Prevalence of microalbuminuria in maturity onset primarily non-insulin-requiring diabetes mellitus: Effect of disease duration,glycemic control,and mean systemic blood pressure

Because of the frequency of late cardiovascular complications in maturity onset non-insulin-dependent (Type II) diabetes mellitus, there have been few studies regarding nephropathy in this patients population. The authors have analyzed the prevalence of microalbuminuria and the nature of clinical manifestations associated with elevated albumin excretion rate (AER) in a large poputation presenting with Type II diabetes. Among 318 patients studied during 1986, pathologically elevated 24 h AERs were found in 59%. The rate of microalbuminuria among 205 Type I diabetic patients screened during the same interval was 43%. AER was found to be positively correlated with duration of disease (p<0.0008) and metabolic control as determined by measurement of glycosylated hemoglobin (HaA1_c) (p<0.002). There was only a modest agreement between AER and mean systemic blood pressure. The high prevalence of microalbuminuria in Type II diabetic patients and its known association with increased mortality emphasize the need for long-term follow up studies in order to clarify whether elevated AER in this patient populationsis predictive for overt diabetic nephropathy.     

Microalbuminuria and its associated risk factors in a representative sample of Italian Type II diabetics

A multicenter population-based study was undertaken from 1983 to 1985 in 12 diabetes centers in Lombardy, in order to assess the prevalence of microalbuminuria and clinical proteinuria. Out of a total population of 17,704 diabetics, 1,155 were randomly selected within four strata of duration of disease and albumin excretion rate (AER) assessment was carried out in 541 unselected subjects. Albuminuria was evaluated from an overnight urine collection using a radioimmunoassay. The overall prevalence rates were 25.8% for microalbuminuria (30≤AER <350 μg/min) and 3.0% for macroalbuminuria (AER≤350 μg/min). In Type II diabetes the rate of microalbuminuria increases with duration of disease up to 10 years and then tends to level off. This could be due to the existence of two subgroups of diabetics with different life expectancy and different degree of risk of nephropathy. The Italian prevalence of microalbuminuria appears to be rather similar to that of other studies, while the prevalence of macroalbuminuria is quite low with respect to middle and northern Europe, indicating a rather slow rate of progression to clinical proteinuria. This could be explained on the basis of differing protein intakes. The cases with AER≥30 μg/min, ≥70 μg/min, and ≥350 μg/min have been compared with matched diabetic controls with AER≤15 μg/min. Blood pressure did not appear as a predictive factor for cases with AER≥30 μg/min, but was close to significance for AER≥70 μg/min (DBP: p=.06) and appeared clearly significant for AER≥350 μg/min (DBP: p=.03; SBP: p=.04).     

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.     

Factors associated with progression to macroalbuminuria in microalbuminuric Type 1 diabetic patients: the EURODIAB Prospective Complications Study

Aims/hypothesis Type 1 diabetic patients who develop microalbuminuria are clearly disadvantaged in terms of their risk of morbidity and mortality from renal and cardiovascular diseases. It is therefore important to identify potential factors that can predict progression to macroalbuminuria.Methods This is a 7-year follow-up study of 352 microalbuminuric Type 1 diabetic patients from 31 European centres. Risk factors at baseline were compared in patients who progressed to macroalbuminuria and in patients who remained microalbuminuric or reverted to normoalbuminuria. Risk factors and albumin excretion rate (AER) were measured centrally.Results Over 7.3 years, 13.9% of the microalbuminuric patients progressed to macroalbuminuria, 35.5% remained microalbuminuric and 50.6% reverted to normoalbuminuria. Independent baseline risk factors for progression to macroalbuminuria were HbA₁c (7.9% vs 6.8%, p=0.004), AER (64.4 vs 44.9 µg/min, p=0.0001) and—after adjusting for diabetes duration, HbA₁c and AER—body weight (72 vs 67 kg, p=0.05). Independent factors associated with regression to normoalbuminuria were diabetes duration (15 vs 18 years, p=0.004), AER (37.2 vs 44.9 µg/min, p=0.0001) and—after adjusting for diabetes duration, HbA₁c and AER—waist-to-hip ratio (0.83 vs 0.86, p=0.05) and incidence of peripheral neuropathy at baseline (24% vs 38%, p=0.001). Blood pressure and smoking did not emerge as risk factors at baseline for the outcome of microalbuminuria.Conclusions/interpretation A significant fraction of microalbuminuric Type 1 diabetic patients will progress to overt proteinuria. Patients with higher AER values, sub-optimal metabolic control, excess body fat and peripheral neuropathy may carry a particularly high risk of clinical nephropathy requiring aggressive therapeutic intervention.Abbreviations AER albumin excretion rate - CVD cardiovascular disease - Gamma GT gamma-glutamyltransferase - OR odds ratio - PCS Prospective Complications Study - RR relative risk - SERR standardised estimates of relative risk - SREs standardised regression effects - vWF von Willebrand Factor     

Predictors of the development of microalbuminuria in patients with Type 1 diabetes mellitus: a seven-year prospective study

Aims To determine risk factors for the development of persistent microalbuminuria (albumin excretion rate (AER) ≥ 30 μg/min) in Type 1 diabetes mellitus. Methods One hundred and forty-eight initially normotensive Type 1 diabetic patients with normal albumin excretion (< 30 μg/min) were followed prospectively in hospital diabetes outpatient clinics for a median of 7 years. Main outcome measures were: progression to persistent microalbuminuria (albumin excretion rate ≥ 30 μg/min on at least two consecutive occasions); rate of change of albumin excretion rate; development of arterial hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 95 mmHg or commencement of antihypertensive therapy). Results In a median follow-up period of 7 years (range 6 months to 8 years), 14 patients progressed to persistent microalbuminuria, a cumulative incidence of 11% (95% confidence interval 6.36–16.94). AER remained persistently < 30 μg/min in 109 subjects and 25 developed intermittent microalbuminuria. In those who developed persistent microalbuminuria, baseline AER (16.2 (13.9–19.1) vs. 5.2 (3.8–9.2) μg/min, P < 0.01), blood pressure (136 (123–148)/80 (74–85) vs. 121 (118–124)/72 (70–73) mmHg, P < 0.05), and HbA₁ (10.2 (9.1–11.4) vs. 9.0 (8.7–9.4)%, P < 0.05) were higher than in those who continued to have persistent normoalbuminuria, retinopathy was more severe and height (1.64 (1.57–1.71) vs. 1.70 (1.69–1.72) m, P < 0.05) less. In multivariate analysis, baseline AER was the strongest predictor of the development of persistent microalbuminuria (P < 0.0001), followed by mean arterial pressure (P = 0.02) and HbA₁ (P = 0.05). Conclusions The level of AER, raised blood pressure and poor glycaemic control are the most important predictors of the development of microalbuminuria in Type 1 diabetes.     

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.     

Microalbuminuria in insulin-dependent diabetes: Prevalence and practical consequences

Urinary albumin excretion in a representative sample of 679 patients with Type I (insulin-dependent) diabetes, 18 to 50 years of age, was investigated. Patients on antihypertensive therapy were excluded. Urinary albumin excretion was examined in one 24 hour urine sample using an ELISA technique. Twenty-three per cent of the patients had microalbuminuria, i.e., 30–300 mg albumin/24 h. The prevalence of microalbuminuria was independent of sex, age, insulin dose and diabetes duration. In the majority of those cases in which microalbuminuria was found during the first 10 years of diabetes, the concentrations were in the lower range, i.e., 30–50 mg/24 h. The prevalence of incipient nephropathy (urinary albumin excretion in a single urine sample of 51–300 mg/24 h) increased with diabetes duration. In patients with inciplent nephropathy hemoglobin A_1c tended to be, and blood pressure was, elevated compared with age, sex, and duration matched patients with normal urinary albumin excretion rates (p=0.08 and p<0.001, respectively). Urinary albumin excretion and blood pressure were significantly correlated in the total group (n=401, r=0.2, p<0.001). On the basis of these findings practical guidelines for the handling of patients with microalbuminuria are proposed.     

Prospective study of development of microalbuminuria and retinopathy in Brazilian IDDM patients

With the aim to study potential risk factors for the development of microalbuminuria and retinopathy, baseline characteristics were examined in 50 Brazilian IDDM patients folowed for 4.48 years with a 2-year reexamination. During the study, 3 patients (6%) aged 25.9 ± 4.4 years, duration of diabetes 8.1 ± 4.2 years, died from acute complications without microalbuminuria and retinopathy after a follow-up of 2.1 ± 0.7 years. The standardized mortality rate for the group was 0.84 per 1000 (95% CL, 0.31, 1.83) in comparison to 0.14 per 1000 in the general population. From 34 normoalbuminuric individuals ate baseline (urinary albumin excretion rate (AER) ≤ 20 μg/min in ≥ 2 overnight urine collections), 10 developed microalbuminuria with an incidence density of 6.5 cases per 100 person-years (95%CL, 2.23, 10.16). Spontaneous normalization of AER was found in 2 of 4 patients with microalbuminuria at cycle 2. Multiple stepwise regression analysis demonstrated that baseline AET (p = 0.03), but not glycated hemoglobin, blood pressure or duration of diabetes, predicted end-of-study AER. From 36 patients without retinopathy, 10 developed nonproliferative retinopathy with an incidence density of 6.6 cases per 100 person-years (95%CL, 2.85, 10.54). Retinopathy was associated with duration (p = 0.05) and age at diagnosis of diabetes (p = 0.01). A tendency with baseline AER (p = 0.06) was also noted. No patient developed macroalbuminuria, proliferative retinopathy or hypertension. By the end of our study, in a cohort of young IDDM patients followed in a developing country, 6% died from acute complications and 15 patients (44.1%) developed retinopathy and/or microalbuminuria. Our results suggest that the only predictor of end-of-study AER was baseline AER. Also, duration of diabetes and age at diagnosis appear to be risk factors for retinopathy. Received: 22 May 1999 / Accepted in revised form: 3 March 2000     

Indomethacin But Not Metoprolol Reduces Exercise-induced Albumin Excretion Rate in Type 1 Diabetic Patients with Microalbuminuria

The effects of a single oral dose of indomethacin (1 mg kg^?1), metoprolol (1.5 mg kg^?1) and placebo on exercise-induced albumin excretion rate (AER) were compared in a randomized, crossover design in 14 normotensive, young Type 1 diabetes patients, nine of them with microalbuminuria (AER > 15 μg min^?1) and five without microalbuminuria at rest. The albumin excretion rate, blood pressure, heart rate, blood glucose, and plasma concentrations of indomethacin and metoprolol were determined before and after 30 min submaximal physical exercise. In microalbuminuric patients the rise in albumin excretion rate after exercise on indomethacin (7 μg min^?1) was lower than after placebo (29 μg min^?1, p < 0.001) whereas the rise in albumin excretion rate with metoprolol during exercise (18 μg min^?1) did not differ from placebo (p = 0.48), in spite of the expected less marked increase in blood pressure. In normoalbuminuric patients no significant increase in albumin excretion rate was noted by exercise in any of the treatment periods. A tendency to a linear correlation (r = ?0.54, p = 0.07) was seen between the plasma concentration of indomethacin and the inhibition of exercise-induced increase in albumin excretion rate. No correlations were observed between exercise-induced changes in albumin excretion rate and systolic blood pressure, heart rate or blood glucose. In conclusion, acute indomethacin treatment, presumably through inhibition of renal prostaglandin synthesis, reduces the exercise-induced rise in albumin excretion rate in Type 1 diabetic patients with microalbuminuria. Such an effect was not seen after acute administration for the beta-1-adrenoceptor blocking drug metoprolol, in spite of a less marked rise in blood pressure.     

糖尿病患者尿白蛋白排泄率与骨密度相关性研究

为探讨糖尿病患者尿白蛋白排泄率（AER）与骨密度（BMD）的相关性,测定了106例糖尿病患者和20例正常人（对照组）24小时AER,根据糖尿病患者AER分为Ⅰ组即正常蛋白尿组、Ⅱ组即微量白蛋白尿组、Ⅲ组即大量白蛋白尿组,并分别测定其L2～4椎体、股骨近端BMD。结果显示,除Ⅰ、Ⅱ组男性患者腰椎BMD与对照组无明显差异外,其余各组、各部位BMD与对照组相比均明显下降（P＜0.01）;男女糖尿病AER正常患者分别与同性别对照组相比,其BMD亦降低（P＜0.01）。糖尿病患者中,Ⅲ组BMD明显低于Ⅰ、Ⅱ组（P＜0.05）。提示糖尿病肾病患者BMD比正常人低,大量蛋白尿组BMD较其它组显著下降。     

Prevalence of systolic and diastolic dysfunction in patients with type 1 diabetes without known heart disease: the Thousand & 1 Study

Aims/hypothesis

Heart failure is one of the leading causes of mortality in type 1 diabetes. Early identification is vitally important. We sought to determine the prevalence and clinical characteristics associated with subclinical impaired systolic and diastolic function in type 1 diabetes patients without known heart disease.

Methods

In this cross-sectional examination of 1,093 type 1 diabetes patients without known heart disease, randomly selected from the Steno Diabetes Center, complete clinical and echocardiographic examinations were performed and analysed in uni- and multivariable regression models.

Results

The mean (SD) age was 49.6 (15)?years, 53% of participants were men, and the mean duration of diabetes was 25.5 (15)?years. Overall, 15.5% (n?=?169) of participants had grossly abnormal systolic or diastolic function, including 1.7% with left ventricular ejection fraction (LVEF)?<?45% and 14.4% with evidence of long-standing diastolic dysfunction. In univariable models, clinical characteristics associated with abnormal myocardial function were: age (per 10 years), OR (95% CI) 2.1 (1.8, 2.4); diabetes duration (per 10 years), 1.7 (1.4, 1.9); systolic BP?≥?140 mmHg, 2.7 (1.9, 3.8); diastolic BP?≥?90 mmHg, 1.8 (1.0, 3.1); estimated (e)GFR?<?60 ml min^?1 1.73 m^?2, 3.8 (2.5, 5.9); microalbuminuria, 2.0 (1.3, 3.0); macroalbuminuria, 5.9 (3.8, 9.3); proliferative retinopathy, 3.6 (2.3, 5.8); blindness, 10.1 (3.2, 31.6); and peripheral neuropathy, 3.8 (2.7, 5.3). In multivariable models only age (2.1 [1.7, 2.5]), female sex, (1.9 [1.2, 2.8]) and macroalbuminuria (5.2 [2.9, 10.3]) remained significantly associated with subclinical grossly abnormal myocardial function.

Conclusions/interpretation

Subclinical myocardial dysfunction is a common finding in type 1 diabetes patients without known heart disease. Type 1 diabetes patients with albuminuria are at greatly increased risk of having subclinical abnormal myocardial function compared with patients without albuminuria. Echocardiography may be particularly warranted in patients with albuminuria.     

Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients

Aims/hypothesis Increased concentrations of C-reactive protein and interleukin-6, a finding suggestive of the presence of inflammation, have been observed in Type 2 diabetes. In such patients, C-reactive protein was predictive of diabetic nephropathy. Studies on low-grade inflammatory markers and nephropathy in Type 1 diabetic patients have shown conflicting results. Therefore we studied whether low-grade inflammation is associated with diabetic nephropathy in Type 1 diabetic patients.Methods We divided 194 Type 1 diabetic patients into three groups from the Finnish Diabetic Nephropathy Study based upon their albumin excretion rate. Patients with normoalbuminuria (n=67) had no antihypertensive medication or signs of cardiovascular disease, while patients with microalbuminuria (n=64) or macroalbuminuria (n=63) were all treated with an angiotensin-converting enzyme inhibitor, a drug that could attenuate low-grade inflammation. As a measure of insulin sensitivity we used estimated glucose disposal rate. C-reactive protein was measured by radioimmunoassay and interleukin-6 by high sensitivity enzyme immunoassay.Results C-reactive protein was higher in micro- and macroalbuminuric patients compared to normoalbuminuric patients (normoalbuminuria 2.0±1.7, microalbuminuria 2.6±1.7, macroalbuminuria 2.9±2.5 mg/l; p=0.016), while interleukin-6 increased in parallel with the severity of the renal disease (1.9±1.5, 2.9±3.3, 3.6±3.1 ng/l; p<0.0001). In multiple regression analysis albumin excretion rate was the only variable independently associated with C-reactive protein (p=0.03), whereas albumin excretion rate (p=0.0003), HDL-cholesterol (p=0.0135) and duration of diabetes (p=0.0176) were independently associated with interleukin-6.Conclusions/interpretation Low-grade inflammatory markers are associated with diabetic nephropathy in Type 1 diabetic patients. The predictive value needs to be assessed.Abbreviations DN diabetic nephropathy - CRP C-reactive protein - eGDR estimated glucose disposal rate - FinnDiane finnish diabetic nephropathy study - MDRD modification of diet in renal disease     

Continuous subcutaneous insulin infusion is more effective than multiple daily insulin injections in preventing albumin excretion rate increase in Type 1 diabetic patients

Aims To compare the effect of continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) on albumin excretion rate (AER) in Type 1 diabetic patients. Methods In a 3‐year multicentre retrospective observational study, 110 Type 1 diabetic patients treated with CSII were compared with 110 patients treated with MDI matched at baseline for age, sex, diabetes duration and HbA_1c. At entry, 90 patients in each group had normal AER and 20 persistent microalbuminuria. AER, estimated glomerular filtration rate (eGFR), HbA_1c, lipids and blood pressure were assessed. Results HbA_1c was lower in the CSII than in the MDI group (8.1 ± 0.9 vs. 8.4 ± 1.3%; P < 0.005 after 3 years). Blood pressure and eGFR were similar during the study. AER [median (95% confidence interval)], similar at baseline [6.0 μg/min (9, 21) in the CSII group vs. 4.4 (8, 16) in the MDI group, NS] was significantly lower in the patients treated with CSII both at year 2 and at year 3 of follow‐up [4.7 μg/min (6, 12) vs. 6.4 (13, 29), P < 0.002]. This difference was observed even when normo‐ and microalbuminuric patients were analysed separately. Nine patients progressed to microalbuminuria in the MDI group and only one in the CSII group. Nine patients regressed to normoalbuminuria in the CSII group, whereas only two regressed to normoalbuminuria in the MDI group. Conclusions Despite a small benefit in terms of improved glycaemic control, CSII therapy may be useful in decreasing the progressive increase in AER in Type 1 diabetic patients.     

Regression of microalbuminuria in type 1 diabetic patients: results of a sequential intervention with improved metabolic control and ACE inhibitors

Abstract The objective was to evaluate the effect of improved metabolic control and ACE inhibition used sequentially in the treatment of type 1 diabetic patients with microalbuminuria. We studied 44 consecutive type 1 diabetic patients with microalbuminuria not previously treated with ACE inhibitors. Improved metabolic control (optimisation period) was attempted for 6–12 months and patients with persistent microalbuminuria were subsequently treated with ACE inhibitors. Stepwise logistic regression analysis included the variables age, age at diabetes onset, duration of diabetes, HbA1c, initial albumin excretion rate (AER) and mean blood pressure as predictors of final AER. Thirty per cent of patients regressed to normoalbuminuria after the optimisation period, and 58% of them maintained normal AER 4.5±1.3 years later (3–7 years). Patients achieving normoalbuminuria had lower baseline AER (53±22 vs. 94±63 mg/24 h, p=0.012). The initial AER level was the only factor associated with final AER (r=0.58, p=0.021). Thirty patients with persistent microalbuminuria were treated with ACE inhibitors for two years, 35.5% of whom regressed to normal AER. Patients achieving normoalbuminuria after ACE inhibitor treatment had lower baseline AER (55±24 vs. 132±75 mg/24 h, p=0.03). The initial AER was the sole predictor of final AER (r=0.51, p<0.013). Overall, the sequential use of improved metabolic control and ACE inhibitor therapy resulted in long-term normalisation of AER in 47.4% of patients. The sequential implementation of improved metabolic control and ACE inhibitor therapy had a long-term beneficial effect in type 1 diabetic patients with microalbuminuria. We propose that type 1 diabetic patients with microalbuminuria could benefit from a period of metabolic improvement before the initiation of ACE inhibitor therapy.     

Comparison of renal resistive index among patients with Type 2 diabetes with different levels of creatinine clearance and urinary albumin excretion

Diabet. Med. 29, 1043–1046 (2012) Aim To evaluate the prevalence of increased renal resistive index and related factors among patients with Type 2 diabetes with different levels of creatinine clearance and urinary albumin excretion. Methods Laboratory analyses, including calculation of 24‐h urinary albumin excretion and 24‐h creatinine clearance, and renal doppler ultrasonography to measure renal resistive index, were carried out for patients newly diagnosed with Type 2 diabetes mellitus. Results Participants were classified into four groups according to 24‐h creatinine clearance and 24‐h urinary albumin excretion levels. Group 1 was composed of 73 patients (54.1%) with normal 24‐h creatinine clearance and 24‐h urinary albumin excretion. Group 2 was composed of 34 (25.2%) patients with normal 24‐h creatinine clearance and increased 24‐h urinary albumin excretion. Group 3 was composed of 14 (10.4%) patients with decreased 24‐h creatinine clearance and normal 24‐h urinary albumin excretion. Group 4 was composed of 14 (10.4%) patients with both decreased 24‐h creatinine clearance and increased 24‐h urinary albumin excretion . In total, 41 patients (30.4%) had increased renal resistive index levels. Comparison of the four groups with respect to increased renal resistive index revealed: among group 1 patients, 10 (13.7%) had increased renal resistive index levels; among group 2 patients, 14 (41.2%) had increased renal resistive index levels; among group 3 patients, eight (57.1%) had increased renal resistive index levels; among group 4 patients, nine (64.3%) had increased renal resistive index levels (P < 0.0001 for trend). In multivariate regression, 24‐h creatinine clearance (P < 0.0001), but not 24‐h urinary albumin excretion, was related to increased renal resistive index levels. Conclusion Renal resistive index levels were highest in patients with Type 2 diabetes with both decreased 24‐h creatinine clearance and increased 24‐h urinary albumin excretion, whereas they were lowest in patients with normal creatinine clearance and normal urinary albumin excretion.     

The etiology of microalbuminuria in early non-insulin-dependent diabetes mellitus

Glomerular or tubular contribution for microalbuminuria was estimated by assessing albumin excretion rate (AER) in glomerular urine obtained by l-arginine infusion (AI) and glomerular filtration rate (GFR) in 20 non-insulin-dependent diabetes mellitus (NIDDM) patients before and after glycemic control, and in 19 age-matched controls. Glycemic control normalized AER during AI, while it decreased AER before AI, though it was still above normal. Glycemic control increased tubular reabsorption rate of albumin, but it was still less than normal. Tubular reabsorption rate of albumin declined in close relation with duration of diabetes mellitus, while AER in glomerular urine had no correlation with the duration. GFR had no correlation with AER before or during AI. In conclusion, impaired tubular reabsorption of albumin plays a key role for microalbuminuria in NIDDM.     

Apolipoprotein C-III protein concentrations and gene polymorphisms in Type 1 diabetes: associations with microvascular disease complications in the DCCT/EDIC cohort

AIM: We investigated the associations of apolipoprotein C-III (apoCIII) protein and apoCIII gene variation with microvascular disease complications in Type 1 diabetes. METHODS: The serum apoCIII concentration, and both a T(-455)-->C and a SacI gene polymorphisms were determined in 409 patients in the DCCT/EDIC cohort of patients with Type 1 diabetes. Correlations with albumin excretion rate (AER) and the severity of retinopathy were investigated. RESULTS: Higher apoCIII concentrations were associated (P<.0001) with increased triglycerides (r=.78), total (r=.61) and LDL (r=.40) cholesterol, apoAI (r=.26), and apoB (r=.50), AER (r=.08), and the severity of retinopathy (ETDRS score, r=.11), and these relationships persisted after controlling for age, gender, body mass index (BMI), and HbA1c level. The apoCIII concentration was significantly higher in the group of patients with macroalbuminuria (AERs 300 mg/24 h) compared to the groups with microalbuminuria (AER 40-299 mg/24 h; P<.0001) or normoalbuminuria (AER <40 mg/24 h) (P<.0001). The apoCIII concentration also was significantly higher in the group of patients with severe retinopathy (ETDRS 10-23) compared to those with moderate (ETDRS 4-9; P<.02) or mild retinopathy (ETDRS 1-3; P<.0001). Neither the T(-455)-->C polymorphism nor a SacI polymorphism in the 3' UTR were associated with circulating apoCIII concentrations, nor the severity of nephropathy or retinopathy. CONCLUSIONS: Elevated apoCIII levels have been associated with increased macrovascular disease risk. In the DCCT/EDIC cohort of patients, there was an independent positive association of apoCIII level with microvascular complications of Type 1 diabetes.     

Higher dietary salt intake is associated with microalbuminuria,but not with retinopathy in individuals with type 1 diabetes: the EURODIAB Prospective Complications Study

Aims/hypothesis

High dietary salt intake has been associated with elevated BP and may also have a deleterious effect on microvascular complications. We studied the cross-sectional associations between dietary salt intake (estimated from 24 h urinary sodium excretion) and urinary potassium excretion on the one hand, and the prevalence of microvascular complications on the other, in individuals with type 1 diabetes.

Methods

We measured sodium and potassium concentrations in two 24 h urine samples in 1,212 individuals with type 1 diabetes (40?±?10 years old, 51% men) who participated in the EURODIAB Prospective Complications Study. We used multiple logistic regression analyses to investigate associations between dietary salt intake and microvascular complications adjusted for age and sex, and additionally for BMI, smoking, urinary potassium excretion, antihypertensive medication and physical activity, and total energy, protein, alcohol, saturated fat and fibre intake.

Results

After full adjustment, 1 g/day higher dietary salt intake was positively associated with the presence of microalbuminuria (OR 1.06 [95% CI 1.01, 1.10]), but not macroalbuminuria (OR 0.99 [95% CI 0.94, 1.05]), non-proliferative retinopathy (OR 1.00 (95% CI 0.96, 1.04]) or proliferative retinopathy (OR 1.02 (95% CI 0.95, 1.08]). After excluding individuals with cardiovascular disease and/or antihypertensive medication (n?=?418), we found a non-significant association with microalbuminuria (OR 1.04 [95% CI 0.99, 1.10]) and macroalbuminuria (OR 1.05 [95% CI 0.96, 1.16]). The association between dietary salt intake and microalbuminuria was stronger in individuals with a BMI above 25 kg/m² (OR 1.11 [95% CI 1.04, 1.18]) than in those with BMI below 25 kg/m² (OR 1.03 [95% CI 0.97, 1.09]). No significant associations were found between urinary potassium excretion and microvascular complications.

Conclusions/interpretation

In individuals with type 1 diabetes, higher dietary salt intake, as determined by 24 h urinary sodium excretion, may be positively associated with microalbuminuria, particularly in overweight individuals.     

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.     

Lipid abnormalities predict progression of renal disease in patients with type 1 diabetes

Aims/hypothesis

We studied the impact of baseline lipid variables on the progression of renal disease in a large nationwide prospective cohort of patients with type 1 diabetes.

Methods

A total of 2,304 adult patients with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were evaluated. Data on progression of renal disease were verified from medical files and patients were followed for 5.4?±?2.0 (mean ± SD) years.

Results

High triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL₃-cholesterol concentrations predicted incident microalbuminuria. Progression to macroalbuminuria was predicted by high triacylglycerol and ApoB. When AER was entered into the model, triacylglycerol was no longer an independent predictor, but when patients with normal AER and microalbuminuria at baseline were pooled, triacylglycerol, HbA_1c, male sex and AER were all independent predictors of renal disease. High total cholesterol, LDL-cholesterol, non-HDL-cholesterol and triacylglycerol as well as low HDL-cholesterol, HDL₂-cholesterol, ApoA-I and ApoA-II concentrations were predictive of progression to end-stage renal disease. However, when estimated GFR was entered into the model, only total cholesterol remained an independent predictor of progression.

Conclusions/interpretation

Lipid abnormalities, particularly high triacylglycerol concentrations, increase the risk of progression of renal disease.