Comment on PCO2 in renal cortex.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
W M Deen
Publications and source records attributed to W M Deen.
Glomerular dysfunction in nephrotic humans with minimal changes or focal glomerulosclerosis.
Fractional clearances (theta) of uncharged dextrans (radii 28-60 A) were used to characterize glomerular dysfunction in 34 nephrotic humans with either minimal-change nephropathy (MCN) or focal, segmental glomerulosclerosis (FSGS). A theoretical analysis of theta of dextran with a heteroporous membrane model revealed a similar alteration, more marked in FSGS than MCN. The number of restrictive pores perforating the major membrane component was reduced in parallel with the prevailing glomerular filtration rate (GFR). Parallel shuntlike pores in the remaining membrane component were more prominent, pointing to impaired size selectivity. However, the theta of large (60 A) dextrans attributable to these shunts exceeded control in FSGS only, suggesting that coexistent impairment of charge selectivity contributed importantly to the proteinuria in MCN. Membrane properties returned toward normal when MCN remitted. Glomerular morphometry revealed the frequency of epithelial filtration slits to vary with the extent of membrane dysfunction. Despite offsetting hypertrophy of remnant glomeruli in FSGS, a loss of filtration surface due to sclerosis likely contributed to the more marked reductions in pore number and GFR observed in this disorder than in MCN.
Adolescent↗
Analysis of pulsatile pressures and flows in glomerular filtration.
Previous mathematical models of glomerular filtration have ignored the pulsatility of the glomerular capillary pressure, using only steady-state equations and time-averaged pressures and flows. Because the actual pressure pulses are rapid and of large amplitude and because the governing equations are nonlinear, it is questionable whether the effects of the pressure pulses average out in the manner that has been assumed. We have developed a model that includes sinusoidal variations in the glomerular transcapillary hydraulic pressure (delta P) and the afferent arteriolar plasma flow rate over each cardiac cycle. The analysis suggests that the previously ignored time derivatives in the luminal mass balance equations are not negligible. The amplitude of the oscillations in delta P was found to be sufficient to reverse the direction of the transmural fluxes over part of each cardiac cycle, at the more efferent locations in a capillary. However, the time-averaged values of single-nephron glomerular filtration rate and sieving coefficients for macro-molecules from the pulsatile model differed from that for a steady-state formulation by less than 0.1 and less than or equal to 10%, respectively. We conclude that use of the usual steady-state assumption introduces negligible errors in calculating glomerular membrane parameters from experimental data.
Animals↗
Reversible hexadimethrine-induced alterations in glomerular structure and permeability.
Female Munich-Wistar rats received hexadimethrine (HDM) i.v. until the onset of proteinuria (PEAK)--a period of not more than 30 min. There were four experimental groups: C (control), H (HDM only), HH (HDM and heparin), and HHD (identical to HH but with dextran clearances measured). Rats in groups HH and HHD received a heparin bolus after the PEAK period, whereas rats in group H did not. HDM led to dramatic increases in both albumin and IgG excretion. Glomerular filtration rate and renal plasma flow rate were reduced by 30 to 50% after HDM infusion. Neutral dextran clearances for radii greater than 30 A were elevated during the PEAK period, and, concurrently, there was extensive intraglomerular microthrombosis, obliteration of foot processes, and disruption of filtration slit diaphragms. One hour later, glomerular filtration rate, renal plasma flow rate, dextran clearances, and proteinuria returned to baseline in groups HH and HHD but not in group H. Recovery in heparin-treated rats was associated with reversal of HDM-associated morphological alterations. Membrane pore-size parameters calculated from the dextran clearances indicate that HDM leads to a detect in glomerular size-selectivity. The facts that maximal albuminuria tended to precede maximal excretion of IgG and that increases in albumin excretion were proportionately greater than those of dextran or IgG suggest that HDM also leads to a time-dependent defect in glomerular charge-selectivity.
Albuminuria↗
Theoretical effects of network structure on glomerular filtration of macromolecules.
A parallel network model was developed to examine the effects of a distribution of capillary lengths on the filtration of macromolecules by the glomerulus. When networks having different distributions of capillary lengths (but similar values of single nephron glomerular filtration rate) were compared, the filtrate-to-plasma concentration ratio (theta s) for neutral macromolecules was found to increase as the vessel lengths became less uniform. Because anatomical studies have demonstrated that the glomerulus is in fact a heterogeneous network, this implies that the conventional modeling assumption of identical capillaries in parallel leads to an overestimation of effective pore sizes. However, simulations employing various pore-size distributions demonstrated that the expected errors in estimating membrane-pore parameters are generally negligible. Furthermore, the dependence of theta s on hemodynamic inputs such as glomerular plasma flow rate and transmembrane hydraulic pressure difference was insensitive to the assumed distribution of capillary lengths. We conclude that models based on dimensionally uniform capillary networks remain valid for interpreting clearance data for macromolecules.
Capillaries↗
Theoretical model for predicting rates of nitrosamine and nitrosamide formation in the human stomach.
A mathematical model has been developed to estimate the rates of formation of nitrosamines and nitrosamides in the human stomach, under a variety of physiological and environmental conditions. The model combines a detailed description of the kinetics of N-nitrosation with mass balance equations which account for gastric emptying, dilution and absorption. The simulations were based on a typical schedule of dietary inputs, and included variations in gastric pH and in the volume of the stomach contents over a 24-h period. Consideration of these transient phenomena allowed a distinction to be made between amines or amides present in the diet and in gastric or salivary secretions. A comparison of the theoretical results with available data on the nitrosation of proline suggests that the model accurately predicts gastric rates of nitrosamine formation under control conditions, and correctly represents the strong catalytic effects of thiocyanate and the inhibitory effects of ascorbic acid or ascorbate ion. The results further suggest that nitrosoproline (NPro) excretion is not an accurate index of gastric nitrosation under physiological (low-dose) conditions, even when corrections are made for dietary intake of NPro. The predicted rates of formation of N-nitrosodimethylamine (NDMA), even for a diet high in dimethylamine, were found to be a factor of approximately 10(2) to 10(3) lower than published estimates of the dietary exposure to preformed NDMA. Thus, these findings do not support the hypothesis that gastric formation of NDMA from dietary dimethylamine poses a serious additional health risk. The results are presented in a graphical and tabular form which makes it possible to readily estimate the rates of formation of other nitrosamines or nitrosamides in the stomach, under various assumed conditions.
Ascorbic Acid↗
Use of ascorbic acid to inhibit nitrosation: kinetic and mass transfer considerations for an in vitro system.
Ascorbic acid and ascorbate ion (denoted together as ASC) inhibit nitrosation by competing for the nitrosating agents formed from nitrite (e.g. N2O3, NO+ and NOSCN). ASC is oxidized irreversibly by this reaction and the nitrite equivalents are reduced to nitric oxide (NO). In open, aerobic systems the effective stoichiometry of the reaction between ASC and nitrite is not fixed, but is determined by a competition between the physical removal of NO (and NO2) from the system and the oxidation of NO by dissolved O2. The oxidation of NO reconverts it to a nitrosating agent which may react again with the remaining ASC. To determine the conditions under which ASC is most effective as a nitrosation inhibitor, we examined the kinetics of the reactions between nitrite and ASC and between nitrite and proline. These reactions were studied in open shaker flasks as functions of pH, anion composition (SCN- and Cl-), temperature, and gas-liquid mass transfer rate. At lower mass transfer rates, at lower pH and/or in the presence of SCN- or Cl-, relatively more ASC was consumed by a given amount of nitrite. Increased temperature caused more or less ASC to be consumed by a given amount of nitrite, depending on the conditions. A mathematical model of the reactions and mass transfer steps was developed which describes each of these features. The model predicts the variable stoichiometry of the reaction between nitrite and ASC in open, aerobic systems, and clarifies the mechanisms by which ASC inhibits nitrosation.
Ascorbic Acid↗
Effects of ascorbic acid and thiocyanate on nitrosation of proline in the dog stomach.
To elucidate the factors governing the formation of N-nitrosamines in the stomach, the formation of N-nitrosoproline (NPro) was studied under controlled conditions, using a dog equipped with a Thomas cannula. Solutions containing nitrite, proline and in some cases ascorbic acid and/or SCN-, were infused into the stomach and samples taken to determine gastric [nitrite], [NPro], [ASC], [SCN-] and pH as functions of time. (Brackets indicate molar concentrations; ascorbic acid and ascorbate ion are denoted together by ASC.) Previous work showed that the rapid decline of [nitrite] in the stomach was due primarily to absorption. Additional experiments here in which ASC, proline or NPro were infused together with a non-absorbable marker, in the absence of nitrite, demonstrated that there was negligible absorption or secretion of these substances in the stomach. Thus, changes in [ASC] and [NPro] with time could be interpreted quantitatively in terms of rates of chemical reaction and dilution of the stomach contents. A mathematical model, based on mass balance equations for the various chemical species and chemical kinetic data obtained previously from in vitro studies, was developed for this purpose. The ability of ASC to inhibit nitrosation (by reaction with nitrite) was shown to be highly dependent on initial [ASC] and on the rate of entry of O2 into the stomach from blood. The rate of NPro formation in the absence of ASC and SCN-, the inhibitory effects on nitrosation of ASC and the catalytic effects of SCN-, were all accurately predicted by the mathematical model. This suggests that similar models may prove useful in estimating rates of intragastric N-nitrosation reactions in humans, under various assumed conditions.
Animals↗
Analysis of PCO2 variations in the renal cortex. I. Single nephron.
A mathematical model was developed to predict differences in CO2 partial pressure between afferent arterioles and peritubular capillaries, based on the flow rate and composition of afferent arteriolar blood. Buffering reactions in blood were described by use of conditions of chemical equilibrium and electroneutrality in separate plasma and red cell compartments, with inclusion of such factors as the effect of hemoglobin oxygenation (alkaline Bohr effect) and formation of carbamino compounds. Steady-state mass balance equations allowed the prediction of peritubular capillary blood composition based on the inputs of blood from the efferent arteriole and the addition of water, CO2, NaHCO3, and NaCl derived from tubule reabsorbate. Models developed previously to describe the rates of glomerular filtration, and of proximal tubule reabsorption of HCO3- and CO2, were combined with the peritubular capillary model to allow realistic simulations for a single superficial nephron. The predicted difference of 5.5 mmHg between the CO2 partial pressures in peritubular capillaries and afferent arterioles (delta PCO2) was in good agreement with values reported for normal Munich-Wistar rats. For a given afferent arteriolar blood composition, the calculated delta PCO2 generally decreased with increasing blood flow rate. At a given blood flow rate and afferent PCO2, delta PCO2 decreased as afferent plasma HCO3- concentration was increased. When afferent PCO2 was varied at constant blood flow rate and HCO3- concentration, delta PCO2 changed in parallel with afferent PCO2.
Animals↗
Analysis of PCO2 variations in the renal cortex. II. Countercurrent exchange.
In an effort to explain the relatively high values of CO2 partial pressure (PCO2) that have been measured in the superficial renal cortex of the rat, we developed a mathematical model based on the concept of countercurrent exchange between blood vessels. The model includes the possibility of exchange of CO2 between interlobular arteries and veins throughout the cortex, and between "terminal" arterioles and venules (those associated with the most superficial nephrons). The effect of countercurrent exchange is to amplify the increases in PCO2 that occur in the microcirculation of individual nephrons, which are due to the addition of metabolic CO2 and reabsorbed HCO3- and CO2 to peritubular capillaries. The model is formulated in terms of correlations that describe blood buffering equilibria in peritubular capillaries and in interlobular arteries and veins, and steady-state mass balances for the interlobular vessels. By use of physically reasonable vascular permeability values, simulations for the normal euvolemic Munich-Wistar rat yielded values of the surface-to-arterial PCO2 difference (delta PCO2) comparable to previously measured values. Predicted variations in delta PCO2 with afferent arteriolar blood flow rate and systemic arterial PCO2 were also in accord with available data. These results suggest that the amplifying effect of countercurrent exchange is in fact adequate to explain the high values of PCO2 measured in surface structures. The solutions to the mass balance equations are in closed analytical form and can be readily adapted to describe countercurrent exchange in the renal cortex of solutes other than CO2.
Animals↗
"Intact nephrons" as the primary origin of proteinuria in chronic renal disease. Study in the rat model of subtotal nephrectomy.
Single nephron filtration rate of albumin (SNGFRAlb) was measured in remnant nephrons of Munich-Wistar rats 4-6 wk after subtotal nephrectomy (NPX). Serial thin-section histological analysis was then conducted on the same glomeruli by light microscopy. SNGFRAlb ranged from 1 to 15 times normal. However, a direct relationship between abnormalities of structure and function was not seen, e.g. the glomeruli with the fewest structural abnormalities and marked hyperfiltration often had the highest SNGFRAlb. Moreover, the majority of glomeruli had minimal structural abnormalities. Normalization of the markedly elevated glomerular capillary pressure (PGC) in these glomeruli was accomplished by acute intravenous infusion of verapamil, which decreased SNGFRAlb by 9-83% without affecting the single nephron filtration rate of water (SNGFRH2O). 1-2 wk after subtotal NPX, all glomeruli were hyperfiltering and had elevated PGC. The fractional clearance of larger (greater than 36 A) dextrans was selectively increased in these glomeruli that lacked discernible damage by light microscopy. Verapamil normalized PGC, reduced proteinuria to 48 +/- 4% of baseline, and improved glomerular size selectivity without altering SNGFRH2O. Proteinuria after subtotal NPX thus originates largely from glomeruli with minimal structural abnormalities. The defect in size selectivity is largely attributed to the prevailing high PGC, producing large, nonselective channels on the glomerular capillary wall. The observations raise the possibility that in chronic renal diseases, the reduction in proteinuria often seen after therapeutic measures, including antihypertensive medication, may reflect their functional effect on the relatively intact glomeruli rather than their structure-sparing effect on severely damaged glomeruli, which contribute little to the proteinuria.
Animals↗
Models of the medullary microcirculation.
Explore the source record for details and available documents.
Animals↗
Role of abnormally high transmural pressure in the permselectivity defect of glomerular capillary wall: a study in early passive Heymann nephritis.
To explore the mechanism of glomerular permselectivity defect in passive Heymann nephritis, an experimental model of human membranous glomerulopathy, Munich-Wistar rats were subjected to both micropuncture assessment of glomerular hemodynamics and whole kidney clearance measurements of graded size dextrans 10 days after injection of sheep anti-rat tubular antigen (anti-Fx1A). Compared with normal control rats, anti-Fx1A-treated animals were characterized by marked proteinuria (65 +/- 8 micrograms/min versus 6 +/- 1, p less than 0.001), markedly and significantly higher glomerular transcapillary hydraulic pressure difference (40 +/- 1 mm Hg versus 33 +/- 1, p less than 0.001), depressed ultrafiltration coefficient and impaired glomerular size-selective function as determined by fractional clearance of dextrans. Calculation of membrane parameters based on a recently defined heteroporous membrane model revealed abnormally high availability of non-size selective, large pore pathways in the glomerular capillary wall of the rats with passive Heymann nephritis. To ascertain the role of the altered hemodynamic pattern in the observed defect in the size-selective function of the glomerular capillary wall, glomerular transcapillary hydraulic pressure difference was manipulated experimentally in these proteinuric rats by intra-aortic infusion of acetylcholine or angiotensin II. These agents respectively suppressed and augmented glomerular transcapillary hydraulic pressure difference and brought about a decline of and a further rise in fractional clearance of larger dextrans along with parallel changes in both urine protein excretion rate and availability of nonselective channels. These results indicate that the permselectivity defect in passive Heymann nephritis is attributable, at least in part, to impaired size selectivity of the glomerular capillary wall caused by a prevailing abnormally high transcapillary hydraulic pressure difference.
Animals↗
Functional nature of glomerular injury in progressive diabetic glomerulopathy.
We describe in physiological terms the increasing glomerular capillary wall (GCW) dysfunction of 20 patients with diabetic glomerulopathy and heavy proteinuria. The clearances of uncharged polysaccharide markers of graded size were used to probe the glomerular filter on three occasions over a 24-mo period. The findings were analyzed with a theoretical model of solute transport that depicts most of the GCW as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway. Initially, the mean glomerular ultrafiltration coefficient Kf is computed to have been 3-5 times lower and mean pore radius of the major membrane component (r0) 2 A smaller than normal control values. In contrast, the model computes the fraction of filtrate volume permeating the nondiscriminatory shunt pathway (omega 2) to have been sixfold elevated above control values and to have correlated strongly in individual patients with the fractional clearances of albumin (r = .72) and of IgG (r = .73). Sequential studies after 12 and 24 mo revealed an invariable decline in glomerular filtration rate (GFR). Fractional clearances of albumin and IgG increased with time in most patients but declined in a few instances (20-25%). Change in omega 2 tended to occur in parallel with fractional protein clearance, regardless of its direction. We conclude that in progressive diabetic glomerulopathy GFR declines because of a loss by glomerular capillaries of ultrafiltration capacity, proteinuria is largely a consequence of increasingly impaired barrier-size selectivity, and the foregoing injuries reflect damage to different parts of the GCW and may become dissociated from one another with the passage of time.
Adult↗
Control of bicarbonate and fluid reabsorption in the proximal convoluted tubule.
Explore the source record for details and available documents.
Absorption↗
Theoretical effects of a distribution of capillary dimensions on glomerular ultrafiltration.
Simple network models were developed to examine the effects of a distribution of capillary dimensions on the filtration of fluid in the renal glomerulus. Two idealized networks were considered, one with parallel capillaries of varying length, and the other with parallel capillaries of varying radius. It was found that for a fixed value of the ultrafiltration coefficient (Kf), the product of hydraulic permeability and total capillary surface area per glomerulus, any assumed heterogeneity of capillary dimensions lowered the single nephron glomerular filtration rate (SNGFR) below that predicted for uniform capillaries in parallel. This implies that, to the extent that the capillaries are not identical, a given filtering surface area is used less efficiently. A consequence of this is that for a given set of measured glomerular pressures and flows, a model which assumes identical capillaries will underestimate the value of Kf for the actual (heterogeneous) glomerular network. The effects of a distribution in capillary lengths were found to be more pronounced, in general, than those of a distribution in radii. Considering only heterogeneity in capillary length, and characterizing the effective length distribution using available data in the literature, it was found that calculating Kf using the customary assumption of identical capillaries will underestimate the true value by approximately 30%, under typical micropuncture conditions in the rat. The predicted dependence of SNGFR on afferent plasma flow rate, transmural hydraulic pressure difference, and afferent protein concentration was quite similar, however, whether capillary dimensions were assumed to be uniform or heterogeneous.
Animals↗
Axial heterogeneity and filtered-load dependence of proximal bicarbonate reabsorption.
A theoretical model was developed to examine the role of physical and chemical factors in the control of bicarbonate reabsorption in the renal proximal tubule. Included in the model were axial and radial variations in the concentrations of HCO3-, CO2 and related chemical species in the tubule lumen and epithelial cells. Relations between these concentrations and the solute fluxes across the brush border and basolateral membranes were also included, as were reaction rate and equilibrium expressions to describe the various buffering processes in the lumen and cells. The two most critical membrane parameters, the rate constant for H+ secretion at the brush border and the effective permeability of HCO3- at the basolateral membrane, were evaluated by comparing model predictions with available free-flow micropuncture data in the rat. It was found that the experimental observations could be explained only by decreasing one or both of these membrane parameters with axial position, suggesting a progressive decrease in HCO3- reabsorptive capacity along the tubule. For single nephron filtered loads of HCO3- up to about 1,400 pmol/min, absolute bicarbonate reabsorption was predicted to increase nearly in proportion to filtered load, whereas it was calculated to be relatively constant at higher filtered loads, irrespective of how filtered load was assumed to be varied. These predictions are in excellent agreement with most of the available micropuncture data in rats, as is the prediction that HCO3- reabsorption should change in parallel with CO2 partial pressure in the filtrate, at a given filtered load of HCO3-. Certain discrepancies between the model predictions and experimental observations are evident at very high filtered loads, and the implications of these are discussed in terms of possible adaptive responses of the tubule.
Animals↗
Role for angiotensin II in an overt functional proteinuria.
A partial renal vein constriction (RVC) was induced acutely in Munich-Wistar rats. RVC caused a marked reduction in glomerular plasma flow rate, and rises in glomerular transcapillary hydraulic pressure difference and efferent arteriolar resistance. These changes were associated with a marked increase in urinary protein excretion, on average from a baseline level of 8 to approximately 120 mg/24 hrs per kidney. Infusion of saralasin, an angiotensin II (AII) antagonist, largely normalized these indices, including urinary protein excretion (to approximately 35 mg/24 hrs per kidney), despite continued RVC. In separate rats, fractional clearances of neutral [125I]dextrans (molecular radii = 18-60 A) (CDEX/CIN) were measured. RVC caused a significant increase in CDEX/CIN for large dextrans (greater than or equal to 44A), but not small dextrans (less than or equal to 42A). Saralasin infusion led to a partial return toward baseline values of CDEX/CIN for the large dextrans. On the basis of the heteroporous membrane theory for glomerular filtration, the glomerular sieving defect during RVC was attributed to an increase in the relative fluid flux through a group of large non-selective pores. A marked alteration in glomerular microcirculatory pattern induced by enhanced action of endogenous AII in turn seemed to account largely, although not entirely, for the impairment of glomerular size-selectivity during RVC.
Angiotensin II↗