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.     

Microalbuminuria in diabetes: relationships between urinary albumin excretion and diabetes-related variables

A single observer reviewed 842 of the 917 known diabetic patients registered with 40 GPs in the Poole area. Fifty-nine per cent (493) of those reviewed submitted a timed overnight urine collection to measure albumin excretion rate (AER) and overnight albumin/creatinine ratio (ON-Alb/Creat); 43 samples were excluded because of urinary tract infection and/or proteinuria. A random urine sample was obtained in 607 diabetic patients to measure the random albumin/creatinine ratio (R-Alb/Creat); 68 specimens were excluded because of infection and/or proteinuria, and in a further 10 samples urinary creatinine was not measured. Stepwise multiple regression analyses found significant associations with the following variables: for AER, blood glucose (p = 0.001), smoking category (p = 0.002), sex (p = 0.034), and systolic blood pressure (p = 0.035); for R-Alb/Creat, blood glucose (p = 0.001), retinopathy (p = 0.004), systolic blood pressure (p = 0.004), diastolic blood pressure (p = 0.015), coronary artery disease (p = 0.02), sex (p = 0.034), and vibration sense (p = 0.038). Interestingly, glycosylated haemoglobin was not a significant determinant of albuminuria in either analysis.     

Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes

Aims/hypothesis

An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes.

Methods

The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10^?4 were followed up in 3,750 additional patients with type 1 diabetes from seven studies.

Results

The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p?<?5?×?10^?8). In the replication group, a nominally significant association (p?=?0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p?=?0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.

Conclusions/interpretation

This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.     

Relationships between heart rate variability and urinary albumin excretion in patients with type 2 diabetes

BACKGROUND: Although in type 1 diabetes the close association between heart rate variability and urinary albumin excretion (UAE) is recognized even in patients with normoalbuminuria, this association has not yet been fully established in patients with type 2 diabetes. Therefore, we investigated the association in patients with type 2 diabetes. PATIENTS AND METHODS: All the hospital's 185 inpatients with type 2 diabetes were prospectively enrolled. Heart rate variability was evaluated by coefficients of variance of RR intervals (CVRR). RESULTS: The mean age, duration of diabetes, and hemoglobin A1C of the patients were 59.7+/-9.9 years, 10.4+/-7.8 years, and 9.7+/-2.3%, respectively. An analysis of the patients showed a significant negative correlation between CVRR and log10-transformed (log) UAE (R=-0.3340, P <0.0001). CVRR showed a significant negative correlation with age, duration of diabetes, hemoglobin AIC, systolic blood pressure, diastolic blood pressure, and triglyceride level. Log UAE showed a significant positive correlation with body mass index, hemoglobin A1C, systolic blood pressure, diastolic blood pressure, total cholesterol, and triglyceride level. In the macroalbuminuric group (UAE above 300 mg/g creatinine; n=57), although CVRR showed a significant negative correlation with log UAE (R=-0.3571, P= 0.0064), but in normoalbuminuric (UAE below 30 mg/g Cr; n=79) and in microalbuminuric groups (30 to 300 mg/g Cr; n = 49), CVRR and log UAE showed no correlation. CONCLUSIONS: Our data suggest that in type 2 diabetes, the association between CVRR and UAE is significant only in patients with macroalbuminuria.     

2型糖尿病尿白蛋白排泄和视网膜病变相互关系研究

目的了解老年２型糖尿病（２ＤＭ）患者尿白蛋白排泄（ＵＡＥ）与视网膜病变（ＤＲ）之间的关系。方法对２４３例老年２ＤＭ患者同时进行了２４ｈＵＡＥ测定、眼底检查和详细的临床资料分析。结果①ＤＲ的发生率随ＵＡＥ的增加而增加,正常、微量和大量白蛋白尿患者,ＤＲ的发生率分别为１１７％、７６０％和８３３％,增殖性ＤＲ发生率分别为１８％、１４７％和３６７％;同样,白蛋白尿的发生率亦随ＤＲ的出现和进展而明显增高;②有白蛋白尿,但不伴ＤＲ的患者,其白蛋白尿常由其他非糖尿病性疾病所致。结论老年２ＤＭ患者ＵＡＥ与ＤＲ的发生密切相关,ＤＲ的存在与否对其白蛋白尿的病因有重要提示价值。     

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.     

Miglitol increases the adiponectin level and decreases urinary albumin excretion in patients with type 2 diabetes mellitus

Postprandial hyperglycemia is associated with increased cardiovascular mortality; therefore, lowering postprandial hyperglycemia seems crucial in type 2 diabetes mellitus. We assessed the effect of 2 different postprandial glucose-lowering agents, the alpha-glucosidase inhibitor miglitol and the meglitinide analogue mitiglinide, on metabolic profile and atherosclerosis-related markers. Glucose levels, insulin levels, lipid profile, serum adiponectin, pulse wave velocity (PWV), and urinary albumin excretion rate (AER) were assessed before and after 3 months in 28 patients with type 2 diabetes mellitus randomly allocated to either miglitol 150 mg/d or mitiglinide 30 mg/d. Both agents improved postprandial glucose levels but exhibited different patterns of insulin levels. Body mass index (BMI) tended to decrease with miglitol (P = .06), and homeostasis model assessment of insulin resistance and AER significantly decreased (P < .05 and P < .001, respectively) with miglitol; these changes were not obtained with mitiglinide. Pulse wave velocity did not change. The 3-month changes in 1,5-anhydroglucitol levels were significantly more with miglitol than with mitiglinide (P = .007). Adiponectin levels were significantly increased only with miglitol (P < .01), and the 3-month changes were significantly more with miglitol than with mitiglinide (P = .048). The significant increase in adiponectin by miglitol was inversely correlated with the ratio of the 60-minute change in blood glucose at 3 months divided by the change at baseline (r = -0.59, P = .020), which was independent of the effect of age, sex, changes in hemoglobin A(1c) and BMI, and the baseline concentration of adiponectin. The present comparative study indicated favorable effects of miglitol on BMI, homeostasis model assessment of insulin resistance, adiponectin, and AER, which are markers related to insulin resistance and atherosclerosis. Future studies are needed to elucidate the long-term effect.     

2型糖尿病患者肾小球滤过率与尿白蛋白的关系

目的探讨2型糖尿病患者慢性肾脏病(CKD)的患病率及肾小球滤过率与尿白蛋白排泄间的关系。方法收集自2008年1月至2009年12月在江苏省省级机关医院就诊的2型糖尿病患者资料,采用MDRD公式评估肾小球滤过率(eGFR),CKD定义为存在白蛋白尿或者eGFR60 ml/(min·1.73 m2)。白蛋白尿定义为尿白蛋白/肌酐比值(ACR)≥30 mg/g。采用多项式回归及曲线拟合分析eGFR与尿ACR之间的关系。结果研究纳入1521例2型糖尿病患者,平均年龄(63.9±12.0)岁,CKD及白蛋白尿的患病率分别为31.0%和28.9%。eGFR≥90、60~89、30~59、15~29 ml/(min·1.73 m2)患者白蛋白尿的患病率分别为19.9%、34.5%、65.6%和100%。在正常蛋白尿、微量白蛋白尿及大量白蛋白尿患者中,肾功能不全的比率分别为3.0%、9.3%和40.4%。多项式回归分析显示当患者尿ACR90 mg/g时,eGFR下降缓慢且稳定保持在90 ml/(min·1.73 m2)以上,而当尿ACR≥90 mg/g时,eGFR则迅速下降。结论 2型糖尿病患者CKD及白蛋白尿发生率高,对2型糖尿病人群进行CKD的筛查应该同时检测尿白蛋白与eGFR,为了延缓CKD的进展,应尽早对白蛋白尿进行干预治疗。     

Urinary excretion of glycated albumin in insulin-dependent diabetic patients with normal urinary albumin excretion

Summary Glycation involves both circulating proteins, such as albumin, and structural proteins, such as the components of the glomerular basement membrane. A preferential excretion of glycated albumin (more anionic at physiological pH compared with unmodified plasma albumin) has been reported by some authors, but not by others. We therefore investigated the selectivity index (renal clearance of non-glycated albumin/clearance of glycated albumin) in 25 insulin-dependent diabetic patients with normal urinary albumin excretion and in 19 well-matched control subjects. The selectivity index was significantly higher in diabetic patients than in control subjects: 1.38±0.05 SEMvs 0.98±0.02, p<0.0001. This result is not consistent with a preferential urinary excretion of glycated albumin, at least in normoalbuminuric uncomplicated insulin-dependent diabetic patients.     

Ambulatory pulse pressure and progression of urinary albumin excretion in older patients with type 2 diabetes mellitus

We studied whether ambulatory blood pressure monitoring added to office blood pressure in predicting progression of urine albumin excretion over 2 years of follow-up in a multiethnic cohort of older people with type-2 diabetes mellitus. Participants in the Informatics for Diabetes Education and Telemedicine study underwent a baseline evaluation that included office and 24-hour ambulatory blood pressure measurement and a spot urine measurement of albumin-to-creatinine ratio (ACR). Measurements of albumin-to-creatinine ratio were repeated 1 and 2 years later. In bivariate analyses, ambulatory 24-hour pulse pressure was the blood pressure variable most strongly associated with follow-up ACR. Repeated-measures mixed linear models (n = 1040) were built adjusting for baseline ACR ratio, clustered randomization, time to follow-up, and multiple covariates. When both were entered into the model, ambulatory 24-hour pulse pressure and office pulse pressure were independently associated with follow-up ACR (beta [SE] = 0.010 [0.002], P < 0.001, and 0.004 [0.001], P = 0.002, respectively). Cox proportional hazards models examined associations with progression of albuminuria in 954 participants without macroalbuminuria at baseline, adjusting for all of the covariates independently associated with follow-up ACR in mixed linear models. Ambulatory 24-hour pulse pressure, but not office pulse pressure, was independently associated with progression of albuminuria (P = 0.015 and 0.052, respectively). The adjusted hazards ratio (95% CI) per each 10-mm Hg increment in ambulatory pulse pressure was 1.23 (1.04 to 1.42). In conclusion, ambulatory pulse pressure may provide additional information to predict progression of albuminuria in elderly diabetic subjects above and beyond office blood pressure.     

Smoking is associated with urinary albumin excretion: an evaluation of premenopausal patients with type 2 diabetes mellitus

Cigarette smoking and an increase in urinary albumin excretion are associated with high mortality in patients with type 2 diabetes mellitus. We tested the hypothesis that the presence of a smoking habit correlates with increased urinary albumin excretion in premenopausal Japanese women with type 2 diabetes mellitus. The study consisted of 20 premenopausal Japanese patients with type 2 diabetes mellitus in the current-smokers group (age, 45 +/- 4 years, mean +/- SD). The control group consisted of 35 age-matched never-smoker patients (age, 45 +/- 5 years). Serum triglyceride levels were higher and high-density lipoprotein cholesterol levels were lower in the current-smokers group than in the never-smokers group (P < .05 and P < .01, respectively). Furthermore, fasting plasma insulin concentrations and the homeostasis model assessment index were higher in the current-smokers group than in the never-smokers group (P < .005 and P < .001, respectively). Urinary albumin excretion also was higher in the current-smokers group than in the never-smokers group (P < .0001). Multivariate logistic analysis revealed that urinary albumin excretion is independently associated with current smoking in Japanese premenopausal with type 2 diabetes mellitus (odds ratio, 1.79; 95% confidence interval, 1.08-3.87; P < .01). The results of this study show that current smoking is associated with an increased level of urinary albumin excretion, suggesting that smoking was a risk factor in the development of increased urinary albumin excretion in these patients.     

2型糖尿病尿白蛋白排泄率与血栓调节蛋白的相关性研究

目的　探讨2型糖尿病(T2DM)患者尿白蛋白排泄率(UAER)与血栓调节蛋白(TM)的相关性。　方法　68 例T2DM患者分为正常白蛋白尿(NAU)组,微量白蛋白尿(MAU)组,临床白蛋白尿(CAU)组。30 例健康人作对照(NC)组。检测各组对象的血浆TM 水平、血小板计数(PC)、血小板平均容积(MPV)、血小板分布宽度(PDW)。　结果　MAU组和CAU组UAER显著高于NC组(P<0.01)。T2DM患者血浆TM含量均高于NC组(P<0.01)。UAER与TM水平呈正相关(r=0.798,P<0.05)。T2DM患者PC与NC组比较差异有统计学意义(P<0.01)。MPV、PDW在MAU组和CAU组显著高于NC组(P<0.01)。　结论　T2DM患者UAER与TM水平呈正相关。两者对糖尿病肾病的早期诊断及血管内皮细胞损伤程度的评价有重要意义。T2DM患者的PC、MPV和PDW高于NC组,且随着UAER的升高而增加。     

Effect of intensive blood pressure control with valsartan on urinary albumin excretion in normotensive patients with type 2 diabetes

BACKGROUND: Diabetes is the most common cause of renal failure in the United States, and data regarding the effects of aggressive blood pressure (BP) therapy in normotensive patients with type 2 diabetes are inadequate. METHODS: A total of 129 type 2 diabetic patients with a BP of <140/80 to 90 mm Hg without overt albuminuria were randomized to either intensive BP control (diastolic BP goal 75 mm Hg) using an angiotensin II receptor blocker, valsartan, versus moderate BP control (diastolic BP 80 to 90 mm Hg with placebo initially) to evaluate the effect on the change in urinary albumin excretion (UAE) from baseline. RESULTS: The mean entrance BP was 126 +/- 8.8/84 +/- 2.4 mm Hg. The mean follow-up period was 1.9 +/- 1.0 years. During the follow-up period, the mean BP was 118 +/- 10.9/75 +/- 5.7 for the intensive v 124 10.9/80 6.5 mm Hg for the moderate BP groups (P < .001). No difference was observed in change in creatinine clearance or serum creatinine from baseline between the two groups. An analysis of covariance model for change in log (UAE + 1), adjusting for age, HBA(1c), duration of diabetes, baseline log (UAE + 1), sex, and ethnicity resulted in a significant treatment difference at 2 years (P = .007) with intensive BP control reducing log (UAE+1) compared with moderate BP control. CONCLUSION: Intensive BP control with valsartan to <120/80 mm Hg in normotensive patients with type 2 diabetes and normo- or microalbuminuria significantly decreased the progression of UAE and in some cases caused regression of UAE.