Urinary excretion of beta-thromboglobulin and N-acetyl-beta-D-glucosaminidase in type 1 diabetes: potential indicators of early nephropathy?

While microalbuminuria indicates the glomerular damage of early diabetic nephropathy, tubular abnormalities also occur at an early stage of diabetic renal disease. Urinary excretion of beta-thromboglobulin (BTG) and N-acetyl-beta-D-glucosaminidase (NAG) was measured in 132 normotensive Type 1 (insulin-dependent) diabetic patients with no evidence of overt renal disease, of whom 35 had microalbuminuria and the remainder had normal urinary albumin excretion. Of 21 patients in whom there was a detectable urinary BTG concentration, only 8 (38%) had a concurrently abnormal urinary albumin excretion. NAG excretion was elevated in 22 (63%) of the 35 patients with microalbuminuria; significant associations were also identified between urinary NAG excretion and smoking habit (x2 = 12.7, p less than 0.001) and glycated haemoglobin (r = 0.49, p less than 0.01). It is concluded that measurement of urinary BTG is not of sufficient sensitivity to be of value in the detection of early diabetic renal disease, but measurement of urinary NAG may be of value in the detection of diabetic nephropathy at a potentially reversible stage.     

Increase in serum prorenin precedes onset of microalbuminuria in patients with insulin-dependent diabetes mellitus

Abstract Aims/hypothesis. The renin-angiotensin system is possibly involved in the pathogenesis of diabetic nephropathy. The most striking change in renin-angiotensin system components in blood of patients with diabetic nephropathy is an increased prorenin concentration. We investigated prospectively serum concentrations of renin-angiotensin system components and the time course of prorenin increase in normoalbuminuric diabetic patients developing microalbuminuria. Methods. Patients (n = 199) with Type I (insulin-dependent) diabetes mellitus and normoalbuminuria at baseline were prospectively followed for 10 years. The prorenin concentrations and other variables possibly associated with the occurrence of microalbuminuria, were investigated by Cox-regression analysis. Results. Of the patients 29 developed microalbuminuria. Glycated haemoglobin values were higher at baseline in these patients. Serum prorenin was similar at baseline but rose in the 29 patients before the development of microalbuminuria and was stable in patients with stable albumin excretion. Renin, angiotensinogen and angiotensin converting enzyme serum concentrations were stable in both groups. Prorenin and glycated haemoglobin were independent prognostic factors for the development of microalbuminuria. A prognostic index, based on these variables, was constructed to estimate the relative risk of developing microalbuminuria. Conclusions/interpretation. Increase in serum prorenin precedes onset of microalbuminuria in normotensive patients with insulin-dependent diabetes mellitus. High concentrations of prorenin in combination with high values of glycated haemoglobin can be used as a predictor of development of microalbuminuria. [Diabetologia (1999) 42: 1006–1010] Received: 30 December 1998 and in revised form: 1 April 1999     

Urinary excretion of retinol-binding protein in type 1 (insulin-dependent) diabetic patients with microalbuminuria and clinical diabetic nephropathy

The urinary excretion of retinol-binding protein (RBP) was studied in 101 insulin-dependent diabetic patients allocated to three groups according to 24-h urinary albumin excretion rate (UAE) (median of three urine collections): group 1 (n=45), normal UAE<30 mg/24h; group 2 (n=27), microalbuminuria (UAE 30–300 mg/24 h); and group 3 (n=29), clinical diabetic nephropathy (UAE>300 mg/24 h). We used 23 healthy subjects as controls. Fractional clearance of RBP (FC-RBP) and its 24-h urinary excretion rate (URBP) were higher in each diabetic group than in healthy subjects, the highest values being found in group 3. Groups 1 and 2 did not differ in URBP and FC-RBP. There was a correlation between FC-RBP and haemoglobin A1c in both the total diabetic cohort (P<0.001) and in diabetic patients in groups 1 and 2 with a glomerular filtration rate of more than 90 ml/min (P<0.05). No correlation was found between FC-RBP and UAE and/or duration of diabetes in any of the diabetic groups. We conclude that the increased urinary excretion of RBP, indicating proximal tubular dysfunction, is already present in normoalbuminuric insulindependent diabetic patients and correlates with metabolic control. Further deterioration in proximal tubular function was not observed in microalbuminuric patients, but is a late event in clinical diabetic nephropathy.     

Post-exercise Albuminuria Does Not Predict Microalbuminuria in Type 1 Diabetic Pantients

To investigate whether post-exercise urinary albumin excretion in Type 1 diabetic children and adolescents may prospectively predict the development of microalbuminuria, we have assessed post-exercise urinary albumin excretion before and after 6.2 ± 1.7 years of follow-up in 66 diabetic children and adolescents. Post-exercise urinary albumin excretion rose significantly above the pre-exercise values in diabetic patients by 2.7 (-3.8 to 84.2) μ min^?1 (p < 0.001) and in a group of 9 healthy individuals by 3.9 (-0.7 to 13.7) μg min^?1 (p < 0.02) without significant differences betbeen groups. Post-exercise albuminuria was greater in postpubertal than prepubertal 9.8 vs 4.3 μg min^?1 (p < 0.03) and pubertal 9.8 vs 6.0 μg min^?1 (p < 0.02) patients; post-exercise changes in urinary albumin excretion were also positively related to glycated haemoglobin (r = 0.293; p < 0.05). Eight out of 66 patients developed microalbuminuria at follow-up. Urinary albumin excretion at follow-up was comparable between patients with normal and abnormal post-exercise urinary albumin excretion; moreover post-exercise urinary albumin excretion was within the normal range in 5 out of 8 patients with microalbuminuria at follow-up. In conclusion post-exercise albuminuria does not seem to be a useful predictor of the onset of microalbuminuria in Type 1 diabetic children and adolescents.     

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

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

西洛他唑对2型糖尿病尿白蛋白排泄率的影响

目的探讨西洛他唑治疗2型糖尿病早期肾病的临床疗效.方法将60例血压正常伴微量白蛋白尿的2型糖尿病患者,随机分为两组：治疗组30例,予口服西洛他唑片（50 mg,bid）;对照组30例,予口服安慰剂维生素B1（10 mg,bid）,两组均治疗3个月.观察患者治疗前后尿白蛋白排泄率（UAER）的变化.结果治疗组与治疗前比较,UAER明显下降（P＜0.01）,下降幅度达51.6%,约3%病人仅有轻微头痛反应.对照组治疗前后UAER无明显变化（均P＞0.05）.结论西洛他唑能显著降低糖尿病尿白蛋白的排泄,对糖尿病早期肾病具有治疗作用,且安全性好.     

The prevalence of hypercholesterolaemia and its relationship with albuminuria in insulin-dependent diabetic patients: an epidemiological study.

To assess the prevalence of hypercholesterolaemia and its relationship with metabolic control and urinary albumin excretion in Type 1 diabetic patients, all 1577 insulin-dependent patients attending the outpatient clinic at the Steno Memorial Hospital were studied. None had previously received lipid-lowering drugs. Hypercholesterolaemia, defined as plasma concentration of cholesterol above 6.4 mmol l-1 was found in 156 patients (10%) (95%) confidence intervals (CI) 8.4-11.5%) compared with 11% in the Danish background population. Compared with the normolipidaemic diabetic patients, the hyperlipidaemic patients were older (42 vs 37 years: p less than 0.001, 95% CI for difference in means 3-7 years), they had a higher glycosylated HbA1C (9.2 vs 8.6%, p less than 0.001, 95% CI for difference in means 0.4-1.3%) and their urinary albumin excretion was 32 vs 12 mg 24 h-1, p less than 0.001. Of the 1577 diabetic patients, 1084 patients (73%) had normal urinary albumin excretion (UAE less than 30 mg 24 h-1), 255 (17%) had microalbuminuria (UAE 30-300 mg 24 h-1) and 136 (9%) had overt clinical nephropathy (UAE greater than 300 mg 24 h-1). The plasma concentration of cholesterol rose significantly with increasing urinary albumin excretion; normoalbuminuric 4.78 mmol l-1 +/- 1.06 (mean +/- SD); microalbuminuric: 5.12 mmol l-1 +/- 1.23 and macroalbuminuric: 4.89 mmol l-1 +/- 1.38 (p less than 0.001). The influence of metabolic control on the plasma level of cholesterol was of only minor clinical importance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria

In various renal diseases, including diabetic nephropathy, detection of podocytes in the urine indicates severe injury to podocytes in the glomeruli. Pioglitazone is a newly developed antidiabetic agent that attenuates insulin resistance. The aim of the present study was to determine whether pioglitazone affects urinary albumin excretion (UAE) or the number of urinary podocytes or both in type 2 diabetes patients with microalbuminuria. Twenty-eight patients with normotensive type 2 diabetes and microalbuminuria (18 men and 10 women; mean age, 52.5 years) and 30 age-matched normotensive controls (20 men and 10 women; mean age, 51.5 years) were included in the study. Urinary podocytes were detected by immunofluorescence with a monoclonal antibody against podocalyxin. Patients were randomly assigned to 2 groups: a pioglitazone-treatment group (30 mg/day, n = 14) and a placebo group (n = 14). Treatment was continued for 6 months. Podocytes were absent in the urine of healthy controls, but detected in 17 of 28 diabetic patients (60.7%). UAE was reduced from 96.7 +/- 50.5 microg/min to 39.7 +/- 22.9 microg/min (P <.01) in the pioglitazone-treatment group, and the number of urinary podocytes was reduced from 0.9 +/- 1.0 cells/mL to 0.1 +/- 0.2 cells/mL (P <.001). Neither UAE nor the number of urinary podocytes was affected in the placebo group. These data indicate that pioglitazone is effective for reducing UAE and podocyte injury in early-stage diabetic nephropathy.     

Progression of borderline increases in albuminuria in adolescents with insulin-dependent diabetes mellitus

We aimed to determine the natural history of borderline increases in albuminuria in adolescents with insulin-dependent (Type 1) diabetes mellitus (IDDM) and factors which are associated with progression to persistent microalbuminura. Fifty-five normotensive adolescents with IDDM and intermittent microalbuminura (overnight albumin excretion ratte of 20–200 μg min⁻¹ on one of three consecutive timed collections, n = 29) or borderline albuminura (mean overnight albumin excretion rate of 7.2–20 μg min⁻¹ on one of three consecutive timed collections, n = 30) were followed prospectively at 3 monthly intervals. The endpoint was persistent microalbuminuria defined as a minimum of three of four consecutive overnight albumin excretion rates of greater than 20 μg min⁻¹ . One hundred and forty-two adolescents with IDDM and normoalbuminura were also followed prospectively. Fifteen of the 59 patients (25.4 %) with intermittent (9/29) or borderline (6/30) albuminura progressed to persistent microalbuminura (progressors) over 28 (15–50) months [median (range)] in comparison with two of the 142 patients with normoalbuminuria at entry (relative risk =12.6; p =0.001). Progressors to persistent microalbuminura were pubertal and had higher systolic (p = 0.02) and diastolic (p = 0.02) blood pressure, and HbA_lc (p = 0.004) than non-progressors. All patients remained normotensive. Glomerular filtration rate, apolipoproteins, dietary phosphorus, protein and sodium intakes, and prevalence of smoking did not differ between progressors and non-progressors. Total renin was higher in the diabetic patients without a difference between progressors and non-progressors. In conclusion there is a relatively high rate of progression to persistent microalbuminuria in pubertal adolescents with borderline increases in albuminura and duration greater than 3 years. These patients require attention to minimize associated factors of poor metabolic control and higher blood pressure in the development of incipient nephropathy. © 1997 John Wiley & Sons, Ltd.     

Determinants of development of microalbuminuria in normotensive patients with type 1 and type 2 diabetes.

The purpose of this study was to identify the risk factors responsible for the development of microalbuminuria in diabetes. Two cohorts of 340 Type 1 and 258 Type 2 normotensive diabetic subjects were followed up for 24 months to evaluate progression to nephropathy. Sixteen Type 1 (4.7%) and 20 Type 2 (7.7%) patients developed persistent micro- or macroalbuminuria. Retinopathy, levels of glycated haemoglobin and the urinary albumin excretion rate (UAER) were indicative of progression in both cohorts. Cardiovascular disease in Type 1 and systolic blood pressure in Type 2 diabetes were the other risk factors. Logistic regression analysis showed that glycated haemoglobin levels [odds ratio (95% confidence interval) 2.08 (1.34, 3.21), p = 0.0007 in Type 1 and 1.77 (1.27, 2.45), p = 0.0005 in Type 2] and retinopathy [1.95 (1.09, 3.41), p = 0.02 in Type 1 and 2.87 (1.45, 5.69), p = 0.002 in Type 2] were risk factors in both cohorts. Male sex [2.06 (1.05, 4.03), p = 0.03] and the UAER [1.06 (1.001, 1.13), p = 0.04] in Type 1 patients, and systolic blood pressure [1.66 (1.05, 2.52), p = 0.02] in Type 2, were the other predictors. It is concluded that in normotensive Type 1 and Type 2 diabetic subjects glycemic control and retinopathy are the most important contributors to the development of incipient nephropathy.     

Efficacy of urinary N-acetyl-β-D-glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus: a cross-sectional study

We assessed the prognostic accuracy of urinary N-acetyl-β-D-glucosaminidase (NAG), an early proximal tubular damage marker for the onset of diabetic nephropathy. The study included 491 eligible participants with 76 healthy controls, 194 type 2 diabetes mellitus (T2DM) patients with 0–5, 5–10, 10–15, and 15–20 years of T2DM duration, 71 microalbuminuric patients, 100 diabetic nephropathy patients, and 50 non-diabetic nephropathy patients. Fasting glucose, serum fructosamine, HbA1C, urinary microalbumin, serum creatinine, estimated glomerular filtration rate (eGFR), serum NAG, and urinary NAG were estimated. We compared urinary NAG activity with other well-established markers of diabetic nephropathy like microalbuminuria, eGFR, and serum creatinine. Urinary NAG excretion was increased by 8 and 12 folds in T2DM patients of 10–15 and 15–20 years of diabetes duration (p < 0.0001), respectively, without the appearance of microalbuminuria. The urinary NAG activity increased 16 and 18 fold in moderately increased albuminuria and diabetic nephropathy patients, respectively (p < 0.0001), without any change in non-diabetic nephropathy patients. A cutoff value of 3 U/L of urinary NAG has demonstrated a sensitivity of 96.1 % and a specificity of 100 % discriminating healthy controls from patients with T2DM duration of 10–15 years (AUC 1.000) and 15–20 years (AUC 0.999); microalbuminuria (AUC 0.999), and diabetic nephropathy (AUC 1.000). Urinary NAG excretion gradually increases with the increase in duration of diabetes and appeared much before the microalbuminuria, decreased eGFR, and increased serum creatinine. Thus, the urinary NAG may be considered as a potential site-specific early tubular damage marker leading to diabetic nephropathy.

     

Microalbuminuria in Long-term Insulin-dependent Diabetes Mellitus

ABSTRACT Albumin excretion rate was determined by radioimmunoassay in overnight urine from 102 normotensive patients with insulin-dependent diabetes mellitus of more than 10 years' duration. Based on two samples, 16 patients (16%) exhibited microalbuminuria, defined as a mean excretion rate >20 μg/min. Microalbuminuric patients were significantly younger at onset of diabetes but did not differ from normoalbuminuric patients concerning age or duration of diabetes. Nonetheless, diastolic and mean arterial blood pressures were significantly higher in the microalbuminuric group. The existing glycemic control, assessed by glycosylated hemoglobin (HbA_1C) was better in normoalbuminurics, but not significantly so. The albumin excretion rate in microalbuminuric patients correlated significantly (p<0.01) to diastolic (r=0.69) and to mean arterial blood pressure (r=0.69), but did not correlate to HbA_1C. Thus, it is concluded that even normotensive patients with signs of early diabetic nephropathy, i.e. microalbuminuria, exhibit small, but significant increases in blood pressure.     

Transcapillary escape rate and relative metabolic clearance of glycated and non-glycated albumin in Type 1 (insulin-dependent) diabetes mellitus

Summary The transcapillary escape rate and relative plasma disappearance of glycated and non-glycated albumin were measured in 25 male Type 1 (insulin-dependent) diabetic patients using a double tracer technique. The patients were divided into three groups on the basis of their urinary albumin excretion: group 1, normal albumin excretion (<30 mg/24h) (n=8); group 2, microalbuminuria (30–300 mg/24 h) (n=9); and group 3, clinical nephropathy (>300 mg/24 h) (n=8). Six male age-matched non-diabetic persons served as control subjects. The transcapillary escape rate of glycated albumin was similar in group 1 and control subjects (4.7±2.1 versus 5.1±1.7%), but significantly increased in group2 (7.0±1.7%,p<0.05) and in group 3 (7.9±3.1%,p<0.05). The transcapillary escape rate of glycated albumin was slightly lower than that of non-glycated albumin in all groups, but significant only in normal control subjects. No difference in the catabolic rate of glycated and non-glycated albumin was found. We conclude that the in vivo effects of glycation on the clearance and transcapillary passage of albumin are small and not likely to play any significant role in the development of late diabetic microvascular complications.     

Assessment of microalbuminuria and glycated hemoglobin in type 2 diabetes mellitus complications

ObjectiveTo relate microalbuminuria with the degree of glycaemic control in type 2 diabetic patients and determine the prevalence of poor glycemic control amongst the normotensive diabetes mellitus (NDM) and hypertensive diabetes mellitus (HDM) with or without microalbuminuria.MethodsA total of 95 type 2 diabetes mellitus patients and 30 healthy controls were randomly selected and studied. 17 of the 95 patients were normotensive diabetic with microalbuminuria, 40 of them were HDM presenting with microalbuminuria and 38 were NDM without microalbuminuria. Their blood was obtained for fasting plasma glucose and glycated haemoglobin while their urine was obtained for albumin and creatinine estimation and the ratio was calculated.ResultsOut of the 95 diabetic patients studied, 57 (60%) of them had microalbuminuria while 38 (40%) had normoalbuminuria. The mean ages in the diabetics with microalbuminuria were higher than those without microalbuminuria (P=0.054 6). The mean glycated haemoglobin was the highest (5.95±2.06)% in NDM with microalbuminuria when compared with HDM with microalbuminuria (5.83±1.62)% and that in (5.66±2.49)% in NDM without microalbuminuria (P=0.000 9). Similarly, fasting plasma glucose was the highest (9.09±4.31) mmol/L in NDM with microalbuminuria than those without microalbuminuria (7.70±3.33) mmol/L (P=0.000 1). The prevalence of poor glycaemic control was the highest (29%) in NDM with microalbuminuria while the least (21%) in NDM without microalbuminuria.ConclusionsThe risk of microalbuminuria increases with poor glycemic control. Persistent increase in glycated haemoglobin may be an indicator of worsening albumin creatinine ratio and diabetic nephropathy. Therefore, regular screening for microalbuminuria in addition to continuous (3-monthly) glycated HbA1c estimation is advised.     

巯甲丙脯酸对糖尿病肾病蛋白尿、肾血浆流量和血浆过氧化脂质的影响

观察了30例伴微白蛋白尿或临床蛋白尿的NIDDM患者用Captopril或常规治疗4周后尿白蛋白及血浆过氧化脂质(LPO)水平的变化,结果表明,常规治疗后尿白蛋白无改变,而Captopril治疗后尿白蛋白减少,肾血浆流量增加,但尿白蛋白的减少与平均动脉压的降低无相关性。Captopril对肌酐清除率、血脂,血尿钾钠亦无明显影响。糖尿病患者血浆LPO水平高于健康对照者,Capropril治疗后降低,而常规治疗后无明显变化。以上结果提示,Captopril具有减少尿蛋白排泄及抗脂质过氧化作用。     

Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy

Microalbuminuria is a reliable predictor of the eventual development of overt diabetic nephropathy and blood pressure is known to accelerate the course of this nephropathy. In the present studies, the effect of a 6-week treatment by placebo (n = 7), nifedipine (n = 7) and captopril (n = 8) on renal function and urinary excretion of albumin (UAE) was investigated in normotensive, insulin-dependent, diabetic patients with incipient nephropathy (UAE greater than 15 micrograms/min). No change in arterial pressure, renal function or UAE was observed in the placebo group. In response to captopril and nifedipine, mean arterial pressure decreased slightly and similarly in both groups. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increased to a similar extent in the nifedipine group, thus resulting in no change in filtration fraction (FF). In response to captopril, GFR was unchanged whilst ERPF increased; as a consequence FF decreased. Opposite changes in UAE were observed in response to the two treatments; UAE decreased by 40% in the captopril group and by 40% in nifedipine-treated patients. These results indicate that intrarenal changes may be crucial with respect to the effect of therapy on UAE. It is suggested that only agents which reduce FF and probably intraglomerular capillary pressure, such as converting enzyme inhibitors, alter UAE and may possibly interfere with the course of incipient diabetic nephropathy in normotensive patients.     

Effects of Long-term Enalapril Treatment on Persistent Microalbuminuria in Normotensive Type 2 Diabetic Patients: Results of a 4-year,Prospective, Randomized Study

The beneficial effect of long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor on urinary microalbumin excretion (UAE) and renal function was investigated in a 4 year, randomized prospective study in normotensive patients with non-insulin-dependent (Type 2) diabetes mellitus. Sixty-two normotensive patients with Type 2 diabetes mellitus and microalbuminuria but normal renal function were randomized to receive either enalapril 5 mg day⁻¹ or no treatment. In the enalapril-treated patients, UAE was reduced from 115.4 ± 80.1 to 95.6 ± 61.7 mg 24 h⁻¹ after 12 months (p<0.05) and to 75.3 ± 44.8 mg 24 h⁻¹ after 48 months (p<0.001). In the untreated group, UAE increased slowly from 93.9 ± 69.9 to 150.0 ± 144.5 mg 24 h⁻¹ after 48 months. No changes in creatinine clearance, blood pressure or HbA_1C were seen in either group during the 4-year period. In normotensive Type 2 diabetic patients with early stage of diabetic nephropathy, the ACE inhibitor enalapril may have a beneficial effect by decreasing microalbuminuria. This effect is long-lasting and probably independent of the antihypertensive action of the drug.     

Microalbuminuria as Identified by a Spot Morning Urine Specimen in Non-insulin-treated Diabetes: an Eight-year Follow-up Study

This study followed up a cohort of patients with microalbuminuria identified on a spot morning urine sample 8 years earlier and aimed to determine if a spot morning urinary albumin concentration was able to identify patients with non-insulin treated diabetes at increased risk of mortality and progression to nephropathy. In 1984, 47 of 216 patients chosen by random selection from our teaching hospital-based diabetes clinic were identified as having microalbuminuria (urinary albumin concentration 35–300 μg ml^?1). Subjects were compared with an age-matched control group from the 1984 cohort who did not have microalbuminuria. Eight years later, 22 of 47 (46.8 %) patients with microalbuminuria had died compared to 10 of 47 (21.3 %) patients without albuminuria (p < 0.05). The majority of deaths were from cardiovascular disease (53.1 %). Logistic regression showed microalbuminuria to be an independent predictor of mortality, not influenced by age, duration of diabetes, blood pressure, glycosylated haemoglobin or creatinine at the initial examination. Eight years later, in the group with initial microalbuminuria, eight still had microalbuminuria and five patients had developed nephropathy. In the group without albuminuria in 1984, only one patient had progressed to microalbuminuria and no patients to nephropathy. In conclusion, a spot urinary albumin concentration is of value in identifying patients with an increased risk of mortality or progression to nephropathy, and is simple to obtain at a clinic.     

Glomerular epithelial foot processes and filtration slits in IDDM patients

Summary Diabetic nephropathy is associated with functional changes in the glomerular filtration barrier but the structural counterpart remains unknown. Width of glomerular epithelial cell foot processes and of filtration slits were determined by morphometric methods in 11 non-diabetic kidney donors and in 28 diabetic patients with albumin excretion rates ranging from normal to proteinuria. Foot process width was estimated from the ratio of tuft surface density to length density of slits. At high magnification independently sampled, perpendicularly cut slits were classified. Foot process width on peripheral basement membrane was increased in microalbuminuric compared to normoalbuminuric diabetic patients (p<0.05) but showed no significant correlation with the level of albumin excretion when patients with increased barrier permeability were considered. Width of filtration slits in normo- and microalbuminuric diabetic patients exceeded that in non-diabetic control subjects (p<0.05). Filtration slits were narrower in patients with overt proteinuria than in patients with microalbuminuria (p<0.05) and correlated with glomerular filtration rate in all of the diabetic patients (r=0.65, p<0.005). The results show that insulin-dependent diabetic patients with nephropathy present changes of epithelial cells and filtration slits, demonstrable already in the stage of microalbuminuria. The mechanism of albumin leakage is not achieved by these measures. The dimension of filtration slits may play a contributing role in the level of glomerular filtration rate in diabetic patients.Abbreviations IDDM Insulin-dependent diabetes mellitus - GFR glomerular filtration rate - AER albumin excretion rate - HbA_1c glycated haemoglobin - ND non-diabetic control subjects - D_NA diabetic patients with normal albumin excretion rate - D_MI diabetic patients with microalbuminuria - D_P diabetic patients with proteinuria - CV coefficient of variation (SD/mean) - FPW_PBM width of foot processes on peripheral basement membrane - FPW_MES width of foot processes on glomerular mesangium - ANOVA analysis of variance - PBM peripheral basement membrane     

Reduced urinary excretion of epidermal growth factor in incipient and overt diabetic nephropathy

To study the relationship between glomerular and tubular function we investigated glomerular filtration rate (GFR), urinary albumin excretion, and urinary excretion of epidermal growth factor (EGF, a mitogenic peptide synthesized in the renal tubular cells) in normal subjects (group I, n = 7) and in Type 1 (insulin-dependent) diabetic patients with normoalbuminuria (group II, n = 11); with incipient nephropathy (microalbuminuria) (group III, n = 9); with nephropathy and normal GFR (group IV, n = 12); and with reduced GFR (group V, n = 8). EGF (nmol 24 h-1) decreased with progressive glomerular involvement, from 7.9 (4.1-10.5) (median and range) in group I, to 6.7 (1.3-9.2) in group II, 5.0 (3.6-7.4) in group III, 4.1 (2.5-9.5) in group IV, and 1.1 (0.1-2.5) in group V. The urinary excretion of EGF was significantly reduced in patients with elevated UAE (group III, IV, and V) compared with normal control subjects (p less than 0.05). A significant correlation between urinary excretion of EGF and GFR (r = 0.71, p less than 0.001) and an inverse correlation between the urinary excretion of EGF and albumin (r = -0.35, p less than 0.05) was demonstrated in the Type 1 diabetic patients with GFR greater than 90 ml min-1. Our study demonstrates that urinary excretion of epidermal growth factor diminishes with increasing nephron impairment, and that renal tubular function as judged by the excretion of EGF is reduced early in the development of diabetic kidney disease.