Increased plasma concentration of von Willebrand factor in insulin dependent diabetics with incipient nephropathy.
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Biomedical subjects
Publications and source records attributed to T Jensen.
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Albuminuria in Type 1 (insulin-dependent) diabetes is not only an indication of renal disease, but a new, independent risk-marker of proliferative retinopathy and macroangiopathy. The coincidence of generalised vascular dysfunction and albuminuria, advanced mesangial expansion, proliferative retinopathy, and severe macroangiopathy suggests a common cause of albuminuria and the severe renal and extrarenal complications associated with it. Enzymes involved in the metabolism of anionic components of the extracellular matrix (e.g. heparan sulphate proteoglycan) vulnerable to hyperglycaemia, seem to constitute the primary cause of albuminuria and the associated complications. Genetic polymorphism of such enzymes is possibly the main reason for variation in susceptibility.
The urinary excretion of albumin and retinol binding protein were measured in 51 recently diagnosed Type 1 diabetic patients and 48 control subjects, matched for age and sex. The diabetic patients, admitted consecutively to the Steno Memorial Hospital, were all studied 3 to 6 months after the onset of diabetes. Urinary albumin excretion (median and 95% confidence interval) was similar in the diabetic patients and normal control subjects (8 (6-11) vs 8 (6-11) mg 24-h-1, NS). Four diabetic patients had urinary albumin excretion in the microalbuminuric range of 30-300 mg 24-h-1. There was no significant difference between the two groups in urinary excretion of retinol binding protein. The distribution among the individuals of both urinary proteins was positively skewed and similar in the two groups. In conclusion, no significant differences in the urinary excretion of albumin and retinol binding protein were found between recently diagnosed Type 1 diabetic patients and normal subjects.
We compared sodium phosphotungstic acid and magnesium chloride precipitation method for high-density lipoprotein (HDL) cholesterol quantitation with the ultracentrifugation method in 64 insulin-dependent diabetic patients with plasma triglyceride less than 3 mmol/l. The cholesterol content of HDL after precipitation of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) was 86% +/- 3% of the cholesterol content of HDL (q greater than 1.063) determined after ultracentrifugation at q = 1.063 (1.33 +/- 0.05 mmol/l vs 1.55 +/- 0.06 mmol/l; p less than 0.001). HDL cholesterol determined after precipitation closely correlated to HDL cholesterol determined after ultracentrifugation (r = 0.97; p less than 0.001). The absolute difference between the HDL cholesterol values obtained by the two methods was correlated to HDL cholesterol (ultracentrifugation) (r = 0.75; p less than 0.001), but it was not correlated to VLDL cholesterol, LDL cholesterol, triglyceride, HbA1c, blood glucose or serum albumin. LDL cholesterol calculated by use of Friedewald's formula was 108% +/- 4% of the cholesterol content of LDL (q = 1.019 to 1.063), determined after ultracentrifugation, but the calculated and the ultracentrifugally determined LDL cholesterol values were closely correlated (r = 0.98; p less than 0.001). These results suggest that during sodium phosphotungstic acid and magnesium chloride precipitation of plasma from diabetic patients, a constant fraction of HDL cholesterol is co-precipitated, resulting in a systematic difference in HDL cholesterol quantitation when compared with the ultracentrifugation method.
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A highly sensitive enzyme linked immunoadsorbent assay for determining retinol-binding protein in urine and serum is described. Commercially available reagents are used. The standard curve ranges from 1.2-24 micrograms/l, recovery of retinol-binding protein added to urine was 99-102% (n = 10) and dilution of urine was linear. The within-assay coefficient of variation ranged from 1.2-3.1% and the day-to-day coefficient of variation from 9.2-10.5% depending on concentration. The correlation with urinary retinol-binding protein determined by radioimmunoassay was good (n = 90, r = 0.95). In vitro experiments show that retinol-binding protein is stable in urine with pH 5.2.
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To assess whether decreased aerobic work capacity was associated with albuminuria in insulin dependent diabetics aerobic capacity was measured in three groups of 10 patients matched for age, sex, duration of diabetes, and degree of physical activity. Group 1 comprised 10 patients with normal urinary albumin excretion (less than 30 mg/24 h), group 2 comprised 10 with incipient diabetic nephropathy (urinary albumin excretion 30-300 mg/24 h, and group 3 comprised 10 with clinical diabetic nephropathy (urinary albumin excretion greater than 300 mg/24 h). Ten non-diabetic subjects matched for sex, age, and physical activity served as controls. Oxygen uptake was similar in the four groups at rest and during a 75 W workload. Maximal oxygen uptake was also similar in the control subjects and group 1 (median 41.7, (range 29.1-53.0) ml/kg/min v 38.5 (26.6-59.2) ml/kg/min, respectively), but was significantly lower in group 2 (27.7 (13.9-44.3) ml/kg/min) and group 3 (22.6-36.7) ml/kg/min). The difference in maximal oxygen uptake between groups 1 and 2 was 10.8 ml/kg/min (95% confidence interval 3.6 to 23.4 ml/kg/min) and between groups 1 and 3, 11.7 ml/kg/min (4.9 to 22.5 ml/kg/min). These differences were not explained by differences in metabolic control or the degree of autonomic neuropathy. Thus the insulin dependent diabetics with only slightly increased urinary albumin excretion had an appreciably impaired aerobic work capacity which could not be explained by autonomic neuropathy or the duration of diabetes. Whether the reduced capacity is due to widespread microangiopathy or another pathological process affecting the myocardium remains to be established.
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Type 1 (insulin-dependent) diabetic patients with clinical nephropathy have a more than ten-fold increase in mortality of cardiovascular diseases compared with diabetic patients without nephropathy. The risk factors for cardiovascular disease, plasma concentrations of lipoproteins and fibrinogen, were investigated in 74 long-term diabetic patients: 37 with normal urinary albumin excretion, 20 with incipient nephropathy and 17 with overt clinical nephropathy based on urinary albumin excretion. The groups were matched according to sex, age and diabetes duration. The concentration of plasma cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride and fibrinogen rose with increasing urinary albumin excretion. The plasma concentrations of these lipoproteins and fibrinogen were 11-14% higher in the patients with incipient nephropathy and 26-87% higher in the patients with overt clinical nephropathy compared with the patients without nephropathy. The plasma concentration of high density lipoprotein cholesterol was unaffected by albuminuria. Patients with normal urinary albumin excretion and HbA1c greater than 8.0% had significantly higher very low density lipoprotein- and lower high density lipoprotein cholesterol concentrations compared with patients with HbA1c less than 8.0%. Simple addition of the described risk factors can only account for a minor part of the greatly increased cardiovascular mortality in patients with diabetic nephropathy. An additional and possibly more decisive factor might be a change in the arterial wall, a change which promotes lipid accumulation and/or facilitates thrombus formation.
Seven to ten percent of patients with cystic fibrosis had serum antibodies to the catalase antigen of Aspergillus fumigatus in three cross-sectional surveys between 1977 and 1984. A total of 208 patients participated at least once, and the cumulated frequency of catalase antibodies in 94 patients included in all three surveys was 16%. The titre range was 1 to 16. The prevalence rate of Aspergillus fumigatus in sputum was 50% for a 2.5-year observation period. Catalase antibodies were strongly associated with the occurrence of Aspergillus fumigatus in sputum (p = 0.003), and the microorganism was more numerous in colonized patients with catalase antibodies than in those without such antibodies (p = 0.004). Patients with Aspergillus fumigatus in sputum and a positive catalase antibody test tended to have an adverse development as regards lung function compared to both carriers without antibodies and non-carriers. The observed differences could not, however, be related to different rates of chronic Pseudomonas aeruginosa infection.
The concentrations of IgG subclass immunoglobulins were determined by radial immunodiffusion in serum from 126 patients with cystic fibrosis (CF). The results were compared to values from age-matched healthy children and adults and correlated to patients age, duration of chronic Pseudomonas aeruginosa infection and lung function parameters. Fifty-two percent of the patients had an elevated concentration of at least one of the IgG subclasses; IgG1 28%, IgG2 16%, IgG3 18% and IgG4 48%. There was significant correlation between elevated serum levels of IgG2, and to a lesser extent IgG3, with decreased lung function (for FEV1; p = 0.0001, and p = 0.001 respectively) and high levels of antipseudomonas precipitins (p = 0.008, and p = 0.002). A similar correlation was not found for IgG1 and IgG4. IgG subclasses vary in their ability to promote phagocytosis and to activate complement and it is possible that individual differences in the IgG subclass pattern could explain the variable course of this disease.
N-acetylcysteine (NAC) is known to be a scavenger of free oxygen radicals, and recent in vitro studies have demonstrated that it is also able to inhibit leukocyte function. The clinical significance of these effects is, however, not known. In this study we have measured the effect on human blood neutrophil and monocyte function of a single 400 mg dose of NAC administered orally. Administration of NAC to ten healthy volunteers resulted in significant reduction of neutrophil chemiluminescence response following activation by opsonized zymosan as compared to four non-treated persons acting as controls. No effect was observed on the chemotaxis of either cell type or on monocyte chemiluminescence response. These findings suggest that NAC may be beneficial in clinical conditions like cystic fibrosis, where tissue damage may be a consequence of the effects of increased release of toxic oxygen radicals and proteolytic enzymes.
A 5.5-year survey revealed 9 patients with allergic bronchopulmonary aspergillosis (ABPA) and 1 patient with a highly probable diagnosis among 200 Danish patients with cystic fibrosis (CF). The incidence of ABPA was 0.9 (0.4-1.7, 95% confidence limits) per 100 patients per year. All the patients with definite or probable ABPA had serum antibodies to the Aspergillus fumigatus catalase antigen, and in 5 patients the appearance of catalase antibodies during the incipient phase of ABPA was documented. 29 patients without ABPA also had catalase antibodies, but in lower levels than ABPA patients (p = 0.006). The 6-month prevalence rate of A. fumigatus in sputum was 80 and 72% in the 2 groups, respectively. The finding of catalase antibodies in some CF patients without ABPA may indicate the occurrence of a symptom-poor form of pulmonary aspergillosis.