridine calcium channel blockers are comparable with angiotensin-converting enzyme inhibitors and more effective than dihydropyridine calcium channel blockers for reducing proteinuria in type 2 diabetics with advanced kidney disease. Based on the combined evidence from epidemiologic and intervention studies, it seems prudent to make proteinuria reduction a mandatory consideration in the selection of antihypertensive regimens.     

Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: The HUNT II Study

BACKGROUND: The cardiovascular risk implications of a combined assessment of reduced kidney function and microalbuminuria are unknown. In elderly persons, traditional cardiovascular risk factors are less predictive, and measures of end organ damage, such as kidney disease, may be needed for improved cardiovascular mortality risk stratification. METHODS: The glomerular filtration rate was estimated from calibrated serum creatinine, and the urine albumin-creatinine ratio (ACR) was measured in 3 urine samples in 9,709 participants of the second Nord-Tr?ndelag Health Study (HUNT II), a Norwegian community-based health study, followed for 8.3 years with a 71% participation rate. RESULTS: An estimated glomerular filtration rate (EGFR) at levels of less than 75 mL/min/1.73 m(2) was associated with higher cardiovascular mortality risk, whereas a higher ACR was associated with higher risk with no lower limit. Low EGFR and albuminuria were synergistic cardiovascular mortality risk factors. Compared with subjects with an EGFR greater than 75 mL/min/1.73 m(2) and ACR below the sex-specific median who were at the lowest risk, subjects with an EGFR of less than 45 mL/min/1.73 m(2) and microalbuminuria had an adjusted incidence rate ratio of 6.7 (95% confidence interval, 3.0-15.1; P < .001). The addition of ACR and EGFR improved traditional risk models: 39% of subjects with intermediate risk were reclassified to low- or high-risk categories with corresponding observed risks that were 3-fold different than the original category. Age-stratified analyses showed that EGFR and ACR were particularly strong risk factors for persons 70 years or older. CONCLUSIONS: Reduced kidney function and microalbuminuria are risk factors for cardiovascular death, independent of each other and traditional risk factors. The combined variable improved cardiovascular risk stratification at all age levels, but particularly in elderly persons where the predictive power of traditional risk factors is attenuated.     

Diabetic Renal Disease in Patients with Type 2 Diabetes Mellitus

Over the last 35 years an increasing number of patients with type 2 diabetes mellitus have developed advanced renal disease and the need for dialysis. At present in the US, about 50% of the patients in dialysis units have type 2 diabetes mellitus. The explanation for the increase in the number of patients with type 2 diabetes mellitus in end-stage renal disease programs is not completely clear, but the overall number of patients with this type of diabetes is rapidly increasing - and is expected to continue to increase over the next years. The diagnosis of renal disease in type 2 diabetes mellitus is usually straightforward, and is mainly dependent upon measurements of urinary albumin or urinary protein excretion as well as serum creatinine measurements. Renal biopsies or exact glomerular filtration rate measurements are rarely necessary. Microalbuminuria is the first sign of renal disease in diabetes mellitus. It predicts overt nephropathy and cardiovascular disease. Several studies document that albuminuria and microalbuminuria can be reduced by treatment with antihypertensives, especially agents that block the renin angiotensin system. New studies show that end-stage renal disease can be postponed by the use of angiotensin II receptor antagonists. ACE inhibitors are also useful, and dual blockade of the renin angiotensin system has been utilized as well. However, generally speaking, patients with proteinuria have a poor prognosis. Screening for microalbuminuria is therefore proposed, and glycemic control and blood pressure should be optimized.     

Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study

Diabetic nephropathy has developed into a worldwide epidemic and is responsible for the majority of end-stage renal disease in most countries. Antihypertensive treatment slows the progression of the disease. In addition, blockade of the renin-angiotensin system reduces the degree of albuminuria and angiotensin II receptor blockers (ARBs) have been shown to delay the progression from microalbuminuria to overt proteinuria in patients with diabetes. However, few studies have examined whether the initial stage of diabetic nephropathy (i.e. the development of microalbuminuria) in patients with type 2 diabetes can be slowed or prevented by ARB treatment. The Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) study is a placebo-controlled, multicentre, double-blind, parallel group study investigating the effect of the ARB, olmesartan medoxomil, on the incidence of microalbuminuria. A total of 4400 type 2 diabetes patients with normoalbuminuria will be randomized to treatment with 40 mg of olmesartan medoxomil once daily or placebo. Goal blood pressure will be 130/80 mmHg. The primary endpoint of the study is the occurrence of microalbuminuria. In ROADMAP, we will also assess as secondary endpoints the effects of olmesartan on fatal and non-fatal cardiovascular events in patients with diabetes. In addition, within subgroups of the ROADMAP patients, the effects of olmesartan on retinopathy and other microvascular circulations will be analysed. The study is expected to last a median of 5 years. The ROADMAP study will answer the question whether an ARB can prevent or delay the onset of microalbuminuria and whether this translates into protection against cardiovascular events and renal disease.