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W M Deen

Publications and source records attributed to W M Deen.

At least 73 records · Page 4Linked to original sources
PubMed1986

Effect of colloid volume expansion on glomerular barrier size-selectivity in humans.

Colloid volume expansion magnifies proteinuria in subjects with the nephrotic syndrome. To elucidate this phenomenon, we performed differential solute clearances prior to and following infusion of hyperoncotic albumin in 21 nephrotic subjects and seven healthy controls. Urinary excretion rate and fractional clearance of albumin (radius = 36 A) and immunoglobulin G (radius = 55 A) increased significantly in nephrotic subjects. However, urinary albumin excretion rate was unchanged in controls. The fractional clearances of dextrans of broad size distribution (radii = 28 to 58 A) were markedly altered in both groups following albumin infusion. A heteroporous model which depicts the major portion of the glomerular capillary wall as an isoporous membrane (pore radius approximately 55 A) and the minor portion as a non-discriminatory shunt, revealed the latter to be much more prominent in nephrotic subjects than in controls, and to be enlarged further following albumin infusion. By contrast no increase in pore size of the non-shunt pathway occurred in either group. We infer that enhancement of a pre-existing defect of glomerular size-selectivity in nephrotic subjects accounts, in large part, for exaggerated proteinuria in the colloid volume-expanded state. Increases in glomerular perfusion rate and pressure associated with plasma hypervolemia may mediate this alteration in glomerular membrane-pore structure.

Capillary Permeability↗
PubMed1986

Mechanisms for nitrite loss from the stomach.

Nitrite loss from the stomach was studied using dogs equipped with Thomas cannulas for direct access to the stomach lumen. Solutions containing sodium nitrite and non-absorbable volume marker (polyethylene glycol, PEG) were infused into the stomach, and samples were taken over 60 min to determine the concentration of 'total nitrite' (including NO2-, HNO2 and other species in equilibrium with NO2-) and rate of dilution of the stomach contents as a function of time. Changes in stomach volume were also measured. Nitrite loss was found to be very rapid, with total nitrite concentrations declining to less than half the initial levels in 10 min. The decay in total nitrite concentrations was due predominantly to gastric absorption, with small additional contributions from dilution of the stomach contents (inferred from PEG concentrations) and chemical reactions (from in vitro kinetic data). Results for initial nitrite concentrations varying over a range of 0.15-4.5 mM showed absorption to be first order in total nitrite. The permeability-area product for nitrite absorption (PA) was about 0.6 l/h, and was unaffected by the addition of 1 mM SCN- or Cl-. All of these results are consistent with nitrite absorption in the form of NO2- or HNO2. Buffering the infusate with HCO3- to increase luminal pH from approximately 2 to 7 caused a three-fold reduction in the apparent value of PA. When pentagastrin was used to stimulate acid secretion, nitrite absorption was only half as fast as when acid secretion was inhibited with cimetidine, or when no drug was given. This effect could not be explained by variations in luminal pH, and suggests that acid secretion either decreases PA or is accompanied by active secretion of nitrite. Based on these data, a mathematical model was developed to stimulate the physical and chemical factors governing nitrite concentrations in the stomach.

Animals↗
PubMed1986

Nature of the glomerular capillary injury in human membranous glomerulopathy.

A differential solute clearance technique was used to evaluate glomerular capillary wall function in 20 patients with membranous glomerulopathy and massive proteinuria. The clearance of inulin, the filtration fraction, and the fractional clearance of uncharged dextrans of a radius of 28-48 A were depressed significantly below control values in 20 healthy volunteers (P less than 0.01). In contrast, the fractional clearance of dextrans of radius greater than 50 A was elevated markedly. A theoretical model of solute transport that depicts the major portion of the glomerular capillary wall as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway revealed the calculated glomerular ultrafiltration coefficient to be five times lower and mean pore radius of the major membrane component to be 4 A smaller than control values. However, the fraction of filtrate volume permeating the shunt pathway was three- to fourfold above control values and correlated strongly in individual patients with the fractional clearance of albumin (r = 0.76) and of IgG (r = 0.80). Lowering renal plasma flow by 24% during indomethacin therapy in seven patients resulted in a 74% reduction in proteinuria accompanied by a corresponding diminution of filtrate formed through the shunt pathway. Morphometric analysis of glomerular ultrastructure revealed the magnitude of depression of the glomerular filtration rate and of urinary protein leakage to be related strongly to changes in the epithelial layer of the glomerular capillary wall, but not to the density of subepithelial immune deposits. We conclude that glomerular capillaries in membranous glomerulopathy are characterized by a loss of ultrafiltration capacity and of barrier size-selectivity, and that subepithelial immune deposits do not provide a structural basis for these functional alterations.

Dextrans↗
PubMed1985

Pharmacokinetics of nitrate in humans: role of gastrointestinal absorption and metabolism.

A model to describe the response of the blood pool to an oral dose of nitrate in humans has been developed. The permeability-area product of the small intestine to nitrate was estimated by comparing simulations from a three-compartment model with published data for blood nitrate concentration following nitrate ingestion. The transport of nitrate from the bloodstream to the lumen of the large intestine and the metabolism of nitrate by enteric bacteria were examined by including an additional compartment representing the large bowel. The simulations indicate that the bacteria of the large intestine may be responsible for about half of the extrarenal removal of nitrate from the body. This prediction was tested experimentally by comparing the urinary recoveries of 15NO3- in conventional and germfree rats following an i.p. dose of Na15NO3. The mean urinary recovery in germfree rats (71% of dose) substantially exceeded that in rats with conventional bacterial flora (54%). This suggests that of the 40-45% of a nitrate dose that is metabolized in the body rather than excreted in urine as nitrate, approximately half is metabolized by mammalian processes and approximately half by enteric bacteria. This conclusion is consistent with that obtained from our pharmacokinetic model of nitrate in humans.

Animals↗
PubMed1985

Heteroporous model of glomerular size selectivity: application to normal and nephrotic humans.

A heteroporous model of the glomerular filtration barrier was developed and used to interpret dextransieving data in healthy volunteers (normal controls), in patients with nephrotic range proteinuria (grouped as grades I-III, according to severity), and in a group of previously nephrotic patients whose proteinuria was in remission ("resolved controls"). Several hypothetical pore-size distributions were compared in terms of their ability to describe the selective increases in the fractional clearance of large dextrans observed with increasing severity of proteinuria. The most successful model examined was based on the assumption that the major portion of the capillary wall functions as an isoporous membrane, but that a small fraction of the filtrate passes through pores that are unable to discriminate among dextrans of different sizes. The value of the membrane parameter that reflects the relative importance of the nonselective pores was found to increase in parallel with the fractional clearance of immunoglobulin G; it increased progressively in going from normal controls to resolved controls to grades I-III nephrotics. The observed patterns of protein excretion could not, however, be explained entirely by a loss of glomerular size selectivity. Variations in membrane selectivity on the basis of molecular charge and/or molecular configuration are also likely to have been important.

Glomerular Filtration Rate↗
PubMed1984

Analysis of the factors influencing peritubular PCO2 in the rat.

We have developed a mathematical model to assess the relative contributions of several factors to the high CO2 partial pressures observed in rat peritubular capillaries. This model is based on a single nephron and focuses specifically on the CO2 partial pressure differences (delta PCO2) between peritubular capillaries and the afferent arteriole. The model is formulated by writing steady-state mass balances for the glomerulus, proximal tubule, and peritubular capillaries in addition to equilibrium relationships for CO2, HCO3-, blood protein buffers, and hemoglobin carbamino compounds. Principal input parameters include glomerular blood flow rate, rates of HCO3- and water reabsorption, and the rate of metabolic CO2 production. Under conditions representative of normal Munich-Wistar rats, the model predicts delta PCO2 to be 4.1 mmHg, in approximate agreement with experimental observations reported elsewhere. Metabolic CO2 production is responsible for roughly half of this predicted delta PCO2, the remainder being attributable to reabsorption processes. In examining the sensitivity of delta PCO2 to changes in physiological conditions, we consistently found it to be inversely related to glomerular blood flow rate. The influence of changes in HCO3- reabsorption on delta PCO2 is variable and highly dependent on the arterial acid-base status and the ratio of HCO3- reabsorption to water reabsorption.

Acid-Base Equilibrium↗
PubMed1984

Proximal HCO3- reabsorption and the determinants of tubular and capillary PCO2 in the rat.

Studies were carried out in Munich-Wistar rats to define the CO2 partial pressure (PCO2) profile in the surface tubules and capillaries of the kidney and to relate these measurements to proximal tubular HCO3- reabsorption, renal blood flow, and O2 consumption. In euvolemic rats, PCO2 in Bowman's space (BS) was 12.5 mmHg higher than in arterial blood, indicating CO2 addition to the arterial tree as it traverses the cortex. PCO2 further rose by 3.9 mmHg between the efferent arteriole (EA) and the peritubular capillaries (PC) (P less than 0.01) and by 4.9 mmHg between BS and the early proximal tubule (EP) (P less than 0.01). In studies with paired measurements, PCO2 in EP was 1.8 mmHg higher than in the adjacent PC (P less than 0.05). HCO3- reabsorption in EP (first 0.4-1.25 mm) was 579 pmol X min-1 X mm-1 (34.3 +/- 4.6% of the filtered load). By use of a model of facilitated diffusion of CO2 across the cell, the trans-epithelial PCO2 gradient in EP can be accounted for by the CO2 generated from HCO3- reabsorption, assuming an intracellular pH of 7.3. In the vascular compartment, roughly half the rise in PCO2 between the afferent arteriole (estimated to equal BS PCO2) and PC can be accounted for by metabolic CO2 production and half by titration of blood buffers by reabsorbed HCO3-.

Acid-Base Equilibrium↗
PubMed1984

Analysis of microvascular water and solute exchanges in the renal medulla.

A theoretical model has been developed to simulate solute and water transport in the medullary microcirculation of the normal hydropenic rat. The model is formulated in terms of a countercurrent vascular unit consisting of one descending (DVR) and several ascending vasa recta (AVR) extending from the corticomedullary junction to the tip of the papilla. Steady-state mass balances relate gradients in NaCl, urea, and plasma protein concentrations and variations in the flow rates of plasma and red blood cells to permeability properties of the vasa recta and erythrocytes. In contrast to previous models, transmural volume fluxes are assumed to be present in both DVR and AVR. Available micropuncture measurements suggesting net volume removal from DVR within the inner medulla are found to be consistent with NaCl reflection coefficients in DVR between 0.10 and 0.80. The hydraulic permeability in the DVR is estimated to be greater than 0.18 X 10(-6) cm X s-1 X mmHg-1. Based on currently available data, reliable bounds cannot yet be placed on the hydraulic permeability of the AVR. The vascular unit is predicted to accomplish substantial net removal of NaCl and water from the inner medullary interstitium but relatively little removal of urea. Red cells leaving the inner medulla in the AVR are found to be slightly dehydrated. It is calculated that at a given blood flow rate, the lower the initial medullary hematocrit, the more effective the vascular unit is at removing water. Several unresolved issues are discussed, including the role of the capillary plexus that joins DVR with AVR. To the extent that the volume uptake observed in the exposed papilla in structures beyond the DVR occurs in the capillary plexus and not in the AVR, estimated values of AVR hydraulic permeability are reduced, as is predicted overall volume uptake by the vascular unit in the inner medulla.

Animals↗
PubMed1984

Mammalian nitrate biochemistry: metabolism and endogenous synthesis.

The metabolic fate of an oral dose of 3.5 mmol 15N-labelled nitrate was investigated in young adults. An average of 60% of the 15N-nitrate dose appeared in the urine within 48 h; less than 0.1% appeared in the faeces. Some of the 15N label of nitrate was found in the urine (3%) and faeces (0.2%) in the form of ammonia and urea; the remainder of the dose was attributed to nitrate loss via metabolism to other reduced nitrogen compounds. Studies with germ-free rats indicated that half of the nitrate metabolism is due to mammalian processes. These and previous studies show that not all of the nitrate excreted in the urine is of dietary origin but evolves from endogenous synthesis. An oral dose of 15N-ammonium acetate was incorporated into urinary 15N-nitrate in rats, suggesting that ammonia is a precursor of nitrate. Furthermore, Escherichia coli lipopolysaccharide was found to be a potent stimulus of nitrate excretion (nine-fold increase), due to an increased rate of synthesis. Two other types of experimentally induced inflammatory states - injection of carrageenan and of turpentine - enhanced nitrate synthesis. It is proposed that the pathway of nitrate biosynthesis may be the result of oxidation of reduced nitrogen compounds by oxygen radicals generated by an activated reticuloendothelial system.

Acetates↗
PubMed1983

Biophysical basis of glomerular permselectivity.

The mammalian glomerular capillary wall normally restricts the transmural passage of plasma proteins while offering little resistance to the filtration of water and small solutes. The basis for this selectivity has been explored extensively in recent years, through clearance measurements of endogenous (mainly albumin, transferrin, and immunoglobulins) and exogenous (horseradish peroxidase) proteins, and a variety of nonprotein polymers such as dextrans and polyvinylpyrrolidone. In conjunction with efforts to localize particulate and soluble tracers by high resolution ultrastructural techniques, such measurements have now made it possible to define the determinants of the glomerular filtration of macromolecules in terms of discrete structural barriers as well as such biophysical influences as hemodynamics and the molecular size- and charge-selective characteristics of the capillary wall. These experimental approaches have been aided greatly by the development of theoretical models that enable investigators to describe macromolecular filtration in terms of hydrodynamic principles applied to isoporous membranes. Although the initial models failed to consider the important role of membrane fixed negative-charge characteristics in influencing protein filtration, this shortcoming has led to the recent introduction of a theoretical model that also takes this factor into consideration. The aim of this brief review is to summarize these various theoretical approaches to the understanding of glomerular permselectivity and, wherever possible, to cite specific tests of these theories based on experimental studies in humans and animals.

Animals↗
PubMed1983

Metabolic fate of an oral dose of 15N-labeled nitrate in humans: effect of diet supplementation with ascorbic acid.

The metabolic fate of a p.o. dose of 3.5 mmol 15N-labeled nitrate has been investigated in 12 healthy young adults. Samples of urine, saliva, plasma, and feces were collected over a period of 48 hr following administration of the dose. Subjects received either 60 mg of ascorbic acid, 2 g of ascorbic acid, or 2 g of sodium ascorbate per day. An average of 60% of the 15NO3- dose appeared in the urine as nitrate within 48 hr. Less than 0.1% appeared in the feces. The 15N label of nitrate was also found in the urine (3%) and feces (0.2%) in the form of ammonia or urea. The fate of the remaining 35% of the 15NO3- dose administered is unknown. No effect of ascorbic acid or sodium ascorbate on the nitrate and nitrite levels of plasma, saliva, urine, or feces was observed. A one-compartment pharmacokinetic model was used to describe the relationships between intake, plasma concentration, and urinary excretion of nitrate. The half-life of nitrate in the body was found to be approximately 5 hr, and its volume of distribution was about 30% of body weight. Daily endogenous biosynthesis of nitrate was estimated to be about 1 mmol/day.

Administration, Oral↗
PubMed1982

Glomerular charge alterations in human minimal change nephropathy.

A theoretical model of charge and size selectivity for the glomerulus has been applied to human data. Using previously published values for GFR, renal plasma flow, systemic oncotic pressure, and fractional clearances of neutral dextrans, albumin, salivary amylase, and transferrin, membrane parameters describing the glomerular barrier were determined for normal individuals under control conditions and during lysine infusion (which retards tubule protein reabsorption), and for patients with minimal change nephropathy (MCN). To permit the estimation of membrane charge from fractional clearances, molecular charge values for human transferrin (-9.4 Eq/mole) and human salivary amylase (-4.1) were determined by measuring electrophoretic mobilities of these proteins in polyacrylamide gels. Assuming no large changes in the transmural hydraulic pressure difference (delta P), the glomerular ultrafiltration coefficient (Kf, the product of hydraulic permeability and capillary surface area) was calculated to be reduced by greater than 50% in MCN. The effective pore radius (approximately 55 A) is virtually unaltered in MCN, suggesting that the decline in Kf is due to a reduced number of pores. The degree of albuminuria observed in MCN is attributable to an approximately 50% reduction in the concentration of fixed negative charges in the glomerular capillary wall. The concentrations of fixed charges calculated from albumin data in normal individuals (140 to 160 mEq/liter) and in patients with MCN (60 to 90 mEq/liter) are insensitive to the assumed values of delta P.

Albumins↗
PubMed1982

Mechanisms of proteinuria in human glomerulonephritis.

We evaluated glomerular barrier function in 28 patients with glomerulonephritis. Neutral dextrans of graded size were used to characterize the size-selective properties of the barrier. Charge selectivity was characterized by electrofocusing excreted urinary proteins. A fractional IgG clearance (relative to freely permeable inulin), smaller or greater than 100 x 10(-5) was used to distinguish patients with minor (group I, n = 13) and major (group II, n = 15) urinary IgG leakage, respectively. Fractional clearances of smaller dextrans (radii 20-50 A) were similar, but those of larger dextrans (radii 52-60 A) were elevated in group II relative to group I patients. A model of solute transport through a bimodal pore size distribution revealed the values for pore radius in the lower mode to approximate 51-55 A in both group I and group II patients. Pore radius in the upper mode, by contrast, was much larger in group II than in group I patients, approximating 87-97 vs. 72-77 A, respectively. Electrofocusing of urinary protein from group I patients revealed mostly albumin (isoelectric point 5.2). In group II patients, however, immunoglobulin excretion was copious. Moreover, the distribution of anionic, neutral, and cationic species (isoelectric points 5.5-8.5) in urinary and plasma eluates of IgG2 and IgG4 was similar. We conclude that when glomerulonephritis is associated with selective albuminuria, as in group I,, there is an isolated reduction of electrostatic retardation of relatively small anionic proteins. Major urinary IgG leakage (group II), however, appears to result from the development in the glomerular membrane of a subpopulation of enlarged pores that are highly permeable towards proteins of large size and varying charge.

Albuminuria↗
PubMed1981

Determinants of the glomerular filtration of proteins.

We showed previously that a theoretical model treating the glomerular capillary wall as a membrane with uniformly distributed fixed negative charges can account for the observed filtration rates of charged derivatives of dextran in the rat. Using measurements of electrophoretic mobility to estimate effective molecular charge, a necessary input parameter, we present evidence that this model is also consistent with reported filtration rates of several proteins in the rat. Apparent fixed-charge concentrations calculated for serum albumin and three forms of horseradish peroxidase are in the range of 100-130 meq/liter, comparable to the 120-170 meq/liter obtained for charged dextrans. Theoretical effects of hemodynamic changes on filtration of charged macromolecules are considered. With increases in glomerular plasma flow rate (QA) or transcapillary hydraulic pressure difference (delta P), the filtrate-to-plasma concentration ratio (theta) is generally predicted to decrease for neutral or anionic macromolecules but to increase for cationic substances. The more highly charged the macromolecule (cationic or anionic), the more sensitive theta is to such hemodynamic perturbations. For serum albumin, absolute filtration rates are predicted to increase as much as twofold for moderate decreases in QA combined with increases in delta P. Alterations in protein molecular charge offer an attractive explanation for changes in protein filtration during acidosis or alkalosis.

Acid-Base Imbalance↗
PubMed1980

Chemical kinetic and diffusional limitations on bicarbonate reabsorption by the proximal tubule.

It is accepted that bicarbonate reabsorption in the proximal tubule is mediated by H+ secretion, but several aspects of this process have remained controversial. To examine some of these issues, we have developed a model that allows for spatial variations in the concentrations of CO2, HCO3-, and H2CO3 within the tubule lumen and cell cytoplasm, passive transport of these substances across cell membranes, carbonic anhydrase-catalyzed interconversion of HCO3- and CO2 within the cell and at the luminal membrane surface, and the corresponding uncatalyzed reactions in lumen and cell. Most of the required kinetic and transport parameters were estimated from physicochemical data in the literature, whereas intracellular pH and HCO3- permeability at the basal cell membrane, found to be the most significant parameters under normal conditions, were adjusted to yield reabsorption rates of "total CO2" (tCO2, the sum of CO2, HCO3- and H2CO3) comparable to measured values in the rat. Our results suggest that for normal carbonic anhydrase activity, almost all tCO2 leaves the lumen as CO2, yet the transepithelial differences in CO2 partial pressure does not exceed approximately 2 mm Hg. Electrochemical potential gradients favor substantial passive backleak of HCO3- from cell to lumen. Gradients in CO2 partial pressure remain small during simulated inhibition of carbonic anhydrase, with approximately 70% of tCO2 leaving the lumen as H2CO3 in this case, and the remainder as CO2. Predicted tCO2 reabsorption rates for carbonic anhydrase inhibition are approximately of normal, in good agreement with recent measurements in the rat, indicating that the concept of "carbonic acid recycling" is viable.

Absorption↗
PubMed1980

Theoretical model for glomerular filtration of charged solutes.

Previous experimental studies have revealed that for a given molecular size, the glomerular capillary wall restricts the passage of polyanions more than that of neutral macromolecules, and restricts transport of the latter more than that of polycations. We have developed a theoretical model of this charge-selectivity based on the following principal assumptions: a) all ions (tracer macromolecule and univalent cations and anions) obey a modified Nernst-Planck flux expression, including terms for convection and size-selective retardation; b) the capillary wall has a homogeneous distribution of fixed negative charges; and c) Donnan equilibria exist at the surfaces of this "membrane." To allow specific application of the model we measured electrophoretic mobilities of narrow fractions of dextran sulfate (DS) and diethylaminoethyl dextran (DEAE), and used these to estimate effective molecular charge as a function of molecular size. Based on these measurements and fractional clearance data for DS and DEAE reported previously for the normal Munich-Wistar rat, the capillary wall has an apparent fixed charge concentration of 120--170 meq/liter. The effects of this membrane charge on the filtration of water and on the transcapillary electrical potential difference are also discussed.

Animals↗