Differentiation of glomerular, tubular, and normal proteinuria: determinations of urinary excretion of beta-2-macroglobulin, albumin, and total protein.

A low molecular weight beta(2)-globulin (beta(2)-microglobulin), albumin, and total protein were measured in concentrated 24-hr urine specimens from 20 healthy subjects and 30 patients with clinical proteinuria of glomerular or tubular type. Classification of proteinuria was made on the basis of clinical diagnosis and size distribution of urinary proteins after gel chromatography. The molecular radii (Stokes' radii) of beta(2)-microglobulin and albumin, estimated by gel chromatography, were 15 A and 35 A. The average 24-hr urinary excretion in healthy subjects was 0.12 mg for beta(2)-microglobulin, 10 mg for albumin, and 80 mg for total protein. The patients with renal glomerular disorders had normal or only somewhat increased excretion of beta(2)-microglobulin, despite considerably increased excretion of albumin and total protein. Most of the patients with tubular dysfunction excreted large amounts of beta(2)-microglobulin, although they excreted normal or only slightly increased amounts of albumin and only moderately increased quantities of total protein. Consequently, the ratio or urinary albumin/urinary beta(2)-microglobulin was high in glomerular proteinuria (1100: 14,200), intermediate in normal proteinuria (33: 163), and low in tubular proteinuria (1.0: 13.3). Determinations of urinary clearances of beta(2)-microglobulin and albumin in four healthy subjects and 11 patients indicated that increased excretions of the two proteins were associated with increased clearances. The results suggest that quantitative determinations of urinary beta(2)-microglobulin and urinary albumin may be useful for detecting disorders of the renal handling of plasma proteins. The findings also seem to suggest a selective tubular reabsorption of the two proteins. Estimates on sera revealed a close correlation between serum levels of beta(2)-microglobulin and creatinine and also a greatly raised serum concentration of beta(2)-microglobulin after bilateral nephrectomy.

Proinsulin, intact insulin, and fibrinolytic variables and fibrinogen in healthy subjects. A population study.

OBJECTIVE: As high serum insulin predicts impaired fibrinolysis and proinsulin reacts in most conventional insulin assays, we hypothesized that proinsulin could link low fibrinolytic activity and hyperinsulinemic conditions. RESEARCH DESIGN AND METHODS: We explored the relationship between fibrinolysis and plasma fibrinogen on the one hand and specific insulin and proinsulin on the other, in a healthy population sample of 165 men and women, 25-74 years of age, from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Study. Specific insulin and proinsulin were measured by enzyme-linked immunosorbent assay. Partial correlation coefficients, adjusted for age and sex, were calculated. RESULTS: Plasma fibrinogen levels were related to insulin (r = 0.25, P < 0.01) and proinsulin (r = 0.29, P < 0.001), as was plasminogen activator inhibitor (PAI)-1 activity (r = 0.36 and r = 0.29, respectively; P < 0.001). Tissue Plasminogen activator (tPA) activity correlated inversely to insulin (r = 0.35, P < 0.001) and proinsulin (r = - 0.36, P < 0.001). In a multivariate analysis taking also smoking and anthropometric and metabolic measurements into account, fasting proinsulin was a significant predictor of high plasma fibrinogen level. Insulin and proinsulin levels were not related to tPA activity. High levels of postload insulin, triglycerides, and diastolic blood pressure, but not proinsulin, predicted high PAI-l activity. CONCLUSIONS: In a healthy population, the relationship previously described between high insulin levels and impaired fibrinolysis is not attributable to confounding from proinsulin. Elevated proinsulin levels are associated with high fibrinogen levels.

Relationship of cigarette smoking and snuff dipping to plasma fibrinogen, fibrinolytic variables and serum insulin. The Northern Sweden MONICA Study.

The influence of cigarette smoking and use of smokeless tobacco on plasma fibrinogen level, fibrinolytic variables, glucose tolerance and serum insulin was studied in a randomly selected population sample consisting of 604 men and 662 females between 25 and 64 years. Subjects were grouped according to tobacco habits as follows: regular smokers (> 1 cig/day), ex-smokers, snuff dippers, and non-tobacco users. An oral glucose tolerance test was performed on 54% of the participants. Tissue plasminogen activator (tPA) activity and plasminogen activator inhibitor type 1 (PAI-1) activity were used to study fibrinolysis. Men who smoked had 0.34 g/l (95% CI 0.17 to 0.49) higher fibrinogen level than non-tobacco users and numbers of cigarettes smoked correlated with plasma fibrinogen levels (r = 0.21, P = 0.006). Female smokers had significantly higher fibrinogen levels than ex-smokers but the difference compared with non-smokers was not significant. Snuff dipping did not affect fibrinogen levels. We found no relationship between tPA activity, PAI-1 activity and tobacco use. Post-load plasma glucose was lower in women who smoked, otherwise no influence of tobacco use on glucose levels was seen. Lower post-load insulin levels (-8.8 mU/ml, 95% CI -2.4 to -16.3) than in non-smokers were also found in women who smoked. This was only partially explained by a lower body mass index in smokers. We conclude that cigarette smoking is associated with increased fibrinogen levels, unaltered fibrinolysis, normal glucose tolerance and insulin levels. The use of smokeless tobacco, as moist oral snuff, does not appear to affect these potential cardiovascular risk factors.

Fibrinogen and fibrinolytic variables in relation to anthropometry, lipids and blood pressure. The Northern Sweden MONICA Study.

Fibrinolysis is dependent upon plasminogen activator (tPA) activity while high fibrinogen levels increase the risk of thromboembolic events. From a cross-sectional population sample of 1558 men and women aged 25 to 64 years, plasma fibrinogen, tPA activity and plasminogen activator inhibitor-1 (PAI) activity were determined using specific assays. Associations with body mass index (BMI), waist-hip ratio (WHR), serum lipids and blood pressure were calculated with uni- and multivariate models where age and smoking were also introduced. In men age, truncal obesity, short height and low HDL cholesterol independently predicted fibrinogen (R2 0.20) while in women obesity per se, total cholesterol, systolic blood pressure, smoking and age were predictors (R2 0.29). tPA activity was negatively associated with BMI and serum triglyceride levels and positively with age in both sexes. In men diastolic blood pressure (R2 0.22) and in women WHR further independently predicted low fibrinolytic activity. HDL was associated with greater fibrinolysis in women (R2 0.15). Relationships with PAI-1 activity were essentially the reverse of tPA but stronger. Prospective interventional studies are needed to answer the question of causality.

Regular leisure time physical activity predicts high activity of tissue plasminogen activator: The Northern Sweden MONICA Study.

BACKGROUND: Leisure time physical activity protects against the development of cardiovascular disease, partly by lowering blood pressure, cholesterol and body weight. Little is known about the effects of regular exercise on fibrinolytic variables in the population. METHODS: In a population sample of 733 men and 774 women aged 25-64 years physical activity during leisure time was related to fibrinolytic variables. RESULTS: The activity of tissue plasminogen activator (tPA) increased linearly with greater physical activity, the difference between sedentary and most active subjects being 28.9% in men and 11.6% in women. The tPA mass concentrations decreased by 27.4% and 28.0% in men and women respectively, as did also plasminogen activator inhibitor (PAl-1) activity; 38.5% and 30.6%. Tests for trend were significant (P < 0.001) for all but tPA activity in women. Adjusting for age, body mass index and waist:hip ratio only slightly decreased three relationships. When taking triglyceride into account, tPA activity and PAl-1 activity (in men) were no longer significantly related to physical activity level but lower tPA mass concentrations and PA1-1 activity (in women) were still found in those who exercised regularly. Further adjustment for insulin levels abolished all differences, except for PA1-1 activity in women. CONCLUSION: Greater leisure time physical activity is associated with an increased fibrinolytic activity. This may contribute to less cardiovascular disease in subjects who exercise regularly.

Hyperinsulinemia predicts low tissue plasminogen activator activity in a healthy population: the Northern Sweden MONICA Study.

Fibrinogen levels predict atherothrombotic disease, and impaired fibrinolysis has been proposed as a risk factor for myocardial infarction. Fibrinolysis is mainly dependent on the activity of tissue plasminogen activator (tPA) and its inhibitor plasminogen activator inhibitor type-1 (PAI-1). Oral glucose tolerance tests were performed in 318 randomly selected healthy men and 324 women aged 25 to 64 years. tPA activity was strongly predicted by fasting insulin in both univariate analysis (r = -.37 and -.34 in men and women, respectively) and multivariate analysis with age, anthropometric measurements, lipids, and blood pressure included. Fasting insulin was the strongest predictor of PAI-1 activity (r = .49 and .51). In women, the influence of fasting insulin level on tPA and PAI-1 activity was consistently stronger after than before menopause, and a threshold effect was seen with distinctly lower fibrinolytic activity in the highest quartile of insulin (> 7.0 mU/L). In men, the relation between insulin and fibrinolytic variables was linear. Fibrinogen levels were not related to insulin or glucose levels after adjustment for age and other risk factors in a multiple regression. Subjects with previously unknown diabetes or impaired glucose tolerance tended to have elevated fibrinogen and PAI-1 activity and decreased tPA activity. Our data support previous findings of a strong correlation between insulin and PAI-1 activity in small highly selected groups, and extend them to randomly selected population samples. The strong inverse relation between endogenous insulin levels and tPA activity has not previously been demonstrated in a healthy population.

A turbidimetric immunochemical method for determination of serum beta 2-microglobulin using a centrifugal analyzer.

A turbidimetric immunochemical method has been developed for quantitation of serum-beta 2-microglobulin. The serum samples are pre-treated with polyethyleneglycol to decrease the background turbidity and a centrifugal analyzer is used for the absorbance measurements. The within-assay coefficient of variation was 4.6% when 58 serum samples with a mean value of 2.0 mg/l were analyzed in duplicate. The sensitivity of the method is below 0.5 mg/l. When serum samples were analyzed by both the turbidimetric method and a radioimmunoassay a correlation coefficient of 0.989 was obtained. The turbidimetric method is simple, cheap and has a high capacity which makes it suitable for routine determinations of serum beta 2-microglobulin in a clinical laboratory.

Intralesional T lymphocyte phenotypes and HLA-DR expression in Melkersson-Rosenthal syndrome.

An immunohistochemical double-staining technique was used to characterize the infiltrating mononuclear lymphocytes in frozen sections from 3 patients with Melkersson-Rosenthal syndrome. The in situ expression of HLA-DR antigens on different cell types was also investigated. The majority of mononuclear cells could be classified as T-lymphocytes because of their Leu 4 antigen expression. Most of the T-lymphocytes were confined to the helper/inducer lymphocyte subset since they reacted with Leu 3a antibodies. However, big infiltrates of suppressor/cytotoxic lymphocytes with the Leu 2a phenotype were noted in some specimens. These cells were situated between the ducts of the salivary glands. Virtually all mononuclear infiltrating cells carried HLA-DR antigens. HLA-DR expressing keratinocytes were found in the biopsy from one patient. The present study indicates that a local immune response may be important in the pathogenesis of the oro-facial lesions in Melkersson-Rosenthal syndrome.

beta 2-Microglobulin in clinical medicine.

The production of beta 2-microglobulin in normal subjects is quite constant, about 0.13 mg/h . kg. The catabolism almost exclusively through renal elimination. The protein readily passes the glomerular membrane; subsequently more than 99.9% of the filtered beta 2-microglobulin is reabsorbed and degraded in the proximal tubules, only about 5 micrograms/h of the protein appearing in the final urine. Proximal tubular dysfunction leads to an increased urinary concentration. The serum level of beta 2-microglobulin is determined by the glomerular filtration rate and the rate of synthesis. Increased production, with raised serum levels, is sometimes observed in malignancy--mainly at an advanced state, in conditions with neoplastic proliferation of lymphoid B-cells or in inflammatory disorders connected with an activation of the lymphopoetic system. In body fluids, other than plasma and urine, the content of beta 2-microglobulin seems to often reflect a local production. In this review a presentation of the current status and usefulness of beta 2-microglobulin measurements in clinical medicine is included.

Serum C-reactive protein in elderly men and women: association with mortality, morbidity and various biochemical values.

OBJECTIVE: The primary aim of this study was to define the distribution and the prognostic value of serum C-reactive protein (s-CRP) measured by a high-sensitivity method in elderly subjects of both genders with special reference to the distribution below 10 mg/l. As a secondary aim, a possible gender difference of s-CRP was examined. MATERIAL AND METHODS: Baseline s-CRP was described in a population-based sample of opposite-sex, twin-pairs (197 F, 189 M available for blood-sampling) aged 71-80 years (mean age 74.5 years), considering mortality through the next 4 years, morbidity (myocardial infarction, angina pectoris, congestive heart failure, arterial hypertension, venous thromboembolism, stroke, diabetes, gout, psoriasis, rheumatoid arthritis) before and after blood sampling, biochemical values (serum levels of urate, urea, ApoA1, ApoB, folate, FSH, LH, oestradiol, progesterone, testosterone, cortisol) and anthropometric measurements (body mass index (BMI), circumference of waist, buttocks and hips). RESULTS: The level of s-CRP did not deviate substantially from what has been reported for younger subjects. Higher values indicated an increased risk of cardiovascular morbidity and diabetes in women but not in men. The s-CRP level was associated with serum levels of urate, progesterone, folate, ApoA1, ApoB and the quotient ApoB/ApoA1 as well as with BMI and waist circumference. CONCLUSIONS: For the 71-80 years age group, s-CRP below the 80th percentile (4.3 mg/l) seems to have prognostic capacity mainly in women. The highest association with mortality as well as with cardiovascular diseases, diabetes and rheumatoid arthritis is found for s-CRP above 10 mg/l, which is the arbitrary lower level for the earlier routine low-sensitivity s-CRP methods. The association of s-CRP with serum urate, folate and the ApoB/ApoA1 quotient should be considered.

Beta 2-microglobulin and its binding activity in serum from patients with SLE.

Repeated determinations of beta 2-microglobulin (beta 2m) and beta 2-microglobulin binding activity (beta 2m ba) in serum were performed during a follow-up of 23 patients with SLE. beta 2m was determined by a radioimmunoassay. Individual mean values were raised in 65% of the patients. The mean value for all patients, 2.9 mg/l, was significantly higher than that of the controls. The beta 2m concentrations parallelled the clinical disease activity in several cases with different disease manifestations. The beta 2m ba was determined by precipitation of 125I-labelled beta 2m with polyethylene glycol. Increased beta 2m ba was found in 26% of the SLE patients with the 90th percentile in 40 healthy subjects being taken as the upper normal limit. There were, however, no significant differences between the mean values for beta 2m ba in the patients and the controls. Patients with systemic lupus erythematosus (SLE), suffering exacerbation of their disease, had a higher mean beta 2m ba than those with less active disease. Variations of the serum beta 2m ba occurred especially in patients with active disease but did not seem to reflect the clinical course. The beta 2m ba was recovered in the IgG peak when SLE serum was subjected to gel chromatography on Sephadex G-200.

Increased level of HLA-DR-expressing T lymphocytes in peripheral blood from patients with idiopathic dilated cardiomyopathy.

Peripheral blood leukocytes from 14 patients with idiopathic dilated cardiomyopathy (IDC), 13 patients with ischemic congestive heart failure, and 12 controls were characterized using different antibodies. The proportions of B lymphocytes, T lymphocytes, and the different T lymphocyte subsets were estimated. No difference between the three groups could be found in the various T and B cells subpopulations. Using a two-color direct immunofluorescence technique, the occurrence of circulating T helper/inducer (Leu-3a) and T cytotoxic/suppressor cells (Leu-2a) expressing HLA-DR antigens was examined. Only IDC patients demonstrated increased levels of HLA-DR-positive T helper/inducer cells (2.8 +/- 2.4%) and T cytotoxic/suppressor cells (2.8 +/- 2.3%) as compared with patients with ischemic congestive heart failure (0.8 +/- 0.7 and 1.0 +/- 1.0%, respectively) and controls (0.6 +/- 0.5 and 0.9 +/- 0.6%, respectively). When individual IDC patients were studied, 4 out of 12 patients had an increased level of HLA-DR-expressing T helper/inducer cells, and 7 out of 12 patients had elevated HLA-DR-positive T cytotoxic/suppressor cells. The findings suggest that activation of the T lymphocytes may be of importance in the pathogenesis of IDC.

Phenotypes of peripheral blood leukocytes in Melkersson-Rosenthal syndrome.

Peripheral blood leukocytes from 5 patients with Melkersson-Rosenthal syndrome (MRS) were characterized with an immunoenzymatic staining technique utilizing ten different mouse monoclonal antibodies to cell surface antigens. No gross abnormalities could be found in the various T and B cell subpopulations. However, the proportion of cells expressing the IL-2 receptor was slightly increased, indicating the occurrence of activated lymphocytes in the circulation. Furthermore, in all 5 patients a large proportion of a non-phagocytic, Leu-M1-expressing, granulocyte-like cells of low density was found, probably reflecting the presence of activated granulocytes in the blood in MRS patients. The findings suggest that activation of both the lymphocyte and the granulocyte systems may be of importance in the pathogenesis of MRS.

Serum beta-2-microglobulin in Sjögren's syndrome.

The serum concentration of beta-2-microglobulin was determined with a radioimmunoassay in 52 patients with keratoconjunctivitis sicca, 29 of whom had Sjögren's syndrone. Eleven (38%) of the patients with Sjögren's syndrome had high serum values. These cases had a higher mean age and a higher frequency of the complete triad of Sjögren's and of antinuclear antibodies than had the lower value cases. The sicca components per se did not seem to influence the serum concentration of beta-2-microglobulin. Most of the few complications occurred in patients with high values.

Biochemical values in persons older than 82 years of age: report from a population-based study of twins.

According to international standards, reference values for biochemical tests should be obtained in disease-free subjects and for therapies that may influence measurement values. For elderly persons, especially the very old, such a requirement is difficult to meet, since few of these individuals are free of ongoing or former diseases. The present study of a population-based Swedish twin sample comprises 535 individuals (186 males, 349 females) who were at least 82 years of age at blood sampling. Survival over a 6-year period is used as a reference of overall health. Baseline test values for subjects surviving 6 years are compared with results for persons who died in the follow-up period. Results, including mean and median values, standard deviations and ranges, were given for both genders in the total sample. Cases outside the 5th and 95th percentiles were then excluded, as were those who died during the follow-up period. In a third step, cases with disorders and therapies known to influence measurement values were also excluded. The risk of dying during the observation period was calculated across measurements from the lowest and highest 10th and 20th percentiles. The specific impact of proximity to death on the biochemical values, in addition to age effects, was analysed by comparing co-twins discordant for survival over 7 years. Increased mortality was indicated for subjects of both genders with high serum levels of urea, urate, gamma-GT, free thyroxin and plasma homocysteine. In females, low serum values for albumin and total cholesterol were associated with increased mortality. A lower cholesterol level was found 4 years before death, while a lower HDL-cholesterol level was associated with an increased risk of death across the entire 7-year period.

Association of biochemical values with morbidity in the elderly: a population-based Swedish study of persons aged 82 or more years.

BACKGROUND: Various inter-dependent factors influence serum biochemical values. In the elderly, the impact of these factors may differ compared with younger age groups and therefore population-based studies among older people are needed. The specific morbidity in old age, including also various types of drug therapy, should be observed. METHODS: Various biochemical tests in 349 females and 186 males over 81 years of age were carried out and the associations of biochemical values with morbidity, drug therapy, anthropometry and gender were estimated. RESULTS: Biochemical serum values deviate in various diseases, characterized by increased frequency in the elderly, i.e. congestive heart failure, osteoporosis, hip fractures, depression and dementia. All of these diseases present a tendency to increased homocysteine, usually combined with low folate. Cases with intact cognitive function throughout the six years after sampling are characterized by low homocysteine, which is the opposite of what is found in dementia. Furthermore, congestive heart failure is associated with impaired creatinine clearance and increased urea and urate, and osteoporosis and hip fractures are characterized by low albumin and cholesterol. Increased values for urate and impaired creatinine clearance are found in coronary diseases. In gout, multiple biochemical changes take place. For cases with a history of diabetes, arterial hypertension, peptic ulcer and malignancy, few changes are found compared with the values of the total sample. Furosemide therapy is associated with the same pattern as congestive heart failure, and laxative treatment is characterized by low folate and high homocysteine values.

The effect of metabolic regulation on microvascular permeability to small and large molecules in short-term juvenile diabetics.

The microvascular permeability to small and large molecules was studied during good and poor metabolic regulation in ten short duration juvenile diabetics. The following variables were measured; daily urinary albumin and beta2-microglobulin-excretion rates, whole body transcapillary escape rate of albumin (TER), glomerular filtration rate (GFR), capillary filtration coefficient (CFC), and capillary diffusion capacity (CDC). The urinary albumin and beta2-microglobulin concentration were measured by sensitive radioimmunoassays; TER was detemined from the initial disappearance of intravenously injected 125I-labelled human serum albumin; GFR was measured on the forearm by straingauge plethysmography and CDS for 51Cr-EDTA clearance; CFC was measured on the forearm by straingauge plethysmography and CDC, for 51Cr-EDTA was determined in the jyperaemic anterio tibial muscle by the local clearance technique. All the above mentioned variables, except CDC, were significantly increased during poor metabolic regulation, indicating a functional microangiopathy. The mechanisms of these alterations appear to be increased filtration pressure in the microcirculation and/or increased porosity of the microvasculature. The findings of increased microvascular albumin passage are compatible with the hypothesis that the organic - histologicallly demonstrated - diabetic microangiopathy is a long-term effect of periods of increased extravasation of plasma proteins, with subsequent protein deposition in the microvascular wall, i.e. the concept to plasmatic vasculosis.