Renal protein handling in man, modified by insulin administration, stress situations and hypertension.
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Albuminuria↗
Biomedical subjects
H J Gundersen
Publications and source records attributed to H J Gundersen.
Acute effects of insulin on plasma noradrenaline and the cardiovascular system.
It is now known that insulin has marked acute effects on plasma noradrenaline and the cardiovascular system. These effects of insulin are not due to hypoglycemia and occur without changes in plasma adrenaline. Intravenous injection of insulin in juvenile diabetics increased plasma noradrenaline and heart rate and decreased glomerular filtration rate, renal and peripheral blood flow, and plasma volume. Urinary excretion rates of beta-2-microglobulin and urinary volume decreased after insulin, whereas urinary albumin excretion increased. When blood glucose was maintained by glucose infusion after insulin, glomerular filtration rate and renal blood flow remained unaltered whereas plasma noradrenaline, heart rate, and urinary albumin excretion increased and beta-2-microglobulin excretion decreased. Decreases in glomerular filtration rate and renal blood flow after insulin are thus due to the fall in blood glucose. Rise in albumin excretion after insulin is probably of glomerular origin and not caused by the fall in blood glucose or by changes in renal hemodynamics. In patients with long-term diabetic nephropathy and albuminuria, insulin decreased albumin excretion (probably due to renal vasoconstriction) and plasma noradrenaline did not increase. In alloxan-diabetic rabbits the increase in heart rate after insulin was not abolished by autonomic blockade. In short-term streptozotocin-diabetic rats, muscle capillary endothelial cells showed a reduced number of free micropinocytotic vesicles. The number was nearly normalized 1 hr after intramuscular injection of insulin. The mechanism of action of insulin on plasma noradrenaline, heart rate, plasma volume, and urinary albumin excretion is not known. The rise in plasma noradrenaline after insulin may be compensatory to hypovolemia or to antagonizing effects of insulin on some actions of noradrenaline. The findings in streptozotocin-diabetic rats suggest that insulin may be essential for the normal function of capillary endothelial cells.
Adult↗
The rate of synthesis and breakdown of glomerular basement membrane material at the transition 'normal to diabetes' and 'diabetes to normal'.
A considerable enlargement of the renal glomeruli is present very early after the acute onset of juvenile diabetes mellitus. In the hypertrophied glomeruli the surface area of the capillary walls, the filtration surface, is increased, and thereby also the amount of basement membrane in the capillary wall. The rate of development of this type of diabetic basement membrane accumulation has been studied in streptozotocin diabetic rats with 4- and 47-day duration of diabetes. During the first 4 days a 40% increase in the total amount of peripheral basement membrane material occurs, whereas the following period up to 47 days shows no further change. The structural changes of the glomerular capillaries seen in conjunction with the basement membrane accumulation comprise an enlargement of the filtration surface and capillary luminal volume. In another experiment, 4-week diabetic animals were transplanted with pancreatic islets. The renal structures were studied quantitatively after 4 weeks of normalization. It was found that the increased amounts of basement membrane material were still present.
Animals↗
Precise quantitation of glomerular basement membrane morphology.
Quantitative microscopical methods for studying the glomerular capillary basement membrane are described, mainly in terms of precision and overall experimental efficiency. The methods provide absolute data for basement membrane thickness, total surface and total volume, and for glomerular capillary dimensions, namely total length, total surface and average diameter, as well as for mesangial cell and matrix volumes. The impact of these methods on current research in glomerular structure and pathology is illustrated by results from a number of recent studies of human and experimental diabetes.
Animals↗
Oral glucose increases urinary albumin excretion in normal subjects but not in insulin-dependent diabetics.
An oral glucose load increased urinary albumin excretion significantly in six normal subjects (from a mean basal value of 4.6 microgram/min to 16.9 microgram/min at 30-90 min after oral glucose). Urinary excretion of beta-2-microglobulin did not change after oral glucose whereas urinary volume increased. Administration of the water vehicle did not increase albumin excretion. Oral glucose had no effect on urinary albumin excretion in six insulin-dependent diabetics. The effect of oral glucose was not identical to the changes observed after intravenous insulin because oral glucose urinary volume and did not change beta-2-microglobulin excretion whereas insulin decreased both parameters.
Adolescent↗
A strong correlation between glomerular filtration rate and filtration surface in diabetic kidney hyperfunction.
The direct relationship between glomerular filtration surface and glomerulaf filtration rate was studied in a group of eight short term, young diabetics exhibiting a 50 per cent elevated glomerular filtration rate with a 2-fold variation within the group. A close correlation was obtained between glomerular filtration surface and glomerular filtration rate, r = 0.8. This supports the idea that the increase in glomerular capillary surface may be a main factor in diabetic kidney hyperfunction. The possible long term implications of the functional and morphologic abnormalities are discussed.
Adult↗
Stereology--or how figures for spatial shape and content are obtained by observation of structures in sections.
Stereology is a geometrically and statistically defined body of simple methods for estimating morphological quantities of three-dimensional (3-d) structures from measurements made on two-dimensional (2-d) sections. The straightforwardness and the strength of its theoretical basis is illustrated by some newer methods applied in experimental clinical research. Contrary to expectation, the reduction in information from 3-d structures to 2-d sections brings about only a minor increase in the statistical uncertainty of the central moments of most of the fundamental structural characteristics. The sole exceptions are the number of isolated structures and the degree of connectedness in 3-d space, structural quantities the importance of which is limited to the questions of (neo)genesis and communications, respectively. In general, the overall variation in morphometry is determined more by biological than methodological variation. Therefore, stereology is part of the broad spectrum of modern quantitation techniques the sensible application of which depends primarily on common sense in the experimental technique and in the definition of the biological question. The ease and the simplicity of the measurements contrasted by the still quite elaborate and difficult histological preparations of tissue mean that the automation of the measuring process alone is not sensible.
Animals↗
Early functional and morphologic vascular renal consequences of the diabetic state.
Renal hyperfunction and hypertrophy are characteristic findings in the early diabetic state, both in diabetes mellitus and in experimental diabetes. A number of structure-function relationships and their likely mechanisms are discussed. The metabolically induced hypertrophy of glomerular capillaries possibly plays a central role. Its cause is not known, but recent results on its time-course emphasize the probable long-term consequences of the irreversibility of the accumulation of basement membrane material.
Albuminuria↗
Determination of membrane thickness distribution from orthogonal intercepts.
This report deals with the reconstruction of the distribution of membrane thickness T from that of orthogonal length Lo, measured in random section planes. In such planes the membrane appears as a band and the linear distance from one of its boundaries perpendicular to the opposite one is the length of the orthogonal intercept. Using a membrane model, an integral equation relating the probability density functions of orthogonal intercept length f(lo) and membrane thickness g(tau) is derived. Relations between moments are derived and the analytic solution to the problem of reconstructing g(tau) from f(lo) is given. The parametric approach by which it assumed that g(tau) has some known analytic form with unknown parameters is considered, and the use of a suggested analytic form for describing the thickness distribution of the human glomerular basement membrane is discussed.
Basement Membrane↗
Early and late changes in the diabetic kidney.
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Animals↗
Evaluation of a procedure for systematic semiquantitative analysis of glomerular ultrastructure in human renal biopsies.
A method is described for systematic semiquantitative investigation of glomerular ultrastructure in renal biopsies from patients with glomerulonephritis. Three glomeruli per biopsy were studied by electron microscopy. Ten systematically recorded micrographs at x12,000 and a montage covering the whole glomerular cross-section at x3,000 were analyzed from each glomerulus. The severity of each of 34 different ultrastructural lesions was semiquantitatively evaluated on a 4-degree scale, 0 to +++. The usefulness of the method was evaluated by calculating different parameters for the reproducibility of semiquantitative scoring, representativeness of micrographs, and representativeness of glomeruli. The reliability of the method was considered good or acceptable with respect to 17 of the lesions. Ten lesions obtained a high reproducibility of scoring but the usefulness of the scores was limited due to a segmental and/or focal distribution of these lesions. The evaluation of these lesions can be improved by analyzing a larger number of micrographs, or glomeruli, or both. Seven lesions were so rare in the present biopsies that no statistical evaluation was possible. When applied to a large number of biopsies, this practical and useful method allows a reproducible comparison of the patterns of ultrastructural lesions in various types of glomerulonephritis.
Basement Membrane↗
[Glomerular changes in diabetes mellitus].
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Diabetic Nephropathies↗
The acute effect of insulin on renal haemodynamics and protein excretion in diabetics.
The effect of IV injection of 7 to 8 I. U. of insulin on renal haemodynamics and on urinary excretion of beta-2-microglobulin and of albumin was examined in 5 juvenile diabetics. Plasma glucose decreased from a mean value of 250 mg/100 ml to 117 mg/100 ml during the first 85 min after insulin. None of the patients had symptoms of hypoglycaemia and plasma adrenaline did not increase. There was no change in arterial blood pressure after insulin whereas pulse rate increased from 66/min to a maximum of 75/min. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were decreased by 9 per cent and 13 per cent, respectively, during the first 90 min after insulin (2 p less than 0.01). There was also a statistically significant decrease in urine flow and urine secretion of several electrolytes, while filtration fraction remained almost constant. IV insulin decreased urinary excretion of beta-2-microglobulin and increased albumin excretion (2 p less than 0.05). The albumin excretion induced by insulin is most likely due to increased amounts of filtered albumin, the mechanism of which remains unexplained.
Adult↗
The basement membrane controversy.
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Basement Membrane↗
Growth hormone enhances basement membrane thickening in experimental diabetes. A preliminary report.
Injection of porcine growth hormone (200 microgram) or saline 5 days a week for 16 to 20 weeks in streptozotocin-diabetic rats showed that compared to saline growth hormone produced a 2 1/2-fold larger increase in glomerular capillary basement membrane thickness (2p = 0.027). The possible significance of this effect of an elevated level of growth hormone for diabetic microangiopathy is discussed.
Animals↗
Distribution of membrane thickness determined by lineal analysis.
The expected statistical distributions of intercept length are derived in terms of geometrical probability density functions pertaining to plates with known thickness penetrated by lines with random orientation. These expressions provide arithmetic and graphical solutions for obtaining distributions of membrane thickness and reciprocal membrane thickness from empirical distributions of intercept lengths. Furthermore, general relationships between probability density functions of distributions of intercept length and membrane thickness are derived as well as those between their moments. Examples of the application of the method to biological samples are given, and estimated distributions of glomerular basement membrane thickness are compared to those obtained by an independent, direct method. Various sources of bias, which in practice may occur due to departures from the sample model, are discussed and the influence of some of them is estimated. The knowledge of the probability density function of reciprocal intercepts makes it possible to perform a correction of the distribution of measured intercept length, which to some extent eliminates bias.
Animals↗
The precision of unbiased estimates of numerical density of endothelial cells in donor cornea.
The precision of estimates of central corneal endothelial density was studied in 16 human corneas stained by alizarine red and trypane blue. Estimates based on central counts and estimates based on peripheral counts were considered separately. The numerical density was estimated employing an unbiased sampling technique. From central counts estimates with an error of less than five per cent could be obtained. From peripheral counts a maximum precision of mean +/- 12.2 per cent could be obtained. The theoretical maximum precision was calculated by application of a variance component model. The precision of estimates was calculated for 1, 2 and 4 test areas of different sizes. Economy of sampling was evaluated by comparison of the actual precision to the theoretical maximum precision of estimates.
Cell Count↗
Analysis of heart rate variations in patients with multiple sclerosis. A simple measure of autonomic nervous disturbances using an ordinary ECG.
A simple method requiring only an ordinary ECG apparatus and a ruler has shown a hitherto unknown abnormality of the autonomic nervous sysyem in patients with multiple sclerosis. The main findings were that both long-term and short-term variations in heart rate were reduced in patients wirh multiple sclerosis. The reduction was comparable with that observed in other patients with autonomic abnormalities-for example, long-term diabetics-but in addition patients with multiple sclerosis presented unexpected large shifts in pulse rate levels, lasting from a few to 10 or 20 beats.
Adult↗