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.     

Prior long term glycaemic control and insulin therapy in insulin-dependent diabetic adolescents with microalbuminuria

Adolescence seems to be a period of increased risk for the initiation of diabetic renal disease in insulin-dependent diabetic children. Poor glycaemic control is a risk factor for diabetic nephropathy. We have therefore evaluated prior long-term glycaemic control in 23 diabetic adolescents with microalbuminuria (albumin excretion rate (AER) 20-200 micrograms/min, median 39.0 micrograms/min) and in 23 matched diabetic controls with AER less than 20 micrograms/min (median 9.3 micrograms/min). Glycaemic control was assessed by mean HbA1 and clinic blood glucose levels over a period ranging from 12 to 84 months (median 48 months). Mean HbA1 was 13.6 +/- 2.0% in the microalbuminuric subjects, compared to 11.5 +/- 2.2% in the controls (P less than 0.002); mean blood glucose levels were 13.5 +/- 3.0 and 11.4 +/- 3.0 mmol/l, respectively (P less than 0.02). There appeared to be a 'threshold effect' (mean HbA1 greater than 12.0%), above which the development of microalbuminuria was more likely. More patients with microalbuminuria than controls had been treated with a single rather than twice-daily insulin injections (P less than 0.001), and glycaemic control was significantly worse in patients treated with one injection. We conclude that poor long term glycaemic control is a risk factor for microalbuminuria, and that improving control during childhood is likely to reduce the prevalence of later microalbuminuria. Two insulin injections, of combined intermediate and short-acting preparations, are more likely to provide better control than a single daily insulin dose.     

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.

     

Correlation between urinary activity of N-acetyl-β-d-glucosaminidase (NAG) and albumin excretion rate in type II (non-insulin-dependent) diabetic subjects

Summary Different kidney diseases are often associated with high urinary excretion of N-acetyl-β-D-glucosaminidase (NAG), a lysosomal enzyme involved in the breakdown of glycoproteins, whose activity is also increased in diabetic patients with poor metabolic control or vascular complications. In order to evaluate the relationship between renal function and urinary NAG levels in diabetes mellitus, 30 type II diabetic patients without evidence of kidney disease and 18 control subjects were studied. In each subject 24-h urinary excretion rates of NAG (fluorimetric method), albumin and β₂-microglobulin (radioimmunoassay), together with⁵¹Cr-EDTA clearance were performed. In diabetic patients urinary levels of NAG (356±25vs 162±9.2 nmol/h/mg creatinine, p<0.0001) and albumin (21±2.5vs 4.3±0.5 mg/24h, p<0.0001) were significantly higher than in the controls, while β₂-microglobulin levels and⁵¹Cr-EDTA clearance did not differ in the two groups. Moreover in diabetic patients NAG and albumin levels were positively and significantly correlated (r=0.63, p<0.001). These results suggest that urinary NAG excretion rate may be altered early in diabetic patients with apparently normal renal function; its diagnostic value seems to be similar to that of the albumin excretion rate.     

Urinary N-acetyl-β-D-glucosaminidase (NAG) activity in the early detection of diabetic nephropathy

One of the serious outcomes of diabetes mellitus is nephropathy. Measurement of microalbuminuria is a routine clinical practice for screening the diabetic nephropathy, but the injury to the kidney may be happening even without microalbuminuria. The association between urinary enzyme activities of N-acetyl-β-D-glucosaminidase (NAG) and angiotensin converting enzyme (ACE) and urine microalbumin was assessed in this study to define the possible biofactor for detection of early diabetic nephropathy. Urinary enzyme activities of NAG and ACE and urine microalbumin of 24 h, serum ACE, and some other clinical features are investigated in 35 type 2 diabetic patients. Glycated hemoglobin (HbA1c), triglycerides, serum ACE, and urine NAG were significantly elevated in diabetic groups compared to the healthy controls. There was no relation between urine NAG and microalbuminuria except in the group of diabetic patients which had urine NAG activity upper than 25 IU/ml; there was a correlation between urine NAG and serum ACE. We may conclude that before the finding of microalbumin in urine, the elevated urine NAG, as an early indicator of renal damage, is associated with serum ACE which is related to kidney vascular microangiopathies.     

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.     

Urinary transferrin excretion in type 1 (insulin-dependent) diabetes mellitus.

Urinary excretion of transferrin and albumin was studied by radioimmunoassay in 47 adult patients with Type 1 diabetes and 28 control subjects. Median (range) urinary transferrin excretion rate was significantly elevated in the diabetic group 0.58 (0.02-2663.3) micrograms min-1 compared with the control group 0.04 (0.01-0.28) micrograms min-1, p less than 0.001. Urinary transferrin:creatinine ratios (x 10(2)) were different in diabetic 47 (0.6-958.0) micrograms mmol-1 and control groups 0.7 (0.06-2.3) micrograms mmol-1, p less than 0.001). There were correlations between urinary transferrin and albumin excretion rates in diabetic (r = 0.78, p less than 0.001) and control groups (r = 0.81, p less than 0.05). Forty (85%) diabetic patients had elevated transferrin excretion rates, 18 (38.3%) had elevated albumin excretion rates. All diabetic patients with elevated albumin excretion rates had elevated transferrin excretion rates. Twenty-one (77.8%) of the patients with normal albumin excretion rates had elevated transferrin excretion rates. Urinary excretion of N-acetyl-beta-D-glucosaminidase was greater in diabetic patients than control subjects (142 vs 58 mumol h-1 l-1, p less than 0.001). There were correlation between transferrin and N-acetyl-beta-D-glucosaminidase excretion (r = 0.67, p less than 0.01) and albumin and N-acetyl-beta-D-glucosaminidase excretion (r = 0.63, p less than 0.01) in the diabetic group. Elevated urinary transferrin excretion rate may be a marker for renal dysfunction in diabetes mellitus.     

Elevated urinary prostaglandin excretion and the effect of indomethacin on renal function in incipient diabetic nephropathy

We investigated whether the glomerular synthesis of prostaglandins modulates the glomerular filtration rate and urinary albumin excretion in incipient diabetic nephropathy (defined as urinary albumin excretion between 30 and 300 mg/24 h (microalbuminuria) in two out of three sterile ketone-free 24-h urine collections in patients having insulin-dependent diabetes mellitus (IDDM) without hypertension or other kidney disease). The urinary excretion of prostaglandin E2 was significantly elevated in 8 insulin-dependent diabetic patients with incipient nephropathy as compared with 9 normoalbuminuric IDDM patients and 11 healthy controls: 317 (182-1273); 95 (67-225); 132 (54-263) pg/min, respectively (2p less than 0.01). Glomerular filtration rate (single bolus 51Cr-EDTA technique) and albuminuria (radioimmunoassay) were measured twice within 2 weeks in 8 females having IDDM with incipient nephropathy. The study design was a randomized double-blind trial with the patients receiving either indomethacin (150 mg/day) or placebo for 3 days prior to the kidney function studies. Indomethacin treatment induced a significant reduction in urinary prostaglandin E2 excretion (73%) (2p less than 0.01), urinary albumin excretion rate diminished from 207 (63-253) to 87 (49-147) mg/24 h (2p less than 0.01), fractional clearance of albumin declined (70%) (2p less than 0.01). Glomerular filtration rate remained stable (108 (88-133) versus 110 (95-142) ml/min). Blood glucose and blood pressure were comparable during the placebo and indomethacin treatment (12.6 +/- 3 versus 13.4 +/- 5 mmol/l and 122/79 +/- 3/9 versus 122/82 +/- 4/10 mmHg, respectively). Our results suggest that enhanced glomerular synthesis of vasodilating prostaglandins may accelerate microalbuminuria in incipient diabetic nephropathy.     

Lipid pattern,apolipoproteins A1 and B and lipoprotein (a) in type 1 diabetic patients with microalbuminuria

The plasma lipid changes commonly observed in patients with diabetic nephropathy may play a major role in determining the increased cardiovascular risk in these patients. Contrasting results have been reported on the patterns of lipids and lipoproteins in diabetic subjects with microalbuminuria. We examined 20 patients with type 1 (insulin-dependent) diabetes who had a urinary albumin excretion >30 mg/24 h (11 males and 9 females, age range 16–45 years, mean diabetes duration 11.7 years) and 20 type 1 diabetic patients without microalbuminuria matched for sex, age, diabetes duration, daily insulin requirement and degree of metabolic control. In all patients we measured plasma total cholesterol, highdensity lipoprotein (HDL)-cholesterol, triglycerides, apolipoproteins A₁ and B and lipoprotein (a) [Lp(a)]. No significant differences were found for any parameter between subjects with a urinary albumin excretion <20 mg/ 24 h and microalbuminuric patients. Moreover in nondiabetic controls the levels of plasma Lp(a) and of the other parameters measured were not significantly different from those of the two diabetic groups. Our results suggest that in type 1 diabetic patients with fairly good glycaemic control microalbuminuria is not associated with significant changes in the lipoprotein pattern.     

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)     

Muscle protein breakdown in uncontrolled diabetes as assessed by urinary 3-methylhistidine excretion

Summary In an attempt to evaluate muscle protein catabolism in patients with uncontrolled diabetes, urinary excretion of 3-methylhistidine was measured in eight diabetic subjects, during poor control and after achievement of satisfactory control. The results were compared with the excretion values of ten healthy subjects fed a similar amount of meat. In the diabetic patients in poor metabolic control, 3-methylhistidine excretion was significantly increased compared with the healthy subjects, and returned to normal when a satisfactory glycaemic control was achieved. No significant differences were observed between ketonuric and non-ketonuric uncontrolled patients. Improved glycaemic control reduced 3-methylhistidine excretion in both insulin-dependent and non-insulin-dependent diabetes. These results suggest increased protein catabolism causing muscle protein loss and negative nitrogen balance in diabetic patients with poorly controlled disease.     

Endothelins and markers of renal damage in recently diagnosed hypertensive patients

Endothelin has been identified as a potent vasoconstrictor. The aim of this study was to evaluate urinary endothelins and their relation to other markers of renal damage, such as microalbuminuria, creatinine, and N-acetyl-beta-glucosaminidase (NAG), in a group of recently diagnosed (less than 1 year) hypertensive subjects and a control group. We selected 50 subjects and divided them into two groups: 27 hypertensive patients (15 females and 12 males) without previous pharmacologic therapy, and 23 healthy, normotensive subjects (12 females and 11 males). All patients underwent a history and physical examination, chest x-ray, electrocardiography, funduscopy, and hematologic and biochemical analyses. Endothelins, microalbuminuria, creatinine, and NAG values were also determined in 24-hour urine samples. Creatinine, microalbuminuria, and NAG values were found to be higher in hypertensive than in normotensive subjects. The hypertensive group showed a nonsignificant elevation of total endothelin. In conclusion, the determination of elevated urinary endothelin does not appear to be an early marker of organ damage in hypertensive subjects. The urinary excretion of protein, creatinine, and NAG was higher in hypertensive subjects. A positive correlation was found between the urinary excretion of endothelins and markers of renal damage, microalbuminuria and NAG values. The relationship between endothelins and hypertension was without statistical significance.     

Endothelins and Markers of Renal Damage in Recently Diagnosed Hypertensive Patients

Endothelin has been identified as a potent vasoconstrictor. The aim of this study was to evaluate urinary endothelins and their relation to other markers of renal damage, such as microalbuminuria, creatinine, and N-acetyl-β-glucosaminidase (NAG), in a group of recently diagnosed (less than 1 year) hypertensive subjects and a control group. We selected 50 subjects and divided them into two groups: 27 hypertensive patients (15 females and 12 males) without previous pharmacologic therapy, and 23 healthy, normotensive subjects (12 females and 11 males). All patients underwent a history and physical examination, chest x-ray, electrocardiography, funduscopy, and hematologic and biochemical analyses. Endothelins, microalbuminuria, creatinine, and NAG values were also determined in 24-hour urine samples. Creatinine, microalbuminuria, and NAG values were found to be higher in hypertensive than in normotensive subjects. The hypertensive group showed a nonsignificant elevation of total endothelin. In conclusion, the determination of elevated urinary endothelin does not appear to be an early marker of organ damage in hypertensive subjects. The urinary excretion of protein, creatinine, and NAG was higher in hypertensive subjects. A positive correlation was found between the urinary excretion of endothelins and markers of renal damage, microalbuminuria and NAG values. The relationship between endothelins and hypertension was without statistical significance.     

Urinary Infection and Albumin Excretion in Insulin-dependent Diabetes Mellitus: Implications for the Measurement of Microalbuminuria

The frequency of urinary infection was determined using quantitative microbiology in 172 insulin-dependent diabetic patients repeatedly being tested for microalbuminuria over 18 months on at least six occasions. The point prevalence of urinary infection at first screening for microalbuminuria was 3 %. Over the period of study, 20 of the patients (12 %) showed evidence of urinary infection, defined as a pure growth of a recognized pathogen >10⁷ l⁻¹. Infection was more common in women than men (20 % vs 5 %, p<0.01) and was significantly associated with the presence of peripheral neuropathy (p<0.05). Infection was not related to patient age, duration of diabetes, glycaemia, blood pressure, retinopathy or autonomic neuropathy. There were no significant within-patient differences in albumin excretion, glycaemic control or blood pressure in relation to the presence and absence of urinary infection. In only one patient (5 %) did urinary infection significantly increase the urinary albumin excretion and this was associated with pyuria. We conclude that the presence of urinary infection does not apparently affect the measurement of urinary albumin excretion unless pyuria is present. Unless diabetic patients are symptomatic, examination of the urine for infection is probably unwarranted when testing for microalbuminuria.     

Increase of activity of angiotensin-converting enzyme in insulin-dependent diabetic patients with permanent microalbuminuria]

Angiotensin I Converting Enzyme (ACE), which is synthesized by vascular endothelial cells, can be elevated in some diabetic subjects. To study if serum ACE can be elevated in subjects with high risk for malignant microangiopathy, 34 normotensive type I, insulin-dependent diabetic subjects with persistent microalbuminuria (30-300 mg/24 h) were compared for serum ACE activity (Liebermann's method) with 30 normotensive, normoalbuminuric type I, insulin-dependent diabetic subjects of same age (33 +/- 15 (M +/- SD) vs 39 +/- 14 years), sex (13 F/21 M vs 15 F/15 M), stage of retinopathy (14 vs 16 nil/11 vs 7 background/6 vs 4 preproliferative/3 vs 3 proliferative), HbA1c (7.7 +/- .9 vs 8.2 +/- 1.0%). Serum ACE activity of diabetic subjects were also compared with 120 age and sex related healthy controls. Serum ACE activity was higher in type I, insulin-dependent diabetic subjects with microalbuminuria than in those with normoalbuminuria (406 +/- 114 vs 359 +/- 97 IU/l; p = 0.05), or in controls (307 +/- 95 IU/l; p = 0.0001). Normoalbuminuric subjects also had higher ACE activity than controls (p = 0.02). In diabetic subjects, serum ACE activity was not related to diabetes duration (r = 0.1; ns), stage of retinopathy (r = 0.06; ns), HbA1c (r = 0.02; ns), or to blood pressure (r = 0.03; ns), but was related to urinary albumin excretion (r = 0.28; p = 0.03) in diabetic subjects. However, stage of retinopathy was related to diabetes duration (r = 0.74; p = 0.0004) and to age (r = 0.42; p = 0.003) in these subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary growth hormone excretion during puberty in type 1 (insulin-dependent) diabetes mellitus

The excretion of urinary growth hormone was measured by a highly sensitive direct immunoradiometric assay in a cross-sectional study during puberty in 70 children with Type 1 (insulin-dependent) diabetes mellitus and 94 normal children. In normal children (n = 24) and diabetic children (n = 17) overnight urinary growth hormone excretion correlated significantly with the mean overnight plasma concentration (r = 0.70, p less than 0.001, and r = 0.70, p less than 0.001), indicating that urinary GH excretion reflects the circulating endogenous GH level. Overnight urinary growth hormone excretion increased during puberty. In normal and in diabetic children there was a peak in boys at genital stage 4 (both p less than 0.01), and in girls at breast stage 2 (both p less than 0.02). The diabetic children excreted more urinary growth hormone than the normal children at every pubertal stage. Excretion of albumin, retinol binding protein and N-acetyl-beta-D-glucosaminidase was measured in urine from 38 diabetic children. Urinary growth hormone correlated weakly with urinary albumin (r = 0.49, p less than 0.01), retinol binding protein (r = 0.42, p less than 0.01), and N-acetyl-beta-D-glucosaminidase (r = 0.43, p less than 0.01). Urinary GH excretion was not related to blood glucose control (HbA1) in boys (n = 31) or girls (n = 39). The measurement of urinary growth hormone provides an assessment of endogenous growth hormone during puberty in normal and diabetic children. However, caution must be exercised in interpreting urinary growth hormone data from diabetic patients with increased excretion of albumin and retinol binding protein.     

Estimation of B-cell function by the urinary excretion rate of C-peptide in diabetic patients: comparison with C-peptide response to glucagon and to a mixed meal

This study examined the relationship between the C-peptide response to intravenous glucagon and mixed meal stimulation and the 24 h urinary excretion rate of C-peptide and its urinary excretion during the glucagon test in nine control subjects, eighteen Type 1 (insulin-dependent) and twenty-two Type 2 (non-insulin-dependent) diabetic patients. Compared to controls (61.0 +/- 7.1 micrograms), the 24-h urine excretion rate of C-peptide was 8.2 +/- 3.1 micrograms (p less than 0.001) in Type 1 and 89.8 +/- 12.9 micrograms (p = NS) in Type 2 diabetic patients. C-peptide urinary excretion rate during the glucagon test was 6.92 +/- 1.11 micrograms, 0.42 +/- 0.10 microgram (p less than 0.001) and 6.47 +/- 1.13 micrograms (p = NS) respectively. Fasting serum C-peptide values were 1.53 +/- 0.16 ng/ml in controls, 0.42 +/- 0.09 ng/ml in Type 1 (p less than 0.0001) and 2.08 +/- 0.22 ng/ml in Type 2 diabetics (p = NS); C-peptide areas under the curve after glucagon stimulation were, respectively, 241.6 +/- 20.3 ng/ml, 29.2 +/- 5.9 ng/ml (p less than 0.0001) and 170.9 +/- 17.9 ng/ml (p less than 0.03) and after the meal test they were 204.7 +/- 15.6, 68.7 +/- 19.8 ng/ml (p less than 0.0001) and 265.5 +/- 32.9 ng/ml (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

A six-year follow-up of the relationship between N-acetyl-beta-glucosaminidase and albuminuria in relation to retinopathy.

Fifty patients with Type 1 diabetes mellitus were observed over 6 years. Serum and urinary N-acetyl-beta-glucosaminidase (NAG) activity, and albuminuria were measured in groups of patients subdivided according to ophthalmological findings. Significantly higher mean serum NAG activity was found at the beginning of the study in patients who later developed diabetic retinopathy in comparison with those who did not (geometric mean (2SD range) 19.7 (12.4-31.2) vs 14.4 (9.5-22.7) U l-1, p less than 0.01). Urinary NAG activity was significantly higher in all groups of diabetic patients than in healthy control subjects (p less than 0.05). A significant increase in albumin:creatinine ratio during the study was found in patients with newly developed diabetic retinopathy compared with patients who did not (at 6 years 1.33 (0.40-4.43) vs 0.75 (0.24-2.31) g mol-1, p less than 0.01). No differences in either biochemical variable were found between hypertensive and normotensive diabetic patients at the end of the study. The results suggest that both serum NAG activity and albuminuria may serve as early functional indicators of diabetic retinopathy.     

Further evidence for tubular dysfunction in insulin dependent diabetes

There is evidence that increased excretion of urinary enzymes and low-molecular mass proteins indicate impaired tubular function. The excretion of N-acetyl-beta-d-glucosaminidase (NAG), lysozyme, and ribonuclease in Type I diabetic patients with (n = 19) and without (n = 17) persistent proteinuria (urinary protein excretion > 0.5 g/day) was investigated and compared with this exretion in 30 weight- and gender-matched nondiabetic subjects without renal disease. Urinary NAG excretion was significantly higher in diabetic patients with and without persistent proteinuria (1.16 ± 0.09 and 3.19 ± 1.2 Umol/L creatinine, respectively) compared to controls (0.37 ± 0.03 Umol/L creatinine p < 0.01). In addition, the urinary excretion of lysozyme and ribonuclease was significantly increased in diabetic patients. Urinary NAG was found to correlate positively with albuminuria and proteinuria (r = 0.95 and 0.93, respectively), as well as with ribonuclease and lysozyme (r = 0.93 and 0.60; p < 0.01) in patients with persistent proteinuria. Furthermore, NAG excretion was significantly related to the duration of diabetes (r = 0.36; p < 0.05). No relationship existed between urinary NAG and serum creatinine, beta-2-microglobulin, and degree of metabolic control (HbA₇). The lysozyme excretion, but not NAG excretion, was significantly related to hypertension in patients with clinical proteinuria. In conclusion, our results suggest a relationship between the development of tubular dysfunction and the impairment of glomerular function in diabetic nephropathy. An increased excretion of NAG and low-moecular mass proteins may indicate early nephropathy.     

The Natural Course of Microalbuminuria in Insulin-dependent Diabetes: A 10-year Prospective Study

The purpose of this study was to describe the clinical course in patients followed right from the onset of microalbuminuria to the development of diabetic nephropathy. A 10-year prospective follow-up of 209 consecutive normotensive insulin-dependent diabetic patients with normal urinary albumin excretion (UAE <30 mg 24 h^?1), age 34 (18–50) years and duration of diabetes 17 (10–30) years was performed. Twenty-four-hour urinary albumin excretion was measured every 4 months, glycated haemoglobin and supine blood pressure was measured annually. Two-hundred (96%) patients completed 10 (range 5–10) years follow-up. Twenty-nine (15%) patients developed persistent microalbuminuria (UAE 30–300 mg 24 h^?1). Eight of these have progressed to nephropathy and one had died of diabetic nephropathy. Multiple stepwise logistic regression analysis demonstrated baseline urinary albumin excretion (p = 0.0016) and glycated haemoglobin (p = 0.0014) but not blood pressure as predictors of development of microalbuminuria within the following 10 years. The median annual increase in urinary albumin excretion was 27 (range 17–65)% in the 29 patients developing microalbuminuria. The median duration from onset of microalbuminuria to development of nephropathy was 7 years. The prevalence of patients receiving antihypertensive treatment (BP > 140/90 mmHg) increased from 10% at onset of microalbuminuria to 45% 4 years after onset of microalbuminuria. The prevalence of patients with proliferative retinopathy increased from 7% at onset of microalbuminuria to 28% 4 years after onset of microalbuminuria. The incidence of persistent microalbuminuria in normotensive insulin-dependent diabetic patients is 2% per year, and development of persistent microalbuminuria is a strong predictor of overt nephropathy. Development of hypertension is frequent in the early course of microalbuminuria and treatment modalities for normotensive patients with microalbuminuria are urgently needed.