The Relationship Between Long-term Glycaemic Control and Diabetic Nephropathy

Urine albumin excretion was studied by two widely accepted methodsin 210 patients with insulin-dependent diabetes mellitus andrelated to the mean of serial glycosylated haemoglobin (HbA₁)measurements made every 3 months during the previous 6 years.Microalbuminuria (albumin excretion rate > 20 µg/min)was present in 9.5 per cent of patients when defined by a 24-hourcollection and 8.1 per cent of patients when defined by a timedovernight urine sample. Those with microalbuminuria, as estimatedfrom a timed overnight urine sample, had a longer duration ofdiabetes but otherwise did not differ in age, duration of diabetesor arterial blood pressure from patients whose albumin excretionrate was 20 µg/min or less irrespective of the methodof urine collection. The mean and the most recent HbA₁ levelsdiffered significantly between the normal and the microalbuminuriagroups when defined by the 24-hour albumin excretion rate (p<0.001,p<0.01), but no significant difference between these groupswas found when albumin excretion rates were calculated fromthe timed overnight urine sample. Albumin excretion rate, examinedin relation to mean HbA₁, increased significantly with worseningglycaemic control whether measured over 24 hours or overnight(p<0.05, p< 0.01). These findings support an associationbetween glycaemic control and microalbuminuria, but the correlationis weak, dependent on the method of urine collection and isjust as good for a relatively short-term as for a long-termmeasure of average blood glucose.     

Single-void urine samples can be used to estimate quantitative microalbuminuria

The excretion of small quantities of urinary albumin (microalbuminuria) may predict renal failure in diabetes. The measurement of microalbuminuria with radioimmunoassays has been based on 24-h, overnight, and 3- to 4-h collections. To determine whether single-void urine samples can be used to estimate 24-h excretion, we compared the results of 24-h outpatient urine collections with single-void samples corrected for creatinine from diabetic and nondiabetic subjects. The overall correlation of single-void sample results expressed as microgram albumin per milligram creatinine with 24-h excretion (mg/24 h) was excellent (r = .82, P less than .001). More important, in the diabetic patients the sensitivity and specificity of detecting 24-h microalbuminuria in the abnormal range were at least 94 and 96%, respectively. Single-void urine specimens adjusted for creatinine discriminate between normal and abnormal levels of microalbuminuria, as determined in 24-h urine collection, with high specificity and sensitivity.     

2型糖尿病患者尿白蛋白排出量与血脂代谢异常的关系

目的探讨2型糖尿病患者尿白蛋白排出量与血脂代谢异常的关系。方法根据尿白蛋白排出率(UAER)将73例2型糖尿病患者分为正常白蛋白尿(UAER<20μg/min)、微量白蛋白尿(UAER 20~200μg/min)和大量白蛋白尿(UAER>200μg/min)3个亚组,并选择28例健康人作为正常对照组。所有研究对象测定空腹血糖(FPG)、糖化血红蛋白(HbA1c)、血总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白A1(apoA1)、载脂蛋白B(apoB)、脂蛋白a[LP(a)]。结果2型糖尿病各组FPG及HbA1c与正常对照组的差异有显著性意义(P<0.01),而2型糖尿病三组之间FPG及HbA1c的差异无统计学意义。方差分析显示,4组间TG,HDL-C,LDL-C,LP(a)的差异有显著意义(F分别为4.75,5.22,4.32,6.48;P<0.05或P<0.01)。多元线性回归分析显示,尿白蛋白排出量与TG和FPG成正相关(r2=0.196)。结论2型糖尿病患者血脂代谢异常与尿白蛋白排出率有一定的关系,血脂含量改变越明显,尿白蛋白排出率越高,血脂异常是糖尿病肾病的重要影响因素。     

Association of serum bilirubin levels with albuminuria in patients with essential hypertension

ObjectivesThis study was undertaken to evaluate the relationship between serum bilirubin concentrations and the degree of urinary albumin excretion in hypertensive patients.Design and methodsA total of 120 hypertensive subjects were enrolled, in which 80 (67%) with normoalbuminuria (albumin excretion rate [AER] of < 20 μg/min), 30 (25%) with microalbuminuria (AER of 20–200 μg/min) and 10 (8%) with macroalbuminuria (AER > 200 μg/min). Logarithmic (log) transformation of urinary albumin excretion was carried out before performing correlation and regression analysis.ResultsPatients with micro- or macroalbuminuria had significantly lower serum bilirubin concentrations (P = 0.004). By multivariate regression analysis, serum bilirubin concentration was an independent determinant of albuminuria and had an inverse correlation with log (urinary albumin excretion) in hypertensive patients (β = ? 0.189, P = 0.023).ConclusionsThese findings may partly explain the pathogenetic processes that link microalbuminuria and enhanced cardiovascular risk in hypertensive patients.     

2型糖尿病微量白蛋白尿与颈总动脉内膜中层厚度的相关性研究

目的研究2型糖尿病微量白蛋白尿与颈总动脉内膜中层厚度(CIMT)的关系。方法选取2型糖尿病150例,根据尿微量白蛋白排泄率(UAER)分为DM-A组52例(UAER20μg/min),DM-B组54例(UAER在20~200μg/min之间),DM-C组54例(UAER200μg/min);并设立正常对照组20例,测定其颈总动脉内膜中层厚度,观察尿微量白蛋白与颈总动脉内膜中层厚度的关系。结果糖尿病组CIMT明显高于正常对照组,糖尿病各亚组中,DM-B组及DM-C组的CIMT均显著高于DM-A组(P0.01),DM-C组的CIMT显著高于DM-B组(P0.01)。结论尿微量白蛋白排泄率越高,颈总动脉内中膜中层厚度增加。     

不同时段尿白蛋白在诊断早期糖尿病肾脏损伤中的应用

目的 研究糖尿病患者不同时段尿白蛋白(urinary albumin)的排泌情况及尿白蛋白在诊断早期糖尿病肾脏损伤中的应用.方法 收集中山医院门诊及住院糖尿病患者及健康对照组3 d内不同时间段的尿液,分析尿白蛋白天内、天间的排泌变化情况;以24 h尿白蛋白为标准判断肾脏早期损伤情况,比较不同时段尿及时间点尿与24 h尿白蛋白的相关性、诊断特异度及敏感度;评估随机尿的诊断特异度及敏感度,推导随机尿最佳诊断水平.结果尿白蛋白天间变异较大,以尿Cr和尿量分别校正后可降低变异.糖尿病组中尿白蛋白使用尿Cr校正后变异系数(CV)小于尿量校正(CV分别为49%±23%vs 64%±30%).尿白蛋白天内排泌呈节律性变化.不同尿液留取方式中夜间尿尿白蛋白/尿Cr(ratio of urinary concentrations of albumin and creatinine,ACR)与24 h尿白蛋白定量相关性最好(R~2=0.976),优于晨尿ACR(R~2=0.900)、午间餐后尿ACR(R~2=0.584)和随机尿ACR(R2=0.791).以24 h尿白蛋白总量作为判断标准进行受试者操作特性曲线(ROC曲线)分析显示,随机尿ACR的判断值为27.7 μg/mg尿Cr(存在男女性别差异:男性12.8μg/mg尿Cr vs性27.0μg/mg尿Cr).最小阴性似然比0.011时推导随机尿ACR的排除判断值为13.0 μg/mg尿Cr;最大阳性似然比481.000时推导随机尿ACR的确诊判断值为87.4 μg/mg尿Cr.结论 尿Cr较尿量能更好地降低尿白蛋白天内变异,但仍无法完全消除变异.夜尿ACR与24 h尿白蛋白定量相关性最好,可替代24 h尿白蛋白定量.随机尿ACR作为最方便留取的尿液标本亦可以较好地替代24 h尿白蛋白定量,但应考虑引入尿Cr后带来的性别间差异.以13.0 μg/mg及87.4 μg/mg作为随机尿ACR的排除判断值及确诊判断值可以便于临床医师基本排除或确定白蛋白尿的出现.     

Is there a physiological variability for albumin excretion rate? Study in patients with diabetes type 1 and non-diabetic individuals

BACKGROUND: To determine the intraindividual coefficient of variation (CV(i)) of albumin excretion rate (AER). METHOD: We studied 76 patients with type 1diabetes and 66 non-diabetic subjects (ND) under routine clinical conditions providing three timed overnight urine samples for urinary albumin determination by radioimmunoassay. RESULTS: Patients and ND had similar CV(i) of AER (50.7+/-33.3 vs. 58.1+/-33.2% P=0.12). Intermittent microalbuminuric subjects (one out of 3 AER >20 microg/min) had higher CV(i) of AER than normoalbuminuric and persistent microalbuminuric patients, [84.9 (37.1-145. 3) vs. 39.8 (4.9-124.8) vs. 34.6 (12.1-116.5)% P=0.0007] without difference between the two latter groups. In patients, the independent factor associated with the CV(i) of AER in multiple regression analysis was age (r(2)=0.08; P=0.01). Sensitivity (95% CL) and specificity of first AER for diagnosing microalbuminuria was 85.7% (42.0-99.2) and 91.3% (81.4-96.4). CONCLUIONS: Our findings suggest the variability of AER was physiological, unrelated to diabetic condition. First AER could be used for screening of microalbuminuria followed by a second one when the patient has AER >20 microg/min in the first. This would result in low cost for screening and diagnosis of microalbuminuria, that is not always feasible in routine clinical practice in developing countries using three urine samples.     

Enhanced urinary excretion of albumin and β2 microglobulin in essential hypertension induced by atrial natriuretic peptide

Atrial natriuretic peptide (ANP) was given as an intravenous bolus injection (2.0 µg kg^-1) to 12 essential hypertensive patients (EH) and 10 normotensive control subjects (C) in order to study the effect of ANP on urinary excretion of albumin and β₂-microglobulin, and on glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF). After the ANP injection, urinary excretion of albumin increased significantly (p<0.01) in EH from 7.3 µg min to 125 µg min (medians) and in C from 2.9 µg min^-1 to 8.1 µg min ^-1 (p<0.05). Urinary excretion of β_2-microglobulin increased in EH from 70 ng min^-1 to 1022 ng min^-1 (p<0.01) and in C from 118 ng min^-1 to 170 ng min^-1 (p<0.01). The increase in urinary excretion of both albumin (p<0.01) and B₂-microglobulin (p<0.01) was significantly more pronounced in EH than in C. GFR and RPF were almost unchanged in both groups. FF rose to the same degree in the two groups. The increase in fractional excretion of sodium and in urine volume after ANP was enhanced in EH. It is concluded that ANP in pharmacological doses increased urinary excretion of albumin and β₂-microglobulin to a considerably larger extent in essential hypertensive patients than in normotensive control subjects.     

Reduced glomerular size- and charge-selectivity in clinically healthy individuals with microalbuminuria

Abstract. The pathophysiologic mechanism behind microalbuminuria, a potential atherosclerotic risk factor, was explored by measuring fractional clearances of four endogenous plasma proteins of different size and electric charge (albumin, β2-microglobulin, immunoglobulin G, and immunoglobulin G₄). Twenty-eight clinically healthy individuals with microalbuminuria, defined as a urinary albumin excretion of 6.6–150μg min^-1, and 60 matched control subjects were studied. Fractional immunoglobulin G clearance was higher (geometric means (95% confidence intervals)) 3.0 (2.3–3.9) × 10^-6, n= 28, vs. 2.1 (1.8–2.4) × 10^-6, n= 60; P= 0.02), whereas the ratio immunoglobulin G clearance/immunoglobulin G₄ clearance was lower (geometric means (95% confidence intervals)) 1.8 (1.4–2.2), n= 28, vs. 2.3 (2.0–2.5), n= 60; P= 0.03) in microalbuminuric than in normoalbuminuric individuals. Fractional β₂-micro-globulin clearance was similar in the two groups. Since total IgG and the IgG₄ subclass are of similar size and configuration but electrically neutral and negative, respectively; these findings indicate that microalbuminuria is associated with decreased size- and charge-selectivity of the glomerular vessel wall. Hypotheti-cally, such alterations may reflect generalized vascular abnormalities linking microalbuminuria to athero-genesis.     

New semiquantitative dipstick test for microalbuminuria.

OBJECTIVE: We compared a new semiquantitative dipstick test for microalbuminuria (Micral-Test) with a quantitative immunoturbidimetric method. RESEARCH DESIGN AND METHODS: This correlation study was performed at a pediatric and medical outpatient clinic at a university hospital. Overnight urine samples containing less than 200 mg/L albumin from 186 diabetic patients were analyzed. RESULTS: The correlation coefficient between the new semiquantitative method and the immunoturbidimetric reference method was 0.82. Elevated albumin concentration was defined as greater than 20 mg/L albumin in overnight urine, and the prevalence of samples with values above this level was 28%. By this definition, the Micral-Test assay level greater than or equal to 20 mg/L had a sensitivity of 92.3% and a specificity of 82.1%. Of the diabetic subjects, 84.9% were correctly classified as having elevated urinary albumin concentration or not. CONCLUSIONS: The Micral-Test is useful for in-clinic screening for elevated urinary albumin concentration and monitoring the development of urinary albumin excretion in the low microalbuminuric range.     

The relationship between long-term glycaemic control and diabetic nephropathy.

Urine albumin excretion was studied by two widely accepted methods in 210 patients with insulin-dependent diabetes mellitus and related to the mean of serial glycosylated haemoglobin (HbA1) measurements made every 3 months during the previous 6 years. Microalbuminuria (albumin excretion rate > 20 micrograms/min) was present in 9.5 per cent of patients when defined by a 24-hour collection and 8.1 per cent of patients when defined by a timed overnight urine sample. Those with microalbuminuria, as estimated from a timed overnight urine sample, had a longer duration of diabetes but otherwise did not differ in age, duration of diabetes or arterial blood pressure from patients whose albumin excretion rate was 20 micrograms/min or less irrespective of the method of urine collection. The mean and the most recent HbA1 levels differed significantly between the normal and the microalbuminuric groups when defined by the 24-hour albumin excretion rate (p < 0.001, p < 0.01), but no significant difference between these groups was found when albumin excretion rates were calculated from the timed overnight urine sample. Albumin excretion rate, examined in relation to mean HbA1, increased significantly with worsening glycaemic control whether measured over 24 hours or overnight (p < 0.05, p < 0.01). These findings support an association between glycaemic control and microalbuminuria, but the correlation is weak, dependent on the method of urine collection and is just as good for a relatively short-term as for a long-term measure of average blood glucose.     

Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study

OBJECTIVE: To evaluate prospectively putative risk factors for development of microalbuminuria and macroalbuminuria in type 1 diabetes. RESEARCH DESIGN AND METHODS: Prospective observational study of a cohort of type 1 diabetic patients followed in the outpatient clinic at Steno Diabetes Center for < or =10 years (median 9 years). We followed 537 patients aged > or =18 years with type 1 diabetes, with duration of diabetes > or =5 years, with normoalbuminuria (urinary albumin excretion rate < or =30 mg/24 h), and who were not taking antihypertensive medication. Risk factors for development of microalbuminuria and macroalbuminuria were evaluated. RESULTS: The mean progression of urinary albumin excretion rate was 7.6% (SE 0.8) per year. During follow-up, 134 patients (25%) progressed to persistent microalbuminuria or macroalbuminuria (>30 mg/24 h in two of three consecutive urine samples). Cox multiple regression analysis using baseline values of putative predictors of progression showed the following significant predictors of progression from normoalbuminuria to microalbuminuria or macroalbuminuria: baseline log urinary albumin excretion rate 2.63 (relative risk; 95% CI 1.65-4.19), HbA(1c) 1.13% (1.04-1.23), presence of any retinopathy 1.90 (1.26-2.88), and smoking 1.61 (1.11-2.33). Sex, duration of diabetes, arterial blood pressure, serum creatinine, height, and social class were not risk factors. CONCLUSIONS: Our study suggests that several potentially modifiable risk factors predict the development of microalbuminuria and macroalbuminuria in type 1 diabetic patients.     

Comparison of urinary albumin excretion rate in overnight urine and albumin creatinine ratio in spot urine in diabetic patients in general practice

OBJECTIVE: To evaluate whether measurement of albumin creatinine ratio (ACR) on a spot urine specimen can replace a timed overnight collection of urine albumin excretion rate (UAER) in patients with diabetes in primary care. DESIGN: Patients with diabetes attending R?nvik Health Centre were asked to bring a timed overnight collection of urine for measurement of UAER. They were also asked to void a urine specimen for measurement of albumin creatinine ratio. SETTING: Primary health care. SUBJECTS: One-hundred-and-six persons with diabetes (47 women, 59 men) aged 13 to 78 years. RESULTS: The sensitivity and specificity of ACR with cut-off values of 2.5 mg/mmol for men and 3.5 mg/mmol for women compared to UAER with cut-off value of 20 mg/24 h was 90%. CONCLUSIONS: Spot urine ACR analysed on a DCA 2000 can replace a timed (overnight) collection of urine and measurement of UAER when diabetic patients are reviewed in general practice. This simplifies procedures for the patient as a timed urine collection is no longer necessary. Another advantage is that the results are available after 7 min.     

Smoking cessation A comparative,randomised study between management in general practice and the behavioural programme SmokEnders

Objective - To evaluate whether measurement of albumin creatinine ratio (ACR) on a spot urine specimen can replace a timed overnight collection of urine albumin excretion rate (UAER) in patients with diabetes in primary care. Design - Patients with diabetes attending Rønvik Health Centre were asked to bring a timed overnight collection of urine for measurement of UAER. They were also asked to void a urine specimen for measurement of albumin creatinine ratio. Setting - Primary health care. Subjects - One-hundred-and-six persons with diabetes (47 women, 59 men) aged 13 to 78 years. Results - The sensitivity and specificity of ACR with cut-off values of 2.5 mg/mmol for men and 3.5 mg/mmol for women compared to UAER with cut-off value of 20 mg/24 h was 90%. Conclusions - Spot urine ACR analysed on a DCA 2000 can replace a timed (overnight) collection of urine and measurement of UAER when diabetic patients are reviewed in general practice. This simplifies procedures for the patient as a timed urine collection is no longer necessary. Another advantage is that the results are available after 7 min.     

糖尿病肾病患者尿液 NGAL 蛋白的定性及定量检测比较

目的：明确尿液中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的定性及定量检测在糖尿病肾病早期诊断中的意义。方法将74例糖尿病患者按其24 h 尿微量清蛋白排泄率（UAER）分为正常蛋白尿组26例（DN1组,UAER＜30 mg/24 h）,微量蛋白尿组24例（DN2组,UAER 介于30～300 mg/24 h）及大量蛋白尿组24例（DN3组,UAER＞300 mg/24 h）,同时建立对照组25例。同时测定各组尿 NGAL 蛋白的活性及水平并比较两种检测结果。结果各组患者尿 NGAL 活性条带均较对照组明显清晰（P ＝0．000）,大量蛋白尿组 NGAL 活性较正常蛋白尿组高（P ＜0．05）,微量蛋白尿组与正常蛋白尿组比较差异无统计学意义（P ＞0．05）;定量检测则提示大量蛋白尿组 NGAL 水平与其他3组存在区别,大量蛋白尿组 NGAL 排出量高于微量蛋白尿组、正常蛋白尿组及对照组（P ＝0．000）,对照组与正常蛋白尿组、微量蛋白尿组三者间两两比较差异无统计学意义（P ＞0．05）。结论对糖尿病肾病患者而言,尿 NGAL 蛋白活性检测比尿微量蛋白排泄率检测及 NGAL 定量检测敏感,有可能成为糖尿病肾病早期诊断的新型指标。     

Exercise-induced proteinuria in well-trained athletes.

We studied the rate of urinary excretion of albumin, alpha 1-microglobulin (as an indicator of the renal tubular involvement), sodium, potassium, and creatinine in the basal state (overnight urine collection) and after physical exercise (training session) in 10 professional cyclists, to verify whether protein excretion is increased even in well-trained athletes after physical effort. In addition, we wanted to understand whether the origin of exercise-induced proteinuria was glomerular, tubular, or both. Compared with the basal state (overnight collection), exercise significantly (P less than 0.01) increased the excretion rate of albumin (4.2 +/- 2.6 micrograms/min vs 18.1 +/- 10.6 micrograms/min, mean +/- SD), Na, and K, and also the urinary volume. Creatinine output was not affected by exercise. The mean (+/- SD) overnight excretion rate of albumin by athletes was quite similar to that found for 91 healthy nonathletes at rest (4.6 +/- 2.7 micrograms/min). The mean exercise-related excretion of alpha 1-microglobulin by the athletes significantly exceeded the overnight value (6.6 vs 0.3 mg/L, P = 0.037). Our study indicates that (a) albuminuria furnishes the greater contribution to the increase in exercise-induced proteinuria; (b) the exercise proteinuria is both glomerular and tubular in origin, and is reversible; (c) the enhanced protein requirement of athletes may in part be due to the recurrent excretion of proteins in the urine after physical effort.     

Screening for microalbuminuria in patients with diabetes mellitus: frozen storage of urine samples decreases their albumin content

The influence of storage on urinary albumin concentration was prospectively studied with use of overnight urine specimens (Albustix negative) from 73 diabetic patients. From each urine sample four aliquots were taken. One was stored at 4 degrees C and assayed within two weeks, the other three were stored at -20 degrees C and assayed within two weeks and after two and six months. Albumin concentration was measured with laser immunonephelometry. The detection limit, 1 mg/L, suffices for the screening of diabetic patients for microalbuminuria. After storage for two and six months at -20 degrees C, significantly lower albumin concentrations were found. The difference was mainly caused by lower concentrations found in urine samples in which a precipitate had formed, which was the case in 22 and 25 samples, respectively. Thus, freezing of urine samples for determination of low concentrations of albumin may yield falsely low results. Urine samples are best stored at 4 degrees C and assayed within two weeks.     

Increased urinary haemoglobin in diabetics with microalbuminuria--measured by an ELISA

A solid-phase sandwich enzyme immunoassay for the determination of urinary haemoglobin is described. A screening study was performed to establish whether occult haematuria/haemoglobinuria is present in diabetic patients with elevated urinary albumin excretion. Non-insulin-dependent diabetic patients (145) aged 66.5 years +/- 5.6 with a known duration of diabetes of 10.4 years +/- 6.8 were studied. They delivered a first morning urine sample at consecutive outpatient visits. Erythrocytes were lysed by freezing of the urine samples. The patients were categorized into three groups according to urinary albumin concentration (UAC) as measured by radio-immunoassay. Forty-five patients with microalbuminuria i.e. UAC greater than 20- less than or equal to 200 micrograms/ml had an elevated urinary haemoglobin concentration (UHC) of 38.5 micrograms/l compared to 90 patients with normal UAC and a UHC of 7.7 micrograms/l, p less than 10(-4). A further increase was seen in 10 proteinuric patients, UHC 161.8 micrograms/l, p less than 0.05. The urinary concentration of albumin and haemoglobin were significantly correlated, r = 0.49, p less than 10(-8). In 32 insulin-dependent diabetics the findings were similar. There was no correlation between either age or known duration and the haemoglobin concentration. In 42 normal subjects, the UHC was 3.6 micrograms/lx/divided by 6.1. Haematuria has formerly been described in patients with diabetic nephropathy alone. The present findings suggest that occult haematuria/haemoglobinuria is already present in patients with microalbuminuria.     

Effects of losartan on urinary secretion of extracellular matrix and their modulators in type 2 diabetes mellitus patients with microalbuminuria

PURPOSE: Angiotensin II receptor Type 1 antagonists postpone the development of nephropathy in type 2 diabetes mellitus (DM). We hypothesize that Losartan may ameliorate renal function in diabetic patients through the regulation on the generation of transforming growth factor (TGF)-beta and fibrinolytic regulators. METHODS: Twenty-two type 2 DM patients with microalbuminuria were treated with 50-100 mg/day of Losartan for 6 months. Urinary secretion of TGF-, plasminogen activator inhibitor-1 (PAI-1), tissue and urokinase plasminogen activators (tPA and uPA) fibronectin, collagen IV and plasma levels of TGF-beta, PAI-1, tPA and uPA of the patients before and after the treatment were analyzed using enzyme-linked immunoabosorbance assay. RESULTS: Losartan effectively reduced arterial blood pressure and urinary albumin excretion. The levels of TGF-beta in urine, but not in plasma, were reduced after 2, 4 and 6 months of the treatment (-32% to -48%, P < 0.05 or 0.01). Urinary or plasma levels of PAI-1, tPA or uPA, and urinary secretion of fibronectin or collagen IV were not significantly altered by Losartan treatment. Urinary levels of collagen IV positively correlated with uPA, and that of fibronectin negatively correlated with PAI-1 in the patients (P < 0.01). Urinary TGF-beta negatively correlated uPA in urine of the patients (P < 0.01). CONCLUSION: Losartan reduced urinary excretion of TGF-beta and albumin in type 2 DM patients with microalbuminuria. Fibrinolytic regulators and TGF-beta are implicated in the regulation of ECM turnover in kidneys of the patients with diabetic nephropathy.     

Microalbuminuria in Type 1 Diabetes Is Associated With Enhanced Excretion of the Endocytic Multiligand Receptors Megalin and Cubilin

OBJECTIVE

Proteinuria is the hallmark of diabetic nephropathy; yet, glomerular histology does not fully explain mechanisms contributing to proteinuria. Our objective was to identify proteins in the urine of individuals with type 1 diabetes and microalbuminuria that might implicate a mechanistic pathway operative in proteinuria.

RESEARCH DESIGN AND METHODS

Using a GeLC/MS platform proteomics approach, we compared the urine proteome from 12 healthy nondiabetic individuals, 12 subjects with type 1 diabetes yet normal urinary albumin excretion rates, and 12 subjects with type 1 diabetes and microalbuminuria (type 1 diabetes + microalbuminuria).

RESULTS

The abundance of megalin and cubilin, two multiligand receptors expressed in kidney proximal tubule cells and involved with the reuptake of filtered albumin and megalin/cubilin ligands, was significantly increased in type 1 diabetes + microalbuminuria urine, compared with both nonalbuminuric groups.

CONCLUSIONS

Aberrant shedding of megalin and cubilin could contribute to albuminuria in diabetes and to deficiency states of important vitamins and hormones.Excess urinary albumin excretion (UAE) (30–299 mg/day), termed microalbuminuria, portends incipient diabetic nephropathy. Mechanisms contributing to proteinuria in diabetic nephropathy are incompletely understood but likely involve pathology within the glomerulus, including endothelial cell injury, glomerular basement membrane thickening, loss of slit diaphragm veracity, and podocytopenia (1). Additionally, in the proximal tubule (PT), decreased protein reabsorption likely occurs (1,2); data from diabetic animals suggest that altered PT handling and diminished albumin retrieval contribute to albuminuria (3,4). Because ∼70% of the urinary proteome originates from kidney or genitourinary tissues (5,6), we used the GeLC/MS platform proteomics approach to compare the urine proteome from 1) nondiabetic individuals, 2) subjects with type 1 diabetes yet normal UAE, and 3) subjects with type 1 diabetes and microalbuminuria (type 1 diabetes + microalbuminuria), so as to identify proteins that might implicate a mechanistic pathway operative in proteinuria.