Effective Glomerular Filtration Pressure and Single Nephron Filtration Rate During Hydropenia, Elevated Ureteral Pressure, and A

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Effective glomerular filtration pressure and single nephron filtration rate during hydropenia, elevated ureteral pressure, and acute volume expansion with isotonic saline

Vittorio E. Andreucci, … , Floyd C. Rector Jr., Donald W. Seldin

J Clin Invest. 1971;50(10):2230-2234. https://doi.org/10.1172/JCI106719.

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Free-flow and stop-flow intratubular pressures were measured in rats with an improved Gertz technique using Landis micropipets or a Kulite microtransducer. In hydropenia, average single nephron glomerular filtration rate was 29.3 nl/min, glomerular hydrostatic pressure (stop-flow pressure + plasma colloid osmotic pressure) was 70 cm H2O and mean glomerular effective filtration pressure was 12.7-14.3 cm H2O, approaching zero at the efferent end of the glomerulus. Thus, the glomerulus is extremely permeable, having a filtration coefficient four to five times greater than previously estimated. Mean effective filtration pressure and single nephron glomerular filtartion rate fell with elevated ureteral pressure and rose with volume expansion, more or less proportionately. Changes in effective filtration pressure were due primarily to increased intratubular pressure in ureteral obstruction and to reduced plasma colloid osmotic pressure in volume expansion; glomerular hydrostatic pressure remained constant in both conditions and thus played no role in regulation of filtration rate.

Find the latest version: https://jci.me/106719/pdf Effective Glomerular Filtration Pressure and Single Nephron Filtration Rate during Hydropenia, Elevated Ureteral Pressure, and Acute Volume Expansion with Isotonic Saline

VIrroRio E. ANDEucci, JAIME HERRERA-ACOSTA, FLOYD C. RECrOR, JR., and DONALD W. SELDIN From the Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas 75235

A B S T R A C T Free-flow and stop-flow intratubular pres- the glomerular membrane. The exact value of these sures were measured in rats with an improved Gertz forces is not known due to inaccessibility of the glo- technique using Landis micropipets or a Kulite micro- merulus. Gertz, Mangos, Braun, and Pagel (1) suggested transducer. In hydropenia, average single nephron glo- that glomerular hydrostatic presure (PG)1 could be es- merular filtration rate was 29.3 nl/min, glomerular hy- timated from intratubular pressure in nephrons in which drostatic pressure (stop-flow pressure + plasma colloid filtration was stopped by an oil block; PG was assumed osmotic pressure) was 70 cm H20 and mean glomerular to be the sum of the stop-flow pressure (SFP) and ar- effective filtration pressure was 12.7-14.3 cm H20, ap- terial oncotic pressure. Gertz estimated net effective proaching zero at the efferent end of the glomerulus. filtration pressure (EFP) as the difference between Thus, the glomerulus is extremely permeable, having a SFP and free-flow intratubular pressure (ITP). Un- filtration coefficient four to five times greater than previ- fortunately, SFP obtained with this method has ranged ously estimated. Mean effective filtration pressure and between 85.7 cm H20 (1) and 35 cm H20 (2). More- single nephron glomerular filtartion rate fell with ele- over, the calculation of EFP by Gertz et al. (1, 3) is vated ureteral pressure and rose with volume expansion, incorrect in that it does not account for the rise in more or less proportionately. Changes in effective filtra- glomerular oncotic pressure owing to continuous filtration pressure were due primarily to increased intra- tion during free flow (4). tubular pressure in ureteral obstruction and to reduced In the present studies we found that an important plasma colloid osmotic pressure in volume expansion; artifact may arise during the measurement of SFP as a glomerular hydrostatic pressure remained constant in result of repeated injections of small amounts of saline both conditions and thus played no role in regulation of into the blocked tubule through the pressure-measuring filtration rate. pipet. Consequently, we have refined the method to avoid this source of error. In addition, in calculating the EFP, INTRODUCTION we have taken into account the rise in protein concentration that occurs within the glomerulus as a result of fil- The driving force for glomerular filtration is the bal- tration. Finally, the relation between the various glomeru- ance of hydrostatic and oncotic pressures acting across lar Starling forces and single nephron glomerular filtration rate (SNGFR) was examined in rats during hy- Dr. Andreucci's present address is II Clinica Medica, Universita' di Parma, Italy. Dr. Herrera-Acosta's present 1Abbreviations used in this paper: EFP effective filtration address is Instituto Nacional de la Nutricion, Hospital de pressure; FF, filtration fraction; GFR, total kidney filtra- Enfermedades de la Nutricion, Mexico 7, D. F., Mexico. tion rate; ITP, intratubular pressure; PG, glomerular hydro- Dr. Herrera-Acosta was an International Fellow of the static pressure; 7r., oncotic pressure in the afferent arteriole; U. S. Public Health Service, Grant F05-TW1196. 7re, oncotic pressure in the efferent arteriole; RBF, renal Received for publication 3 June 1971 and in revised form blood flow; SFP, stop-flow pressure; SNGFR, single neph- 16 July 1971. ron glomerular filtration rate. 2230 The Journal of Clinical Investigation Volume 50 1971 dropenia, elevated ureteral pressure, and acute volume served might be related to the fact that rats in groups I expansion with isotonic saline. and II weighed 180-222 g, while those in group III weighed 250-300 g. In all groups, ITP was approxi- METHODS mately 20 cm H20 and PG was approximately 70 cm H20. Sprague-Dawley rats, anesthetized with Inactin (100 mg/ EFP at the afferent end of the glomerulus was approxi- kg), were prepared for micropuncture (5). In rats studied mately 25 cm H20 and at the efferent end of the glo- during elevated ureteral pressure (group I), a catheter in the left ureter was raised to 25 cm above the kidney. Bi- merulus was very close to zero, ranging from 1.6 to 2.9 carbonate-saline was infused at 0.02 ml/min during hydro- cm H20. Mean glomerular EFP ranged from 12.7 to penic control periods and during elevated ureteral pressure. 14.3 cm H20. SNGFR ranged from 27.0 to 32.5 nl/min Animals undergoing saline diuresis received bicarbonate- (mean = 29.3 ±0.8; n = 132). saline at the following rates: Group II, mild volume expansion. 10%o of body weight Elevated ureteral pressure (group I, 13 rats). When over a period of 45 min, then at a rate equal to urine flow ureteral pressure was raised to 25 cm H20, GFR fell (0.1-0.2 ml/min). from 1.49 ml/min to 0.83 ml/min and RBF rose 8%. Group III, massive volume expansion. 0.4 ml/min through- ITP increased to 29.2 cm H20 but SFP did not change. out the experimental period. 60 min were allowed for equili- Since 7ra also was relatively constant, calculated Pa was bration before starting micropuncture collections or pressure measurements. unchanged. Because of the rise in ITP, the EFP at the Total kidney filtration rate (GFR) and SNGFR were afferent end of the glomerulus fell to 15.4 cm H20. EFP measured as previously described (5) using tritiated or at the efferent end of the glomerulus was again close to "C-labeled inulin. Filtration fraction (FF) and renal blood zero (3.5 cm H20). Mean glomerular EFP fell to 9.4 flow (RBF) were calculated from renal extraction of inulin; to Peritubular blood was obtained from the left renal vein by puncture with and SNGFR was reduced 12.7 nl/min. heparinized micropipets. Plasma protein concentrations were capillary hydrostatic pressure rose from a control of 16 measured by the Lowry technique. cm H20 to 22 cm H20. Intratubular pressures during free-flow and stop-flow con- Mild volume expansion (group II, 12 rats). During ditions were measured either by the Landis technique (6) mild volume expansion, GFR and RBF increased 25 and using lissamine green-filled micropipets or with a Kulite microtransducer (7). SFP was measured in tubules blocked 20% respectively, while Na excretion rose from 0.09 with castor oil (1). Initially, with the Landis technique, we IhEq/min to 3.83 uEq/min. A slight, but significant in- observed that tubular fluid was forced into the lissamine crease was observed in both ITP and SFP. Plasma pro- green-filled pipet while the tubule was being filled with oil. tein concentration and 7ra decreased markedly. Calculated When this tubular fluid was ejected back into the oil-blocked tubule in order for the dye to be visible at the pipet tip, SFP Pa fell slightly to 62.7 cm H20. Afferent EFP was un- was artifactually elevated by several centimeters H20. This changed. As a result of a fall in plasma protein concen- source of error could be avoided by maintaining slight posi- tration and FF, efferent EFP was no longer close to tive pressure in the Landis pipet while filling the tubule zero, but instead rose to 17.5 cm H20. Mean glomerular with oil so that tubular fluid did not enter the pipet tip. When this precaution was observed, values of SFP obtained EFP rose to 22.1 cm H20 and SNGFR rose to 34.5 nl/ with the Landis technique were almost identical with those min. Peritubular capillary hydrostatic pressure rose 3 obtained with the Kulite microtransducer: 42.6 and 44.4 cm cm H20. H20 in two groups of hydropenic rats (Table I, groups I Massive volume expansion (group III, 21 rats). Dur- and II) with the Landis technique and 44.8 cm H20 (Table I, group III) with the Kulite microtransducer. When SFP in massive volume expansion GFR rose 19%, RBF in- was measured by both methods in the same animal, the dif- creased 15%, and sodium excretion increased from 0.09 ference between the mean values obtained with each method oEq/min to 16.7 IEq/min. ITP increased to 28.1 cm was 0.8 cm H20 (n = 12). H20, while SFP rose to 57.7 cm H20. EFP rose to 29.6 PG was calculated as PG = SFP +7r ; where 7ra is the oncotic pressure in the afferent arteriole calculated from the cm H20 at the afferent end of the glomerulus and to 23.1 arterial plasma protein concentration by the Landis-Pappen- cm H20 at the efferent end. Mean EFP rose to 26.3 cm heimer equation (4). EFP at the afferent end of the glo- H20 while SNGFR rose to 46.0 nl/min. Peritubular merulus was calculated as Aff EFP = PG -7ra- ITP. EFP capillary hydrostatic pressure rose from 16 to 21 cm at the efferent end of the glomerulus was calculated as Eff EFP = PG- 7re - ITP, where ire is the oncotic pressure in H20. the efferent arteriole calculated from the plasma protein concentration in the efferent arteriole; the latter was ob- DISCUSSION tained from the equation [Prot]aff/i-FF (8). Glomerular It has been assumed, on the basis of indirect evidence, EFP was calculated as EFP = P -7rG-ITP, where IrG is the mean glomerular oncotic pressure (ia-re)/2. that glomerular hydrostatic pressure is 70-80 mm Hg (9-11). The studies of Gertz et al. (1, 3), Krause, RESULTS Dume, Koch, and Ochwadt (12) and Koch et al. (13) Results are summarized in Table I. appeared to confirm such values, whereas several other Hydropenia. There was close agreement in the three investigators using the same technique obtained much hydropenic control groups. The slight differences ob- lower values (2, 14-17). Our experience with the Gertz

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2232 V. E. Andreucci, J. Herrera-Acosta, F. C. Rector, Jr., and D. W. Seldin 60 yu 0.70 + 168 x ever, changes in SNGFR and EFP are approximately ra 0.94 proportional (Fig. 1). Both EFP and SNGFR fell with 50 / elevation of ureteral pressure and rose with volume ex- i' Massive Volume The mean line these Expansion pansion. regression through points 40- / had a slope of 1.68 nl/min per cm H20 and an intercept $NGFR f Mild Volume Expansion near the origin (r = 0.94). These observations suggest ni/min 30 I Hydropenia that there is no significant change in glomerular permeability in partial ureteral obstruction or saline diuresis. 20/ Since both ureteral obstruction and volume expansion are known to 10 / Partial Ureteral Obstruction induce renal vasodilatation, it is interesting to compare the manner in which EFP changed in these two conditions. Despite 8% increase in RBF in ureteral 10 20 30 40 obstruction and 15-20% during saline diuresis, PG re- EFP cmH2O mained constant (Table I). This indicates that, to the FIGURE 1 Relationship between glomerular effective filtra- extent that renal vasodilatation occurred, both afferent tion pressure (EFP) and single nephron filtration rate and efferent arterioles dilated proportionately. The (SNGFR) in the rat kidney. The values of SNGFR are mechanism responsible for this precise between mean +SE. interplay afferent and efferent arteriolar resistances is not clear. Most theories concerned with autoregulation and con- technique for measuring SFP suggests that a major trol of renal vascular tone have focused primarily on the cause of discrepant results is the variable amount of afferent arteriole and to a lesser extent on the efferent fluid injected into the oil-blocked tubule through the arteriole. The finding of constant PG, however, suggests pressure-measuring pipet. When this error is avoided, that both afferent and efferent arterioles respond in we obtained SFP and calculated PG of 45 and 70 cm H20, parallel to changes in neural tone, interstitial pressure, respectively. These values are lower than the values ob- local concentrations of angiotensin II, or other unidenti- tained by Gertz et al. (1, 3), but similar to those ob- fied factors. (It is unlikely that the renin-angiotensin tained by other investigators (2, 14-17).2 The PG in the system is involved in the maintenance of constant PG in range of 70 cm H20 (50 mm Hg) in rats with BP of the present studies since renin release is enhanced in 110-130 mm Hg (within the autoregulation range) in- ureteral constriction and suppressed in saline diuresis.) dicates that the pressure drop across the afferent ar- An alternative possibility is that afferent arteriolar tone teriole is greater than across the efferent arteriole, i.e., is the primary target of control by one or more factors, resistance to blood flow is greater in the afferent than and that efferent arteriolar resistance responds secon- in the efferent arteriole. darily, possibly by a passive myogenic mechanism, in a As a consequence of the lower PG than previously sus- manner to maintain PG constant. Not only do these pected, the mean EFP is also lower, ranging from 12.7 changes in efferent tone serve to maintain constant PG, to 14.3 cm H20. One of the most unexpected features of but they also serve to regulate the transmission of hy- the present studies was the finding that EFP was nearly drostatic forces to the peritubular capillary bed (capil- zero at the efferent end of the glomerulus, indicating lary pressure in all of the present experiments despite that glomerular filtration was approaching an equilib- constant PO) and thus possibly to exert indirect control rium state. These findings indicate that the glomerulus over tubular reabsorption. is extremely permeable, having a filtration coefficient In ureteral obstruction the fall in mean glomerular four to five times greater than that previously estimated. EFP was due primarily to the rise in ITP, although Gertz et al. (3) suggested that the glomerular filtra- the effect of this rise in ITP was somewhat blunted by tion coefficient was not constant, but instead changed in the fall in FF and consequent reduction in mean glo- different physiologic conditions. They found that during merular oncotic pressure. Despite increased blood flow, saline diuresis, the rise in SNGFR was greater than filtration still tended to approach equilibrium; efferent the calculated rise in EFP, suggesting a significant in- EFP was only 3.5 cm H20. crease in glomerular permeability. In our studies, how- In both mild and massive saline diuresis, the rise in 2Recent studies by Blantz et al. in our laboratory using mean glomerular EFP was entirely attributable to the mutant Wistar rats (generously supplied by Dr. K. Thurau dilution of plasma proteins, the fall in FF contributed and Dr. J. Boylan) and a servo-null micropressure trans- only a minor effect8 and PG remained constant. In con- ducer have shown that PG measured by direct puncture of six glomeruli averaged 70 cm H20, agreeing with the values 8 One possible error might arise from the calculation of obtained indirectly by SFP measurements. PG in these rats efferent EFP on the basis of whole kidney FF. The calcula- did not change in saline diuresis. tions are probably valid in hydropenia since Brenner and Determinants of Glomerular Filtration 2233 trast to both hydropenia and partial ureteral obstruction, 4. Landis, E. M., and J. R. Pappenheimer. 1963. Exchange of substances through the capillary walls. Handb. Phys- filtration did not approach equilibrium at the efferent iol. Sect. 2. Circulation. 2: 961. end of the glomerulus; efferent EFP was 17.5 cm H20 5. Andreucci, V. E., J. Herrera-Acosta, F. C. Rector, Jr., in mild volume expansion and 23.1 cm H20 in massive and D. W. Seldin. 1971. Measurement of single nephron volume expansion. Although the RBF was significantly glomerular filtration rate by micropuncture. Analysis of higher during volume expansion, failure of filtration to error. Amer. J. Physiol. In press. 6. Landis, E. M. 1926. The capillary pressure in frog reach equilibrium was probably not related to faster mesentery as determined by micropuncture methods. transit through the glomerulus, but more likely to the Amer. J. Physiol. 75: 548. fact that oncotic pressure is an exponential function of 7. Wunderlich, P., and J. Schnermann. 1969. Continuous plasma protein concentation (4). For this reason a FF recording of hydrostatic pressure in renal tubules and of 0.3 would much less rise in on- blood capillaries by use of a new pressure transducer. produce glomerular Pfluiegers Arch. 313: 89. cotic pressure when entering protein concentration is 3.5 8. Bresler, E. H. 1956. The problem of the volume com- g/100 ml than when it is 5.8 g/100 ml. ponent of body fluid homeostasis. Amer. J. Med. Sci. The fact that filtration approaches equilibrium at the 232: 93. efferent end of the glomerulus in hydropenia but not in 9. Winton, F. R. 1951-52. Hydrostatic pressures affecting the flow of the urine and blood in the kidney. Harvey saline diuresis has important implications concerning the Lect. 67. possible mediation of glomerulotubular balance by post- 10. Pappenheimer, J. R. 1955. tber die Permeabilitat Glo- glomerular oncotic forces (19, 20). Because of the rela- merulummembranen in der Niere. Klin. Wochenschr. 33: tively high plasma protein concentration during hydro- 362. penia, changes in GFR induced by altering renal per- 11. Thurau, K. 1964. Renal hemodynamics. Amer. J. Med. 36: 698. fusion pressure will result in marked changes in the on- 12. Krause, H. H., T. Dume, K. M. Koch, and B. Ochwadt. cotic pressure of blood issuing from the glomerulus into 1967. Intratubularer Druck, glomerularer Capillardruck peritubular capillaries, whereas similar changes in GFR und Glomerulumfiltrat nach Furosemid und Hydrochlo- during saline diuresis and a lower plasma protein con- rothiazid. Pfluiegers Arch. 295: 80. 13. Koch, K. M., T. Dume, H. H. Krause, and B. Ochwadt. centration will produce only minor changes in postglo- 1967. Intratubuldrer Druck, glomerularer Capillardruck merular oncotic pressure. This might serve to explain und Glomerulumfiltrat Wahrend Mannit-Diurese. Pfluie- why proximal glomerulotubular balance is precisely gers Arch. 295: 72. maintained in hydropenia and only partially maintained 14. Henry, L. N., C. E. Lane, and M. Kashgarian. 1968. during saline diuresis (21). Micropuncture studies of the pathophysiology of acute renal failure in the rat. Lab. Invest. 19: 309. 15. Wikstrom, D. I., and M. A. Cortney. 1968. Glomerular ACKNOWLEDGMENTS filtration rate and proximal tubular reabsorption as af- This work was supported by U. S. Public Health Service fected by volume expansion in the rat. 2nd Annual Meet- Grant 1 P01 HE 11662. ing American Society Nephrology, Washington 70. (Abstr.) Galla (18) found that superficial nephron FF and whole 16. Jaenike, J. R. 1969. Micropuncture study of methemo- kidney FF are very close. In saline diuresis, however, whole globin-induced acute renal failure in the rat. J. Lab. kidney FF may fall while FF in superficial nephrons does Clin. Med. 73: 459. not change. If we recalculate mean glomerular EFP in 17. Hayslett, J. P., D. T. Domoto, M. Kashgarian, and F. groups II and III on the basis of hydropenic FF, mean H. Epstein. 1970. Role of physical factors in the natri- glomerular EFP would be 20.8 instead of 22.1 cm H20 in uresis induced by acetylcoline. Amer. J. Physiol. 218: group II and 25.6 instead of 26.3 cm H20 in group III. 880. Thus, in saline diuresis when plasma protein concentration is 18. Brenner, B. M., and J. H. Galla. 1971. Influence of low, the actual FF used in the calculation has little effect on postglomerular hematocrit and protein concentration on estimated EFP. rat nephron fluid transfer. Amer. J. Physiol. 220: 148. 19. Lewy, J. E., and E. E. Windhager. 1968. Peritubular REFERENCES control of proximal tubular fluid reabsorption in the rat 1. Gertz, K. H., J. A. Mangos, G. Braun, and H. D. Pagel. kidney. Amer. J. Physiol. 214: 943. 1966. Pressure in the glomerular capillaries of the rat 20. Brenner, B. M., and J. L. Troy. 1971. Postglomerular kidney and its relation to arterial blood pressure. Pfluie- vascular protein concentration: evidence for a causal gers Arch. 288: 369. role in governing fluid reabsorption and glomerulotubu- 2. Rocha, A., M. Marcondes, and G. Malnic. 1971. Micro- lar balance by the renal proximal tubule. J. Clin. Invest. puncture study of individual nephrons in rats with ex- 50: 336. perimental nephrotic syndrome. J. Clin. Invest. In press. 21. Rodicio, J., J. Herrera-Acosta, J. C. Sellman, F. C. 3. Gertz, K. H., M. Brandis, G. Braun-Schubert, and J. W. Rector, Jr., and D. W. Seldin. 1969. Studies on glomer- Boylan. 1969. The effect of saline infusion and hemor- ulotubular balance during aortic constriction, ureteral rhage on glomerular filtration pressure and single neph- obstruction and venous occlusion in hydropenic and ron filtration rate. Pfluiegers Arch. 310: 193. saline-loaded rats. Nephron. 6: 437.

2234 V. E. Andreucci, J. Herrera-Acosta, F. C. Rector, Jr., and D. W. Seldin