Influence of calcium on the determinants of glomerular ultrafiltration.
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Biomedical subjects
B M Brenner
Publications and source records attributed to B M Brenner.
Evidence for a glomerular action of parathormone in the rat.
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Determinants of the transglomerular passage of macromolecules.
In addition to molecular size, at least two other factors influence the transglomerular passage of macromolecules. The hemodynamic determinants of glomerular filtration rate affect macromolecule transport by altering the volume flux through the glomerular capillary wall and the profile of macromolecule concentrations along a glomerular capillary. The electrostatic properties of the glomerular capillary wall markedly restrict the passage of circulating polyanions, relative to neutral macromolecules of similar size. In the normal animal, the combined effects of these various mechanisms ensure that only very small quantities of plasma proteins are filtered. In experimental proteinuric conditions such as nephrotoxic serum nephritis and puromycin-induced nephrosis, reduction in the fixed negative charges on the glomerular capillary wall appears to be largely responsible for the increased transglomerular passage of anionic macromolecules such as albumin. Other evidence suggests that hemodynamic factors may contribute to proteinuria under certain circumstance. The possibility of an increase in number and/or radius of glomerular "pores" being responsible for proteinuria, perhaps the most intuitively obvious and widely held view, has yet to receive direct experimental support.
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Of unglazed pottery and glomerular sieving.
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Determinants of glomerular filtration rate.
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Effects of some vasodilator drugs on transcapillary fluid exchange in renal cortex.
In 23 Munich-Wistar rats with surface glomeruli, the determinants of glomerular ultrafiltration and peritubular capillary uptake of proximal reabsorbate were studied before and during intra-arterial infusions of mildly vasodepressor doses of prostaglandin E1,acetylcholine, and bradykinin. For each drug single-nephron glomerular filtration rate remained unchanged from normal hydropenic values while glomerular plasma flow rate increased, resulting in declines in single-nephron filtration fraction (SNFF). Mean glomerular transcapillary hydraulic pressure difference (delta P) increased or remained unchanged on average. Declines in SNFF were accompanied by reductions in efferent arteriolar oncotic pressure (piE). Filtration pressure equilibrium, equality between pi E and delta P, obtained before but not during drug infusions. In the latter situation values for the glomerular capillary ultrafiltration coefficient were calculated and found to be significantly reduced from published control values. Despite marked falls in pi E during drug infusion, absolute proximal reabsorption was not reduced significantly, due, it is suggested, to the opposing effects of increases in efferent arteriolar plasma flow and interstitial hydraulic pressure.
Acetylcholine↗
Permeability of renal peritubular capillaries to neutral dextrans dextrans and endogenous albumin.
Renal lymph-to-renal vein concentration ratios (CL/CV) for neutral dextrans (18-42 A effective radii) and endogenous serum albumin were measured in rats before and during acute colume expansion with isoncotic plasma or Ringer solution. Under all conditions studied, CL/CV decreased with increasing dextran size, in normal hydropenia falling from 0.93 +/- 0.03 SE at 18 A to 0.24 +/- 0.02 a 42 A (n = 12). Albumin (36 A pradius) behaved in a manner similar to a 40 A dextran, CL/CV averaging 0.33 +/- 0.03 (n = 12) in hydropenia. For all dextran sizes studied and for albumin, CL/CV decreased markedly during either form of volume expansion. Ringer loading produced significantly greater decreases in CL/CV for the larger dextrans and albumin than did plasma loading, and also resulted in much greater increases in renal lymph flow, while causing increases in whole kidney fluid reabsorption similar to those with plasma loading. With a compartmental model in which diffusion of dextrans and albumin from capillary lumen to interstitium is opposed by capillary uptake of tubule reabsorbate, these results are interpreted to indicate that connective reflection coefficients for dextrans with radii great than or equal to 36 A and albumin are essentially equal to 1. Indirect evidence is therefore provided that albumin and the larger globulins exert their full osmotic pressures across the walls of peritubular capillaries.
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Transport of molecules across renal glomerular capillaries.
Direct measurements of the pressures and flows governing the formation of glomerular ultrafiltrate have been made possible in recent years by virtue of 1) the discovery of rats and monkeys possessing glomerular capillaries on the renal cortical surface, accessible to micropuncture, and 2) technological advances that permit measurement of intracapillary hydraulic pressure and assessment of the change in colloid osmotic pressure along the glomerular capillary network. Based on these direct measurements, evidence has been obtained to indicate that glomerular capillary hydraulic pressure and hence the net driving force for ultrafiltration are lower than previously believed. By the efferent end of the glomerular capillary network, net filtration of fluid ceases, owing to a reduction in the net driving force to zero. Evidence in the rat indicates that the process of ultrafiltration is highly dependent on glomerular plasma flow rate. Studies in rats with surface glomeruli have also made possible an assessment of the factors that govern the transport of macromolecules across the highly specialized capillary network. In addition to molecular size, transcapillary movement of macromolecules is influenced by the glomerular filtration rate, since total transport reflects the combined contributions of convection as well as diffusion. Molecular charge has also been found to be an important determinant of the transport of macromolecules, very likely contributing to the marked restriction to the transcapillary movement of albumin. This electrostatic restriction to the transport of polyanions such as albumin, by some fixed, negatively charged component(s) of the glomerular capillary wall, is markedly reduced in primary glomerular injury. Evidence indicates that glomerular injury results in loss of these fixed negative charges from the capillary walls, providing an attractive explanation for the enhanced filtration of albumin, and hence the proteinuria, observed in a variety of glomerulopathic states.
Albumins↗
Permselectivity of of the glomerular capillary wall. Studies of experimental glomerulonephritis in the rat using neutral dextran.
Polydisperse [3h] dextran was infused into eight Munich-Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN), thereby permitting direct measurements of pressures and flows in surface glomeruli and fractional clearances for dextrans [(U/P) dextran/(U/P) inulin] ranging in radius from 18 to 42 A. Despite glomerular injury, evidenced morphologically and by a marked reduction in the glomerular capillary ultrafiltration coefficient, the glomerular filtration rate remained normal because of a compensating increase in the mean net ultrafiltration pressure. In NSN rats, as in normal controls, inulin was found to permeate the glomerular capillary wall without measurable restriction, and dextrans were shown to be neither secreted nor reabsorbed. For dextran radii of 18, 22, 26, 30, 34, 38, and 42 A, (U/P) dextran/(U/P) inulin in NSN and control rats, respectively, averaged 0.90 vs. 0.99, 0.81 vs. 0.97, 0.63 vs. 0.83, 0.38 vs 0.55, 0.20 vs. 0.30, 0.08 vs. 0.11, and 0.02 vs. 0.03. Using a theory based on macromolecular transport through pores, the results indicate that in NSN rats, effective pore radius is the same as in controls, approximately 50 A. In NSN, however, the ratio of total pore surface area to pore length, a measure of the number of pores, is reduced to approximately 1/3 that of control, probably due to a reduction in capillary surface area. These results suggest that proteinuria in glomerular disease is not due simply to increases in effective pore radius or number of pores, as previously believed. Using a second theoretical approach, based on the Kedem-Katchalsky flux equations, dextran permeability across glomerular capillaries was found to be slightly lower, and reflection coefficient slightly higher in NSN than in control rats.
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Permselectivity of the glomerular capillary wall. Studies of experimental glomerulonephritis in the rat using dextran sulfate.
To determine whether the increased filtration of serum proteins after glomerular injury is the consequence of altered electrostatic properties of the glomerular capillary wall, we measured fractional clearances of the anionic polymer, dextran sulfate, in nine Munich-Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN). In agreement with previous studied from this laboratory, whole kidney and single nephron glomerular filtration rates were normal in NSN rats despite histological evidence of glomerular injury, and despite a marked reduction in the glomerular capillary ultrafiltration coefficient to approximately one-third of normal. In the companion study (9), it was shown that in NSN rats the mean fractional clearances of neutral dextrans over the range of effective molecular radii from 18 to 42 A were reduced, compared to normla. In contrast, in the present study the mean fractional clearances for dextran sulfate over the same range of molecular radii were significantly greater than those found previously for normal Munich-Wistar rats. The fractional clearance of dextran sulfate molecules of the same molecular radius as serum albumin (approximately 36 A) was increased markedly, from 0.015 +/- 0.005 (SEM) in nonnephritic controls to 0.24 +/- 0.03 in NSN (P less than 0.001). The sialoprotein content of glomeruli, estimated by the colloidal iron reaction, was reduced in NSN rats as compared to normal controls. It is concluded that the abnormal filtration of anionic serum proteins, such as albumin, seen in glomerulopathies is, at least in part, the consequence of loss of fixed negative charges from the glomerular capillary wall.
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Permselectivity of the glomerular capillary wall to macromolecules. I. Theoretical considerations.
The transport of macromolecules across the renal glomerular capillary wall has been described theoretically using flux equations based on (a) restricted transport through small pores, and (b) the Kedem-Katchalsky formulation. The various assumptions and limitations inherent in these two approaches are discussed. To examine the coupling between macromolecular solute transport and the determinants of glomerular filtration rate, these flux equations were combined with mass balance relations which allow for variations in the transmembrane driving forces along a glomerular capillary. It was predicted, using both pore theory and the Kedem-Katchalsky equations, that fractional solute clearance should be strongly dependent on the determinants of glomerular filtration rate when convection and diffusion both contribute to solute transport. When convection becomes the sole mechanism for transcapillary solute transport, however, fractional solute clearance is essentially independent of changes in the determinants of glomerular filtration rate. Consequently, unless diffusion is absent, fractional solute clearances alone are insufficient to characterize the permselective properties of the glomerular capillary wall, since these values may be altered by changes in glomerular pressures and flows as well as changes in the properties of the capillary wall per se.
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Permselectivity of the glomerular capillary wall to macromolecules. II. Experimental studies in rats using neutral dextran.
To determine the permselectivity characteristics of the glomerular capillary wall, known molecular size fractions of [3H]dextran, prepared by gel chromatography, were infused into normally hydrated Wistar rats, thus permitting simultaneous measurement of Bowman's space/plasma water (BS/P) and urine/plasma water (U/P) concentration ratios, along with glomerular pressures and flows. Since (BS/P)inulin = 1.01 +/- 0.01 SE(n = 34, radius = approximately 14 A) and since (BS/P)dextran/(BS/P)inulin equaled (U/P)dextran/(U/P)inulin for dextrans ranging in molecular radius from 21 to 35 A, these findings validate that dextrans are neither secreted nor reabsorbed. For dextran radii of 20, 24, 28, 32, 36, 40, and 44 A, (U/P)dextran/(U/P)inulin averaged 0.99, 0.92, 0.69, 0.42, 0.19, 0.06, and 0.01, respectively. In accord with theoretical predictions that these fractional dextran clearances should vary appreciably with changes in glomerular transcapillary pressures and flows, an increase in glomerular plasma flow rate, induced in these same rats by plasma volume expansion, resulted in a highly significant lowering of fractional clearance of all but the smallest and largest dextrans studied. These findings emphasize that fractional solute clearances alone are inadequate to describe the permselective properties of the glomerular capillary wall unless glomerular pressures and flows are also known. This sensitivity of fractional dextran clearance to changes in plasma flow indicates that dextrans are transported across the capillary not only by bulk flow but also to an important extent by diffusion.
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Permselectivity of the glomerular capillary wall: III. Restricted transport of polyanions.
The clearance of albumin relative to that of inulin is greatly exceeded by that of uncharged dextrans of the same effective molecular radius (approximately 36A), less than 0.01 vs. 0.20 in normal hydropenic rats. This marked difference in fractional clearances of albumin and neutral dextran suggests that some factor in addition to molecular size retards the transglomerular passage of albumin. Since albumin is a polyanion in physiological solution, we tested the effect of charge on macromolecular permeability by infusing the anionic polymer, dextran sulfate (approximately 2.3 sulfate groups per glycosyl residue), into seven normal hypropenic Munich-Wistar rats. For dextran sulfate with an effective radius of approximately 36A, the fractional clearance was reduced essentially to that found for albumin (approximately 0.01). This enhanced restriction of dextran sulfate, relative to neutral dextran, was also noted for smaller and larger dextran sulfate molecules. These differences in the transport of dextran sulfate vs. dextran suggest electrostatic repulsion of charged macromolecules by some component of the glomerular capillary wall, perhaps the negatively charged sialoprotein which coats glomerular epithelial cells. Loss of this polyanionic coat, as has been reported to occur in proteinuric disorders, might thereby account for the enhanced transmural passage of albumin.
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Reversible hemodynamic defect in glomerular filtration rate after ischemic injury.
In Wistar rats with surface glomeruli 3 h of nearly complete occlusion of the left renal artery resulted in uniform falls (similar to50%) in ipsilateral whole-kidney glomerular filtration rate (GFR) and single-nephron GFR (SNGFR) and in urinary findings consistent with impaired water reabsorption. Since the fall in SNGFR was accompanied by a proportional fall in glomerular plasma flow rate (GPF), and since net ultrafiltration pressure at afferent and efferent ends of the glomerular capillary was unchanged from preischemic levels, these findings suggest that the fall in SNGFR was a hemodynamic consequence of the fall in GPF. To test this hypothesis, GPF was restored to preischemic levels by means of acute infusion of homologous, isoncotic plasma. GPF and SNGFR uniformly increased, on average to preischemic levels, whereas net ultrafiltration pressure at afferent and efferent ends of the glomerular capillary again remained essentially unchanged. These studies demonstrate that the fall in SNGFR in this model of ischemic injury is causally related to the accompanying fall in GPF. Of interest, despite this reversal of the defect in GFR, fractional water reabsorption remained impaired. This restoration of GFR but not reabsorption by plasma infusion abruptly converts this ischemic lesion from nondiuretic to diuretic.
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Hydraulic and oncotic pressure measurements in inner medulla of mammalian kidney.
The vasa recta are thought to play an important role in the transfer of water andsolutes within the renal medulla. Hydraulic pressures were measured in vasa recta onthe surface of the exposed papilla in young Munich Wistar rats, and blood was collected from these microvessels for determination of total protein concentration and calculation of colloid oncotic pressure. In descending vasa recta at the base of the exposed papilla, mean hydraulic pressure was 9.2 plus or minus 0.4 (SE) mmHg and plasma protein concentration averaged 7.1 plus or minus 0.4 g/100 ml. Corresponding valuesin ascending vasa recta at the same level were 7.8 plus or minus 0.4 mmHg and 5.6 plusor minus 0.3 g/100 ml. respectively. The protein concentrations correspond to calculated oncotic pressures of 26 and 18 mmHg in descending and ascending vasa recta, respectively. We interpret these findings as evidence for net water uptake by the vasa recta in the renal inner medulla for which the driving forces are the transcapillary hydraulic and oncotic pressure differences.
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Dynamics of glomerular ultrafiltration in the rat. VIII. Effects of hematocrit.
This study was undertaken in an effort to examine the effects of selective variations in systemic hematocrit on the preglomerular, glomerular, and postglomerular micocirculation in the rat. By isovolemic exchange transfusions, systemic hematocrit (control 51 ml/100 ml) was either reduced (21 ml/100 ml, N equal 7 rats) or elevated (62 ml/100 ml, N equal 7). Single nephron glomerular filtration rate varied inversely and filtration fraction varied directly with the changes in hematocrit. The fall in filtration fraction with decreased hematocrit was due to a decline in the measured glomerular transcapillary hydraulic pressure difference and to a marked increased in the initial glomerular plasma flow rate. Afferent (RA)and efferent (RE) arteriolar resistance declined with the fall in hematocrit; RA fell proportionately more than did RE. The rise in filtration fraction with the elevation in hematocrit was due to a marked increase in in part due to a relatively greater rise in RE than in RA. These findings provide an attractive explanation for the general tendency for filtration fraction to vary directly with hematocrit in anemic and polycythemic states in man.
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Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafiltration and proximal tubule fluid reabsorption in the rat.
In 26 Wistar rats with surface glomeruli, the determinants of glomerular ultrafiltration and peritubular capillary uptake of proximal reabsorbate were studied before and during intravenous infusions of norepinephrine or angiotensin II. Regardless of whether renal perfusion pressure (AP) was permitted to increase, both hormones produced elevations in single nephron filtration fraction due to declines in glomerular plasma flow with little change in nephron glomerular filtration rate. The resulting large increases in the efferent arteriolar oncotic pressure, piE, were accompanied by equivalent increases in the mean glomerular transcapillary hydraulic pressure difference, deltaP. Equality of piE and deltaP, denoting filtration pressure equilibrium, obtained before and during infusion of either hormone. Por both hormones, when elevations in AP were allowed, marked and roughly proportional increases in the resistance to blood flow through single afferent and efferent arterioles occurred, whereas when increases in AP were prevented by partial aortic constriction increases in resistance were confined primarily to the efferent arteriole. Tespite the marked increases in piE, absolute rates of proximal tubule fluid reabsorption, on the average, were unchanged by these hormones due to the opposing effects of marked decreases in efferent arteriolar plasma flow rate and, to a lesser extent, increases in peritubular capillary hydraulic pressure.
Angiotensin II↗
Determinants of glomerular filtration in experimental glomerulonephritis in the rat.
Pressures and flows were measured in surface glomerular capillaries, efferent arterioles, and proximal tubules of 22 Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN). Linear deposits of rabbit and rat IgG and C3 component of complement were demonstrated in glomerular capillary walls by immunofluorescence microscopy. Light microscopy revealed diffuse proliferative glomerulonephritis, and proteinuria was present. Although whole kidney and single nephron glomerular filtration rate (GFR) in NSN (0.8 plus or minus 0.04 SE2 ml/min and 2 plus or minus 2 nl/min, respectively) remained unchanged from values in 16 weight-matched NORMAL HYDROPENIC control rats (0.8 plus or minus 0.08 and 28 plus or minus 2), important alterations in glomerular dynamics were noted. Mean transcapillary hydraulic pressure difference (deltaP) averaged 41 plus or minus 1 mm Hg in NSN versus 32 plus or minus 1 in controls (P LESS THAN 0.005). Oncotic pressures at the afferent (piA) end of the glomerular capillary were similar in both groups ( 16 mm /g) but increased much less by the efferent end (piE) in NSN (to 29 plus or minus 1 mm Hg) than in controls (33 plus or minus 1, P less than 0.025). Hence, equality between deltaP and piE, denoting filtration pressure equilibrium, obtained in control but not in NSN rats. While glomerular plasma flow rate was slightly higher in NSN (88 plus or minus 8 nl/min) than in controls (76 plus or minus 6, P greater than 0.2), the failure to achieve filtration equilibrium in NSN rats was primarily the consequence of a marked fall in the glomerular capillary ultrafiltration coefficient, Kf, to a mean value of 0.03 nl/(s times mm Hg), considerably lower than that found recently for the normal rat, 0.08 nl/(s times mm Hg). Thus, despite extensive glomerular injury, evidenced morphologically and by the low Kf, GFR remained normal. This maintenance of GFR resulted primarily from increases in deltaP, which tended to increase the net driving force for filtration, and thereby compensate for the reduction in Kf.
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